Clinical trial NCT04495179
Conditions: Progressive Metastatic Castrate-Resistant Prostate Cancer
Keywords: Prostate Cancer
Sponsor: AstraZeneca
Start date: 2020-08-04; Completion date: 2022-08-08
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with metastatic castration-resistant prostate cancer (mCRPC).

Detailed description:
This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with mCRPC. Participants in each arm will be stratified by the presence of measurable soft tissue metastasis (per Response Evaluation Criteria in Solid Tumours \[RECIST v1.1\]) or bone-only metastasis (per Prostate Cancer Working Group 3 \[PCWG3 criteria\]). There will be no formal comparisons between treatment arms.

AZD4635 plus durvalumab (Arm A) will consist of 80 participants with mCRPC previously treated with one or more approved new hormonal agent(s) (NHAs) and one or more taxanes or participants who are taxane ineligible.

AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants mCRPC previously treated with docetaxel and one prior NHA.

As of November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program level, not related to any safety issues. Ongoing participants in Arm A may continue treatment as planned.

Arms: arm 1: AZD4635 plus durvalumab (Arm A) will consist of participants with mCRPC previously treated with one or more approved NHAs (eg, abiraterone acetate, enzalutamide, apalutamide and/or darolutamide), and one or more taxanes, or participants who are taxane ineligible. arm 2: AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of participants with mCRPC previously treated with docetaxel and one prior NHA (either abiraterone acetate or enzalutamide but not both (prior apalutamide is not allowed in Arm B).
Interventions: intervention 1: AZD4635 intervention 2: Durvalumab intervention 3: Cabazitaxel
Intervention descriptions: intervention 1: Subjects will receive AZD4635 orally daily intervention 2: Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B. intervention 3: Subjects will receive intravenous cabazitaxel every 3 weeks

Protocol documents:
Prot_000.pdf: 
•
Protocol number: D8731C00002
•
Document title: A Phase II, Open-label Study to Assess the 
Efficacy, Safety, and Tolerability of AZD4635 in
•
Combination with Durvalumab and in Combination with 
Cabazitaxel and Durvalumab in Patients
•
Who Have Progressive Metastatic Castrate-Resistant Prostate 
Cancer (AARDVARC)
•
NCT number: NCT04495179
•
Version number: 3.0
•
Date of the document: 24 Nov 2020 


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Clinical Study Protocol
Study Intervention
AZD4635
Study Code
D8731C00002
Version
3.0
Date
24 November 2020
A Phase II, Open-label Study to Assess the Efficacy, Safety, and Tolerability 
of AZD4635 in Combination with Durvalumab and in Combination with 
Cabazitaxel and Durvalumab in Patients Who Have Progressive Metastatic 
Castrate-Resistant Prostate Cancer (AARDVARC)
Sponsor: AstraZeneca AB 
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
Investigational New Drug (IND) Number: 138166
European Clinical Trials Database (EudraCT) number: 2020-000209-10
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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A me n d me nt N u m ber: 2
St u d y  I nter ve nti on: A Z D 4 6 3 5
St u d y  P hase: II
S h ort Title: P hase II t w o -ar m st u d y of A Z D 4 6 3 5 i n c o m bi nati o n wi t h d ur val u ma b a n d i n 
c o m bi nat i on wi t h ca bazit a x el a n d d ur valu ma b i n pati e nts wit h m C R P C
St u d y Acr o n y m : A A R D V A R C, A 2 A R i n hi bit or a n d D ur V al u ma b A ssess me nt of R es p o nse i n 
C R P C 
Me dic al M o nit or  N a me a n d C o nt act I nf or m ati o n will be pro vi de d se p ar atel y
I nter n ati o n al c o-o r di n ati n g i n vesti g at or : P P D


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2 (Global)
24-Nov-2020
Amendment 1 (Global)
07-Sep-2020
Original Protocol
31-Jan-2020
The Protocol Amendment Summary of Changes Table is provided below for the current 
amendment and in Appendix N for previous amendments. 
Amendment 2, 24-November-2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the council of the European Union.
Overall Rationale for the Amendment:
The global protocol was amended due to the Sponsor’s decision to close enrolment in Arm A. 
A few additional corrections and clarifications were included in this amendment. 
A summary of changes and the rationale for each change are tabulated below.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis
Alignment to updates made in 
Sections 2, 3, 4, and 9. 
These edits were made for 
consistency with the updates 
made to main protocol sections.
Substantial
Site locations were updated.
Revisions were made to align 
with updated assumptions.
Substantial
1.2 Schema
A footnote was added to Figure 1 
(study design) to describe 
decision to stop enrolment in 
Arm A.
The footnote was for consistency 
with the updates made to main 
protocol sections.
Substantial
1.3 Schedule of 
Activities
Paired tumour biopsies were 
edited in both Tables 1 and 2 to 
add samples at the visits 
described in Section 8.6.2.1.
These edits were made for 
consistency with Section 8.6.2.1.
Non-substantial
In Tables 1 and 2, a footnote was 
added to clarify when PET-CT 
scans may be used. 
Information provided in 
Appendix G was added as a 
footnote for clarity.
Non-substantial


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Secti o n # a n d 
N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/
N o n -s u bst a nti al
I n Ta ble 2 ( Ar m B), t he n u m ber 
of partici pa nts re q uiri n g i nte nsi ve 
P K sa m pli n g was i ncrease d fr o m 
6 t o 1 2 e val ua ble partici pa nts.
T hese e dits were ma de f or 
c o nsiste nc y wit h u p dates ma de i n 
Secti o n 8. 5. 1.
S u bsta ntial
I n Ta ble 2 ( Ar m B), a f o ot n ote 
was a d de d t o s pecif y t he n u m ber 
of partici pa nts wit h R E CI S T 
v 1. 1  meas ura ble disease at 
baseli ne t o be e nr olle d a n d 
assi g ne d t o st u d y treat me nt i n 
Ar m B
T hese e dits were ma de f or clarit y 
a n d i n ali g n me nt wit h t he mai n 
secti o ns of t he pr ot oc ol.
N o n -s u bsta ntial
2 I ntr o d ucti o n, 
4. 1 O verall 
Desi g n, a n d 4. 3 
J ustificati o n f or 
D ose
E nr ol me nt i n Ar m A was st o p pe d 
bef ore reac hi n g i nitiall y pla n ne d 
n u m ber of 8 0 partici pa nts. 
O n g oi n g partici pa nts i n Ar m A 
m a y  c o nti n ue treat me nt as 
pla n ne d (ie , as l o n g as t he y 
recei ve cli nical be nefit a n d d o 
n ot meet a n y  disc o nti nuati o n 
criteria ).
As of N o ve m ber 2 0 2 0, t he 
S p o ns or st o p pe d e nr ol me nt i n 
Ar m A f oll o wi n g decisi o ns at t he 
pr o gra m le vel, n ot relate d t o a n y 
safet y iss ues. 
S u bsta ntial
3 O bjecti ves a n d 
E n d p oi nts
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
S u bsta ntial
4. 1. 1 Safet y 
Re vie w 
C o m mitte e
T he safet y re vie w c o m mittee 
(S R C ) deci si o n will be s hare d 
wit h all in vesti gat o rs, b ut 
state me nt t hat t his s h o ul d occ ur
pri or t o f urt her d osi n g of 
T his re visi o n was ma de f or 
c o nsiste nc y wit h t he pr ocess 
descri be d i n t he pr ot oc ol.
N o n -s u bsta ntial
C CI
C CI


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
participants on Arm B was 
deleted.
4.4 End of Study 
Definition
The DCO for primary analysis 
and reporting defined for Arm B 
will be used for both treatment 
arms.
As enrolment in Arm A stopped, 
the DCO previously defined for 
Arm A can no longer be 
completed.
Substantial
For Arm B, the DCO was 
changed to when approximately 
60% of events (death or 
progression) occur.
A 60% maturity is considered 
sufficient to evaluate the updated 
decision criteria, which is what 
the sample size is based on.
Substantial
5.1 Inclusion 
Criteria, 
5.2 Exclusion 
Criteria
For inclusion criterion #8 and 
exclusion criterion #6, the 
minimum creatinine clearance for 
eligibility was lowered from 
50 to 40 ml/min
Available data show that all study 
drugs have only minimal renal 
clearance.
No significant renal toxicity has 
been seen for AZD4635.
The proposed threshold is also in 
line with the guidance for 
durvalumab and cabazitaxel.
Substantial
Exclusion criteria #5 and #11 
were edited to remove duplicate 
information.
These edits were made to 
improve clarity, but do not 
change the criteria.
Non-substantial
For exclusion criterion #29, 
ejection fraction was replaced by 
left ventricular ejection fraction.
These edits were made to 
improve clarity, but do not 
change the criteria.
Non-substantial
6.2.1 AZD4635
Dosing instructions in case of 
vomiting were added.
The instructions were added in 
the protocol for completeness, in 
alignment with the dosing 
instruction provided to each 
participant.
Non-substantial
6.3 Measures to 
Minimise Bias: 
Methods for 
Assigning 
Treatment 
Groups
The section was updated to 
indicate that assignment depends 
on which treatment arm is open 
and to clarify that stratification is 
to ensure a sufficient number of 
participants are enrolled in each 
stratum of Arm B.
As enrolment in Arm A stopped, 
the description of treatment 
assignment was revised 
accordingly.
Substantial
6.7 Dose 
Modification
The maximum duration of 
4 weeks of treatment interruption 
in case of immune-mediated 
toxicity was removed.
Recovery from immune-mediated 
adverse events may require more 
than 4 weeks of treatment 
interruption for full steroid 
treatment and taper.
Substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
7.3 Lost to 
Follow-up
Text regarding the collection of 
information on the vital status of 
participants lost to follow-up was 
added.
These edits were made to clarify 
that the vital status of participants 
lost to follow-up should be 
collected.
Substantial
8.1.1 Tumour 
Assessments 
with RECIST 
v1.1
Text was added to clarify when 
PET-CT scans may be used. 
Information provided in
Appendix G was added in the 
section for clarity.
Non-substantial
8.5.1 
Pharmacokinetics
The number of Arm B 
participants requiring intensive 
PK sampling was increased from 
6 to 12 evaluable participants.
Six participants were added to 
better evaluate the PK effects of 
cabazitaxel added to the 
combination of AZD4635 
+ durvalumab.
Substantial
9.2 Sample Size 
Determination.
Calculation of sample size for 
Arm A was removed.
As enrolment in Arm A stopped, 
calculation of sample size is no 
longer relevant.
Substantial
Calculation of sample size for 
Arm B was updated to reflect 
updated DCO, target value for 
the decision criteria and current 
recruitment estimates.
Revisions were made to align 
with updated assumptions.
Substantial
9.4.1 General 
Considerations, 
9.4.1.2 
Secondary 
Endpoints
Summary tables will not be 
produced for Arm A Data from 
Arm A will be listed only.
As enrolment in Arm A stopped, 
too few participants will be 
enrolled to produce meaningful 
analyses. 
Substantial
9.5 Interim 
Analysis
The futility interim analysis for 
Arm A was removed. A futility 
interim analysis was added for 
Arm B. 
As enrolment in Arm A stopped, 
the futility interim analysis is no 
longer required for Arm A.
A futility interim analysis was 
added in Arm B to decide further 
enrolment in Arm B after 
reviewing data from 
approximately 30 evaluable 
participants (including 
approximately 15 participants 
with RECIST v1.1 measurable 
disease at baseline).  This is due 
to the limited data available for 
this combination.
Substantial
Appendix K 
Fact-P Version 4
Missing page 2 in the appendix 
was added.
Correction.
Non-substantial


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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix L 
COVID-19 
Specifics
The requirements for 
Investigational Product 
administration in case of remote 
visit were clarified.
These clarifications were 
provided to ensure the remote 
location is appropriate to safely 
perform the IP administration.
Substantial
General 
formatting and 
minor editing
The format of table numbering 
was changed back to format used 
in the initial protocol.
Minor formatting and editorial 
changes were made for 
corrections or to ensure 
alignment with updated sections.
Correction and editing
Non-substantial


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................ 13
1.1
Synopsis ........................................................................................................... 13
1.2
Schema............................................................................................................. 21
1.3
Schedule of Activities ....................................................................................... 22
2
INTRODUCTION............................................................................................ 35
2.1
Study Rationale ................................................................................................ 38
2.2
Background ...................................................................................................... 39
2.2.1
Benefit/Risk Assessment................................................................................... 40
3
OBJECTIVES AND ENDPOINTS................................................................... 42
4
STUDY DESIGN ............................................................................................. 46
4.1
Overall Design.................................................................................................. 46
4.1.1
Safety Review Committee................................................................................. 48
4.2
Scientific Rationale for Study Design ............................................................... 49
4.3
Justification for Dose........................................................................................ 50
4.4
End of Study Definition.................................................................................... 52
5
STUDY POPULATION.................................................................................... 54
5.1
Inclusion Criteria .............................................................................................. 54
5.2
Exclusion Criteria ............................................................................................. 57
5.3
Lifestyle Considerations ................................................................................... 60
5.3.1
Meals and Dietary Restrictions ......................................................................... 60
5.4
Screen Failures ................................................................................................. 60
6
STUDY INTERVENTION ............................................................................... 62
6.1
Investigational Products.................................................................................... 62
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 63
6.2.1
AZD4635.......................................................................................................... 63
6.2.2
Durvalumab...................................................................................................... 64
6.2.2.1
Preparation of Durvalumab Dose for Administration with an IV Bag ................ 65
6.2.3
Cabazitaxel....................................................................................................... 65
6.2.3.1
Preparation of Cabazitaxel Dose for Administration with an IV Bag ................. 66
6.3
Measures to Minimise Bias: Methods for Assigning Treatment Groups............. 66
6.4
Study Intervention Compliance......................................................................... 67
6.5
Concomitant Therapy........................................................................................ 68
6.5.1
Permitted Concomitant Medications ................................................................. 69
6.5.2
Prohibited or Restricted Medications ................................................................ 69


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6.5.3
Drug-Drug Interactions..................................................................................... 71
6.5.4
Rescue Medication............................................................................................ 73
6.5.5
Other Concomitant Medications........................................................................ 73
6.6
Cabazitaxel Safety Assessment Arm B.............................................................. 74
6.6.1
Definition of Dose-Limiting Toxicity for Arm B ............................................... 74
6.7
Dose Modification ............................................................................................ 75
6.7.1
Management of Toxicities Related to AZD4635 Therapy .................................. 76
6.7.2
Management of Toxicities Related to Durvalumab Therapy .............................. 77
6.7.2.1
Specific Toxicity Management Guidelines and Dose Modification Information 
for Durvalumab ................................................................................................ 77
6.7.2.2
Durvalumab Infusion-Related Reactions........................................................... 78
6.7.3
Management of Toxicities Related to Cabazitaxel Therapy ............................... 79
6.8
Intervention after the End of the Study.............................................................. 79
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 80
7.1
Discontinuation of Study Intervention............................................................... 80
7.1.1
Procedures for Discontinuation of Study Intervention ....................................... 81
7.2
Participant Withdrawal from the Study.............................................................. 81
7.3
Lost to Follow-up ............................................................................................. 82
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 83
8.1
Efficacy Assessments........................................................................................ 83
8.1.1
Tumour Assessments with RECIST v1.1........................................................... 84
8.1.2
PCWG3 Bone Lesion Assessment..................................................................... 86
8.1.3
Tumour Assessments with iRECIST ................................................................. 86
8.1.4
PCWG3 PSA Criteria........................................................................................ 86
8.2
Safety Assessments........................................................................................... 87
8.2.1
Physical Examinations and Weight.................................................................... 87
8.2.2
Performance Status........................................................................................... 87
8.2.3
Vital Signs and Height ...................................................................................... 87
8.2.4
Electrocardiograms........................................................................................... 87
8.2.5
Echocardiogram/MUGA................................................................................... 88
8.2.6
Concomitant Medications ................................................................................. 88
8.2.7
Clinical Safety Laboratory Assessments............................................................ 88
8.2.8
Other Assessments............................................................................................ 90
8.2.9
Clinical Outcome Assessments.......................................................................... 90
8.2.10
Follow-up Visits ............................................................................................... 91
8.2.10.1
30-day and 90-day Follow-up Visits.................................................................. 91
8.2.10.2
Progression-free Follow-up Visits ..................................................................... 92
8.2.10.3
Survival Follow-Up .......................................................................................... 92
8.3
Adverse Events and Serious Adverse Events..................................................... 92
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 92
8.3.2
Follow-up of AEs and SAEs ............................................................................. 93
8.3.3
Causality Collection.......................................................................................... 94
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 94


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8.3.5
Adverse Events Based on Examinations and Tests ............................................ 94
8.3.6
Hy’s Law.......................................................................................................... 95
8.3.7
Disease Progression.......................................................................................... 95
8.3.8
Reporting of Serious Adverse Events ................................................................ 95
8.3.9
Pregnancy......................................................................................................... 96
8.3.9.1
Paternal Exposure............................................................................................. 96
8.3.10
Medication error ............................................................................................... 97
8.4
Overdose .......................................................................................................... 97
8.5
Human Biological Samples............................................................................... 98
8.5.1
Pharmacokinetics.............................................................................................. 98
8.5.1.1
Determination of Drug Concentration ............................................................. 100
8.5.2
Immunogenicity Assessments ......................................................................... 100
8.5.3
Pharmacodynamics......................................................................................... 101
8.6
Human Biological Sample Biomarkers ........................................................... 101
8.6.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 101
8.6.1.1
Collection of Blood for Immune Cell Research............................................... 101
8.6.1.2
Collection of Plasma Samples for Circulating Tumour DNA........................... 101
8.6.1.3
Collection of Archival Tumour Samples.......................................................... 102
8.6.2
Collection of Optional Biomarker Samples ..................................................... 102
8.6.2.1
Paired Tumour Biopsies.................................................................................. 102
8.7
Optional Genomics Initiative Sample.............................................................. 103
8.8
Health Economics........................................................................................... 103
9
STATISTICAL CONSIDERATIONS.............................................................. 104
9.1
Statistical Hypotheses..................................................................................... 104
9.2
Sample Size Determination............................................................................. 104
9.3
Populations for Analyses................................................................................. 104
9.4
Statistical Analyses ......................................................................................... 105
9.4.1
General Considerations................................................................................... 105
9.4.1.1
Primary Endpoint............................................................................................ 105
9.4.1.2
Secondary Endpoints ...................................................................................... 106
9.4.2
Efficacy .......................................................................................................... 106
9.4.3
Safety ............................................................................................................. 109
9.4.4
Other Analyses................................................................................................ 110
9.4.4.1
Pharmacokinetic Analysis ............................................................................... 110
9.5
Interim Analyses..............................................................................................111
9.6
Data Monitoring Committee ............................................................................111
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 112
11
REFERENCES............................................................................................... 190


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LIST OF FIGURES
Figure 1
Study design............................................................................................ 21
LIST OF TABLES
Table 1
Schedule of Activities for Arm A (AZD4635 plus Durvalumab every 4 
Weeks) .................................................................................................... 22
Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and 
Cabazitaxel every 3 Weeks for First 10 Cycles and then every 4 Weeks) . 27
Table 3
Objectives and Endpoints/Variables......................................................... 42
Table 4
Investigational Products........................................................................... 62
Table 5
Prohibited Medications with AZD4635.................................................... 70
Table 6
Prohibited Medications with AZD4635.................................................... 70
Table 7
Prohibited Medications with Durvalumab................................................ 70
Table 8
Prohibited Medications with Cabazitaxel ................................................. 71
Table 9
AZD4635 Dose Levels for Dose Reductions due to Toxicities ................. 76
Table 10
Cabazitaxel Dose Levels for Dose Reductions due to Toxicities .............. 76
Table 11
AZD4635 Dose Modifications and Discontinuation Criteria for Non-
Haematologic Toxicities .......................................................................... 76
Table 12
Recommended Dose Modifications For Adverse Reactions in 
Participants Treated with Cabazitaxel ...................................................... 79
Table 13
Requirements for Documentation of Progression ..................................... 86
Table 14
WHO Performance Status Scale............................................................... 87
Table 15
Laboratory Safety Variables..................................................................... 89
Table 16
Arm A AZD4635 Sparse PK Sampling Schedule..................................... 99
Table 17
Arm B AZD4635 PK Sampling Schedule (First 12 evaluable 
participants)............................................................................................. 99
Table 18
Arm B AZD4635 Sparse PK Sampling Schedule (All Participants).......... 99
Table 19
Arm B Cabazitaxel PK Sampling Schedule (First 12 Evaluable
Participants)........................................................................................... 100
Table 20
Durvalumab PK and Anti-Drug Antibody Sampling Times.................... 100
Table 21
Populations for Analysis ........................................................................ 105
Table 22
Summary of Methods of Assessment ..................................................... 137
Table 23
Evaluation of Target Lesions ................................................................. 141
Table 24
Examples of CYP1A2 Inhibitors and Inducers....................................... 156


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Table 25
Examples of Substrates of Transporters ................................................. 157
Table 26
Examples of Strong CYP3A4 Inducers and Inhibitors............................ 157
Table 27
Prohibited Medications with Durvalumab.............................................. 158
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 113
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 118
Appendix C
Handling of Human Biological Samples ................................................ 124
Appendix D
Optional Genomics Initiative Sample..................................................... 126
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 130
Appendix F
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST v1.1 in Soft Tissue................................................................... 136
Appendix G
iRECIST Criteria ................................................................................... 142
Appendix H
PCWG3 Criteria (Scher et al. 2016)....................................................... 151
Appendix I
Disallowed Medications......................................................................... 156
Appendix J
Brief Pain Inventory (short form) Example – Not for Participant Use..... 159
Appendix K
FACT-P (Version 4) Example - Not for Participant Use......................... 161
Appendix L
COVID-19 Specifics.............................................................................. 164
Appendix M
Abbreviations ........................................................................................ 168
Appendix N
Protocol Amendment History................................................................. 172


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase II, Open-label Study to Assess the Efficacy, Safety, and Tolerability 
of AZD4635 in Combination with Durvalumab and in Combination with Cabazitaxel and 
Durvalumab in Patients Who Have Progressive Metastatic Castrate-Resistant Prostate Cancer
(AARDVARC)
Short Title: Phase II two-arm study of AZD4635 in combination with durvalumab and in 
combination with cabazitaxel and durvalumab in patients with mCRPC
Rationale: Although novel hormonal agents (NHA) have changed the landscape of treatment 
for metastatic castrate-resistant prostate cancer (mCRPC), for patients who have progressed 
with NHA and docetaxel, there remain limited therapeutic options. While immunotherapy has 
led to impressive responses in a subset of patients with immunologically "activated" tumors, 
this approach has shown little progress in mCRPC. AZD4635 has shown clinical activity in 
mCRPC and appears to have increased efficacy in combination with anti-PD-L1 in prostate 
cancer due to increased immune activation compared to single agent AZD4635 based on the 
results of the ongoing Phase I study D8730C00001. At the data cut-off (DCO) of 
02 December 2019, 8 subjects have achieved objective response (OR) per Response 
Evaluation Criteria in Solid Tumours (RECIST) v1.1. Two subjects (durvalumab combination) 
had complete responses and 6 subjects had partial responses (monotherapy [n = 2] and 
durvalumab combination [n = 4]). Participants with an OR (CR+PR) have had durations of 
response that ranges from 2.30 to 25.82 months with several ongoing response at the DCO.  
The combination of the checkpoint inhibitor pembrolizumab (anti-PD-1) and docetaxel has 
been investigated in the KEYNOTE 365 study where the checkpoint inhibitor was added to 
the standard-of-care (SOC) chemotherapy. It has been reported that pembrolizumab alone 
leads to a relatively low response rate of ~5% and percentage of participants who had a 
Prostate-Specific Antigen (PSA) decline of at least 50 percent (%) from baseline, i.e., PSA50
of 11% (KEYNOTE-199) (Antonarakis et al 2019). In KEYNOTE 365, an ORR of 14% 
(5/36) and PSA50 of 31% (22/71) were reported with the most notable result being a median
radiographic progression-free survival (rPFS) of 8.3 months (Massard et al. 2019) which is 
longer than that reported with single-agent docetaxel (3.9 months [Rathkopf et al. 2018]).
Additionally, the recently published CARD study (de Wit et al. 2019) demonstrated an 
imaging-based median PFS of ~8.2 months for the cabazitaxel arm in a post-NHA, post-
docetaxel unselected mCRPC participant population.
We hypothesise that AZD4635 combined with the checkpoint inhibitor (anti-PD-L1) 
durvalumab and cabazitaxel will lead to an increased rPFS in the post-docetaxel setting by 
decreasing the immunosuppressive environment response and counteracting the effects of 
adenosine (ADO) which can limit the anti-PD1/PDL1.


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Objectives and Endpoints
Objectives
Endpoints/Variables
Primary

To determine the efficacy (as assessed 
by radiographic progression free 
survival [rPFS]) of AZD4635 plus 
durvalumab and separately of
AZD4635 plus durvalumab plus 
cabazitaxel in participants with 
mCRPC.

rPFS, defined as the time from first dose 
until radiographic progression as
assessed by the Investigator per RECIST 
v1.1 (soft tissue) and Prostate Cancer 
Working Group 3 (PCWG3) criteria
(bone) or death from any cause, 
whichever occurs first.
Secondary

To evaluate the safety and tolerability 
of each treatment regimen in 
participants with mCRPC.

Physical examination, laboratory values
(haematology, clinical chemistry, 
urinalysis, and tests for coagulation), 
vital signs, and electrocardiograms 
(ECGs).

Adverse events/serious adverse events 
(AEs/SAEs) collected throughout the 
study, from the time of the informed 
consent form signature through to the 
last safety follow-up visit.

To determine the efficacy of AZD4635 
plus durvalumab and separately of
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of overall 
survival (OS) in participants with 
mCRPC.

OS, defined as the time from first dose 
until death due to any cause regardless 
of whether the participant withdraws 
from study treatment or receives another 
anti-cancer therapy. 


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Objectives
Endpoints/Variables

To determine the efficacy of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of ORR in 
participants with mCRPC.

Confirmed ORR, defined as the 
percentage of participants with a 
confirmed Investigator-assessed 
response of CR or PR using overall 
radiographic response assessed by 
RECIST v1.1 and PCWG-3 criteria 
(bone), and will be based on a subset of 
all treated participants with measurable 
disease at baseline per the site 
Investigator.

To determine the efficacy of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of DoR in 
participants with mCRPC.

DoR, defined as the date of first 
documented response (which is 
subsequently confirmed) until the date 
of documented progression or death in 
the absence of disease progression.

To determine the efficacy of AZD4635 
plus durvalumab and separately of
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of PSA 
response in participants with mCRPC.

Confirmed PSA50 response, defined as 
the proportion of participants achieving 
a ≥50% decrease in PSA from baseline 
to the lowest post-baseline PSA, 
confirmed by a consecutive PSA at least 
3 weeks later and will be based on PSA 
evaluable participants (dosed
participants with an abnormal baseline 
PSA [≥1 ng/mL]).

Investigate the pharmacokinetics (PK)
of AZD4635 when given in 
combination with durvalumab, and 
when given in combination with 
durvalumab plus cabazitaxel.

AZD4635, durvalumab and cabazitaxel 
plasma concentrations and derived PK 
parameters, where deemed appropriate.

To determine the efficacy of AZD4635 
plus durvalumab plus cabazitaxel in 
participants with mCRPC, by adenosine
(ADO) signalling gene expression 
signature in high and low subgroups.

rPFS, defined as the time from first dose 
until radiographic progression, assessed 
by the Investigator per RECIST 1.1 (soft 
tissue) and PCWG3 criteria (bone) or 
death from any cause, whichever occurs 
first by gene expression subgroup.


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Objectives
Endpoints/Variables

To determine the effects of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel on pain and other prostate 
cancer-related symptoms.

Change from baseline in worst pain, 
average pain and pain interference in the 
daily activities scales of the BPI-SF.

Time to pain progression based on 
BPI-SF Item 3 “pain at its worst in the 
last 24 hours ”. 

Change from baseline in the FAPSI-6 as 
derived from 6 items, the FAPSI-8 as 
derived from 8 items within the 
FACT-P, and the PCS as derived from 
the 12 items in the prostrate-specific 
module of the FACT-P.
For Exploratory objectives and endpoints/variables see Section 3 of the protocol.
Overall Design
This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in 
participants with mCRPC. The primary objective is to determine the rPFS of AZD4635 plus 
durvalumab (Arm A) and separately of AZD4635 plus durvalumab plus cabazitaxel (Arm B). 
Participants in each arm will be stratified by the presence of measurable soft tissue metastasis 
(per RECIST v1.1, Appendix F) or bone-only metastasis (per Prostate Cancer Working Group 
3 [PCWG3 criteria, Appendix H]). There will be no formal comparisons between treatment
arms. Secondary endpoints include; safety, OS, confirmed ORR, DoR, confirmed PSA50
response, time to pain progression, and pharmacokinetics (PK). 
AZD4635 plus durvalumab (Arm A) will consist of participants with mCRPC previously 
treated with one or more approved NHAs (e.g., abiraterone acetate, enzalutamide, apalutamide
and/or darolutamide), and one or more taxanes, or participants who are taxane ineligible. As of 
November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program 
level, not related to any safety issues. Ongoing participants in Arm A may continue treatment 
as planned (ie, as long as they receive clinical benefit and do not meet any discontinuation 
criteria).
AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants with 
mCRPC previously treated with docetaxel and one prior NHA (either abiraterone acetate or 
enzalutamide but not both; prior apalutamide is not allowed in Arm B).
Eligible participants must have histologically diagnosed mCRPC with no evidence of small 
cell histology, have had progression of disease ≤6 months prior to study entry (either by 
RECIST v1.1 or bone lesions per PWCG3) and ongoing androgen deprivation with serum 


Cli nical St u d y Pr ot oc ol – 3. 0
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test oster o ne < 5 0 n g/ m L.
P arti cipa nts will be all o cate d t o o ne of t he f o ll owi n g treat m e nt ar ms:
Ar m A : A Z D 4 6 3 5 (
m g P O dail y) pl us d ur val u ma b ( 1 5 0 0 mg I V e ver y 4 wee ks [ Q 4 W ])
N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr o l me nt i n Ar m A f oll owi n g decisi o ns at 
t he pr o gra m le vel, n ot relate d t o a n y safety iss ues. 
or
Ar m B : A Z D 4 6 3 5 (
 mg P O dail y ) pl us d ur val u ma b ( 1 5 0 0 mg I V e ver y 3 wee ks [ Q 3 W ]) 
pl us ca bazit a x el ( 2 0 or 2 5 mg/ m 2 I V Q 3 W as per t he l ocal prescri bi n g g ui deli nes [ n = 8 0 ]).
P arti cipa nts i n Ar m B will recei ve ca bazita xel c he mot h era p y as per t he lo c al  la bel. T his will 
start a p pr o xi matel y 1 h o ur ( or u p t o a ma xi m u m of 2 h o urs) after t he e n d of t he d ur val u ma b 
i nf usi on. Ca bazita xel will be a d mi nistere d as per t he l ocal prescri bi n g g ui deli nes f or a 
ma xi m u m o f 1 0 c y cles. After c y cle 1 0 d ur val u ma b + A Z D 4 6 3 5 will be a d mi nistere d Q 4 W  t o 
har m o nise wit h t he Ar m A  tr e at me nt c ycle le n gt h. 
Ar m B part ici pa nts must recei ve pre me dicat i on t o ma na ge ca bazit a x el-ass ociate d reacti o ns 
( h y perse nsiti vity or ot her) w hic h i ncl u de: 

Pre d nis o ne ( 1 0 m g dail y c o nt i n u o usl y [ or e q ui vale nt ster oi d]) f or t he d urati o n of 
ca bazita xel a d mi nistrati o n

Pri mar y G -C S F pr o p h yla xis ( G-C S F s h o ul d be a d mi nistere d acc or di n g t o t he pr o d uct 
la bel a n d i nstit uti o nal sta n dar ds.)
A n arc hi val t u m o ur sa m ple is re q uire d or t he partici pa nt m ust be willi n g t o u n der g o a baseli ne 
t u mo ur bi o ps y  (see Secti on 8. 6. 1. 3 ). T he c ollecti on of paire d t u m o ur bi o psies will be 
re q ueste d d uri n g t he st u d y, h o we ver t his is o pti o nal (see Secti o n 8. 6. 2. 1 ).
P arti cipa nts i n Ar m A ( A Z D 4 6 3 5 plus d ur val u ma b) will ha ve disease assess me nts/i ma gi n g at 
baseli ne a n d e ver y 8 wee k s ( ± 7 da ys) fr o m t he start of d osi n g f or t he first 2 4 wee ks a n d t he n 
e ver y 1 2 wee ks ( ± 7 da ys) t hereafter. N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d 
e nr o l me nt i n Ar m A f oll owi n g decisi o ns at t he pr o gra m le vel, n ot relate d t o a n y  safety iss ues. 
O n g o i n g partici pa nts i n Ar m A ma y c o nt i n ue treat me nt as pla n ne d (ie, as l o n g as t he y recei ve 
cli nical be nefit a n d d o n ot meet a n y disc o nti nuat i on cri t eria).
P arti cipa nts i n Ar m B ( A Z D 4 6 3 5 pl us d ur val u ma b a n d ca bazita xel) will ha ve disease 
assess me nts/i ma gi n g e ver y 9 wee ks ( ± 7 da ys) fr o m t he start of  d osi n g f or t he first 2 7 wee ks 
a n d t he n e ver y 1 2 wee ks ( ± 7 da ys) t hereafter. A safety assess me nt t o deter mi ne t he safety a n d 
t olera bilit y of t his c o m bi nat i on will be c o n d ucte d b y t he Safet y Re vie w C o m mit tee ( S R C) 
o nce t he first 6 partici pa nts ha ve c o m p lete d a r u n-i n peri o d of at least 1 c ycle (see 
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Secti o n 4. 1. 1 ). 
T he patie nt re p orte d o utc o me ( P R O) i nstr u me nts, a B PI -S F (see A p pe n di x J) a n d FA C T -P (see 
A p pe n di x K ) will be a d mi nistere d t o all p artici pa nts. T hese t w o i nstr u me nts will be use d t o 
assess pai n a n d q ualit y of  life i n st u d y particip a nts a n d t o deter mi ne t he ti me t o pai n 
pr o gressi o n as well as t he c ha n ge i n ma xi mal pai n (see Secti o n 3 ). T hese will be meas ure d as 
s h o w n i n Ta ble 1 a n d Ta ble 2 .
Discl os ur e St ate me nt : T his is a parallel gr o u p treat me nt st u d y wi t h 2 ar ms t hat is o pe n-label.
N u m ber of P artici p a nts: A p pr o xi m atel y 8 0
T he t w o ar m s will e nr oll partici pa nts wi t h metastatic disease d oc u me nte d b y eit her b o ne 
lesio ns o n b o ne sca n or s oft tiss ue disease t hat is e val ua ble f or assess me nt. As of 
N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr ol me nt i n Ar m A f oll owi n g decisi o ns at t he pr o gra m 
le vel, n ot relate d t o a n y s af et y iss ues. Ar m B will e nr oll a n d assi g n t o st u d y treat me nt 
a p pr o xi matel y 8 0 participa nts. At  least 4 0 partici pa nts wit h R E CI S T v 1. 1 meas ura ble disease 
at baseli ne will be e nr o lle d a n d assi g ne d t o stu d y treat me nt i n Ar m B , a n d t he re mai n der of 
pa rtici pa nts i n t he ar m ( n = 4 0 ) ma y ha ve b o ne-o nl y  disease or meas ura ble disease . T he 
pri mar y  a nal ysis, r P F S, will be assesse d, a n d is defi ne d as t he ti me fr o m first d ose t o 
r a dio gra p hic pr o gressi o n as deter mi ne d b y t he I n vesti gat or per R E CI S T v 1. 1 f or s oft tiss ue 
di sease or P C W G 3 f or b o ne disease or deat h fr o m a n y ca use, w hic he ver occ urs first. O verall 
s ur vi val, O R R, D o R, a n d P S A5 0 res p o nse, a n d ti me t o pai n pr o gressi o n will als o be e val uate d 
f or efficac y.
N ote : “E nr o lle d” me a ns a parti ci pa nt ’s, or t heir legall y  acce pta ble re prese ntati ve’s, a gree me nt 
t o partici pate i n a cli nical st u d y fol l owi n g c o m plet i o n of t he i nf or me d c o nse nt pr ocess.
P ote nti al p artici pa nts w h o are scree ne d f or t he p ur p ose of deter mi ni n g eli gi bilit y f or t he st u d y, 
b ut, are n ot assi g ne d i n t he st u d y, are c o nsi dere d “scree n fail ures”, u nless ot her wise s pecifie d 
b y t he pr ot oc ol.
A master l o g of all c o nse nte d partici pa nts will be mai ntai ne d at t he site a n d will d oc u me nt all 
scree n fail ures defi ne d i n Secti o n 5. 4 ). D uri n g t he st u d y , tests f or active C or o na vir us disease 
of  2 0 1 9 (C O VI D - 1 9) i nfecti on ma y be prescri be d , if re q uire d, a n d i n acc or da nce with l ocal 
g ui da nce . 
L ocati o ns: U p t o 5 0 gl o bal sites t o recr uit o ver a p pr o xi matel y 1 8 m o nt hs i n t he U nite d States, 
E ur o pe a n d t he Asia/ P acific re gi o n.
I nter ve nti o n Gr o u ps a n d D ur ati o n :
Ar m A: A Z D 4 6 3 5 ca ps ule 
 m g P O dail y + d ur val u ma b 1 5 0 0 m g I V Q 4 W
N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p p e d e nr o l me nt i n Ar m A fol l owi n g decisi o ns at 
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t he pr o gra m le vel, n ot relate d t o a n y safety iss ues. O n g oi n g partici pa nts i n Ar m A ma y 
c o nti n ue treat me nt as pla n ne d (ie, as l o n g as t he y recei ve cli nical be nefit a n d d o n ot meet a n y 
di sc o nti n uati on cri t eria).
A r m B ( n = ~ 8 0 ): 
A Z D 4 6 3 5 ca ps ule 
 m g P O dail y + d ur val u ma b 1 5 0 0 m g I V Q 3 W  + ca bazita xel 2 0 m g/ m 2
I V Q 3 W or 2 5 m g/ m 2 I V Q 3 W (as per lo c al  prescri bi n g g uideli nes)
Ca bazita xel will be a d mi nister e d for a m a xi m u m of 1 0 c ycles. After C yc le 1 0 
d ur val u ma b + A Z D 4 6 3 5 will be a d mi nistere d Q 4 W t o har mo nise wi t h t he Ar m A  tr e at me nt 
c ycle le n gt h. Partici pa nts ma y c o nt i n ue t o recei ve st u d y i nter ve nti o n u ntil c o nfir me d o bjecti ve 
di sease pr o gressio n as assesse d b y  t he I n vesti gat or, or u nacce pta ble t o xicity or f or as l o n g as 
t he y d o n ot meet a n y ot her disc o nti n uati on cri t eria. O nce partici pa nts ha ve bee n disc o nt i n ue d 
fr om st u d y int er ve nt i on, ot her treat me nt o pti o ns will be at t he discreti o n of t he I n vesti gat or.
I n t his pr ot oc ol AZ D 4 6 3 5, d ur val u ma b a n d ca bazita xel are all referre d t o as eit her st u d y 
dr u gs, st u d y  int er ve ntio ns, i n vest i gati onal pr o d ucts (I Ps), or i n vesti gati onal me dici nal 
pr o d ucts , a n d t hese ter ms are use d i nterc ha n gea bl y.
St atistic al met h o ds
As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr ol me nt i n Ar m A  f oll o wi n g decisi ons at t he 
pr o gra m le vel. F or Ar m A, data will be liste d o nl y .
F or Ar m B, a p pr o xi matel y 8 0 parti ci pa nts will be all ocate d t o A Z D 4 6 3 5 pl us d ur val u ma b pl us 
ca bazita xel at t he rec o m me n de d P hase 2 d ose ( R P 2 D).
T he pri mar y  efficac y e n d p oi nt is rP F S defi ne d as t he ti me fr o m first d ose u ntil ra di o gra p hic 
pr o gressi o n as assesse d b y  t he I n vesti gat or per R E CI S T v 1. 1 (s oft tiss ue) a n d P C W G 3 ( b o ne) 
or deat h fr o m a n y  ca use, w hic he ver c o mes first. F or Ar m B, t he a nal ysis will be descri pt i ve, 
i ncl u di n g s u mmaries fr o m t he Ka pla n-Meier c ur ve. It is a ntici pate d t hat t he st u d y accr ual 
p eri o d will be a p pr o xi matel y  1 4 m o nt hs f or Ar m B. 
 
Ei g ht y partici pa nts will pr o vi de a n est i mate of t he me dia n P F S. C o nfi de nce i nter vals ( CI) will 
be c o nstr ucte d ar o u n d t he me dia n P F S, t o e na ble decisi o ns t o be ma de a b o ut t he li kel y s uccess 
of  fut ure st u di es i n t his p o p ulati o n. 
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Sec o n dar y  e n d p oi nts i ncl u de: safety,  O S, O R R, D o R, P S A5 0 res p o nse, ti me t o pai n 
pr o gressi o n, a n d P K. T he a nal ysis will be descri pt i ve, a n d s u m maries will be prese nte d f or 
Ar m B . T he pri mar y e n d p oi nt (i e, r P F S) will als o be s u m marise d b y A D O si g nalli n g ge ne 
e x pressi o n i n hi g h a n d l o w s u b gr o u ps i n Arm B.
Gi ve n t he li mite d data a vaila ble wit h t he tri pl et c o m bi nat i on, a f utility i nteri m a nal ysis is 
pl a n ne d f or Ar m B base d o n P S A 5 0 res p o nse a n d will be tri g gere d acc or di n g t o t he f oll owi n g:
after a p pr o xi matel y n = 3 0 d ose d part ici pa nts f or t he ar m ha ve ha d t he o p p ort u nity f or sa mple 
c ollect i on f or P S A res p o nse at t he start of We e k 1 3 . It will be base d o n a decisio n  fra me w or k 
(Fre wer et al. 2 0 1 6 ) usi n g pre dicti ve pr o ba bility of a g o o d si g nal bei n g o bser ve d at t he fi nal 
a nal ysis. F urt her details will be pr o vi de d i n t he S A P .  Ot her data a vaila ble at t he ti me will als o 
be c o nsi dere d. T his is pla n ne d f or t he assess me nt of f ut ility,  suc h t hat f urt her recr ui t me nt i nt o 
t he ar m ma y be st o p pe d. H o we ver, partici pa nts alrea d y recr uite d w o ul d c o nti n ue t o be 
f oll owe d u p. Parti ci pa nt recr uit me nt will be pa use d d uri n g t he ti me of t he i nteri m a nal ysis 
o nce t he n u m ber of d ose d partici pa nts i n Ar m B reac hes a p pr o xi matel y 3 5 t o e ns ure 
3 0 e val ua ble partici pa nts f or t he P S A 5 0 res p o nse. Of  t hese partici pa nts, a p pr o xi matel y 
1 5 partici pa nts are t o ha ve R E CI S T v 1. 1 meas ura ble disease at baseli ne a n d t he re mai n der of 
t he partici pa nts ma y ha ve b o ne - o nl y disease or meas ura ble disease.  
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1. 2
Sc he m a
Fi g ure 1
St u d y desi g n
N ote:
As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr ol me nt i n Ar m A. O n g oi n g part ici pa nts i n Ar m A ma y 
c o nti n ue treat me nt as pla n ne d (ie, as l o n g as t he y recei ve cli nical be nefit a n d d o n ot meet a n y 
disc o nti n uati o n criteria).
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1.3
Schedule of Activities
Table 1
Schedule of Activities for Arm A (AZD4635 plus Durvalumab every 4 Weeks)
Screening
Cycle = 28 days (4 weeks)
End-of-
Treatment
Follow-up Visits 
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
onwards
30-
days
(±7 
days)
after 
last 
treatm
ent
90-
days
(±7 
days)  
after 
last 
treat
ment
Progressio
n- Free 
Follow-Upa
(Every 
12 weeks
[±7 days])
Survival 
90 days
(Every 3 
months 
(±7 days)  
after last 
treatment, 
until final 
DCO)
Week 
-4 to -0
1
2
3
5
7
9
11
13+ 
Day (visit window ±3 days 
from Cycle 2, Day 1 
onwards)
-28 to 0
1
8
15
1
15
1
15
1
Informed consent 
X
5.1
Inclusion/exclusion criteria
X
5.1, 5.2
Routine clinical proceduresb
Medical history and
demographics
X
5.1, 5.2
Physical examination 
including weight
X
X
X
X
X
X
8.2.1
WHO performance status
X
X
X
X
X
8.2.2, Table 14
Test for COVID-19c
Tests for active COVID-19 infection may be prescribed, if required.
8.2.8
Vital signs including 
respirations
X
X
X
X
X
X
8.2.3
Height
X
X
8.2.3
12-lead ECG (triplicate)
X (≤14 days)
X
X
8.2.4
Echocardiogram/MUGA
Xd
8.2.5
Concomitant (including 
prior) medication
X
At every visit and may be conducted by phone if not tied to 
a visit. 
X
X
X
(Cancer therapy 
only at these 2 
visits)
8.2.6


Clinical Study Protocol – 3.0
AstraZeneca
AZD4635 - D8731C00002
CONFIDENTIAL AND PROPRIETARY
23 of 193
Table 1
Schedule of Activities for Arm A (AZD4635 plus Durvalumab every 4 Weeks)
Screening
Cycle = 28 days (4 weeks)
End-of-
Treatment
Follow-up Visits 
Details in 
CSP Section 
or Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
onwards
30-
days
(±7 
days)
after 
last 
treatm
ent
90-
days
(±7 
days)  
after 
last 
treat
ment
Progressio
n- Free 
Follow-Upa
(Every 
12 weeks
[±7 days])
Survival 
90 days
(Every 3 
months 
(±7 days)  
after last 
treatment, 
until final 
DCO)
Week 
-4 to -0
1
2
3
5
7
9
11
13+ 
Day (visit window ±3 days 
from Cycle 2, Day 1 
onwards)
-28 to 0
1
8
15
1
15
1
15
1
Routine safety measurementsb
Adverse events
X
At every visit and may be conducted by phone if not tied to 
a visit.
X
X
X
X
Appendix B
Haematology 
X
X
X
X
X
X
X
X
8.2.7, Table 15
Clinical chemistry
X
X
X
X
X
X
X
X
8.2.7, Table 15
Urinalysis
X
X
X
X
X
8.2.7, Table 15
Coagulation (PT/INR/aPTT)
X
X
X
X
X
8.2.7, Table 15
Testosterone level
X
8.2.8
Pharmacokinetic measurements
AZD4635 pre-dose blood 
sample 
X
X
X
(C5 & C7 only)
8.5.1, Table 16
Durvalumab pre-infusion 
blood sample for PK
X
X
X
(C4 & C7 only)
8.5.2, Table 20
Durvalumab post-infusion 
blood sample for PK 
X
X
(C4 only)
X
8.5.2, Table 20
Durvalumab pre-infusion 
blood sample for anti-drug 
antibody
X
X
X
(C4 & C7 only)
X
8.5.2, Table 20


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 4 of 1 9 3
Ta ble 1
Sc he d ule of Acti vities f or  Ar m A ( A Z D 4 6 3 5 pl us D ur v al u m a b e ver y 4 W ee ks)
Scree ni n g
C ycle = 2 8 d a ys ( 4 wee ks)
E n d -of -
Tre at me nt
F oll o w -u p Visits 
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1  
C ycle 2  
C ycle 3
C ycle 4 
o n w ar ds
3 0-
d a ys
( ± 7 
d a ys)
after 
l ast 
tre at m
e nt
9 0-
d a ys
( ± 7 
d a ys)  
after 
l ast 
tre at
me nt
Pr o gressi o
n- Free 
F oll o w -U p a
( Ever y 
1 2 wee ks
[ ± 7 d a ys])
S ur vi v al 
9 0 d a ys
(E ver y 3 
m o nt hs 
( ± 7 d a ys)   
after l ast 
tre at me nt, 
u ntil fi n al 
D C O)
Wee k 
-4 t o - 0 
1 
2 
3 
5 
7 
9 
1 1
1 3 + 
D a y ( visit wi n d o w ± 3 d a ys 
fr o m C ycle 2, D a y 1 
o n w ar ds)
-2 8 t o 0
1 
8 
1 5 
1 
1 5 
1 
1 5 
1
Bi o m ar ker assess me nts
 
 
 
 
 
 
  
 
 
 
 
8. 7
C CI
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 5 of 1 9 3
Ta ble 1
Sc he d ule of Acti vities f or  Ar m A ( A Z D 4 6 3 5 pl us D ur v al u m a b e ver y 4 W ee ks)
Scree ni n g
C ycle = 2 8 d a ys ( 4 wee ks)
E n d -of -
Tre at me nt
F oll o w -u p Visits 
Det ails i n 
C S P Secti o n 
or A p pe n di x
C ycle 1  
C ycle 2  
C ycle 3
C ycle 4 
o n w ar ds
3 0-
d a ys
( ± 7 
d a ys)
after 
l ast 
tre at m
e nt
9 0-
d a ys
( ± 7 
d a ys)  
after 
l ast 
tre at
me nt
Pr o gressi o
n- Free 
F oll o w -U p a
( Ever y 
1 2 wee ks
[ ± 7 d a ys])
S ur vi v al 
9 0 d a ys
(E ver y 3 
m o nt hs 
( ± 7 d a ys)   
after l ast 
tre at me nt, 
u ntil fi n al 
D C O)
Wee k 
-4 t o - 0 
1 
2 
3 
5 
7 
9 
1 1
1 3 + 
D a y ( visit wi n d o w ± 3 d a ys 
fr o m C ycle 2, D a y 1 
o n w ar ds)
-2 8 t o 0
1 
8 
1 5 
1 
1 5 
1 
1 5 
1
Effic ac y me as ure me nts
T u m o ur i ma gi n g ( R E CI S T 
Versi o n 1. 1) C T/ M RI/ P E T f
X
E ver y 8 w ks ( ± 1 w k) fr o m t he st art of d osi n g u ntil 
2 4 w ks, a n d t he n e ver y 1 2 w ks ( ± 1 w k) t here after
X (if re q uire d)
X
8. 1. 1
T u m o ur i ma gi n g ( P C W G 3 
f or b o ne lesi o n assess me nt) 
B o ne sca ns 
X
E ver y 8 w ks ( ± 1 w k) fr o m t he st art of d osi n g u ntil 
2 4 w ks, a n d t he n e ver y 1 2 w ks ( ± 1 w k) t here after
X (if re q uire d)
X
8. 1. 2
P S A
X  
X
X  
X
X
X
X
8. 2. 8
S ur vi val stat us/s u bse q ue nt 
ca ncer t hera p y
X
8. 2. 1 0. 3
e P R O ( B PI-S F) g
X
X  
X
X
X  
X
X
8. 2. 9
e P R O ( F A C T-P) g
X
X  
X
X
X  
X
X
8. 2. 9
St u d y i nter ve nti o n a d mi nistr ati o n
A Z D 4 6 3 5 dis pe nse d ( dail y 
d osi n g)
6. 2. 1
Diar y  re vie w 
X
X
X
X
6. 2. 1 , 6. 4
D ur val u ma b 1 5 0 0 m g I V
X
X
X
X
6. 2. 2. 1
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
2 6 of 1 9 3
a
Partici pa nts will be f oll o we d u p e ver y 1 2 wee ks ( ± 1 wee k) starti n g fr o m t he last date of t he last t u m o ur res p o nse assess me nt u ntil eit her: o bjecti ve P D has bee n c o nfir me d, 
wit h dra wal of c o nse nt, u ntil t he pri mar y D C O f or t he ar m, or u ntil t he st u d y is ter mi nate d b y t he S p o ns or.
b
R o uti ne cli nical a n d safet y assess me nts ma y be d o ne 1 da y pri or t o eac h visit, if re q uire d.
c
D uri n g t he st u d y, tests f or acti ve C O VI D -1 9 i nfecti o n ma y be prescri be d, if re q uire d, a n d i n acc or da nce wit h l ocal g ui deli nes . 
d
A n ec h ocar di o gra m or m ulti ple -gate d ac q uisiti o n ( M U G A) sca n o btai ne d i n t he 6 m o nt hs pri or t o scree ni n g will be acce pta ble u nless t here has bee n a c ha n ge i n t he 
partici pa nt’s car d iac stat us, i n w hic h case t his will be re peate d. If t here is n o ec h ocar di o gra m or M U G A wit hi n 6 m o nt hs pri or t o st u d y e nr oll me nt, t his will be perf or me d at 
scree ni n g. A d diti o nal assess me nts f or ec h ocar di o gra m or M U G A d uri n g t he st u d y will be deter mi ne d as cli nicall y i n dicate d base d o n t he c urre nt a vaila ble data.
f
Per A p pe n di x G , w hile P E T sca ns are n ot c o nsi dere d a de q uate t o meas ure lesi o ns, P E T-C T sca ns ma y be use d pr o vi di n g t hat t he meas ures are o btai ne d fr o m t he C T sca n a n d 
t he C T sca n is of i de ntical dia g n ostic qualit y t o a dia g n ostic C T ( wit h I V a n d oral c o ntrast).
g
T he P R O i nstr u me nts will be a d mi nistere d a n d c o m plete d at t he start of eac h visit.
C CI


Clinical Study Protocol – 3.0
AstraZeneca
AZD4635 - D8731C00002
CONFIDENTIAL AND PROPRIETARY
27 of 193
Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and Cabazitaxel every 3 Weeks for First 
10 Cycles and then every 4 Weeks)
Screening
Cycle = 21 days (3 weeks)
Cycle = 28 
days 
(4 weeks)
End-of-
Treatm
ent
Follow-up Visits 
Details in CSP 
Section or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 to 
10
Cycle 11 
onwards
Week 
-4 to -0
1
1
2
3
4
5
6
7
9
10-32
33+ 
30-
days 
(±7 
days) 
after 
last 
treatm
ent
90-
days 
(±7 
days) 
after 
last 
treat
ment
Progress-
ion-free 
survivala
(Every 
12 weeks
[±7 days])
Survival 
90 days 
Every 3 months 
(±7 days) after 
last treatment, 
until final
DCO)
Day (visit window 
±3 days from 
Cycle 2, Day 1 
onwards)
-28 to 0
1
2
8
15
1
8
15
1
15
1
1
Informed consent 
X
5.1
Inclusion/exclusion 
criteria
X
5.1, 5.2
Routine clinical proceduresb
Medical history and
demographics
X
5.1, 5.2
Physical examination 
including weight
X
X
X
X
X
X
X
8.2.1
WHO performance 
status
X
X
X
X
X
X
8.2.2, Table 14
Test for COVID-19c
Tests for active COVID-19 infection may be prescribed, if required.
8.2.8
Vital signs including 
respirations
X
X
X
X
X
X
X
8.2.3
Height
X
X
8.2.3
12-lead ECG 
(triplicate)
X
(≤14 days)
X
X
8.2.4
Echocardiogram/
MUGA
Xd
8.2.5


Clinical Study Protocol – 3.0
AstraZeneca
AZD4635 - D8731C00002
CONFIDENTIAL AND PROPRIETARY
28 of 193
Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and Cabazitaxel every 3 Weeks for First 
10 Cycles and then every 4 Weeks)
Screening
Cycle = 21 days (3 weeks)
Cycle = 28 
days 
(4 weeks)
End-of-
Treatm
ent
Follow-up Visits 
Details in CSP 
Section or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 to 
10
Cycle 11 
onwards
Week 
-4 to -0
1
1
2
3
4
5
6
7
9
10-32
33+ 
30-
days 
(±7 
days) 
after 
last 
treatm
ent
90-
days 
(±7 
days) 
after 
last 
treat
ment
Progress-
ion-free 
survivala
(Every 
12 weeks
[±7 days])
Survival 
90 days 
Every 3 months 
(±7 days) after 
last treatment, 
until final
DCO)
Day (visit window 
±3 days from 
Cycle 2, Day 1 
onwards)
-28 to 0
1
2
8
15
1
8
15
1
15
1
1
Concomitant 
(including prior) 
medication
X
At every visit and may be conducted by phone if 
not tied to a visit.
X
X
X
X
X
(Cancer therapy 
only at these 2 
visits)
8.2.6
Routine safety measurementsa
Adverse events
X
At every visit and may be conducted by phone if 
not tied to a visit.
X
X
X
X
X
X
Appendix B
Haematologye
X
X
X
X
X
X
X
X
X
X
X
X
8.2.7, Table 15
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
X
X
8.2.7, Table 15
Urinalysis
X
X
X
X
X
X
8.2.7, Table 15
Coagulation 
(PT/INR/aPTT)
X
X
X
X
X
X
8.2.7, Table 15
Testosterone level
X
8.2.8, Table 15


Clinical Study Protocol – 3.0
AstraZeneca
AZD4635 - D8731C00002
CONFIDENTIAL AND PROPRIETARY
29 of 193
Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and Cabazitaxel every 3 Weeks for First 
10 Cycles and then every 4 Weeks)
Screening
Cycle = 21 days (3 weeks)
Cycle = 28 
days 
(4 weeks)
End-of-
Treatm
ent
Follow-up Visits 
Details in CSP 
Section or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 to 
10
Cycle 11 
onwards
Week 
-4 to -0
1
1
2
3
4
5
6
7
9
10-32
33+ 
30-
days 
(±7 
days) 
after 
last 
treatm
ent
90-
days 
(±7 
days) 
after 
last 
treat
ment
Progress-
ion-free 
survivala
(Every 
12 weeks
[±7 days])
Survival 
90 days 
Every 3 months 
(±7 days) after 
last treatment, 
until final
DCO)
Day (visit window 
±3 days from 
Cycle 2, Day 1 
onwards)
-28 to 0
1
2
8
15
1
8
15
1
15
1
1
Pharmacokinetic measurements
First 12 evaluable participants
Pre-dose AZD4635, 
durvalumab and
cabazitaxel blood 
sample 
X
X
(AZD46
35 only)
X
(AZD4
635 
only)
X
(C5 & C7)
(AZD4635 
only)
8.5.1, Table 17
AZD4635 post-dose 
blood samples
X
X
8.5.1, Table 17
Cabazitaxel post-dose 
blood samples
X
X
Table 19
All participants (excluding first 12 evaluable participants)
AZD4635 pre-dose 
blood sample 
X
X
X
(C5 & C7)
8.5.1, Table 18
Durvalumab pre-
infusion blood sample 
for PK
X
X
X
(C4 & C7)
8.5.2, Table 20
Durvalumab post-
infusion blood sample 
for PK
X
X
(C4 only)
X
8.5.2, Table 20


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 0 of 1 9 3
Ta ble 2
Sc he d ule of Acti vities f or Ar m B ( A Z D 4 6 3 5 pl us D ur v al u m a b a n d C a b azit a xel e ver y 3 Wee ks f or Fi rst 
1 0 C ycles a n d t he n e ver y 4 W ee ks)
Scree ni n g
C ycle = 2 1 d a ys ( 3 wee ks)
C ycle = 2 8 
d a ys 
( 4 wee ks)
E n d -of -
Tre at m
e nt
F oll o w -u p Visits 
Det ails i n C S P 
Secti o n or 
A p pe n di x
C ycle 1  
C ycle 2  
C ycle 3
C ycle 4 t o 
1 0
C ycle 1 1 
o n w ar ds
Wee k 
-4 t o - 0 
1 
1 
2 
3 
4 
5
6 
7 
9 
1 0- 3 2
3 3 + 
3 0-
d a ys 
( ± 7 
d a ys) 
after 
l ast 
tre at m
e nt
9 0-
d a ys 
( ± 7 
d a ys) 
after 
l ast 
tre at
me nt
Pr o gress -
i o n-free 
s ur vi v al a
( Ever y 
1 2 wee ks
[ ± 7 d a ys])
S ur vi v al 
9 0 d a ys 
( E ver y 3 m o nt hs 
( ± 7 d a ys) after 
l ast tre at me nt, 
u ntil fi n al
D C O)
D a y ( visit wi n d o w 
± 3 d a ys fr o m 
C ycle 2, D a y 1 
o n w ar ds)
-2 8 t o 0
1 
2 
8 
1 5 
1 
8
1 5 
1 
1 5 
1 
1
D ur val u ma b pre -
i nf usi o n bl o o d sa m ple 
f or a nti -dr u g a nti b o d y 
X
X
X
( C 4 & C 7 o nl y )
X
8. 5. 2 , Ta ble 2 0
Bi o m ar ker
A de n osi ne ( A D O)
si g nalli n g ge ne 
e x pressi o n
X  
X
8. 6. 1. 1
 
 
 
 
 
 
 
 
 
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 1 of 1 9 3
Ta ble 2
Sc he d ule of Acti vities f or Ar m B ( A Z D 4 6 3 5 pl us D ur v al u m a b a n d C a b azit a xel e ver y 3 Wee ks f or Fi rst 
1 0 C ycles a n d t he n e ver y 4 W ee ks)
Scree ni n g
C ycle = 2 1 d a ys ( 3 wee ks)
C ycle = 2 8 
d a ys 
( 4 wee ks)
E n d -of -
Tre at m
e nt
F oll o w -u p Visits 
Det ails i n C S P 
Secti o n or 
A p pe n di x
C ycle 1  
C ycle 2  
C ycle 3
C ycle 4 t o 
1 0
C ycle 1 1 
o n w ar ds
Wee k 
-4 t o - 0 
1 
1 
2 
3 
4 
5
6 
7 
9 
1 0- 3 2
3 3 + 
3 0-
d a ys 
( ± 7 
d a ys) 
after 
l ast 
tre at m
e nt
9 0-
d a ys 
( ± 7 
d a ys) 
after 
l ast 
tre at
me nt
Pr o gress -
i o n-free 
s ur vi v al a
( Ever y 
1 2 wee ks
[ ± 7 d a ys])
S ur vi v al 
9 0 d a ys 
( E ver y 3 m o nt hs 
( ± 7 d a ys) after 
l ast tre at me nt, 
u ntil fi n al
D C O)
D a y ( visit wi n d o w 
± 3 d a ys fr o m 
C ycle 2, D a y 1 
o n w ar ds)
-2 8 t o 0
1 
2 
8 
1 5 
1 
8
1 5 
1 
1 5 
1 
1
 
 
 
 
 
Effic ac y me as ure me nts
T u m o ur i ma gi n g 
( R E CI S T Versi o n 
1 . 1) C T/ M RI/ P E Tf
X g
E ver y 9 w ks ( ± 1 w k) fr o m t he st art of d osi n g u ntil 
2 7 w ks, a n d t he n e ver y 1 2 w ks ( ± 1 w k) t here after
X (if 
re q uire d
X
8. 1. 1
T u m o ur i ma gi n g 
( P C W G 3 f or b o ne 
lesi o n assess me nt) 
B o ne sca ns
X
E ver y 9 w ks ( ± 1 w k) fr o m t he st art of d osi n g u ntil 
2 7 w ks, a n d t he n e ver y 1 2 w ks ( ± 1 w k) t here after
X (if 
re q uire d
X
8. 1. 2
P S A
X  
X
X
X
X  
X  
X
X
8. 2. 8
C CI
C CI
C CI
C CI
C CI
C CI


Clinical Study Protocol – 3.0
AstraZeneca
AZD4635 - D8731C00002
CONFIDENTIAL AND PROPRIETARY
32 of 193
Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and Cabazitaxel every 3 Weeks for First 
10 Cycles and then every 4 Weeks)
Screening
Cycle = 21 days (3 weeks)
Cycle = 28 
days 
(4 weeks)
End-of-
Treatm
ent
Follow-up Visits 
Details in CSP 
Section or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 to 
10
Cycle 11 
onwards
Week 
-4 to -0
1
1
2
3
4
5
6
7
9
10-32
33+ 
30-
days 
(±7 
days) 
after 
last 
treatm
ent
90-
days 
(±7 
days) 
after 
last 
treat
ment
Progress-
ion-free 
survivala
(Every 
12 weeks
[±7 days])
Survival 
90 days 
Every 3 months 
(±7 days) after 
last treatment, 
until final
DCO)
Day (visit window 
±3 days from 
Cycle 2, Day 1 
onwards)
-28 to 0
1
2
8
15
1
8
15
1
15
1
1
Survival 
status/subsequent 
cancer therapy
X
8.2.10.3
ePRO (BPI-SF)h
X
X
X
X
X
X
X
X
8.2.9
ePRO (FACT-P)h
X
X
X
X
X
X
X
X
8.2.9
Study intervention administration
AZD4635 dispensed 
(daily dosing)
6.2.1
Diary review
X
X
X
X
X
6.2.1, 6.4
Durvalumab 1500 mg 
IV
X
X
X
X
X
6.2.2.1


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Table 2
Schedule of Activities for Arm B (AZD4635 plus Durvalumab and Cabazitaxel every 3 Weeks for First 
10 Cycles and then every 4 Weeks)
Screening
Cycle = 21 days (3 weeks)
Cycle = 28 
days 
(4 weeks)
End-of-
Treatm
ent
Follow-up Visits 
Details in CSP 
Section or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 to 
10
Cycle 11 
onwards
Week 
-4 to -0
1
1
2
3
4
5
6
7
9
10-32
33+ 
30-
days 
(±7 
days) 
after 
last 
treatm
ent
90-
days 
(±7 
days) 
after 
last 
treat
ment
Progress-
ion-free 
survivala
(Every 
12 weeks
[±7 days])
Survival 
90 days 
Every 3 months 
(±7 days) after 
last treatment, 
until final
DCO)
Day (visit window 
±3 days from 
Cycle 2, Day 1 
onwards)
-28 to 0
1
2
8
15
1
8
15
1
15
1
1
Cabazitaxel 20 mg/m2
or 25 mg/m2 (per 
locally approved 
label) plus prednisone 
10 mg PO plus 
primary G-CSF 
prophylaxisi
X
X
X
X
6.2.3.1
a
Participants will be followed up every 12 weeks (±1 week) starting from the last date of the last tumour response assessment until either: objective PD has been confirmed, 
withdrawal of consent, until the primary DCO for the arm, or until the study is terminated by the Sponsor.
b
Routine clinical and safety assessments may be done 1 day prior to each visit, if required.
c
During the study, tests for active COVID-19 infection may be prescribed, if required, and in accordance with local guidelines. 
d
An echocardiogram or multiple-gated acquisition (MUGA) scan obtained in the 6 months prior to screening will be acceptable unless there has been a change in the 
participant’s cardiac status, in which case this will be repeated. If there is no echocardiogram or MUGA within 6 months prior to study enrollment, this will be performed at 
screening. Additional assessments for echocardiogram or MUGA during the study will be determined as clinically indicated based on the current available data.
e
Haematology will include a full blood count with differential blood counts.
f
Per Appendix G, while PET scans are not considered adequate to measure lesions, PET-CT scans may be used providing that the measures are obtained from the CT scan and 
the CT scan is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast).
g
At least half of the participants should have RECIST v1.1 measurable disease at baseline (ie, at least 40 participants enrolled and assigned to study treatment in Arm B, 
including approximately 15 participants at the time of interim analysis).
h
The PRO instruments will be administered and completed at the start of each visit.


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i
Participants should be observed closely for hypersensitivity reactions especially during the first and second infusions, as per the local cabazitaxel label. Hypersensitivity 
reactions may occur within a few minutes following the initiation of the infusion of cabazitaxel, thus facilities and equipment for the treatment of hypotension and 
bronchospasm should be available (Section 6.7.3). Dose modifications should be made if participants experience the following adverse reactions per Table 12.


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2
INTRODUCTION
AZD4635 is a novel adenosine2A receptor (A2AR) antagonist agent that acts against cancer by 
blocking adenosine-mediated A2AR signalling in tumour-infiltrating immune cells. A2AR 
signalling suppresses effector T and natural killer cell function and increases the function of 
regulatory T-lymphocyte (T cells) and myeloid derived suppressor cells. AZD4635-mediated 
A2AR blockade is hypothesised to make the tumour microenvironment (TME) less 
immunosuppressive, thus improving anti-tumour immune responses. Modulation of the TME 
with drugs that decrease adenosine (ADO) levels or inhibit the A2AR may reverse these effects 
and enable the host to mount an effective anti-tumour immune response, even in tumour types 
that are not typically responsive to immune checkpoint inhibitors.
Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody (mAb) that 
blocks the interaction of programmed cell death ligand 1 (PD-L1) with programmed cell death 
protein 1 (PD-1) on T cells and with cluster of differentiation 80 (CD80) (B7-1) on immune 
cells and is engineered to reduce antibody-dependent cell-mediated cytotoxicity and 
complement activation. In vitro studies have demonstrated that durvalumab antagonizes the 
inhibitory effect of PD-L1 on primary human T cells, resulting in the restored proliferation of 
interferon gamma (IFN-γ), and in vivo studies have shown that durvalumab inhibits tumour 
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 anti-tumour immune response by 
binding to PD-L1 and shifting the balance toward such a response. 
Cabazitaxel (Jevtana®) a microtubule inhibitor was approved by the United States Food and 
Drug Administration (FDA) and the European Medicines Agency (EMA) in 2010 and 2011, 
respectively, for the treatment of patients with mCRPC previously treated with docetaxel. The 
recommended cabazitaxel approved dose by both agencies is 25 mg/m2 administered Q3W in 
combination with prednisone 10 mg PO daily.
Cabazitaxel approval is based on results from the TROPIC trial (NCT00417079) in which
participants with hormone-refractory metastatic prostate cancer either measurable by RECIST 
criteria or with non-measurable disease with rising PSA levels or with new lesions were 
randomized (n = 755) to receive either cabazitaxel 25 mg/m2 IV Q3W for a maximum of 
10 cycles with prednisone 10 mg PO daily (n = 378), or mitoxantrone 12 mg/m2 IV Q3W for 
10 cycles with prednisone 10 mg PO daily (n = 377) for a maximum of 10 cycles. 
Investigator-assessed tumour response of 14.4% (95% confidence interval [CI]: 9.6-19.3) was 
higher for participants in the cabazitaxel arm than for participants in the mitoxantrone arm
(4.4% [95% CI: 1.6-7.2]), p = 0.0005.
The TROPIC trial demonstrated that cabazitaxel is the first treatment to prolong survival in 
mCRPC since the approval of docetaxel (Villanueva et al. 2011). The FDA and EMA 
approved cabazitaxel in June 2010 and January 2011, respectively, based on this data. On 


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 6 of 1 9 3
1 4 Se pte m ber 2 0 1 7, t he F D A  a p pr o ve d a l o wer d ose of ca bazita xel f or m C R P C ( 2 0 m g/ m2) 
Q 3 W  in c o m bi nat i on wi t h pre d nis o ne. T he P R O S E LI C A trial ( N C T 0 1 3 0 8 5 0) ra n d o mise d 
m C R P C parti ci pa nt s ( n = 1 2 0 0) t o eit her ca bazita xel 2 5 m g/ m 2 I V Q 3 W ( n = 6 0 2) or 2 0 
m g/ m 2 I V Q 3 W ( n = 5 9 8). O verall s ur vi val was t he m ajor ef ficac y o utc o me. Parti ci pa nt s o n 
ca bazita xel 2 0 m g/ m 2 ha d a n esti mate d me dia n O S of 1 5. 1 m o nt hs a n d parti ci pa nt s o n 
ca bazita xel 2 5 m g/ m 2 ha d me di a n O S of 1 5. 9 mo nt hs, t he o bser ve d hazar d rati o ( H R) of O S 
was 1. 0 4 2 ( 9 7. 7 8 % CI: 0. 8 8 6, 1. 2 2 4). N o n ota ble differe nce i n O S was i n s u b gr o u ps base d o n 
t he stratificat i on fact ors of E C O G perf or ma nce stat us sc ore, meas ura bility of  disease, or 
r e gio n.
T his P ha se II i nter nati onal, o pe n -la bel, t w o-ar m, n o n-ra n d o mise d st u d y will e val uate t he 
efficac y, safety a n d t olera bilit y a n d P K of  A Z D 4 6 3 5 gi ve n i n c om bi nati o n wit h d ur val u ma b ,
a n d i n c o m bi nati on wi t h d ur val u ma b pl us ca bazi t a x el, i n ge neticall y u nselecte d patie nts wit h 
m C R P C pre vi o usl y treate d wit h a N H A  a n d d oceta xel ( or o ne or m ore ta xa nes or w h o are 
ta xa ne i neli gi ble [de pe n di n g o n treat me nt ar m ]). Parti ci pa nts i n eac h ar m will be stratifie d b y 
t he prese nce o f meas ura ble s oft tiss ue metastasis ( per R E CI S T v 1. 1 , A p pe n di x F ) or 
b o ne -o nl y  metastasis ( per P C W G 3 criteria , A p pe n di x H ). T here will be n o f or mal 
c o m par is o ns bet wee n treat me nt ar ms. Partici pa nts wit h m C R P C will be all ocate d t o o ne of t he 
f oll owi n g treat m e nt ar ms:
Ar m A: A Z D 4 6 3 5 (
 mg P O dail y) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 4 W )
N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr o l me nt i n Ar m A fol l owi n g decisi o n s at 
t he pr o gra m le vel, n ot relate d t o a n y safety iss ues. O n g oi n g partici pa nts i n Ar m A ma y 
c o nti n ue treat me nt as pla n ne d (ie, as l o n g as t he y recei ve cli nical be nefit a n d d o n ot meet a n y 
di sc o nti n uati on cri t eria).
or
Ar m B : A Z D 4 6 3 5 (
 mg P O dail y) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 3 W ) 
pl us ca bazit a x el ( 2 0 or 2 5 mg/ m 2 I V Q 3 W as per t he l ocal prescri bi n g g ui deli nes) ( n = 8 0)
P arti cipa nts i n Ar m  B m ust recei ve t he foll o wi n g pr e m e dicat i on t o m a na ge 
ca bazita xel-ass o ciate d reacti o ns ( h y perse nsit i vity or ot her): 

Pre d nis o ne ( 1 0 m g dail y c o nt i n u o usl y [ or e q ui vale nt ster oi d]) f or t he d urati o n of 
ca bazita xel a d mi nistrati o n

Pri mar y G -C S F pr o p h yla xis
P arti cipa nts i n Ar m B will recei ve ca bazita xel c he m ot hera p y as per t he lo c al  la bel. T his will
start a p pr o xi matel y 1 h o ur ( or u p t o a ma xi m u m of 2 h o urs) after t he e n d of t he d ur val u ma b 
i nf usi on. Ca bazita xel will be a d mi nistere d as per t he l ocal prescri bi n g g ui deli nes f or a 
ma xi m u m o f 1 0 c y cles. After c y cle 1 0 d ur val u ma b + A Z D 4 6 3 5 will be a d mi nistere d Q 4 W  t o 
C CI
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harmonise with the Arm A treatment cycle length.
Eligible participants must have histologically diagnosed mCRPC with no evidence of small 
cell histology, have had progression of disease ≤6 months prior to study entry based on 
RECIST v1.1 or the presence of bone lesions per PWCG3, and have ongoing androgen 
deprivation with serum testosterone <50 ng/mL. An archival tumour sample or baseline
tumour biopsy is required. The collection of paired tumour biopsies will be requested during 
the study; however, this is optional. 
At baseline eligible participants must have RECIST-measurable disease (target lesions) or 
bony non-measurable disease (non-target bone lesions) (Appendix F). In addition, PSA will be 
evaluated at the start of each cycle as per PCWG3.
Participants in Arm A (AZD4635 plus durvalumab) will have disease assessments/imaging at 
baseline and every 8 weeks (±7 days) from the start of dosing for the first 24 weeks and then 
every 12 weeks (±7 days) thereafter. Note: As of November 2020, the Sponsor stopped 
enrolment in Arm A. Ongoing participants in Arm A may continue treatment as planned (ie, as 
long as they receive clinical benefit and do not meet any discontinuation criteria).
Participants in Arm B (AZD4635 plus durvalumab and cabazitaxel) will have disease 
assessments/imaging every 9 weeks (± 7 days) from the start of dosing for the first 27 weeks 
and then every 12 weeks (± 7 days) thereafter. A safety assessment to determine the safety and 
tolerability of this combination will be conducted by the SRC once the first 6 participants have 
completed a safety run-in period of at least 1 cycle (see Section 4.1.1). Cabazitaxel will be 
discontinued after 10 cycles, and AZD4635 and durvalumab may be continued every 4 weeks.
Participants may continue to receive study intervention until confirmed objective disease 
progression as assessed by the Investigator, or until they suffer from unacceptable toxicity or 
for as long as they do not meet any other discontinuation criteria. Once participants have been 
discontinued from study treatment, other treatment options will be explored at the discretion 
of the Investigator.
The two arms will enrol participants with metastatic disease (see Figure 1). As of November 
2020, the Sponsor stopped enrolment in Arm A. Arm B will enroll and assign to study 
treatment approximately 80 participants. At least 40 participants with RECIST 
v1.1-measurable soft-tissue disease at baseline will be enrolled and assigned to study 
treatment in Arm B, and the remainder of participants in the arm (n = 40) may have bone-only 
disease (on bone scan [per PWCG3]) or measurable disease. The primary objective of the 
study is to assess rPFS. rPFS is defined as the time from first dose to radiographic progression 
as determined by the Investigator according to RECIST v1.1 for soft tissue disease or PCWG3 
for bone disease or death from any cause, whichever occurs first. Overall survival and the 
ORR, DoR, PSA50 response, and time to pain progression will also be evaluated for efficacy.


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A futility interim analysis is planned for Arm B based on PSA50 response for approximately 
n = 30 dosed participants. Of these participants, approximately 15 participants are to have 
RECIST v1.1 measurable disease at baseline and the remainder of the participants may have 
bone-only disease or measurable disease.
For detailed descriptions of the chemistry, pharmacology, efficacy, and safety of AZD4635 
and durvalumab, refer to the respective Investigator’s Brochures (IBs). For detailed 
descriptions of the chemistry, pharmacology, efficacy, and safety of cabazitaxel, refer to the 
respective product labels, either the US prescribing information or the EU Summary of 
Product Characteristics (SmPC).
2.1
Study Rationale
Although novel hormonal agents (NHA) have changed the landscape of treatment for 
mCRPC, for patients who have progressed with NHA and docetaxel, there remain limited 
therapeutic options. While immunotherapy has led to impressive responses in a subset of 
patients with immunologically "activated" tumours, this approach has shown little progress in 
mCRPC. AZD4635 appears to have increased efficacy in combination with anti-PD-L1 in 
patients with mCRPC who have exhausted standard of care options due to increased immune 
activation compared to single agent AZD4635 based on the results of the ongoing Phase I 
study D8730C00001. At the data cut-off (DCO) of 02 December 2019, 8 subjects had 
achieved objective response (OR) per RECIST v1.1. Two subjects (durvalumab combination) 
had complete responses and 6 subjects had partial responses (monotherapy [n = 2] and 
durvalumab combination [n = 4]). The participants with an OR (CR or PR) have had a 
duration of response that ranged from 2.30 to 25.82 months with several participants’ 
durations ongoing at the DCO.
The combination of the checkpoint inhibitor pembrolizumab (anti-PD-1) and docetaxel has 
been investigated in the KEYNOTE 365 study where the checkpoint inhibitor was added to 
the standard-of-care (SOC) chemotherapy. It has been reported that pembrolizumab alone 
leads to a relatively low response rate of ~5% and PSA50 of 11% (KEYNOTE-199) 
(Antonarakis et al 2019). In KEYNOTE 365, an ORR of 14% (5/36) and PSA50 of 31% 
(22/71) were reported with the most notable result being a median radiographic 
progression-free survival (rPFS) of 8.3 months (Massard et al. 2019) which is longer than that 
reported with single-agent docetaxel (3.9 months [Rathkopf et al. 2018]). Additionally, the 
recently published CARD study (de Wit et al. 2019) demonstrated an imaging-based median 
PFS of ~8.2 months for the cabazitaxel arm in a post-NHA, post-docetaxel unselected 
mCRPC participant population. 
While the KEYNOTE-365 provides early evidence to support the combination of 
chemotherapy and checkpoint inhibition in mCRPC, we hypothesise that AZD4635 combined 
with the checkpoint inhibitor (anti-PD-L1) durvalumab and cabazitaxel will lead to an 


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
3 9 of 1 9 3
i ncreased r P F S i n t he p ost-d oceta xel setti n g b y decreasi n g t he i m m u n os u p pressi ve 
e n vir o n me nt a n d c o u nteracti n g t he effects of A D O w hic h ca n li mit t he a nt i-P D 1/ P D L 1 
res p o nse. 
2. 2
B ac k gr o u n d
Pr ostate ca ncer is t he sec o n d m ost c o m m o n ca ncer i n me n. I n 2 0 1 8, o ver 1. 2 mil li on ne w 
cases o f pr ostate ca ncer were dia g n ose d w orl d wi de a n d t here were 3 5 0, 0 0 0 deat hs d ue t o t he 
di sease (Bra y  et al. 2 0 1 8). F or me n re q uiri n g s yste mic thera p y, h or mo nal  t hera p y has bee n t he 
mai nsta y . O nce t he disease bec ome s resista nt t o h or m o nal t hera p y, t he disease is k n o w n as 
castrati o n-resista nt pr ostate ca ncer ( C R P C). Treat me nt f or b ot h metastatic a n d n o n-metastati c 
pr ostate ca ncer has e v o l ve d o ver the past 1 5 years. I n 2 0 0 4 , t he de vel o p me nt of a d oceta xel 
re gi me n f or t he treat me nt of C R P C was t he first c he m ot hera p y t o s h o w a s ur vi val be nefit a n d 
s u bse q ue ntl y beca me t he sta n dar d -of -care c he m ot hera p y f or C R P C. A re gi me n of d oceta xel  
gi ve n Q 3 W ha d a m e d ia n O S of  1 8. 9 mo nt hs ( 9 5 % CI 1 4 1 7. 0 -2 1. 2), w hic h was greater t ha n 
t he s ur vi val of  1 6. 5 mo nt hs ( 9 5 % CI 1 4. 4 – 1 8. 6 m o nt hs) f or a mit o xa ntr o ne c o ntr ol  ar m. T he 
hazar d rati o ( H R) f or deat h was 0. 7 6 ( 9 5 % CI 0. 6 2 -0. 9 4, p = 0. 0 0 9) f or d oceta xel c o m pare d t o 
mit o xa ntr o ne ( Ta n n oc k et al. 2 0 1 4 ). H o we ver, ma n y of t he treat me nts for pr ostate ca ncer, 
i ncl u di n g d oceta xel a n d ca bazita xel f or m C R P C, are n ot s uita ble f or all patient s a n d ma n y 
pati e nts are refract or y t o t hese treat me nts s o alter nati ve treat me nt o pti o ns are nee de d. 
Ne w h or m o nal a ge nts ha ve bec o me sta n dar d of care f or m C R P C a n d i ncl u de e nzal uta mi de 
a n d a birater o ne pl us pre d nis o ne. E nzal uta mi de, a tar gete d a n dr o ge n -rece pt or i n hi bit or t hat 
bl oc ks t he bi n di n g of a n dr o ge n t o t he a n dr o ge n rece pt or , tra nsl ocati on t o t he n ucle us, a n d 
D N A  bi n di n g (Tra n et al. 2 0 0 9 ), was a p pr o ve d f or t he first-li ne treat me nt of patient s wit h 
m C R P C. A birater o ne, a select i ve i n hi bit or of 1 7 α -h y dr o x ylase/ C 1 7, 2 0 -l yase ( C Y P 1 7), was 
als o a p pr o ve d i n c o m bi nat i on wi t h pre d nis o ne f or t he treat me nt of m C R P C i n t he first-li ne 
setti n g (R ya n et al. 2 0 1 3a , R ya n et al . 2 0 1 3 b).
A Z D 4 6 3 5 is bei n g de vel o pe d as m o n ot hera p y  a n d as a n i m m u n o-o nc ol o g y  a ge nt i n 
c o m bi nat i on wi t h d ur valu m a b (a nt i-P D -L 1) a n d d ur val u ma b pl us olecl u ma b (cl uster of 
differe nt iati on 7 3 [ C D 7 3] m o n ocl o nal a nti b o d y), e x pl o iti n g c o m ple me ntar y im m u ne -relate d 
mec ha nis ms t o br oa de n a n d dee pe n cli nical res p o nses. A Z D 4 6 3 5 has s h o w n act i vity i n a 
variet y of  t u mo ur t y p es , wi t h e nc o ura gi n g data bei n g see n f or t he c o m bi nat i on A Z D 4 6 3 5 a n d 
d ur val u ma b i n t he P hase I st u d y. As state d pre vi o usl y , t his P hase II st u d y will e val uate t he 
efficac y, safety a n d t olera bilit y of t he c o m bi nati on of A Z D 4 6 3 5 a n d d ur val u ma b a n d t he 
c o m bi nat i on of A Z D 4 6 3 5 wit h d ur val u ma b a n d ca bazita xel.
 
 
D ur val u ma b (I M FI N ZI ® ) is F D A-a p pr o ve d i n pat ie nts wit h bla d der ur ot helial carci n o ma w h o 
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have disease progression during or following platinum-containing chemotherapy and in 
patients who have disease progression within 12 months of neoadjuvant or adjuvant treatment 
with platinum-containing chemotherapy. Durvalumab is also approved in patients with 
NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy
and radiation therapy. Durvalumab, in combination with etoposide and either carboplatin or 
cisplatin, is also approved for the first-line treatment of adult patients with extensive-stage 
small cell lung cancer (ES-SCLC) (IMFINZI® US Prescribing Information).
Durvalumab is approved by the European Medicines Agency (EMA) as monotherapy for the 
treatment of locally advanced, unresectable NSCLC in adults whose tumours express PD-L1 
on ≥1% of tumour cells and whose disease has not progressed following platinum-based 
chemo-radiation therapy (IMFINZI®, EU SmPC).
Although NHAs have changed the landscape of treatment for mCRPC, for patients who have 
progressed on NHAs and docetaxel, there remain limited therapeutic options. While 
immunotherapy has led to impressive responses in a subset of patients with immunologically 
‘activated’ tumours, this approach has shown little progress in mCRPC. The addition of 
AZD4635 to anti-PD/PDL1 therapy or the combination of anti-PDL1 plus cabazitaxel may 
lead to an improvement in rPFS in these patients. 
2.2.1
Benefit/Risk Assessment
As of December 2019 approximately 300 patients with advanced cancer had been treated with 
AZD4635, either alone or in combination with another cancer drug. As of 02 December 2019
(date of DCO) in the ongoing study D8730C00001, 84 subjects (monotherapy cohorts n = 21 
and combination cohorts n = 63) had been enrolled in the Phase 1a dose escalation cohorts. 
The second segment of the study (Phase 1b) consists of dose expansion cohorts in tumor types 
for which there is a rationale for potential efficacy of the study treatment. As of 02 December
2019, 191 subjects (117 monotherapy cohorts and 74 combination cohorts) had been dosed in
Phase 1b. A pooled dataset for AZD4635 monotherapy and AZD4635 combination cohorts
was generated for the 22 treatment cohorts to enhance the review process.
The median age for the monotherapy participants = 71 years and for the 
combination = 70 years; ECOG performance status was 0-1 in 99% of participants. The 
median number of prior treatment regimens at baseline was 5 (range = 1-10) for all 
participants.
Seventy participants were evaluable for tumour response (monotherapy = 33, 
combination = 37). RECIST v1.1 responses were confirmed in 8 participants: 
(monotherapy=ORR 6.1% [2 PRs]) and (combination = 16.2% [2CRs, 4PRs]). The median 
PFS for the monotherapy cohort was 13.6 weeks (95% CI, 7.1-15.3) and 14.9 weeks (95% CI, 
13.3-29.3) for the combination cohort.


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
4 1 of 1 9 3
P S A  res p o nse ( defi ne d as ≥5 0 % decrease fr o m baseli ne) was o bse r ve d i n 
m o n o t hera p y = 6. 4 % ( 3/ 4 7 partici pa nts ; 9 5 % CI, 1. 3-1 7. 5 % ) a n d c o m bi nat i on = 2 0 % 
( 9/ 4 5 partici pa nts ; 9 5 % CI, 9. 6 -3 4. 6 % ).
M ost c o m m o n relate d A Es ( > 1 0 %) were na usea, v o mit i n g, fati g ue, di zzi ness, decrease d 
a p petite, a n d diarr h oea. E ve nts of na usea a n d v o miti n g see n wit h A Z D 4 6 3 5 treat me nt in 
P hase I st u d y D 8 7 3 0 C 0 0 0 0 1 were re p orte d i n 5 8. 8 % of A Z D 4 6 3 5 treate d s u bjects ( A Z D 4 6 3 5 
I B). T hese e ve nts are ge nerall y mil d t o m o derate ( C T C A E gra de 1 or 2) se verity,  int er mitte nt 
a n d ma na gea ble o n c o nti n ue d treat me nt. T he first o nset ge nerall y has a n o nset i n t he first 
wee k of treat me nt f or b ot h na usea a n d v o mit i n g.
F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h d ur val u ma b a n d A Z D 4 6 3 5 r efer t o 
t he c urre nt versi o ns of  t he I n vesti gat or Br oc h ures (I B) for eac h i nter ve nt i on.
A d verse reacti o ns a n d la b orat or y  a b n or malities occ urri n g i n greater t ha n 1 0 % of partici pa nts 
i n cli nical trials of ca bazita xel were ne utr o pe nia, a nae mia, le u k o pe nia, t hr o m b oc y t o p e nia, 
di arr h oea, fatig ue, na usea, v o mit i n g, c o nsti pati on, ast he nia, a b d o mi nal pai n, hae mat uria, bac k 
pai n a n d a n ore xia. Gra de 3- 4 i nfect i ons were re p orte d i n 2 0 % of partici pa nts o n t he 2 5 m g/ m 2
d ose ar m a n d 1 0 % of parti ci pa nts o n t he 2 0 mg/ m 2 ar m. Fe brile ne utr o pe nia occ urre d i n 9 % of 
parti ci pa nts o n t he hi g her d ose ar m a n d 2 % of  partici pa nts o n t he 2 0 m g/ m 2 ar m. T he most 
c o m m o n reas o ns f or d ose disc o nt i n uati on were fat i g ue a n d hae mat uria.
Refer t o t he U S prescri bi n g i nf or mati o n o r t he E U S mP C f or details o n c urre nt prescri bi n g 
i nf or mat i on . 
After a p pr o xi mate l y 6 partici pa nts o n t he ar m wit h A Z D 4 6 3 5 pl us d ur val u ma b pl us 
ca bazita xel ha ve bee n e nr o lle d a n d treate d f or at least o ne c ycle, we will re vie w t he safety 
i nf or mat i on f or t he A Z D 4 6 3 5 pl us d ur val u ma b pl us ca bazita xel treat me nt ar m, as well as 
a vaila ble P K data , partic ularl y beca use t he c o m bi natio n of  A Z D 4 6 3 5 pl us d ur val u ma b pl us 
ca bazita xel has n ot bee n e val uate d pre vi o usl y. T he S R C ma y c o nsi der re d uci n g t he A Z D 4 6 3 5 
d ose t o 
 m g P O dail y  fr o m 
 mg after t he safet y re vie w if t here are safety a n d t olera bilit y 
c o ncer ns (see Secti o n 4. 1. 1 ). Ris k c o nsi derat i ons i n vie w of t he p ote ntiall y  rela psi n g 
C O VI D -1 9 pa n de mic are detaile d i n A p pe n di x L .
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3
OBJECTIVES AND ENDPOINTS
Table 3
Objectives and Endpoints/Variables
Objectives
Endpoints/Variables
Primary

To determine the efficacy (as assessed 
by radiographic progression free 
survival [rPFS]) of AZD4635 plus 
durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel in participants with 
mCRPC.

rPFS, defined as the time from first dose
to radiographic progression as assessed 
by the Investigator per RECIST v1.1 
(soft tissue) and Prostate Cancer 
Working Group 3 criteria (PCWG3) 
(bone) or death from any cause, 
whichever occurs first.
Secondary

To evaluate the safety and tolerability 
of each treatment regimen in 
participants with mCRPC.

Physical examination, laboratory values
(haematology, clinical chemistry, 
urinalysis, and tests for coagulation), 
vital signs, and electrocardiograms 
(ECGs).

Adverse events/serious adverse events 
(AEs/SAEs) collected throughout the 
study, from the time of the informed 
consent form signature through to the 
last safety follow-up visit.

To determine the efficacy of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel by assessment of overall 
survival (OS) in participants with 
mCRPC.

OS, defined as the time from first dose 
until death due to any cause regardless 
of whether the participant withdraws 
from study treatment or receives another 
anti-cancer therapy.

To determine the efficacy of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of ORR in 
participants with mCRPC.

Confirmed ORR, defined as the 
proportion of participants with a 
confirmed CR or PR using overall 
radiographic response assessed by 
RECIST v1.1 and PCWG-3 criteria 
(bone), and will be based on a subset of 
all treated participants with measurable 


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Objectives
Endpoints/Variables
disease at baseline per the site
Investigator.

To determine the efficacy of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel by assessment of DoR in 
participants with mCRPC.

DoR, defined as the date of first 
documented response (which is 
subsequently confirmed) until the date 
of documented progression or death in 
the absence of disease progression. 

To determine the efficacy of AZD4635 
plus durvalumab and separately of
AZD4635 plus durvalumab plus 
cabazitaxel, by assessment of PSA 
response in participants with mCRPC.

Confirmed PSA50 response, defined as 
the proportion of participants achieving 
a ≥50% decrease in PSA from baseline 
to the lowest post-baseline PSA, 
confirmed by a consecutive PSA at least 
3 weeks later and will be based on PSA 
evaluable participants (dosed
participants with an abnormal baseline 
PSA [≥1 ng/mL]).

Investigate the PK of AZD4635 when 
given in combination with durvalumab, 
and when given in combination with 
durvalumab plus cabazitaxel.

AZD4635, durvalumab and cabazitaxel 
plasma concentration and derived PK 
parameters, where deemed appropriate.

To determine the efficacy of AZD4635 
plus durvalumab plus cabazitaxel in 
participants with mCRPC, by adenosine
(ADO) signalling gene expression in 
high and low subgroups.

rPFS, defined as the time from first dose 
to radiographic progression, assessed by 
the Investigator per RECIST 1.1 (soft 
tissue) and PCWG3 criteria (bone) or 
death from any cause, whichever occurs 
first by gene expression subgroup.

To determine the effects of AZD4635 
plus durvalumab and separately of 
AZD4635 plus durvalumab plus 
cabazitaxel on pain and other prostate 
cancer-related symptoms.

Change from baseline in worst pain, 
average pain and pain interference in the 
daily activities scales of the BPI-SF.

Time to pain progression based on 
BPI-SF Item 3 “pain at its worst in the 
last 24 hours”. 

Change from baseline in the FAPSI-6 as 
derived from 6 items, the FAPSI-8 as 
derived from 8 items within the 
FACT-P, and the PCS, as derived from 


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E n d p oi nts/ V ari a bles
t he 1 2 ite ms i n t he pr ostrate-s pecific 
m o d ule of t he F A C T -P.
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E n d p oi nts/ V ari a bles
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4
S T U D Y D E SI G N
4. 1
O ver all Desi g n
T his is a P hase II, i nter nat i onal, o pe n -la bel, t w o-ar m, n o n- ra n d omise d st u d y  of A Z D 4 6 3 5 i n 
parti ci pa nts wit h mC R P C. T he pri mar y o bject i ve is t o deter mi ne t he r P F S of A Z D 4 6 3 5 pl us 
d ur val u ma b ( Ar m A) a n d se paratel y ofA Z D 4 6 3 5 pl us d ur val u ma b pl us ca bazita xel ( Ar m B ) 
(see Fi g ure 1 ). Partici pa nts i n eac h ar m will be stratifie d b y t he prese nce of meas ura ble s oft 
tiss ue metastasis ( per R E CI S T v 1. 1 , A p pe n di x F ) or b o ne -o nl y  metastasis ( per P C W G 3 
criteria, A p pe n di x H ). T here will be n o f or mal c om paris o ns bet wee n treat me nt ar m s. 
Sec o n dar y  e n d p oi nts i ncl u de; s afet y,  O S, c o nfir me d O R R, D o R, c o nfir me d P S A 5 0 res p o nse,
ti me t o pai n pr o gressi o n, a n d P K.
A Z D 4 6 3 5 pl us d ur v al u m a b ( Ar m A) will c o nsist  of partici pa nts wit h m C R P C pre vi o usl y 
treate d wit h o ne or mor e a p pr o ve d N H As (e. g. , a birater o ne acetate, e nzal uta mi de, a pal uta mi de 
a n d/ or dar ol uta mi de) a n d o ne or more ta xa nes or partici pa nts w h o are ta xa ne i neli gi ble. As o f 
N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr ol me nt i n Ar m A f oll owi n g decisi o ns at t he pr o gra m 
le vel, n ot relate d t o a n y s af et y iss ues. O n g oi n g partici pa nts i n Ar m A ma y c o nti n ue treat me nt 
as pla n ne d (ie, as lo n g as t he y  recei ve cli nical be nefit a n d d o n ot meet a n y disc o nti n uati on 
criteria).
A Z D 4 6 3 5 pl us d ur v al u m a b pl us c a b azit a xel ( Ar m B) will c o nsist of 8 0 parti ci pa nts 
m C R P C pre vi o usl y treate d wit h d oceta xel a n d o ne pri or N H A  ( eit her a birater o ne acetate or 
e nzal uta mi de b ut n ot b ot h; prior a pal uta mi de is n ot per mitte d i n Arm B ).
Eli gi ble partici pa nts m ust ha ve hist ol o gicall y dia g n ose d m C R P C wi t h no e vi de nce of s mall 
cell hist ol o g y, ha ve ha d pr o gressi o n of disease ≤6 m o n t hs pri or t o st u d y  e ntr y eit her b y 
R E CI S T v 1. 1 or b o ne lesi o ns per P W C G 3 a n d ha ve o n g oi n g a n dr o ge n de pri vat i on wi t h ser u m 
test oster o ne < 5 0 n g/ m L.
P arti cipa nts will be all o cate d t o o ne of t he f o ll owi n g treat m e nt ar ms:
Ar m A : A Z D 4 6 3 5 (
 mg P O dail y ) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 4 W )
N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr o l me nt i n Ar m A f oll owi n g decisi o ns at 
t he pr o gra m le vel, n ot relate d t o a n y safety iss ues.
or
Ar m B : A Z D 4 6 3 5 (
 mg P O dail y ) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 3 W ) 
pl us ca bazit a x el ( 2 0 or 2 5 mg/ m 2 I V Q 3 W as per l ocal prescri bi n g g ui deli nes) ( n = 8 0).
P arti cipa nts i n Ar m B will recei ve ca bazita xel c he m ot hera p y as per t he l ocal la bel. T his will 
start a p pr o xi matel y 1 h o ur ( or u p t o a ma xi m u m o f 2 h o urs) after t he e n d of t he d ur val u ma b 
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infusion. Cabazitaxel will be administered as per the local prescribing guidelines for a 
maximum of 10 cycles. After cycle 10 durvalumab + AZD4635 will be administered Q4W to 
harmonise with the Arm A treatment cycle length.
Arm B participants must receive premedication to manage cabazitaxel-associated reactions 
(hypersensitivity or other):

Prednisone (10 mg daily continuously [or equivalent steroid]) for the duration of 
cabazitaxel administration

Primary G-CSF prophylaxis (G-CSF should be administered according to the product 
label and institutional standards).
An archival tumour sample is required or the participant must be willing to undergo a baseline 
tumour biopsy (see Section 8.6.1.3). The collection of paired tumour biopsies will be 
requested during the study; however, this is optional (see Section 8.6.2.1).
Participants in Arm A (AZD4635 plus durvalumab) will have disease assessments/imaging at
baseline and every 8 weeks (± 7 days) from the start of dosing for the first 24 weeks and then 
every 12 weeks (± 7 days) thereafter. During the study, tests for active COVID-19 infection 
may be prescribed, if required, and in accordance with local guidelines. Note: As of 
November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program 
level, not related to any safety issues. Ongoing participants in Arm A may continue treatment 
as planned (ie, as long as they receive clinical benefit and do not meet any discontinuation 
criteria).
If a participant is symptomatic for active COVID-19 infection during a site visit, he may be 
prescribed a COVID-19 test. Dosing may continue while results are awaited, per the 
Investigator’s discretion and local guidelines, and the Medical Monitor/AstraZeneca Study 
Physician should be consulted. For participants who test positive (for COVID-19) the study 
drugs may be temporarily interrupted and later resumed, per the Investigator’s discretion and 
local guidelines, and this should be discussed with the Medical Monitor/AstraZeneca Study 
Physician. Where applicable, home or remote visits may be conducted for study assessments 
and study drug administration (see Appendix L).
Participants in Arm B (AZD4635 plus durvalumab and cabazitaxel) will have disease 
assessments/imaging at baseline and every 9 weeks (± 7 days) from the start of dosing for the 
first 27 weeks and then every 12 weeks (± 7 days) thereafter. A safety assessment to determine
the safety and tolerability of this combination will be completed by the SRC after the first 
6 participants have completed a safety assessment period of at least 1 cycle (see 
Section 4.1.1). 
The participant reported outcome (PRO) instruments, a BPI-SF (see Appendix J) and FACT-P 
(see Appendix K) will be administered to all participants. These two instruments will be used 


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to assess pain and quality of life in study participants. These will be measured as shown in 
Table 1 and Table 2
The two arms will enrol participants with metastatic disease documented by either bone 
lesions on bone scan or with soft tissue disease that is evaluable for assessment. As of 
November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program 
level, not related to any safety issues. Arm B will enroll and assign to study treatment 
approximately 80 participants. At least 40 participants with RECIST v1.1-measurable disease 
(Section 5.1) at baseline will be enrolled and assigned to study treatment in Arm B, and the 
remainder of participants in the arm (n = 40) may have bone-only disease or measurable 
disease. The primary analysis, rPFS, will be assessed, and is defined as the time from first 
dose to radiographic progression as determined by the Investigator per RECIST v1.1 for soft 
tissue disease or PCWG3 for bone disease or death from any cause, whichever occurs first. 
Overall survival, ORR, DoR, PSA50 response, and time to pain progression will also be 
evaluated for efficacy.
A futility interim analysis is planned for Arm B based on PSA50 response for approximately 
n = 30 dosed participants. Of these participants, approximately 15 participants are to have 
RECIST v1.1 measurable disease at baseline and the remainder of the participants may have 
bone-only disease or measurable disease.
4.1.1
Safety Review Committee
Once the first 6 evaluable participants complete at least 1 cycle of study treatment on Arm B, 
the safety and tolerability of the combination of AZD4635 plus durvalumab plus cabazitaxel 
will be assessed by the Safety Review Committee (SRC). The SRC will evaluate all available 
toxicity information (including AEs and laboratory abnormalities that are not DLTs (defined in 
Section 6.6.1), as well as available PK and PD information. In the case of safety and 
tolerability concerns at any point during this time, the study team will consider halting 
recruitment until full analysis and review by the SRC is performed but otherwise recruitment 
will continue through the period of review by the SRC.
The SRC will consist of:

AstraZeneca Study Team Physician, who will chair the committee, or delegate

Parexel Study Team Physician or delegate

Principal Investigator or delegate from the enrolled participants’ investigational site

Global Safety Physician or delegate.
Other Principal Investigators and representatives from AstraZeneca and Parexel, such as 
Study Pharmacokineticist, Study Statistician, Patient Safety Scientist, Study Delivery Leader 


Cli nical St u d y Pr ot oc ol – 3. 0
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ma y als o be i n vite d as a p pr o priate. T he S R C Re mit d oc u me nt f or t his st u d y  will defi ne t he 
e xact me m bers hi p a n d w h o s h o ul d be prese n t for decisi o n s t o be ma de.
F urt her i nter nal or e xter nal e x perts ma y be c o ns ult e d b y t he S R C as necessar y. T he Glo b al  
S af et y P h ysicia n or dele gate s h o ul d al wa ys be prese nt at t he S R C if t here are safet y iss ues f or 
di sc ussi on.
T he decisi o n ma y be t o:

Pr ocee d wi t h recr uit me nt t o Ar m B

E nr ol  a furt her 3 t o 6 e val ua ble parti ci pa nt s a n d/ or

M o dif y or re d uce t he d ose eit her b y a dj ust me nt  of d ose le vels or sc he d ule. (F or i nsta nce, 
if t here are a n y c o ncer ns a b o ut t olera bility t he d ose of A Z D 4 6 3 5 ma y be re d uce d t o 
m g P O dail y fr o m 
 mg dail y )

St o p f urt her recr uit me nt  t o Ar m B.
T he S R C decisi o n will be s hare d wit h all I n vesti gat ors.
4. 2
Scie ntific R ati o n ale f or St u d y Desi g n
Better S O C treat me nts f or pr ostate ca ncer patie nts w h o ha ve e x ha uste d treat me nts are nee de d. 
T he rece nt a n d o n g oi n g res p o nses o bser ve d i n pat ie nts wit h pr ostate ca ncer recei vi n g 
A Z D 4 6 3 5 m o n ot hera p y  or A Z D 4 6 3 5 a n d d ur val u ma b s u g gest f urt her i n vest i gati on is 
warra nte d.
Ar ms will assess t he f o ll owi n g c o m bi nat i on of t hera pies : A Z D 4 6 3 5 pl us a nti -P D -L 1 
( d ur val u ma b) a n d A Z D 4 6 3 5 pl us a nti-P D -L 1 ( d ur val u ma b) pl us ca bazita xel. A Z D 4 6 3 5 
a p pears t o ha ve i ncrease d efficac y i n c o m bi nati o n wit h a nti -P D -L 1 i n pr ostate ca ncer d ue t o 
i ncrease d i m m u ne acti vati on c o m pare d t o si n gle a ge nt A Z D 4 6 3 5 base d o n t he res ults of t he 
P hase I st u d y of t he t w o treat me nts. At  t he data c ut-of f ( D C O) of 0 2 Dece m ber 2 0 1 9, 
8 s u bjects ha ve ac hie ve d o bjecti ve res p o nse ( O R) per Res p o nse E val uati on Cri t eria i n S oli d 
T u m o urs ( R E CI S T) v 1. 1. T w o s u bjects ( d ur val u ma b c o m bi nat i on) ha d c o m plete res p o nses 
a n d 6 s u bjects ha d partial res p o nses ( m o n ot hera p y  [ n = 2] a n d d ur val u ma b c o m bi nat i on 
[ n = 4]). Parti ci pa nts wit h a n O R ( C R + P R) ha ve ha d d urati o ns of res p o nse t hat ra n ges fr o m 
2. 3 0 t o 2 5. 8 2 m o nt hs wit h se veral o n g o i n g res p o nse at t he D C O.
T he c o m b i nati on of t he c hec k p o i nt i n hi bit or pe m br oliz u ma b (a nti-P D -1) a n d d oceta xel has 
bee n i n vest i gate d i n t he K E Y N O T E 3 6 5 st u d y w here t he c hec k p oi nt i n hi bit or was a d de d t o 
t he S O C c he m ot hera p y. It has bee n re p orte d t hat pe m br oliz u ma b al o ne lea ds t o a relati vel y
l ow res p o nse rate of ~ 5 % a n d P S A 5 0 of  11 % ( K E Y N O T E -1 9 9) ( A nt o nara ki s et al 2 0 1 9). I n 
K E Y N O T E 3 6 5, a n O R R of 1 4 % ( 5/ 3 6) a n d P S A 5 0 of  3 1 % ( 2 2/ 7 1) were re porte d wit h t he 
m o st n ota ble res ult bei n g a me dia n ra dio gra p hic pr o gressi o n -free s ur vi val (r P F S) of 
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8. 3 m o nt hs ( Massar d et al. 2 0 1 9 ) w hic h is lo n ger t ha n t hat re p orte d wit h si n gle-a ge nt 
d oceta xel ( 3. 9 m o nt hs [ Rat h k o pf et al. 2 0 1 8 ]). A d dit i onall y, t he rece ntl y p u blis he d C A R D 
st u d y (de Wit  et al. 2 0 1 9) d e mo nstrate d a n i ma gi n g -base d me dia n P F S of ~ 8. 2 m o nt hs f or t he 
ca bazita xel ar m i n a p ost- N H A, p ost -d oceta xel u nselecte d m C R P C partici pa nt p o p ulati o n. 
We  h yp ot hesi ze t hat t he c o m bi nat i on of A Z D 4 6 3 5 pl us t he c hec k p o i nt i n hi bit or (a nti-P D L 1) 
d ur val u ma b pl us ca bazita xel w o ul d lea d t o a n i ncrease d r P F S i n t he p ost-d oceta xel setti n g b y 
decreasi n g t he i m m u n os u p pressi ve e n vir o n me nt a n d c o u nteracti n g t he effects of  A D O w hic h 
ca n li mit t he res p o nse t o c he m ot hera p y a n d a nti-P D -1/a n d i-P D L 1. F or pati e nts w h o ha ve 
pr o gresse d des pite t hera p y  wit h ta xa nes a n d N H A or patie nts w h o will n ot t olerate t hera p y 
wi t h ta xa nes, t here are li mite d o pti o ns. Data fr o m t he P hase I st u d y of  A Z D 4 6 3 5 a n d 
d ur val u ma b as prese nte d a b o ve s u p p orts f urt her e x pl orati o n of t his c o m bi nat i on i n m C R P C .
4. 3
J u stific ati o n f or D ose
Treat me nt st u d y i nter ve nt i on a n d d ose f or t his st u d y are defi ne d as Ar m A a n d Ar m B:

Ar m A: A Z D 4 6 3 5 (
 mg P O dail y ) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 4 W )
N ote: As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr o l me nt i n Ar m A f oll owi n g 
decisi o ns at t he pr o gra m le vel, n ot relate d t o a n y  s afet y iss ues.

Ar m B: A Z D 4 6 3 5 (
 mg P O dail y) pl us d ur val u ma b ( 1 5 0 0 mg I V Q 3 W ) 
pl us ca bazit a x el ( 2 0 or 2 5 mg/ m 2 I V Q 3 W as per t he l ocal prescri bi n g g ui deli nes ) 
pl us pre d nis o ne 1 0 m g dail y  P O c o nti n u o usl y for a ma xi m u m of 1 0 c ycles pl us pri mar y  
G- C S F pr o p h yla xis, after w hic h A Z D 4 6 3 5 will c o nt i n ue at 
m g P O dail y wi t h 
d ur val u ma b 1 5 0 0 m g Q 4 W wi t ho ut ca bazita xel/ pre d nis o ne ( N ote: a 6 partici pa nt safety 
r u n-i n will prece de t he f ull Ar m B e nr o ll me nt of a t otal of n = 8 0).
A Z D 4 6 3 5 (
 m g P O d ail y) pl us D ur v al u m a b ( 1 5 0 0 m g I V)
Data fr o m t he o n g oi n g P hase I st u d y of A Z D 4 6 3 5 b ot h as m o n ot hera p y a n d c o m bi nati o n 
t hera p y wit h d ur valu ma b i n s u bjects wi t h r ela pse d or refract or y s oli d t u mo u rs has 
d e m o nstrate d a fa v o ura ble safet y pr ofile as well as acti vit y i n pr ostate ca ncer i n partic ular. 
T he d ur val u ma b d ose is c o nsiste nt wit h t hat use d i n t he P hase I st ud y of A Z D 4 6 3 5 i n 
c o m bi nat i on wi t h d ur valu ma b a n d t he A Z D 4 6 3 5 d ose of 
 m g is t he rec o m me n de d P hase II
d ose of t he ca ps ule f or m ulat i on f or t his c o m bi nati on base d o n t he data fr o m t he relat i ve 
bi oa vaila bilit y st u d y w hic h was c o n d ucte d t o deter mi ne t he e x p os ure of t he ca ps ule 
f or mulat i on of A Z D 4 6 3 5 i n c om par is o n t o t hat see n wit h t he na n os us pe nsi on i n t he P hase I
st u d y D 8 7 3 0 C 0 0 0 0 1.
T he m ost c o m m o n  A Es see n i n parti ci pa nt s i ncl u de na usea, fati g ue, c o nsti pati on a n d 
di zzi ness. O ne parti ci pa nt i n t he P hase Ia d ose -escalat i on co h ort (
 m g A Z D 4 6 3 5 pl us 
1 5 0 0 m g d ur val u ma b) e x perie nce d Gra de 2 D L Ts of na usea a n d fat i g ue t hat re q uire d d ose 
re d uctio n of  AZ D 4 6 3 5 t o  
m g. T he R P 2 D of A Z D 4 6 3 5 b ot h as m o n ot hera p y  a n d 
C CI
C CI
C CI
C CI
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
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A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
5 1 of 1 9 3
c o m bi nat i on t hera p y  wit h d ur val u ma b was i de ntifie d as  
 m g A Z D 4 6 3 5 na n os us pe nsi on 
dail y  a nd 1 5 0 0 m g d ur val u ma b Q 4 W .
A Z D 4 6 3 5 was i nit iall y d e v elo pe d as a na n os us pe nsi o n, b ut rece nt l y a ca ps ule f or m ulati on was 
de vel o pe d. T he ca ps ule f or m ulat i on has bee n e val uate d f or relat i ve bi oa vaila bilit y i n a st u d y 
of  he alt h y a d ult mal e v olu nteers. I n t his st u d y, at d oses of 
 mg of  A Z D 4 6 3 5, t he ca ps ule 
f or mulat i on was f o u n d t o ha ve a hi g her A U C 0- 4 8 of ~ 1 1 0 % of t he na n os us pe nsi o n a n d C ma x of  
1 2 8 % of t he na n os us pe nsi o n. D ue t o t he hi g her C m a x wi t h t he ca ps ule f or m ulati on , t he 
o verl a p pi n g e x p os ure see n wit h na n os us pe nsi o n f or mulati o n at a 
 m g Q D d ose, a n d t he 
desi re t o mi ni mize Cma x relate d A Es, t he R P 2 D f or t he ca ps ule f or m ulat i on is 
 m g Q D.
A Z D 4 6 3 5 (
 m g P O d ail y) pl us D ur v al u m a b ( 1 5 0 0 m g I V) pl us C a b azit a xel ( 2 0 or 
2 5 m g/ m 2 I V Q 3 W )
As t here is n o pre dicte d dr u g -dr u g i nteracti o n ( D DI) bet wee n A Z D 4 6 3 5 a n d ca bazita xel or 
bet wee n eit her of t hese dr u gs a n d ca bazita xel, w e pl a n t o st u d y t he triplet c o m bi nat i on of 
A Z D 4 6 3 5 pl us d ur val u ma b pl us ca bazita xel i n Ar m B at t he sa me pr o p ose d P hase 2 d ose of 
 mg A Z D 4 6 3 5 ca ps ule f or m ulat i on . I n Ar m B, A Z D 4 6 3 5 at 
 m g ca ps ule f or m ulat i on 
(
 m g ca ps ules) pl us 1 5 0 0 m g d ur val u ma b (Q 3 W ) plus 2 0 m g/ m 2 or 2 5 m g/ m 2 ( or as per 
l ocall y a p pr o ve d la bel) of ca bazita xel ( Q 3 W ) wit h pre d nis o ne 1 0 m g P O t wice dail y 
co nti n u o usl y will  be a d mi nistere d. Ca bazita xel will be a d mi nistere d f or a ma xi m u m o f 
1 0 c yc les. After c ycle 1 0 d ur val u ma b + A Z D 4 6 3 5 will be a d mi nistere d Q 4 W.
D ur val u ma b has bee n d ose d i n 3 -wee k c ycles i n a n u m ber of st u dies w he n use d i n 
c o m bi nat i on wi t h c he mot h era p y. I n t w o st u dies, Astra Ze neca ’s D 4 1 9 S C 0 0 0 0 1 a n d t he 
Ca na dia n Cli nical Trials Gr o u p ( C C T G) st u d y N C T 0 2 5 3 7 4 1 8 d ur val u ma b has bee n 
i n vesti gate d ± tre meli m u ma b. I n a P hase I st u d y of d ur valu ma b ± tre meli m u ma b i n
c o m bi nat i on wi t h mul tiple sta n dar d pl at i n u m-base d c he m ot hera p y  re gi me ns i n partici pa nts 
wi t h inc ura ble a d va nce d or metastatic ca ncer ( N C T 0 2 3 5 7 4 1 8), th e dose escalat i on/ re gi me ns 
i nitiall y incl u de d a fi xe d d ose c o h ort of d ur val u ma b 1 1 2 5 m g pl us tr e meli m u ma b 5 6 m g Q 3 W
c o nc urre nt wit h plati n u m-base d d o u blet c he m ot hera p y  a n d t he n s u bse q ue ntl y, a c o h ort of 
d ur val u ma b 1 5 0 0 m g pl us tr e meli m u ma b 7 5 m g Q 3 W c o nc urre nt wit h c he mot h era p y. At  t he 
last re p orte d data c ut-of f, 1 1 1 partici pa nts ha d bee n d ose d wit h 7 differe nt  c he m ot hera p y 
re gi me ns. O verall, t o xicities were r elate d t o t he c he mot h era p y c ore re gi me n a n d a p peare d as 
e x pecte d i n se verit y a n d fre q ue nc y a n d t here were n o D LTs . To xi cities r elate d t o d ur valu ma b 
a n d tre meli m u ma b were als o t h ose e x pecte d f or t hese a ge n ts, alt ho u g h a n u m ber of p ote ntial 
I O relate d t o xicities s uc h as diarr h oea, s ki n ras h, he patic f u ncti o n c ha n ges or p ne u m o nit is 
were diffic ult t o differe nt iate fr o m t hose re p orte d f or c y t ot o xic a ge nts. As e x pecte d, t here 
were m ore I O rel ate d t o xicities re p o rte d f or d ose le vels c o ntai ni n g tre meli m u ma b. I n ge neral, 
all re gi me ns were t olera ble a n d ma na gea ble at all d ose le vels.
I n a d diti on, P K m o delli n g s u g gest e d t hat a Q 3 W sc he d ule di d n ot i m p ose a si g nifica nt 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI


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increased safety risk based on the expected durvalumab exposures.
Study D419SC00001 evaluated durvalumab 1120 mg plus tremelimumab 75 mg Q3W given 
concurrently with carboplatin AUC 5 mg/mL/min and etoposide 100 mg/m2 Q3W, followed 
by durvalumab 1120 mg monotherapy Q3W. There was one DLT reported in 6 patients 
however, the safety profile of this combination of durvalumab at 1120 mg plus tremelimumab 
75 mg concurrent with platinum doublet chemotherapy using a Q3W schedule was declared 
tolerable and manageable.
Taken together, the totality of data supports the combination of 1500 mg durvalumab 
combined with chemotherapy on a q3 week schedule.
Cabazitaxel 25 mg/m2 administered Q3W was granted FDA approval in 2010 for the treatment 
of patients with mCRPC previously treated with a docetaxel-containing regimen. In 2017, the 
FDA approved a lower dose of cabazitaxel (20 mg/m2) Q3W in combination with prednisone 
for the same indication.
On 17 March 2011 the European Commission issued approval to market cabazitaxel at a 
recommended dose of 25 mg/m2 administered Q3W with oral prednisolone or prednisone for 
hormone-refractory metastatic prostate cancer patients previously treated with a 
docetaxel-containing regimen. Participants on clinical trials treated with cabazitaxel
experienced adverse reactions and laboratory abnormalities. Such events occurring in greater 
than 10% of participants were neutropenia, anaemia, leukopenia, thrombocytopenia, 
diarrhoea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, haematuria, back 
pain and anorexia. Grade 3-4 infections were reported in 20% of participants on the 25 mg/m2
dose arm and in 10% of participants on the 20 mg/m2 arm. Febrile neutropenia occurred in 9% 
of participants on the higher dose arm and 2% on the 20 mg/m2 arm. The most common 
reasons for dose discontinuation were fatigue and haematuria.
Refer to the US prescribing information or the EU SmPC for details on current prescribing 
information. After approximately 6 participants in the arm with AZD4635 plus durvalumab 
plus cabazitaxel have been enrolled and treated for at least one cycle, we will review the 
safety information for the AZD4635 plus durvalumab plus cabazitaxel treatment arm, as well 
as available PK data, particularly because the combination of AZD4635 plus durvalumab plus 
cabazitaxel has not been evaluated previously(see Section 4.1.1).
4.4
End of Study Definition
The end of the study is defined as the last scheduled visit or contact of the last participant 
enrolled in the study. A participant is considered to have completed the study when he has 
completed his last scheduled visit or contact. The DCO for the primary analysis will occur 
when approximately 60% of the participants have progressed or died in Arm B. Data analysis 
will be performed and a CSR will be written based on this dataset. Following the decision to 


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stop enrolment in Arm A, data from Arm A and Arm B will be reported in the same CSR when 
the DCO is reached for Arm B. If required, an additional analysis of OS for Arm B at a later 
DCO may be conducted and a CSR addendum written based on this dataset. In this case, more 
limited data collection for survival, study drug dosing and subsequent cancer therapy for 
Arm B will continue until that time according to the scheduled contact. SAEs will be collected 
per Section 8.3. The clinical study database will be closed to new data after the DCO for the 
final analysis.
Following the primary DCO, any participants still receiving the investigational product (IP) at 
the time of DCO will be allowed to continue to receive the IP while deriving clinical benefit. 
Such participants will continue to be monitored for all SAEs up to 30 days after the last dose 
of IP or 90 days if participant is receiving the IP combined with durvalumab. SAEs will be 
reported to the Sponsor using a paper format. Drug accountability information must still be 
collected until such participants have completed treatment.


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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.
In this protocol, ‘enrolled’ participants are defined as those who sign the informed consent.
5.1
Inclusion Criteria
Age
1
Participant must be 18 years of age inclusive at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Histologically confirmed adenocarcinoma of the prostate

Disease must be metastatic and inoperable and for which there is no curative 
intervention available. Participants may have bone-only disease.

Participants presenting with treatment-emergent neuroendocrine differentiation, but 
not primary small-cell features, are eligible.
3
Known castrate-resistant disease, defined as:

Testosterone level in the castration range (levels < 50 ng/dl) because of a previous, 
and ongoing, androgen-deprivation with luteinizing hormone-releasing hormone 
(LHRH) agonists or antagonists or bilateral orchiectomy. Participants must have 
developed progression of metastases following surgical castration or during medical 
androgen ablation therapy. Participants receiving medical castration therapy with 
gonadotropin-releasing hormone (GnRH) analogues should continue this treatment 
during this study.
4
Evidence of disease progression ≤6 months defined by one or more of the following:

Progression as defined by RECIST v1.1 criteria for assessment of malignant soft 
tissue disease and lymph nodes

Progression of bone lesions on bone scan from a previous or baseline assessment per 
PCWG3

Rising PSA defined as at least two consecutive rises in PSA to be documented over a 
reference value (measure 1) taken at least 1 week apart. The first rising PSA 
(measure 2) should be taken at least 7 days after the reference value. A third 
confirmatory PSA measure is required (2nd and beyond the reference level) to be 
greater than the second measure and it must be obtained at least 7 days after the 2nd
measure. If this is not the case, a fourth PSA measure is required to be taken and be 
greater than 2nd measure. The third (or the fourth) confirmatory PSA should be taken 
within 4 weeks prior to study entry.


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5
Must have measurable disease:

At least 1 documented lesion on either a bone scan or a computed tomography 
(CT)/magnetic resonance imaging (MRI) scan that can be followed for response is 
suitable for repeated measurement
Or

Non-measurable disease must have measurable PSA ≥1.0 ng/mL as the minimum 
starting level for trial entry if the confirmed rise is the only indication of progression 
(excluding small cell carcinoma).
Weight
6
Body weight > 30 kg at screening.
Reproduction
7
Willingness to adhere to the study treatment-specific contraception requirements: 
Participants must be surgically sterile or using an acceptable method of contraception 
(defined as a male condom in conjunction with spermicides) for the duration of the study 
(from the time they sign ICF) and for 12 weeks (3 months) after the last dose of 
AZD4635 and/or durvalumab and for 24 weeks (6 months) after the last dose of
cabazitaxel to prevent pregnancy in a female partner. Participants must not donate or bank 
sperm for 24 weeks after treatment. The reporting of any pregnancy in the female partner 
of a participant is described in Section 8.3.9.1.
Bone Marrow Reserve and Organ Function 
8
Adequate bone marrow reserve and organ function as demonstrated by all of the 
following laboratory values:

Absolute neutrophil count (ANC) ≥1.5 × 109/L

Platelet count ≥100 × 109/L

Haemoglobin ≥9.0 g/dL (≥10.0 g/dL for Arm B)

Creatinine ≤1.5 × ULN concurrent with creatinine clearance ≥40 mL/min (measured 
or calculated by Cockcroft and Gault equation); confirmation of creatinine clearance 
is only required when creatinine is > 1.5 × ULN.
Additional Inclusion Criteria Specific for Arm A
Note: As of November 2020, the Sponsor stopped enrolment in Arm A following decisions at 
the program level, not related to any safety issues. Ongoing participants in Arm A may 
continue treatment as planned (ie, as long as they receive clinical benefit and do not meet any 
discontinuation criteria).
9
Adequate organ function for Arm A as demonstrated by all of the following laboratory 
values:

Alanine aminotransferase (ALT) ≤2.5 × the upper limit of normal (ULN) if no 
demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases.


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
Aspartate aminotransferase (AST) ≤2.5 × ULN if no demonstrable liver metastases 
or ≤5 × ULN in the presence of liver metastases

Total bilirubin (TBL) ≤1.5 × ULN

TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct 
bilirubin
10 Participants in Arm A must have received the following prior therapy:

Maximum of 3 lines of therapy in the mCRPC setting

Prior therapy with one or more NHAs (e.g., abiraterone acetate, enzalutamide, 
apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory 
settings

Prior therapy with one or more lines of taxanes (e.g., docetaxel and/or cabazitaxel)

Alternatively, must be taxane-ineligible

Prior therapy can be in either the hormone-sensitive or the hormone-refractory setting

Participants who were eligible for both Arm A and Arm B will be preferentially 
allocated to Arm B, until enrollment of Arm B is completed.
Additional Inclusion Criteria Specific for Arm B
11 Adequate organ function for Arm B as demonstrated by all of the following laboratory 
values: 

AST and/or ALT ≤1.5 × ULN

TBL ≤ULN

TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct 
bilirubin
12 Participants in Arm B must have received the following prior therapy:

Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory settings

Received no prior cytotoxic chemotherapy other than docetaxel for prostate cancer 
except for estramustine and except adjuvant/neo-adjuvant treatment completed 
> 3 years ago.

Prior therapy with only one NHAs (e.g., abiraterone acetate or enzalutamide; prior 
apalutamide is not permitted) for treatment of mCRPC in either hormone-sensitive or 
hormone-refractory settings.

Be suitable to receive concomitant GCSF during all cycles of cabazitaxel.

Participants who meet inclusion criteria for Arm B will be allocated preferentially to 
that arm until recruitment to that arm is completed.


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Other Inclusion Criteria
13 World Health Organisation (WHO) performance status of 0-1 with no clinical 
deterioration over the previous 2 weeks prior to the 28-day screening period and likely 
able to complete at least 12 weeks of treatment.
14 Normotensive or well controlled blood pressure (BP) (systolic < 150 and diastolic < 90), 
with or without current antihypertensive treatment. If there is a diagnosis or history of 
hypertension, participant must have adequately controlled BP on antihypertensive 
medications.
15 Availability of an archival tumour sample. If an archival tumour sample is not available, 
then a tumour biopsy will be required to obtain a tumour sample.
16 Participants must be able to swallow and retain oral medications (e.g., AZD4635 and/or 
prednisone).
Informed Consent
17 Capable of giving signed informed consent as described in Appendix A and able to 
comply with the requirements and restrictions listed in the informed consent form (ICF) 
and in this protocol.
18 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if treated and there is no evidence of progression for at least 8 weeks after 
treatment is completed and within 28 days prior to the first dose of study intervention.
2
There must be no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone/equivalent) for at least 2 weeks prior to study enrollment. For 
current or prior use of immunosuppressive medication within 14 days before the first dose 
the following will be exceptions to this:

Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular 
injection)

Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone 
or its equivalent

Steroids as premedication for hypersensitivity reactions (e.g., CT scan 
premedication)
3
Participant with a history of pneumonitis.


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4
History of a second malignancy that is progressing and/or received active treatment 
≤3 years before the first dose of study intervention.
5
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, 
including uncontrolled hypertension, active bleeding diatheses, active infection including 
hepatitis B, hepatitis C, and human immunodeficiency virus, chronic gastrointestinal 
diseases (e.g., Crohn's disease, chronic colitis), symptomatic congestive heart failure, 
unstable angina pectoris, uncontrolled cardiac arrhythmia, or active interstitial lung 
disease (ILD). Screening for chronic conditions is not required.
6
Creatinine clearance < 40 mL/min (calculated by Cockcroft-Gault equation).
7
Prior exposure to immune-mediated therapy including, but not limited to anti-CTLA-4, 
anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anti-cancer 
vaccines.
8
History of allogeneic organ transplantation.
9
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or 
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid 
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:

Participants with vitiligo or alopecia

Participants with hypothyroidism (e.g., following Hashimoto syndrome) stable on 
hormone replacement 

Any chronic skin condition that does not require systemic therapy

Participants without active disease in the last 5 years may be included but only after 
consultation with the Study Physician

Participants with coeliac disease controlled by diet alone
10 History of active primary immunodeficiency.
11 Active tuberculosis infection (clinical evaluation that may include clinical history, 
physical examination and radiographic findings, and tuberculosis testing in line with local 
practice).
12 Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
intervention.
Additional Exclusion Criteria Specific for Arm B: Medical Conditions
13 Participant with active grade ≥2 peripheral neuropathy
14 Participant with active grade ≥2 stomatitis
Prior/Concomitant Therapy
15 Any small-molecule, biologic, or hormonal agent from a previous treatment regimen or 
clinical study within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of 


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study intervention. At least 7 days must have elapsed between the last dose of such agent 
and the first dose of study intervention. Exception: androgen-deprivation therapy is 
permitted.
16 History of hypersensitivity to any of the study drugs or any of the study drug excipients 
including hypersensitivity to polysorbate-80 if allocated to cabazitaxel.
17 Nitrosourea or mitomycin C within 6 weeks of the first dose of study intervention.
18 Prescription or non-prescription drugs or other products known to be sensitive BCRP, 
OATP1B1/3, OAT1, OCT1, OCT2, MATE1 and P-gp substrates or to be strong 
inhibitors/inducers of CYP1A2 (see Appendix I), which cannot be discontinued 2 weeks 
prior to Day 1 of dosing and withheld throughout the study, until 2 weeks after the last 
dose of study intervention.
19 Exclusion Criteria for Arm B: Concurrent or planned treatment with strong inhibitors or 
strong inducers of cytochrome P450 3A4/5 (CYP3A4/5) are excluded (a 2-week washout 
period is required for participants already on these treatments) (see Appendix I).
20 Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include but are not limited to St. John’s wort, kava, ephedra (ma huang), 
gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Participants 
should stop using these herbal medications 7 days prior to the first dose of study 
intervention. Exceptions may be agreed, but the circumstances must be reviewed by the 
Medical Monitor/AstraZeneca Study Physician in advance.
21 Ongoing treatment with warfarin (Coumadin).
22 Major surgery (excluding placement of vascular access) within 4 weeks of the first dose 
of study intervention.
23 Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited 
field of radiation for palliation within 2 weeks of the first dose of study intervention.
Prior/Concurrent Clinical Study Experience
24 AZD4635 in the present study (i.e., dosing with AZD4635 previously initiated in a 
different arm in this study) or prior therapy with AZD4635 or any other A2AR antagonist 
or other CD73/CD39 antagonists. 
25 History of allogeneic organ, or other transplant, such as bone marrow transplant.
26 With the exception of alopecia, any unresolved toxicities from prior therapy greater than 
Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 Grade 1 at the 
time of starting study treatment. Participant with chronic Grade 2 unresolved toxicities 
may be eligible following discussion with the Medical Monitor/AstraZeneca Study 
Physician.
27 Concurrent enrollment into another therapeutic clinical trial.
28 Concomitant treatment with another adenosine 1 receptor (A1R) antagonist that would 
increase risk of seizure (e.g., theophylline, aminophylline).


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Diagnostic Assessments
29 Any of the following cardiac criteria:

Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3 ECGs

Any clinically important abnormalities in rhythm, conduction, or morphology of 
resting ECGs, e.g., complete left bundle branch block, third-degree heart block

Any factors that increase the risk of QTc prolongation or risk of arrhythmic events 
such as heart failure, hypokalaemia, congenital long QT syndrome, or family history 
of long QT syndrome or unexplained sudden death under 40 years-of-age

Left ventricular ejection fraction < 55% or the lower limit of normal of the 
institutional standard, ascertained by an echocardiogram or multiple-gated acquisition 
(MUGA) that has been obtained in the 6 months prior to screening. If there has been 
a change in the participant’s cardiac status, or if there has not be an echocardiogram 
or MUGA within the 6 months prior to study enrollment, this should be performed as 
part of the screening assessments.
Other Exclusions
30 Judgment by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
5.3
Lifestyle Considerations
No restrictions are required.
5.3.1
Meals and Dietary Restrictions
Participants in Arm B must refrain from consumption of Seville oranges, grapefruit or 
grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from 7 days 
before the first dose of study intervention until after the final dose.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to a study intervention/entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.
Participants defined as screen failures may be rescreened under certain circumstances. 
Consideration will be given, for example, to the following:


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
Participants with out-of-range laboratory values will be allowed to repeat the relevant 
laboratory safety assessments within the screening period, unless the laboratory values are 
reflective of an established medical condition and are unlikely to improve during the 
screening period.

Participants for whom screening procedures are not completed within the 28-day window.

Participants taking a prohibited medication can be considered for the study after the 
appropriate washout period. This is only applicable in instances where the withdrawal of 
the medication is clinically appropriate and unlikely to adversely affect the condition for 
which the medication has been prescribed.
Other conditions may be discussed with the Medical Monitor/AstraZeneca Study Physician.
Rescreening should be documented so that its effect on study results, if any, can be assessed. 
All rescreened requests need to be discussed by the Medical Monitor/AstraZeneca Study 
Physician.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants should be assigned the same participant number as for the 
initial screening.


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 2 of 1 9 3
6
S T U D Y I N T E R V E N TI O N
St u d y  int er ve nt i ons is defi ne d as a n y I P(s) (i ncl u di n g mar kete d c o m parat or) i nte n de d t o be 
a d mi nistere d t o a st u d y p artici pa nt acc or di n g t o t he st u d y pr ot oc ol. St u d y int er ve nt i on i n t his 
st u d y refers t o A Z D 4 6 3 5, d ur val u ma b a n d ca bazita xel. I n t his pr ot oc ol AZ D 4 6 3 5, d ur val u ma b 
a n d ca bazita xel are als o referre d t o as eit her st u d y dr u gs, stu d y i nter ve ntio ns, I Ps, or 
i n vesti gati onal me dici nal pr o d ucts – a n d t hese ter ms are use d i nterc ha n gea bl y.
O n da ys w he n m ul tiple I Ps are gi ve n t o get her, it is a d vise d t hat A Z D 4 6 3 5 is gi ve n first 
f oll owe d b y d ur val u ma b a n d t he n ca bazita xel.
6. 1
I n vesti g ati o n al P r od ucts
Ta ble 4
I n vesti g ati o n al Pro d ucts
A R M N a me
A a n d B
A a n d B
B o nl y
I nter ve nti o n 
N a me
A Z D 4 6 3 5
D u r v al u m a b
C a b azit a xel
T y pe 
S m all M olec ule
Bi ol o gic
C he m ot hera p y
D ose 
F or m ul ati o n
ca ps ules
vial 
vial
U n it D ose 
Stre n gt h(s)
 m g or 
 m g 
5 0 0 m g vial s ol uti o n f or 
i nf usi o n after dil uti o n, 
5 0 m g/ m L
6 0 m g/ 1. 5 m L s u p plie d 
wit h dil ue nt ( 5. 7 m L)
D os a ge Le vel(s)
 m g P O dail y (A r m A 
a n d A r m B)
1 5 0 0 m g I V Q 4 W
( Ar m A)
1 5 0 0 m g I V Q 3 W
( Ar m B)
2 0 or 2 5 m g/ m 2 I V Q 3 W
as per t he l ocal la bel
( Ar m B o nl y)
R o ute of 
A d mi nistr ati o n
Or al
I ntra ve n o us
I ntra ve n o us
Use
I nter ve nti o n
I nter ve nti o n
I nter ve nti o n
I M P a n d NI M P
I M P
I M P
I M P
S o urci n g
Astra Ze neca
Astra Ze neca
C o m mer cia ll y s o urce d
P ac k a gi n g a n d 
L a belli n g
St u d y i nter ve nti o n will 
be pr o vi de d i n hi g h -
de nsit y p ol yet h yle ne 
( H D P E) b ottles 
i n d ucti o n-s eale d wit h 
desicca nt . Eac h b ottle 
will be la bel le d i n 
acc or da nce wit h G o o d 
Ma n ufact uri n g Practice 
D ur val u ma b will be 
pr o vi de d as a s ol uti o n i n 
clear glass vials . Eac h 
vial will be la belle d i n 
acc or da nce wit h G M P 
A n ne x 1 3 a n d / or per 
c o u ntr y re g ulat or y 
re q uire me nt.
C o m mer cia ll y s o urce d 
st u d y i nter ve nti o n will 
be pr o vi de d.
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
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A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
6 3 of 1 9 3
( G M P) A n ne x 1 3 a n d/ or
per c o u ntr y re g ulat or y 
re q uire me nts.
C u rre nt/ F or mer 
N a me(s) 
-
-
J E V T A N A®
6. 2
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y of I nter ve nti o ns
T he I n vestig at or or desi g n e e m ust c o nfi r m t hat a p pr o priate te m perat ure c o n dit i ons ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all st u d y  int er ve nt i on recei ve d a n d t hat a n y discre pa ncies are 
re p orte d a n d res ol ve d bef ore use of t he st u d y int er ve nt i on.
O nl y partici pa nts e nr o lle d i n t he st u d y ma y recei ve t he stu d y i nter ve ntio n a n d o nl y  a ut h orised 
site staff ma y s u p pl y or a d mi nister t he st u d y int er ve nt i on . All st u d y int er ve nt i ons m ust be 
st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, a n d m o nit ore d ( ma n ual or a ut o mate d) area i n 
acc or da nce wit h t he labelle d st ora ge c o n ditio ns wit h access li mite d t o t he I n vesti gat or a n d 
a ut h or ised si t e st aff.
T he I n vestig at or, i nstituti o n, or t he hea d of t he me dical i nst ituti o n ( w here a p plica ble) is 
res p o nsi ble f or stu d y i nter ve ntio n acc o u nta bilit y,  rec o nciliati on, a n d rec or d ma i nte na nce ( i.e. ,
receipt, rec o nciliat i on, a n d fi nal dis p osit i on rec or ds).
F urt her g ui da nce a n d i nf or mati o n f or t he fi nal dis p osit i on of u n use d st u d y int er ve ntio n s are 
pr o vi de d i n t he P har mac y Ma n ual .
6. 2. 1
A Z D 4 6 3 5
A Z D 4 6 3 5 
 m g P O will be a d mi nistere d o n a c o nt i n u o us sc he d ule i n Ar ms A a n d B u nless 
safety fi n di n gs i n dicate t hat a c ha n ge is re q uire d.
N o r o uti ne pr o p h ylactic a nt i-e met ic treat me nt is re q uire d at t he start of st u d y treat me nt;
h o we ver, parti ci pa nts s h o uld recei ve a p pr o pri ate a nt i-e metic treat me nt at t he first o nset of 
na usea or v o mit i n g. If a parti ci pa nt has a k n o w n hist or y  of na usea a n d v o mit i n g with pri or 
t hera p y, c o nsider t he use of pr o p h ylact ic a nti-e metics. T he y s h o uld c o nt i n ue as re q uire d 
t hereafter, i n acc or da nce wit h l ocal treat me nt practice g ui deli nes. Alter nat i vel y, A Z D 4 6 3 5 
ca ps ules ca n be ta ke n wit h f oo d .
T his I P will be s u p plie d b y Astra Ze neca. A Z D 4 6 3 5 will be dis pe nse d t o partici pa nts wee kl y  or 
pri or t o be gi n ni n g a ne w c ycl e d uri n g sc he d ule d visits t o t he cli nic or b y deli ver y. T he batc h 
n u m ber of t he st u d y  dr u g dis pe nse d t o t he partici pa nt s h o uld be e ntere d o n t he e C R F, if 
a p plica ble.
As per i nter nat i onal g ui da nce o n a nt i-e met ic use i n ca ncer s u bjects ( E S M O, N C C N), 
C CI


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generally a single agent anti-emetic should be considered (e.g., dopamine receptor antagonist, 
antihistamines or dexamethasone).
Dosing and handling instructions and participant emergency contact details will be provided 
to participants in writing.
Whenever possible, all doses of AZD4635 should be taken at approximately the same times 
each day, with or without food. The capsule formulation should not be crushed, chewed, or 
dissolved when taken orally. If vomiting occurs after AZD4635 dosing, the participant should
not re-dose, and the participant should take the allotted dose at the next scheduled time.
Should a participant miss a scheduled dose, the participant will be allowed to take the dose up 
to a maximum of 4 hours after the scheduled dose time. If greater than 4 hours after the 
scheduled dose time have elapsed, the missed dose should not be taken, and the participant 
should take the allotted dose at the next scheduled time. If a participant needs to take the dose 
earlier for any reason, the participant can take the dose up to 4 hours earlier than the scheduled 
dose time. The participant should make every reasonable effort to take the study intervention
on time. A dosing diary will be provided to the participant to record the date and time dose(s) 
were taken. A copy of the dosing diary is provided in the study reference materials (see 
Section 6.4.
Additional information about the IP may be found in the IB.
Each bottle will be labelled as described in Table 4.
6.2.2
Durvalumab
Durvalumab 1500 mg will be administered via IV once every 4 weeks in Arm A. In Arm B 
durvalumab 1500 mg IV will be administered once Q3W for first 10 cycles and then Q4W
thereafter.
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL durvalumab, 26 mM histidine/histidine 
hydrochloride, 275 mM trehalose dihydrate, and 0.02% (weight/volume [w/v]) polysorbate
80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume is 10 mL. IP vials 
are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product should be kept 
in original packaging until use to prevent prolonged light exposure.
Durvalumab will be labelled as described in Table 4. 
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6.2.2.1
Preparation of Durvalumab Dose for Administration with an IV Bag
The dose of durvalumab for administration must be prepared by the Investigator’s or the site’s 
designated Investigational Product Manager using an aseptic technique.
Total time from needle puncture of the durvalumab vial to the start of administration should 
not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
A dose of 1500 mg will be administered using an IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, with a final durvalumab concentration ranging from 1 to 20 mg/mL, and 
delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 30.0 mL of 
durvalumab (i.e., 1500 mg of durvalumab) to the IV bag. Mix the bag by gently inverting to 
ensure homogeneity of the dose in the bag.
Standard infusion time is one hour; however, if there are interruptions during infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.
Do not co-administer other drugs through the same infusion line.
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered; alternatively, 
complete the infusion according to institutional policy to ensure the full dose is administered.
If either the preparation time or the infusion time exceeds the time limits a new dose must be 
prepared from new vials. Durvalumab does not contain preservatives, and any unused portion 
must be discarded. 
6.2.3
Cabazitaxel
Participants allocated to Arm B will receive cabazitaxel 20 mg/m2 or 25 mg/m2 as a 1-hour IV 
infusion (as per local label) on Day 1 of each cycle Q3W for the first 10 cycles according to 
institutional standards of care. Cabazitaxel will be locally sourced from a commercial supplier.
The participant should be pre-medicated with prednisone 10 mg PO continuously.
Pre-medicate with the following intravenous medications at least 30 minutes prior to each 
dose of cabazitaxel to reduce the risk and/or severity of hypersensitivity:

antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent 
antihistamine),

corticosteroid (dexamethasone 8 mg or equivalent), and


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
H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist)
For countries where IV antihistamines are not available, oral antihistamines can be used 
according to local practice. 
Prophylactic antiemetic therapy should be administered according to local institutional 
practices and standards.
Primary prophylactic G-CSF is required at the beginning of each new cycle for all participants 
in the cabazitaxel arm. G-CSF should be administered according to the product label and 
institutional standards. 
6.2.3.1
Preparation of Cabazitaxel Dose for Administration with an IV Bag
Cabazitaxel (JEVTANA) is a sterile, non-pyrogenic, clear yellow to brownish-yellow viscous 
solution and is available in single-dose vials containing 60 mg cabazitaxel (anhydrous and 
solvent free) and 1.56 g polysorbate 80.
Each mL contains 40 mg cabazitaxel (anhydrous) and 1.04 g polysorbate 80.
The DILUENT for JEVTANA is a clear, colourless, sterile, and non-pyrogenic solution 
containing 13% (w/w) ethanol in water for injection, approximately 5.7 mL.
JEVTANA requires two dilutions prior to intravenous infusion. JEVTANA should be diluted 
only with the supplied DILUENT for JEVTANA, followed by dilution in either 0.9% sodium 
chloride solution or 5% dextrose solution.
Do not use PVC infusion containers or polyurethane infusion sets for preparation and 
administration of JEVTANA infusion solution. JEVTANA should not be mixed with any other 
drugs.
For preparation and administration instructions for cabazitaxel, refer to the respective product 
labels, either the US prescribing information or the EU SmPC.
6.3
Measures to Minimise Bias: Methods for Assigning Treatment 
Groups
Treatment arm will be selected by the Investigator based on the inclusion/exclusion criteria 
(Section 4.4) and the open arm(s) (as of November 2020, the Sponsor stopped enrolment in 
Arm A following decisions at the program level, not related to any safety issues).
An IWRS will be used to assign potential participant a unique enrollment number (7-digit e-
code). All participants will be stratified by the presence of measurable soft tissue metastasis 
(per RECIST v1.1) or bone-only metastasis (per PCWG3 criteria) to ensure there is sufficient 


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number of participants in each stratum in Arm B as specified in the Section 4.1.
Investigator(s) should keep a record, the participant screening log, of participants who entered 
pre-study screening. 
The Investigator(s) will: 

Obtain a signed informed consent from the potential participant before any study-specific 
procedures are performed. 

Assign potential participant a unique enrollment number (i.e., E-code) using IWRS. The 
E-code is sequentially issued and will be used to identify the participant on all study-
related documents including the eCRF.

Determine participant eligibility. See Sections 5.1 and 5.2.

Declare if participant has soft tissue disease measurable by RECIST v1.1 or bone-only 
disease measurable by PCWG3 using the IWRS.

Declare if: participant received therapy with one NHA in the setting of mCRPC and 
docetaxel in the setting of mCRPC setting with a maximum of 3 lines of therapy (Arm A)
OR 
participant received prior therapy with one NHA in the metastatic setting and no prior 
taxane for treatment of mCRPC (Arm B).

Allocate eligible participant to the appropriate treatment arm and stratum, if they are 
open.
Allocation will be done centrally via IWRS after participant eligibility is established and prior 
to treatment. Every effort should be made to minimise the time between allocation and starting 
study treatment. It is recommended that participants commence study treatment as soon as 
possible after allocation.
If the participant is found to be ineligible during screening, the participant must be screen 
failed in the IWRS. 
Specific directions concerning the use of the IWRS will be provided in a separate instruction 
manual. If a participant withdraws from participation in the study, then his assigned codes 
cannot be reused.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive the study intervention directly from 
the Investigator or designee, under medical supervision. The date, and time if applicable, of 
dose administered in the clinic will be recorded in the source documents and recorded in the 
eCRF. The dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering the 


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study intervention.
When participants self-administer study intervention (AZD4635) at home the participant will 
be required to complete a dosing diary. Dosing compliance will be reviewed with the
participant at the beginning of a new treatment cycle. The site staff will count and document 
the amount of study drug taken and returned by the participant. If a dose is missed, the reason 
must be noted in the diary.
Compliance will be assessed by direct questioning, counting returned capsules, etc., during the 
site visits and documented in the source documents and eCRF. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF.
Participants should return all unused AZD4635 and empty containers. The Investigator or 
pharmacy must retain records of all study drugs administered. 
A record of the number of study intervention capsules dispensed to and taken by each 
participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration, including start and end dates

Dosage information including dose and frequency
The Medical Monitor/AstraZeneca Study Physician should be contacted if there are any 
questions regarding concomitant or prior therapy.
Participants must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential 
enzyme inducer) or 5 half-lives (whichever is longer) before the start of the study intervention 
until completion of the follow-up visit unless, in the opinion of the Investigator and sponsor, 
the medication will not interfere with the study.
Paracetamol/Acetaminophen, at doses of 2 grams/day, is permitted for use any time during 
the study. Other concomitant medications may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor/AstraZeneca Study Physician.


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6.5.1
Permitted Concomitant Medications
The following concomitant medications will be permitted:

Medical castration therapy with GRH analogues may continue during this study

Erythropoietin at the time of screening for the study may continue, provided the 
participant had been taking it for more than one month at the time study treatment is 
started

Treatment with bisphosphonates or denosumab for the treatment of bone metastases

Treatment with megestrol acetate when prescribed for appetite stimulation

Low molecular weight heparin. It is recommended that participants treated with an 
anticoagulant should have their anticoagulation monitored carefully and dose adjusted 
accordingly. Warfarin (Coumadin) is not permitted.

Hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone 
replacement therapy).
During the cabazitaxel study intervention, participants should receive concomitant 
prophylactic medications and the recommended anti-emetic therapy shown below.

Prednisone (10 mg daily continuously [or equivalent steroid]) for the duration of 
cabazitaxel administration

Primary G-CSF prophylaxis
Administered intravenously 30 minutes before cabazitaxel:

Antihistamine (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent 
antihistamine)

Corticosteroid (dexamethasone 8 mg or equivalent) 

H2 antagonist (ranitidine 50 mg or equivalent H2 antagonist

Antiemetic prophylaxis (oral or intravenous) as needed.
6.5.2
Prohibited or Restricted Medications
The following interventions listed are restricted or prohibited and are to be used with caution 
or not at all as described. Details on disallowed medications are included in Appendix I.


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Table 5
Prohibited Medications with AZD4635
Restricted medication/class of drug:
Additional Information
CYP1A2 inhibitors or inducers (Table 24).
Contribution of CYP1A2 to AZD4635 metabolism appears 
to be approximately 80%. Potent inhibitors or inducers of 
CYP1A2 should be avoided during administration of 
AZD4635. Refer to Appendix I for a list of the prohibited 
medications.
Table 6
Prohibited Medications with AZD4635
Prohibited medication/class of drug:
Additional Information
No other investigational therapy should be given to 
participants. No anticancer agents other than the 
study medications should be given to participants.
If such agents are required for a participant, then the 
participant must first be withdrawn from the study.
Since AZD4635 is an in vitro inhibitor of BCRP 
(IC50 6.2 µM) and OAT1 (IC50 6.6 µM), there is a 
risk of drug-drug interactions (DDIs) with sensitive 
substrates of BCRP (both in the gut and 
systemically) and OAT1 (systemically). Modelling
has predicted a substantial increase in the exposure 
(>2 fold) of certain statins (simvastatin, 
rosuvastatin, and atorvastatin) when 
co-administered with AZD4635. The use of 
sensitive substrates of OATP1B1/3, OCT1, OCT2, 
MATE1 and P-gp is also prohibited in this study, 
pending results from ongoing DDI studies.
Use of potent inhibitors or inducers of BCRP and sensitive 
substrates of OATP1B1/3, OAT1, OCT1, OCT2, MATE1 
and P-gp are prohibited throughout the study period (see 
Appendix I).
Herbal preparations/medications are not allowed 
throughout the study. These herbal medications 
include but are not limited to St. John’s wort, kava, 
ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.
Participants should stop using these herbal medications 7 
days prior to first dose of AZD4635. Exceptions may be 
agreed, but the circumstances must be reviewed by the 
Medical Monitor/AstraZeneca Study Physician in advance.
Table 7
Prohibited Medications with Durvalumab
Prohibited medication/class of drug:
Additional information
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Should not be given concomitantly while the participant is 
on study intervention
Live attenuated vaccines 
Should not be given through 30 days after the last dose of 
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Prohibited medication/class of drug:
Additional information
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions. The following are 
allowed exceptions:
Use of immunosuppressive medications for the 
management of IP-related AEs 
Use in participants with contrast allergies. 
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the participant (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc.).
Epithelial growth factor receptor tyrosine kinase 
inhibitors (EGFR TKIs) 
Should not be given concomitantly. 
Should be used with caution in the 90 days post-last dose 
of durvalumab. 
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with first-generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly.
Table 8
Prohibited Medications with Cabazitaxel
Medication/class of drug:
Additional information
CYP3A inhibitors
Cabazitaxel is primarily metabolised through CYP3A. 
Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, squinavir, telithromycin, 
voriconazole) may increase plasma concentrations of 
cabazitaxel. Avoid strong CYP3A inhibitors.
CYP3A inducers
Cabazitaxel is primarily metabolised through CYP3A. 
Strong CYP3A inducers (e.g., phenytoin, carbamazepine, 
rifampin, rifabutin, rifapentin, phenobarbital) are expected 
to decrease cabazitaxel concentrations. Avoid strong 
CYP3A inducers. In addition, participants should also 
refrain from taking St. John’s Wort.
Live attenuated vaccines
Should not be given through 3 months after the last dose of 
cabazitaxel.
6.5.3
Drug-Drug Interactions
Durvalumab
There is no information to date on DDIs with durvalumab either pre-clinically or in 
participants. As durvalumab is a monoclonal antibody and, therefore, a protein, it will be 


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degraded to small peptides and amino acids and will be eliminated by renal and 
reticuloendothelial clearance. It is therefore not expected that durvalumab will induce or 
inhibit the major drug metabolizing cytochrome P450 pathways. As a result, there are no 
expected pharmacokinetic drug-drug interactions. The mechanism of action of durvalumab 
involves binding to PD-L1, therefore, significant pharmacodynamic drug interactions with the 
commonly administered concomitant medications are not expected. Despite this, appropriate 
clinical monitoring in all of the planned clinical studies will be conducted to evaluate any 
potential DDIs.
Refer to the durvalumab IB.
AZD4635
Two independent in vitro studies using human liver microsomes and specific CYP inhibitors 
suggest that the main enzyme involved in the metabolism of AZD4635 is CYP450 
1A2.Clinical drug interactions with strong inhibitors or inducers of CYP1A2 cannot be ruled 
out.
Therefore, use of moderate and strong inhibitors/inducers of CYP1A2 are not permitted with 
AZD4635. As no inhibition of CYP3A4 was observed at up to 100 μM, CYP3A4 interactions 
with sensitive CYP3A4 substrates at the level of the gut are considered unlikely. The risk has 
been further evaluated using a preliminary PBPK model developed based on in vitro data and 
clinical data from the on-going Phase I study. The potential for a drug interaction with 
midazolam (sensitive CYP3A substrate) was evaluated indicated suggested a minimal impact 
on midazolam exposure (AUC ratio, < 1.15) with Ki CYP3A4 of AZD4635 from 10 –
300 µM AZD4635 is an in vitro inhibitor of BCRP, OATP1A2, OATP1B1, OATP1B3, OAT1, 
OAT3, OCT1, OCT2, and MATE1, with respective IC50 values of 6.2, 2.3, 62, 84, 6.6, 26, 
8.4, 16, and 16 μM. Based on current guidance from the FDA and EMA (FDA Guidance for 
Industry 2020; EMA Guideline 2012), and the predicted exposures of AZD4635, there is a 
potential risk of DDIs with sensitive substrates of BCRP (both in the gut and systemically). In 
addition, based on EMA guidance (EMA Guideline 2012), there is also potentially a risk of 
DDIs with sensitive substrates of OATP1B1/3, OAT1, OCT1, OCT2, and MATE1. Although 
an IC50 could not be calculated up to 100 μM AZD4635, P-gp interactions with sensitive P-gp
substrates at the level of the gut cannot be ruled out. Therefore, use of sensitive substrates of 
these transporters are prohibited. Herbal preparations/medications are not allowed in 
studies D8730C00001, D8730C00002, and D6070C00004. These herbal medications include, 
but are not limited to: St. John’s wort, kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Participants should 
stop using these herbal medications 7 days prior to first dose of AZD4635.
Refer to the AZD4635 IB.


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Cabazitaxel
Cabazitaxel is primarily metabolised through CYP3A. Though no formal drug interaction 
trials have been conducted for cabazitaxel, concomitant administration of strong CYP3A 
inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase 
concentrations of cabazitaxel. Therefore, coadministration with strong CYP3A inhibitors 
should be avoided. Caution should be exercised with concomitant use of moderate CYP3A
inhibitors.
Though no formal drug interaction trials have been conducted for JEVTANA, the concomitant 
administration of strong CYP3A inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, 
rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co-
administration with strong CYP3A inducers should be avoided. In addition, participants 
should also refrain from taking St. John’s Wort.
Refer to the SmPC/USPI for additional information.
6.5.4
Rescue Medication
As a result of immune-mediated AEs (imAEs) that could potentially be experienced by 
participants on durvalumab, steroids and other immunosuppressant rescue medication have to 
be made available to this participant population. The 2 products that fall into the category of 
immunosuppressants are infliximab (e.g., for colitis) and mycophenolate (e.g., for hepatitis).
AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications to the 
sites if local regulations prevent the use of infliximab and mycophenolate in this indication, 
because they are considered off-label for management of immunotherapy related toxicities.
These rescue medications must be receipted, controlled, and administered by the pharmacist 
and stored according to the labelled storage conditions, with temperature excursions reported 
accordingly by the pharmacist.
There is currently no known antidote to AZD4635 and the provided treatment should be 
supportive care for the underlying symptoms.
There is no known antidote to cabazitaxel. The anticipated complications of overdose would 
consist of exacerbation of adverse reactions such as bone marrow suppression and 
gastrointestinal disorders. In case of overdose, the participant should be kept in a specialized 
unit and closely monitored. Participants should receive therapeutic G-CSF as soon as possible 
after the discovery of an overdose. Other appropriate symptomatic measures should be taken.
6.5.5
Other Concomitant Medications
Other medication other than that described above, which is considered necessary for the 
participant’s safety and wellbeing, may be given at the discretion of the Investigator and 


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recorded in the appropriate sections of the Case Report Form (CRF).
6.6
Cabazitaxel Safety Assessment Arm B
6.6.1
Definition of Dose-Limiting Toxicity for Arm B
In Arm B, dose-limiting toxicity (DLT) criteria will be used to assess safety for Arm B in the 
first 6 evaluable participants. Grading of DLTs will be according to the CTCAE, Version 5.0.
A DLT is defined as an AE or abnormal laboratory value that occurs from the first dose of 
AZD4635 plus durvalumab plus cabazitaxel up to and including Day 21, Cycle 1 (the DLT 
period) that is assessed as unrelated to disease progression, intercurrent illness, or concomitant 
medications and that, despite optimal therapeutic intervention, meets any of the following 
criteria:

Haematological toxicities CTCAE ≥Grade 3 not attributed to cabazitaxel alone, except 
for neutropenia, which is addressed as:
Neutropenia ≥ CTCAE Grade 4 or febrile neutropenia present for more than 7 days. 
For AZD4635/cabazitaxel/durvalumab it will not be considered a DLT if attributed to 
cabazitaxel only.
Non-haematological toxicity CTCAE ≥ Grade 3 including:

QTc (Fridericia’s correction) interval >500 msec or QTc increase >60 msec from baseline 
on 2 ECGs at least 30 minutes apart that cannot be attributed to another cause

Convulsions, seizures, or stroke

Nausea, vomiting, or diarrhoea that does not resolve to ≤ Grade 1 within 7 days of 
maximal supporting care

Liver transaminase elevation ≥5 × but ≤8 × ULN that does not downgrade to Grade 2 
within 5 days after onset with optimal medical management, including systemic 
corticosteroids. Transaminase elevation >8 × ULN or total bilirubin >5 × ULN will be 
considered a DLT regardless of duration. Any increase in AST or ALT >3 × ULN and 
concurrent increase in total bilirubin >2 × ULN (Hy’s Law without evidence of 
cholestasis or alternative explanations [e.g., viral hepatitis, disease progression in the 
liver]).

Any other toxicity that is ≥ CTCAE Grade 3 is clinically significant and/or unacceptable, 
does not respond to supportive care, results in a disruption of dosing schedule of more 
than 21 days, or is judged to be a DLT the Investigator in collaboration with the 
AstraZeneca Study Physician, Global Safety Physician, or by the SRC (see Section 4.1.1).
A DLT excludes:

Alopecia of any grade


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 5 of 1 9 3

L y m p h o pe nia of a n y gra de

Is olat e d la b orat or y c ha n ges of a n y gra de wit ho ut cli nical  se q uelae or cli nical si g nifica nce.
A n e val ua ble partici pa nt is defi ne d as a parti ci pa nt w h o has recei ve d A Z D 4 6 3 5 a n d eit her:

Has c o m plete d mi ni m u m safet y e val uat i on re q uire me nts a n d has recei ve d at least 7 5 % of 
t he s pecifie d A Z D 4 6 3 5 d oses of treat me nt c o nc o mita nt l y with d ur val u ma b a n d 
ca bazita xel d uri n g C ycle 1.
Or 

Has e x p erie nce d a D L T d uri n g C ycle 1, t he D L T e val uat i on peri o d, f or Ar m  B. 
N o n -e val ua ble partici pa nts ma y be re place d. 
A n y partici pa nt starte d o n treat me nt i n err or beca use he faile d t o c o m pl y with all of t he 
selecti on cri t eria b ut meets t he criteria of a n e va l ua ble partici pa nt, will be re vie we d o n a case-
b y- case b y t he S R C t o deter mi ne if t he parti ci pa nt s h o uld be i ncl u de d or e xcl u de d i n t he 
decisi o n wi t h re gar d t o recr uit me nt t o Ar m B. 
6. 7
D ose M o dific ati o n
A Z D 4 6 3 5 a n d d ur val u ma b will be a d mi nistere d i n 4 -wee k c ycles d uri n g Ar m A  a n d i n 3- wee k 
c ycles d uri n g Ar m B. I n Ar m B , c ycles will i ncrease t o 4 wee ks after t he partici pa nt has 
c o mplete d te n 3 -wee k c ycles. A Z D 4 6 3 5 d ose re d ucti o ns or h ol ds a n d i nit iati on of s u p p orti ve 
care are all o we d as cli nicall y i n dicate d b y t he Pri nci pal I n vest i gat or. T he d ose f or A Z D 4 6 3 5 is 
m g P O Q D i n c o m bi nat i on wi t h d ur val u ma b. D ose re d ucti o ns f or A Z D 4 6 3 5 will occ ur i n 
m g i ncre me nts. U p t o 2 d ose re d ucti o ns of A Z D 4 6 3 5 f or t o xicit y will be all o we d (see
Ta ble 9 ). All h e mat o l ogi c a n d n o n- he mat olo gi c t o xicities will be gra de d acc or di n g t o t he 
C T C A E, V ersio n  5. 0 crit eria.
T he d ose f or ca bazita xel is 2 5 m g/ m 2 or 2 0 m g/ m 2 per l ocall y a p pr o ve d la bel. T his d ose ca n 
be re d uce d f or ca bazita xel w he n necessar y  as descri be d i n f oll o wi n g secti ons. T he d ose, 
w hic h has bee n re d uce d f or t o xicit y,  must n ot be re -escalate d. If t he starti n g d ose ca bazita xel 
is 2 5 m g/ m2, u p t o a ma xi m u m of  2 d ose re d uctio ns will  be allo we d per parti ci pa nt . If a t hir d 
d ose re d ucti o n is re q uire d per t he m o dificat i ons (see Ta ble 1 0 ), t he parti ci pa nt s h o uld
di sc o nti n ue st u d y tr e at me nt. If t he starti n g d ose ca bazita xel is 2 0 m g/ m 2, u p t o a ma xi m u m o f 
1 d ose re d ucti o n will be all o we d per p artici pa nt. If a sec o n d d ose re d ucti o n is re q uire d per t he 
m o dificati o ns ( Ta ble 1 0 ), t he partici pa nt s h o uld di sc o nti n ue st u d y treat me nt.
If a parti ci pa nt e x perie nces a cli nicall y si g nifica nt a n d/ or u nacce pta ble t o xicit y n ot attri b uta ble 
t o t he disease or disease-relate d pr ocesses u n der i n vesti gati o n, d osi n g will be i nterr u pte d , or 
t he d ose will be re d uce d a n d s u p p orti ve t hera p y will  be a d mi nistere d, as re q uire d. If t he 
t o xicit y d oes n ot res ol ve t o ≤ C T C A E Gra de 2 after 2 wee ks of treat me nt , t he n t he parti ci pa nt
s h o uld be wi t hdra w n fr o m  t he st u d y a n d o bser ve d u ntil res ol uti on of t he t o xicit y u nless 
C CI
C CI


Cli nical St u d y Pr ot oc o l – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
7 6 of 1 9 3
a p pr o ve d b y t he Me dical M o nit or/Astra Ze neca St u d y  P h ysicia n. A n y decisi o n t o wi t hdra w a 
parti ci pa nt fr o m t he st u d y must be di sc usse d with t he Me dical M o nit or/ Astra Ze ne ca St u d y  
P h ysicia n. Ma xi m u m dr u g h o li da y all o we d is 3 wee ks f or n o n -i m m u ne-me diate d t o xi cit y
u nless a gree d wit h t he Me dical M o nit or/ Astra Ze neca St u d y  P h ysicia n. F or i m m u ne-me diate d 
t o xicit y, a lo n ger dr u g h oli da y is per mitte d t o all o w f or a de q uate ster oi d ta per a n d s h o ul d be 
di sc usse d wit h t he Me dical M o nit or/Astra Ze neca St u d y  P h ysicia n.
D ose dela ys f or d ur val u ma b are a d dresse d i n t he D osi n g M o dificat i on a n d To xi cit y 
Ma na ge me nt G ui deli nes ( T M Gs) . H o we ver, d ose r e d ucti o n f or d ur v al u m a b is n ot 
per mitte d i n Ar m A o r  A r m B .
P arti cipa nts t hat di sc o nti n ue o ne st u d y dr u g ma y r e mai n o n t he st u d y a n d recei ve t he ot her
st u d y dr u g (s) as lo n g as t he y  are c o nti n ui n g t o deri ve cli nical be nefit.
Ta ble 9
A Z D 4 6 3 5 D ose Le vels f or  D ose Re d ucti o ns d ue t o To xicities
D ose Le vel
A Z D 4 6 3 5 a
- 1 
 m g P O Q D
- 2
 m g P O Q D
a
T w o d ose re d ucti o n s are all o we d f or A Z D 4 6 3 5 .
Ta ble 1 0
C a b azit a xel D ose Le vels f or  D ose Re d ucti o ns d ue t o To xicities
D ose Le vel
C a b azit a xel
a
C a b azit a xel
a
0
2 5 m g/ m 2
2 0 m g/ m 2
- 1 
2 0 m g/ m 2
1 5 m g/ m 2
- 2
1 5 m g/ m 2
N A
a
Starti n g d ose as per l ocall y a p pr o ve d la bel f or ca bazita xel. 
6. 7. 1
M a n a ge me nt of T o xicities Rel ate d t o A Z D 4 6 3 5
T her a p y
A Z D 4 6 3 5 d ose re d ucti o n a n d disc o nt i n uati on g ui deli nes f or n o n -hae mat ol o gic t o xicit ies are 
s h o w n i n Ta ble 1 1 .
Ta ble 11
A Z D 4 6 3 5 D ose M o dific ati o ns 
a n d Disc o nti n u ati o n Criteri a f or No n-
H ae m at ol o gic T o xicities 
C T C A E , Versi o n 5. 0 T o xicit y Gr a de
Acti o n
Gra de 1 or 2
N o ne re q uire d
Gra de 3 or 4 a n d/ or cli nicall y si g nifica nt a
H ol d A Z D 4 6 3 5
T o xicit y res ol ve d t o Gra de 1, Gra de 2, or baseli ne 
< 1 4 da ys
T o xicit y re mai ns Gra de 3 t o 4 or is cli nicall y 
si g nifica nt a > 1 4 da y s
Restart A Z D 4 6 3 5 at 1 d ose le vel re d ucti o n
Disc o nti n ue A Z D 4 6 3 5
C CI
C CI


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CTCAE, Version 5.0 Toxicity Grade
Action
Recurrence of Grade 3
Reduce one more dose level if available (see
Table 9) or if not discontinue AZD4635
Recurrence of Grade 3 cardiac eventa
Discontinue AZD4635
Recurrence of Grade 4
Discontinue AZD4635
a
Includes significant change in CK/CK-mb ratio (relative index > 5%), increase in heart rate of + 25 bpm 
(up to 100 to 125 bpm) for more than 24 hours or increase in heart rate > 125 bpm for more than 12 hours, and 
QTc prolongation > 500 ms.
6.7.2
Management of Toxicities Related to Durvalumab Therapy
The following general guidance should be followed for management of toxicities related to 
durvalumab.

Treat each of the toxicities with maximum supportive care (including holding 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 assigned dose of durvalumab along with appropriate continuing 
appropriate supportive care.

All toxicities will be graded according to CTCAE, Version 5.0. 
6.7.2.1
Specific Toxicity Management Guidelines and Dose Modification Information 
for Durvalumab
Comprehensive TMGs have been developed to assist investigators with the recognition and 
management of toxicities associated with use of the immune-checkpoint inhibitor durvalumab 
[MED4736] (PD-L1 inhibitor). These TMGs are applicable to the management of participants 
receiving durvalumab as monotherapy. Additionally, these guidelines are applicable when 
durvalumab is used alone or, when other anti-cancer drugs (i.e., antineoplastic chemotherapy, 
targeted agents) are administered concurrently or sequentially with durvalumab as part of a 
protocol-specific treatment regimen. The TMGs provide information for the management of 
immune mediated reactions, infusion-related reactions, and non-immune-mediated reactions 
that may be observed with checkpoint inhibitor monotherapy or combination checkpoint 
inhibitor regimens, with specific instructions for checkpoint inhibitor-specific dose 
modifications (including discontinuation) and treatment interventions. Investigators are 
advised however to use local practice guidelines and consult local references for the 
management of toxicities observed with other anti-cancer treatment. 
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document, and is maintained within the Site Master File. 


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Participants should be thoroughly evaluated and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxic, or other etiologic causes of imAEs. 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 TMGs). In such circumstances, a 
determination of the relationship between AZD4635 and toxicity should be discussed with 
Medical Monitor and/or Sponsor. In the absence of a clear relationship to AZD4635 dosing, 
the investigational study drug AZD4635 may be restarted as monotherapy after toxicities have 
resolved to baseline or Grade 1 within 8 weeks of durvalumab-related toxicity.
These guidelines have been prepared by the Sponsor to assist the Investigator in the exercise 
of his clinical judgment in treating these types of toxicities. These guidelines apply to AEs 
considered causally related to durvalumab monotherapy regimen by the reporting Investigator.
Risks with durvalumab include, but are not limited to, diarrhoea/colitis, pneumonitis/ILD, 
endocrinopathies (i.e., events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis, 
myocarditis, myositis/polymyositis, infusion-related reactions, hypersensitivity reactions, 
pancreatitis, serious infections, and other rare or less frequent inflammatory events including 
neuromuscular toxicities (e.g., Guillain-Barre syndrome, myasthenia gravis). 
Dose reductions for durvalumab are not permitted (except if participant’s weight 
decreases to <30 kg. In case of doubt, the Investigator should consult with the Medical 
Monitor/AstraZeneca Study Physician.
6.7.2.2
Durvalumab Infusion-Related Reactions
In the event of an infusion-related reaction ≤ Grade 2, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event and re-initiated at 50% of the 
initial rate until completion of the infusion (see TMGs). In participants experiencing infusion-
related reactions ≤ Grade 2, subsequent infusions may be administered at 50% of the initial 
rate. The total allowed infusion time should not exceed 8 hours at room temperature.
If a participant experiences an infusion-related reaction, acetaminophen/paracetamol and/or an 
antihistamine (e.g., diphenhydramine) and/or corticosteroid or equivalent medications, per 
institutional standard may be administered prior to subsequent infusions at the discretion of 
the Investigator for secondary prophylaxis of infusion-related reactions. If the infusion-related 
reaction is Grade 3 or higher in severity, treatment with durvalumab will be discontinued.


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As with any monoclonal antibody, allergic reactions to dose administration are possible.
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. The study site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit participants to an intensive care unit if necessary.
6.7.3
Management of Toxicities Related to Cabazitaxel Therapy
The JEVTANA (cabazitaxel) prescribing recommendations provided by the manufacturer will 
be applied should a participant require a dose modification, hold or supportive care for 
toxicity that is clearly attributable to the cabazitaxel.
Dose modifications should be made if participants experience the following adverse reactions 
(Grades refer to Common Terminology Criteria for Adverse Events [CTCAE], Version 5.0).
Table 12
Recommended Dose Modifications For Adverse Reactions in 
Participants Treated with Cabazitaxel
Toxicity
Dose modification
Prolonged grade ≥3 neutropenia (greater than 1 week) 
despite appropriate medication, including G-CSF
Delay treatment until neutrophil count is >1,500 
cells/mm3, then reduce of cabazitaxel dose to 20 
mg/m2. Use G-CSF for secondary prophylaxis.
Febrile neutropenia
Delay treatment until improvement or resolution, and 
until neutrophil count is >1,500 cells/mm3, then 
reduce cabazitaxel dose to 20 mg/m2. Use G-CSF for 
secondary prophylaxis.
Grade ≥3 diarrhoea or persisting diarrhoea despite 
appropriate medication, fluid and electrolyte
replacement
Delay treatment until improvement or resolution, then 
reduce cabazitaxel dose to 20 mg/m2.
Grade ≥2 peripheral neuropathy
Delay treatment until improvement, then reduce to 
20 mg/m2.
Discontinue cabazitaxel treatment if participant continues to experience any of these reactions at 20 mg/m2.
Participants should be observed closely for hypersensitivity reactions especially during the 
first and second infusions, as per the local cabazitaxel label. Hypersensitivity reactions may 
occur within a few minutes following the initiation of the infusion of cabazitaxel, thus 
facilities and equipment for the treatment of hypotension and bronchospasm should be 
available. Severe reactions can occur and may include generalised rash/erythema, hypotension 
and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of 
cabazitaxel and appropriate therapy.
6.8
Intervention after the End of the Study
Intervention after the end of the study will be at the discretion of the Investigator.


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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Any participant who discontinues one or more IP, but not the other(s), may continue on study 
and normal study assessments will continue, if the Investigator believes the participant is 
receiving benefit.
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for follow-up. See the SoA for data to be collected when
study intervention is discontinued (e.g., end of treatment visit) and follow-up and for any 
further evaluations that need to be completed. Study intervention discontinuation will be 
reported to the IWRS by the site. 
Participants may be discontinued from study intervention in the following situations. Note that 
discontinuation from study intervention is NOT the same thing as complete withdrawal from 
the study intervention. Participants who discontinue from study intervention should continue 
the study (i.e., continue with study visits and assessments). Reasons for study intervention 
discontinuation include:

Participant decision. The participant is at any time free to discontinue study intervention 
without prejudice to further treatment

Any AE that in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing or meets the criteria for discontinuation as defined in the dose modification 
guidance or prescribing information for the study intervention(s).

Confirmed disease progression unless in the opinion of the Investigator, the participant is 
still receiving clinical benefit. Participants will continue study intervention until objective 
disease progression, or beyond RECIST v1.1 defined progression if participant is 
receiving clinical benefit, as judged by the Investigator and in the absence of 
discontinuation criteria. Tumour assessments must continue while participant continues to 
receive study treatment as per Section 8.1.1.

Investigator decision or severe non-compliance with the CSP as judged by the 
Investigator and/or AstraZeneca 

Participant started alternative anticancer therapy including another investigational agent

Participant lost to follow-up.
Participants may withdraw from any aspects of the voluntary genetic research (see 
Section 8.7) at any time, without prejudice to further treatment and independent of any 
decision concerning participation in other aspects of the main study.


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See the SoA for data to be collected at the time of treatment discontinuation and follow-up and 
for any further evaluations that need to be completed.
7.1.1
Procedures for Discontinuation of Study Intervention
The Investigator should instruct the participants to contact the site before or at the time if 
study intervention is stopped. A participant that decides to discontinue study intervention will 
always be asked about the reason(s) and the presence of any AEs. The date of last intake of 
study intervention should be documented in the electronic CRF (eCRF) and reported to the 
IWRS. All study interventions should be returned by the participant at their next on-site study 
visit or unscheduled visit. Participants permanently discontinuing study treatment should be 
given locally available standard of care therapy, at the discretion of the Investigator.
Discontinuation of study intervention, for any reason, does not impact on the participant´s 
participation in the study. The participant should continue attending subsequent study visits 
and data collection should continue according to the study protocol. If the participant 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 could be a telephone contact with the 
participant, a contact with a relative or treating physician, or information from medical 
records. The approach taken should be recorded in the medical records. A participant that 
agrees to a modified follow-up is not considered to have withdrawn consent or to have 
withdrawn from the study.
7.2
Participant Withdrawal from the Study
A participant may withdraw from the study at any time at his own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, compliance, 
or administrative reasons. This is expected to be uncommon.
A participant who considers withdrawing from the study must be informed by the Investigator
about modified follow-up options (e.g., telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
A participant who withdraws consent will always be asked about the reason(s) and the 
presence of any AEs. The Investigator will follow up participants as medically indicated. 
AstraZeneca or its delegate will request Investigators to collect information on participants’ 
vital status (dead or alive; date of death when applicable) from publicly available sources at 
the end of the study, in accordance with local regulations. Knowledge of the vital status of all 
participants at study end is crucial for the integrity of the study. 


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If a participant withdraws from the study, it should be confirmed if he still agrees for existing 
samples to be used in line with the original consent. If he requests withdrawal of consent for 
use of samples, destruction of any samples taken and not tested should be carried out in line 
with what was stated in the informed consent and local regulation. The Investigator must 
document the decision on use of existing samples in the site study records and inform the 
Global Study Team.
During the study, COVID-19 tests may be prescribed, if required, and in accordance with local 
guidance. If a participant tests positive, his continued participation in the study and his 
treatment with the study drugs will be discussed with the Parexel and AstraZeneca Medical 
Monitors for this study.
See the SoA (Table 1 or Table 2) for data to be collected at the time of study intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. All 
study treatment should be returned by the participant.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study, the participant should be considered to 
be lost to follow-up with unknown vital status and censored at latest follow-up contact.
As for withdrawn participants (see Section 7.2), Investigators will be requested to collect 
information of the survival status of participants lost to follow-up (see Section 8.2.10.3). 
If vital status is determined as deceased, this will be documented and the participant will 
not be considered lost to follow-up.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.


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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA. Protocol waivers or exemptions 
are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (e.g., blood 
count), and obtained before signing of the ICF, may be utilised for screening or baseline 
purposes - provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
The amount of blood collected from each participant during the first 2 treatment cycles, 
including any extra assessments that may be required, will not exceed approximately 160 mL 
in Arm A and approximately 228 mL in Arm B. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples.
8.1
Efficacy Assessments
Evaluation of objective tumour response in this study will be done using RECIST v1.1 criteria 
in evaluable soft tissue disease. Tumours will be assessed at screening according to the 
treatment arm schedule of assessments. Reassessment of tumours will be done by the same 
methods used to establish baseline tumour measurements.
PCWG3 PSA criteria will also be used to evaluate response and progression. These criteria 
will be followed for determining the change in PSA levels. Prostate-specific antigen levels in 
this study will be measured at screening, at the start of each new treatment cycle, at the end of 
treatment (EOT) visit, at any other time points indicated in the SoA, and as clinically 
indicated.
Disease progression will be deemed to have occurred if 1 or more of the following criteria is 
met:

Soft tissue disease progression as defined by RECIST v1.1


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
Bone lesion progression by PCWG3 (Table 13)

Death
Participants with PSA progression are permitted and encouraged to continue treatment until 
radiographic progression. Sites should monitor PSA by cycle but plan to continue through 
early rises for a minimum of 12 weeks unless there is other evidence of progression.
8.1.1
Tumour Assessments with RECIST v1.1
RECIST v1.1 guidelines for measurable and non-measurable target lesions (TLs) and non-
target lesions (NTLs) and the objective tumour response criteria are presented in Appendix F.
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual participants. Baseline assessments should be 
performed no more than 28 days before the start of study treatment, and ideally should be 
performed as close as possible to the start of study treatment. The methods of assessment used 
at baseline should be used at each subsequent follow-up assessment. While PET scans are not 
considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast).
For Arm A (AZD4635 plus durvalumab), the first follow-up assessment should be after 
Cycle 2 (8 weeks). Follow-up assessments should be performed every 8 weeks ±1 week from 
the start of dosing for the first 24 weeks and then every 12 weeks (±1 week) thereafter. Any 
other sites at which new disease is suspected should also be appropriately imaged. If an 
unscheduled assessment is performed and the participant has not progressed, every attempt 
should be made to perform subsequent assessments at the scheduled visits.
For Arm B (AZD4635 plus durvalumab and cabazitaxel), the first follow-up assessment 
should be after Cycle 3 (9 weeks). Follow-up assessments should be performed every 9 weeks 
±1 week from the start of dosing for the first 27 weeks and then every 12 weeks (±1 week)
thereafter. Any other sites at which new disease is suspected should also be appropriately 
imaged. If an unscheduled assessment is performed and the participant has not progressed, 
every attempt should be made to perform subsequent assessments at the scheduled visits.
Categorisation of objective tumour response assessment will be based on the RECIST v1.1 
guidelines for response of soft tissue lesions: CR (complete response), PR (partial response), 
SD (stable disease), and PD (progression of disease). For participants who only have NTLs at 
baseline, categorisation of objective tumour response assessment will be based on the RECIST 
v1.1 guidelines for response for NTLs: CR, PD, and Non CR/Non PD.


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If the Investigator is in doubt as to whether progression has occurred, particularly with 
response to NTLs or the appearance of a new lesion, it is advisable to continue treatment and 
reassess the participant’s status at the next scheduled assessment or sooner if clinically 
indicated.
To achieve ‘unequivocal progression’ on the basis of non-target disease, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD, 
or PR or CR in target disease, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal PD status.
Calculation or derivation of tumour response variables
At each visit, participants will be programmatically assigned a RECIST visit response of CR, 
PR, SD, non-CR/non-PD, or PD depending on the status of their disease compared to baseline 
and previous assessments.
Progression of TLs will be calculated in comparison to when the tumour burden was at a 
minimum (i.e., smallest sum of diameters previously recorded on study, nadir). In the absence 
of progression, tumour response (CR, PR, SD) will be calculated in comparison to the baseline 
tumour measurements obtained before starting treatment.
If a participant has had a tumour assessment that cannot be evaluated, then the participant will 
be assigned a visit response of no evaluable (NE), unless there is evidence of progression in 
which case the response will be assigned as PD.
Objective response rate is defined as the proportion of participants with measurable disease at 
baseline who have a confirmed CR or PR per RECIST v1.1. For the analysis of ORR an 
“evaluable-for-response” population will be derived and will exclude participants who do not 
have measurable disease at baseline.
A visit response of CR is defined when all TL and NTL lesions present at baseline have 
disappeared (with the exception of lymph nodes which must be <10 mm to be considered non-
pathological) and no new lesions have developed since baseline. A visit response of PR is 
defined when the sum of diameters of the TLs has decreased by 30% or more compared to 
baseline (with no evidence of progression) and the NTLs are at least stable with no evidence 
of new lesions.
In the case of SD (participants who have neither progressed nor achieved at least a PR and are 
evaluable), measurements should have met the SD criteria at least once after the study start.
When the Investigator is in doubt as to whether PD has occurred and therefore reassesses the 
participant at a later date, the date of the initial scan should be declared as the date of 


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pr o gressi o n if t he re peat sca ns c o nfir m pr o gressi o n.
Perce nta ge c ha n ge fr o m baseli ne i n t u m o ur size will be deter mi ne d f or partici pa nt s wit h 
meas ura ble disease at baseli ne a n d is deri ve d at eac h visit b y t he perce nta ge c ha n ge i n t he s u m 
of  t he dia meters of T Ls.
8. 1. 2
P C W G 3 B o ne Lesi o n A ssess me nt
Cate g orisat i on of t u m o ur pr o gressi o n o f b o ne lesi o ns will be base d o n t he P C W G 3 criteria. 
B o ne l esio ns will be assesse d b y b o ne sci nt i gra p h y c o m m o nl y perf or me d wit h tec h neti um- 9 9 
( b o ne sca ns). P ositi ve h ot s p ots o n t he b o ne sca n s h o ul d be c o nsi dere d si g nifica nt a n d 
u ne q ui v ocal sites of mali g na nt disease t o be rec or de d as met astatic b o ne lesi o ns (see Ta ble 
1 3 ).
Ta ble 1 3
Re q uir e me nts f or D oc u me nt ati o n of Pro gressi o n
Visit D ate
Criteri a f or B o ne Pr o gressi o n
Criteri a f or S oft Tiss ue 
Pr o gressi o n
First visit after baseli ne (e x pecte d 
Wee k 8 / Ar m A * a n d
Wee k 9 / Ar m B *)

2 or m o re ne w lesi o ns 
c o m pare d t o baseli ne b o ne 
sca n.

Re q uires c o nfir mati o n at least 
8/ 9 wee ks later wit h ≥2 
a d diti o nal lesi o ns c o m pare d t o 
t he first sca n after baseli ne

Pr o gressi ve disease o n C T or 
M RI b y R E CI S T v 1. 1

Re q uires c o nfir mati o n at least 
3/ 4 wee ks ( b ut n o m ore t ha n 
8/ 9 wee ks).
Fr o m t he 2 n d visit o n war ds p ost -
baseli ne

2 or m o re ne w lesi o ns 
c o m pare d t o t he first b o ne 
sca n after baseli ne.

Re q uires c o nfir mati o n at least 
8/ 9 wee ks later f or persiste nce 
or  i ncrease i n n u m ber of 
lesi o ns

Pr o gressi ve disease o n C T or 
M RI b y R E CI S T v 1. 1

N o c o nfir mati o n re q uire d.
C T, C o m p ute d t o m o gra p h y; M RI, Ma g netic res o na nce i ma gi n g; R E CI S T, Res p o nse E val uati o n Criteria i n S oli d t u m o urs.
* Ti mi n g f or Ar m A a n d Ar m B res p o nse c o nfir mati o n or res p o nse will be differe nt base d o n c ycle le n gt h.
 
 
8. 1. 4
P C W G 3 P S A Criter i a
All p arti ci pa nt s s h o ul d ha ve P S A c ollecte d at scree ni n g, at t he start of eac h ne w treat me nt 
c ycle, at t he e n d of st u d y treat me nt, a n d as i n dicate d i n t he S o A (see Ta ble 1 a n d Ta ble 2 ).
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PSA should also be collected when clinically indicated as per Investigator discretion.
PCWG3 PSA criteria are located in Appendix H.
8.2
Safety Assessments
8.2.1
Physical Examinations and Weight
A physical examination will be performed and weight will be measured. Physical examination 
will be performed at timelines as specified in the treatment arm SoA (Table 1 and Table 2). 
Physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, neurological, 
dermatological, hematologic/lymphatic, and endocrine systems. Height will be measured at 
screening only. Investigators should pay special attention to clinical signs related to previous 
serious illnesses. New or worsening abnormalities may qualify as AEs. See Section 8.3 for 
details.
8.2.2
Performance Status
World Health Organisation (WHO) performance status will be documented as indicated in the 
treatment arm SoA (Table 1 and Table 2).
Table 14
WHO Performance Status Scale
Score
Description 
0
Fully active, able to carry on normal performance without restriction
1
Restricted in physical strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house, office work.
2
Ambulatory and capable of self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
8.2.3
Vital Signs and Height
Vital signs (resting heart rate, systolic and diastolic blood pressure, respiration rate, and body 
temperature), and height (at screening only) will be assessed at the times indicated in the 
treatment arm SoA (Table 1 and Table 2).
8.2.4
Electrocardiograms
Electrocardiograms (ECGs) will be obtained at screening and when clinically indicated.


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Resting 12-lead ECG
Twelve-lead ECGs will be obtained after the participant has been resting supine for at least 
10 minutes prior at times indicated in the screening and the treatment arm SoA (see Table 1
and Table 2). All ECGs should be recorded with the participant in the same physical position.
Three ECG recordings are required during screening (≤14 days prior to Day 1), prior to the 
first dose of study drug intervention Cycle 1 Day 1, and at the EOT visit. Triplicate ECGs 
should be taken about a minute apart within a 5-minute window per time point. A standardized 
ECG machine should be used, and the participant should be examined using the same machine 
throughout the study, when feasible.
The ECG traces will be recorded and reviewed. The Investigator or designated physician will 
review each of the ECGs and may refer the participant to a local cardiologist, if appropriate. If 
an abnormal ECG finding at screening or baseline is considered to be clinically significant by 
the Investigator, it should be reported as a concurrent condition. During the study, clinically 
significant abnormal ECG findings not present at baseline should be reported as AEs (if 
present, the clinical signs and symptoms associated with the abnormal finding should be 
reported as the AE with the ECG abnormality given as explanatory information). For all 
ECGs, details of rhythm, PR, R-R, QRS and QT intervals and an overall evaluation will be 
recorded.
8.2.5
Echocardiogram/MUGA
An echocardiogram or MUGA scan will be conducted on all participants at screening. The 
screening echocardiogram or MUGA scan will not be required if a previous echocardiogram 
or MUGA scan was performed 6 months prior to screening, unless there has been a change in 
the participant’s cardiac status. Additional assessments for echocardiogram or MUGA during 
the study will be determined as clinically indicated based on the current available data.
8.2.6
Concomitant Medications
All concomitant medications and prescribed, over-the-counter, or natural/herbal remedies 
taken or administered 28 days prior to the first dose of AZD4635 through 30 days after the last 
dose of study intervention must be recorded. Concomitant medications (cancer therapy only) 
will also be recorded at the 90-day follow-up and the progression-free survival follow-up 
visits to capture subsequent cancer therapy.
8.2.7
Clinical Safety Laboratory Assessments
See Table 15 for the list of clinical safety laboratory tests to be performed, the screening tests, 
and the treatment arm SoA (Table 1 and Table 2) for the timing and frequency. All 
protocol-required laboratory assessments, as defined in the table, must be conducted in 
accordance with the Laboratory Manual and the SoAs.


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T he I n vesti gat or s h o uld m a ke a n assess me nt of t he a vaila ble res ults wit h re gar d t o cli nicall y 
r ele va nt a b n or malities. T he l a b orat or y res ults s h o ul d be sig ne d a n d date d a n d retai ne d at t he 
st u d y ce ntre as s o urce data f or la b orat or y varia bles.
F or i nf or mat i on o n h o w A Es base d o n l a b orat or y tests s h o uld be rec or de d a n d re p orte d, see 
Secti o n 6. 7 .
Ta ble 1 5
L a b or at or y S afet y V a r i a bles
H ae m at ol o g y
Cli nic al c he mistr y
Hae m o gl o bi n
Al b u mi n
Le u k oc yte
Al kali ne p h os p hatase b
A bs ol ute le u k oc yte differe ntial c o u nt:
A L T b

Ne utr o p hils a
A m ylase c

L y m p h oc ytes a
A S T b

M o n oc ytes
Bicar b o nate H C O 3 d

Bas o p hils
Calci u m, t otal

E osi n o p hils
C hl ori de d
Platelet c o u nt
Creati ni ne cleara nce d,e
C o a g ul ati o n
Ga m ma gl uta m yltra nsferase ( G G T) d
Pr ot hr o m bi n Ti me
Gl uc ose
Or
Lactate de h y dr o ge nase ( L D H)
I nter nati o nal n or malisati o n rati o (I N R) a n d 
acti vate d partial t hr o m b o blasti n ti me (a P T T)
Li pase c
Uri n al ysis
Ma g nesi u m
d
Bilir u bi n, bl o o d, c ol or a n d a p peara nce, gl uc ose, 
ket o nes, p H, pr otei n, a n d s pecific gra vit y
P h os p hate
A d diti o n al Tests
P otassi u m
Pr ostate s pecific a nti ge n ( P S A)
S o di u m
 
T otal bilir u bi n b
T e st oster o ne
T otal pr otei n
C- r eacti ve pr otei n ( C R P)
Ur ea nitr o ge n
Uric aci d
T h yr oi d sti m ulati n g h or m o ne ( T S H) f
Free T 4 f/ Free T 3 f
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a
Ca n be rec or de d as a bs ol ute c o u nts or as perce nta ges.  A bs ol ute c o u nts will be calc ulate d b y Data 
Ma na ge me nt if e ntere d as perce nta ge.  T otal w h ite cell c o u nt t heref ore has t o be pr o vi de d.
b
Te sts f or A LT,  A S T, al kali ne p h os p hatase, a n d t otal bilir u bi n m ust be c o n d ucte d a n d assesse d c o nc urre ntl y. If 
t otal bilir u bi n is ≥ 2 × u p per li mit of n or mal (a n d n o e vi de nce of Gil bert ’s s y n dr o me), t he n fracti onate i nt o 
direct a n d i n direct bilir u bi n.
c
It is prefera ble t hat b ot h a m ylase a n d li pase para meters are assesse d. F or sites w here o nl y 1 of t hese 
para meters is r o uti nel y meas ure d, eit her li pase or a m ylase is acce pta ble.
d
Bicar b o nate ( w here a vaila ble), c h l ori de, creati ni ne cleara nce, ga m ma gl uta m yltra nsferase, ma g nesi u m, 
testi n g are t o be perf or me d at baseli ne, o n Da y 1 ( u nless all scree ni n g la b orat or y cli nical c he mistr y 
assess me nts are perf or me d wit hi n 3 da ys pri or t o Da y 1), a n d if cli nicall y i n dicate d .
e
Creati ni ne cleara nce will be calc ulate d b y data ma na ge me nt usi n g C oc kcr oft -Ga ult ( usi n g act ual b o d y 
wei g ht). 
f
T S H is meas ure d wit hi n 1 4 da ys pri or t o Da y 1 (first i nf usi o n da y), it d oes n ot nee d t o be re peate d at Da y 1. 
Free T 3 or free T 4 will o nl y b e meas ure d if T S H is a b n or mal or if t here is a cli nical s us pici o n of a n A E 
relate d t o t he e n d ocri ne s yste m.
N ote : I n case a partici pa nt s h o ws a n A S T or A L T ≥3 × U L N t o get her wit h t otal bilir u bi n 
≥2 x U L N please refer t o A p pe n di x E ‘Act i ons re q uire d i n cases of  increases i n li ver 
bi oc he mistr y  a n d e valu ati o n of  H y’s La w’, for f urt her i nstr ucti o ns.
8. 2. 8
Ot her Assess me nts
Pr ost ate -s pecific a nti ge n ( P S A) 
Bl o o d sa m ples will  
be c o llecte d f or P S A  
 assess me nt at baseli ne a n d at the start of eac h ne w treat me nt 
c ycle, at t he e n d of st u d y treat me nt, a n d at pr o gressi o n. T he P S A 
 sa m ples will be 
a nal yse d b y a l ocal la b orat or y a n d a ce ntral la b orat or y, res pecti vel y.
Te st oster o ne level m ust be < 5 0 n g/ m L  at t he scree ni n g visit.
C O V I D-1 9 testi n g
D uri n g t he st u d y , C O VI D-1 9 tests m a y be prescri be d, if re q uire d, a n d i n acc or da nce wit h l ocal 
g ui da nce . If a partici pa nt tests p osit i ve, his c o nt i n ue d partici pati o n i n t he st u d y a n d his 
treat me nt wit h t he st u d y dr u gs will be disc usse d with t he Pare xel a n d Astra Ze neca Me dical 
M o ni t ors f or t his st u d y.
8. 2. 9
Cli nic al O utc o me Assess me nts
A Cli nical O utc o m e Assess me nt ( C O A) is a n y assess me nt t hat ma y be i nfl ue nce d b y  hu ma n 
c h o ices, j u d ge me nt, or m oti vati on a n d ma y s u p p ort eit her direct or i n direct e vi de nce of 
treat me nt be nefit. Patie nt Re p orte d O utc o mes ( P R Os) is o ne of t he t y pes o f C O As.
P R Os, a n u m brella ter m referri n g t o all o utc o mes a n d s y m pt o ms, a re directl y re p orte d b y t he 
parti ci pa nt. P R Os ha ve bec o me a si g nifica nt e n d p oi nt w he n e val uati n g effect i ve ness of 
treat me nts i n cli nical trials.  
T he f o ll owi n g P R O i nstr u m e nts will be a d mi nistere d f or a nal ysis of t he P R O e n d p oi nts at  t he 
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start of eac h visit, as per t he Sc he d ule of Act i vities ( Secti o n 1. 3 ): B PI-S F a n d F A C T -P.  Eac h is 
descri be d bel o w .
B rief P ai n I n ve nt or y – S h ort F or m
Wo rst pai n, a verage pai n a n d pai n ’s i nterfere nce with dail y life will be assesse d d uri n g t he 
st u d y int er ve ntio n usi n g t he ( Brief Pai n I n ve nt or y – S h ort F or m) B PI -S F (see A p pe n di x J) at 
t he ti mes o utli ne d i n t he sc he d ule of assess me nts. T he B PI -S F c o m prises a t otal  of 1 5 ite ms 
meas uri n g 2 d o mai ns: pai n se verit y a n d pai n i nterfere nce. Ite ms meas uri n g pai n se verit y 
(incl u di n g ‘w orst pai n ’) are rate d o n a n 1 1 -p oi nt n u meric rati n g scale ( N R S ) [ra n gi n g fr om 
0 = N o  pai n t o 1 0 = Pai n as ba d as y o u ca n i ma gi ne. All B PI -S F i te ms are meas ure d usi n g a 
2 4- h o ur recall peri o d.
F A C T -P
T he F A C T -P was de vel o pe d t o meas ure heal t h r elate d q ualit y of  life (H R Q L ) i n me n wit h 
pr ostate ca ncer ( Es per et al. 1 9 9 7 , Cella et al 1 9 9 3 ). It c o nsists of 4 s u bscales ( p h ysical, 
e moti o nal , f u n ctio nal a n d s oci al/fa mil y well-bei n g) pl us a 1 2 -ite m pr ostate-s pecific m o d ule, 
t he Pr ostate Ca ncer S y m pt o ms ( P C S) s u bscale, w hic h hi g hli g h ts c o ncer ns s pecific t o 
parti ci pa nt s wit h pr ostate ca ncer (see A p pe n di x K ).
I n a d diti on, t he FA C T -P als o s u p p orts t he calc ulat i o n of a trial o ut c o me in de x ( T OI ) sc ore (t he 
s u m of t he p h ysical well bei n g [ P W B ], f unct i onal well bei n g [ F W B ] a n d P C S sc ores), F A C T 
A d va nce d Pr ostate S y m pt o m I n de x -6 [ FA P SI -6], a s y m pt o m  sc ore ma de u p of 6 it e ms fr o m 
wi t hi n t he FA C T -P ( pai n [ n = 3], fat i g ue [ n = 1], wei g ht l oss [ n = 1], a n d c o ncer ns a b o ut t he 
c o n ditio n getti n g w orse [ n = 1]) a n d t he F A C T A d va nce d Pr ostate S y m pt o m I n de x - 8 
[F A P SI - 8], a s y m pt o m sc ore ma de u p of 8 ite ms fr o m wit hi n t he FA C T -P ( pai n [ n = 3], fat i g ue 
[ n = 1], wei g ht l oss [ n = 1], uri nar y  c o n ditio ns [ n = 2], a n d c o ncer ns a b o ut t he c o n dit i on 
getti n g w orse [ n = 1]).
 
 
 
8. 2. 1 0
F oll o w -u p Visits
8. 2. 1 0. 1
3 0- d a y a n d 9 0- d a y F oll o w -u p Visits
A safety f oll ow -u p visi t will be perf or me d a p pr o xi matel y 3 0 ( ± 7) da y s a n d 9 0 ( ± 7) da y s after 
t he st u d y int er ve nt i on(s) are per ma ne nt l y disc o nti n ue d. T he pri mar y p ur p ose of t he f oll ow- u p 
visit s is t o assess a n y A Es o n g oi n g at t he ti me of st u d y int er ve nt i on disc o nt i n uati on a n d t o 
assess a n y ne w A Es t hat ma y ha ve occ urre d si nce disc o nti n uati on. I n a d diti on, a n y ne w 
me dicat i ons will be rec or de d. T his i nf or mati o n ca n be c ollecte d b y  p h o ne. A n y A E, S A E, or 
a b n or mal la b orat or y fi n di n gs that are o n g oi n g at t he ti me of st u d y  int er ve nt i on 
di sc o nti n uati on, or a n y  ne w e ve nts wit hi n 3 0 or 9 0 da ys of last st u d y int er ve nt i on u nless 
C CI


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otherwise indicated in the protocol, must be followed up to resolution or until the event 
becomes stable (or returns to baseline) or is unlikely to resolve further in the opinion of the 
Investigator.
8.2.10.2
Progression-free Follow-up Visits
Participants who discontinue study intervention prior to the occurrence of objective PD will be 
followed with PSA samples and CT/MRI/positron emission tomography (PET) scans and
bone scans, and COAs (BPI-SF and FACT-P) every 12 weeks (±1 week) from the last date of 
the last tumour response assessment until either: objective PD has been confirmed, withdrawal 
of consent, until the primary DCO for the arm, or until the study is terminated by the Sponsor.
8.2.10.3
Survival Follow-Up
Participants will be followed every 3 months after the last dose of study intervention for 
survival and subsequent cancer therapy until the final DCO for the relevant arm. The survival 
follow-up can be done by a medical record review or telephone call at the Investigator’s 
discretion.
Note: when required survival calls will be made in the week following the date of DCO for 
the analysis, and if participants are confirmed to be alive or if the death date is after the DCO 
date these participants will be censored at the date of DCO. When required the status of 
ongoing, withdrawn (from the study) and “lost to follow-up” participants at the time of the OS 
analysis should be obtained by the site personnel by checking the participant’s notes, hospital 
records, contacting the participant’s general practitioner and checking publicly-available death 
registries. In the event that the participant has actively withdrawn consent to the processing of 
their personal data, the vital status of the participant can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.
8.3
Adverse Events and Serious Adverse Events
The Principal Investigator (PI) 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.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events, including SAEs, will be collected from time of signature of ICF throughout 
the treatment period and including the 30-day and 90-day follow-up period.


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If the Investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant
treated by him or her, the Investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs/non-serious AEs/AEs of special interest 
(AESIs) (as defined in Appendix B), will be followed until resolution, stabilisation, the event 
is otherwise explained, or the participant is lost to follow-up.
Any AEs that are unresolved at the participant’s last AE assessment or visit in the study will 
be followed up by the Investigator for as long as medically indicated, but without further 
recording in the CRF. AstraZeneca retains the right to request additional information for any 
participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

AE (verbatim)

The dates when the AE started and stopped

CTCAE, Version 5.0 grade/maximum CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Action taken with regard to IP(s)

Action taken with regard to procedure or concomitant medication

Outcome

Does the Investigator consider this AE an imAE?
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death


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
Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment in relation to other medication
8.3.3
Causality Collection
In this protocol the investigational products are AZD4635, durvalumab and cabazitaxel. The 
Investigator should assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSR.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (CSR). 
Deterioration as compared to baseline in protocol mandated laboratory tests and vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the 
reason for discontinuation of treatment with the investigational product or are considered to be 
clinically relevant as judged by the Investigator (which may include but are not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, e.g., dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator


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uses the clinical, rather than the laboratory term (e.g., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with 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.
8.3.7
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression should not be reported as AEs during the study.
8.3.8
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., 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 the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events 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 


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within one calendar day i.e., immediately but no later than 24 hours of when they become 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
Investigators or other site personnel send relevant CRF modules by fax to the designated 
AstraZeneca representative.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug, and the label such as EU SmPC, USPI or other local label for the active comparator 
product (including any AstraZeneca comparator.). 
8.3.9
Pregnancy
Conception must be avoided during paternal exposure to AZD4635. If a pregnancy in the 
female partner of a participant is reported, the Investigator or other site personnel must inform 
the appropriate AstraZeneca representatives within 1 day i.e., immediately but no later than 
24 hours of when they become aware of it (i.e., within 24 hours of learning of the pregnancy).
Exception to this is if the pregnancy is discovered before the study participant has received 
any study drug. Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.9.1
Paternal Exposure 
Information on the pregnancy of a participant’s partner must be obtained directly from the 
participant’s partner. Therefore, prior to obtaining information on the pregnancy, the 
Investigator must obtain the consent of the participant’s partner.
Pregnancy of a participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring any time from the first date of dosing for 
AZD4635, durvalumab and cabazitaxel until 3 months (Arm A) or 6 months (Arm B) after the 
last dose of the study drugs should, if possible, be followed up and documented until 30 days 
after birth. As deemed appropriate, the pregnancies will be followed up per local guidance and 
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Participants should use condoms in conjunction with spermicides with female partners during 
the study and for 12 weeks (3 months) after the last dose of AZD4635 and/or durvalumab and 
for 24 weeks (6 months) after the last dose of cabazitaxel, and refrain from donating sperm 
from the start of dosing until 24 weeks (6 months) after discontinuing study treatment. If not 
done previously, storage of sperm prior to receiving AZD4635 will be advised to male 
participants with a desire to have children. 
It is not currently known whether AZD4635 affects fertility in humans.
AstraZeneca should be notified of any pregnancy that occurs in partners of participants during 
participation in studies of AZD4635.
Participants in Arm B will be advised on storage of sperm prior to receiving cabazitaxel due to 
the possibility of irreversible infertility/testicular damage due to cabazitaxel therapy.
When the eCRF module is used include the following: The PREGREP module in the eCRF is 
used to report the pregnancy and the PREGOUT is used to report the outcome of the 
pregnancy.
8.3.10
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., 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 1 (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 medication error (see Section 8.3.10) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
8.4
Overdose
If associated with an AE, any dose in excess of the dose specified according to the protocol 
will constitute an overdose. There is currently no known antidote to AZD4635, and the 
treatment of overdose should be supportive for the underlying symptoms. For durvalumab and 
cabazitaxel please refer to Section 6.5.4.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.


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If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when they become 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 overdoses associated with an SAE (see section 8.3.8) and within 30 days 
for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report 
finalisation or six months after issuance of the draft Bioanalytical Report (whichever is 
earlier), unless consented for future analyses.

Pharmacokinetic (PK) samples may be disposed of or anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic 
samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR.

Remaining anti-drug antibody sample aliquots will be retained at AstraZeneca or its 
designee for a maximum of 15 years following issue of the CSR. Additional use includes 
but is not limited to further characterisation of any anti-drug antibodies, confirmation 
and/or requalification of the assay as well as additional assay development work. The 
results from future analysis will not be reported in the CSR.
8.5.1
Pharmacokinetics
This section describes the schedule for collection of samples for AZD4635 and cabazitaxel PK 
assessments. The schedule for collection of PK samples for durvalumab is described along 
with the collection of anti-drug antibody samples in Section 8.5.2.
Venous blood samples (2 mL) each for AZD4635 and cabazitaxel will be collected for 
analyses of AZD4635 and its metabolites and cabazitaxel plasma concentration.
Sparse PK samples for AZD4635 will be collected from Arm A participants according to 


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Table 16. Up to approximately the first 12 evaluable Arm B participants will have additional 
PK samples for AZD4635 collected during Cycle 1 Day 1 and Day 2 according to Table 17. 
Subsequent participants entering the study will have the sparse PK schedule according to 
Table 18. The same 12 evaluable Arm B participants will have cabazitaxel PK samples 
according to Table 19.
Pre-infusion samples can be collected any time (on the same day) prior to dosing. All 
post-dose PK samples will be collected at the specified time ± 5 min for the 0.5 hour time 
point, ± 10 min for the 1 and 1.5 hour time points and within ± 10% of the nominal time for 
later time points (e.g. ± 12 min for a 2 hour sample) to be protocol compliant. The timing of 
the PK samples may be adjusted during the study, dependent on emerging data, in order to 
ensure appropriate characterisation of the plasma concentration-time profiles.
If a participant misses any doses of study drug within 3 days prior to PK sampling, please 
contact the primary study contact as to any effect of the required changes on the timing of the 
PK assessments. All other assessments should continue to be performed as per study plan, 
relative to baseline assessments.
Table 16
Arm A AZD4635 Sparse PK Sampling Schedule
Cycles
Day
Collection Time
1, 3, 5, 7
1
Pre-dose
Table 17
Arm B AZD4635 PK Sampling Schedule (First 12
evaluable 
participants)
Cycle
Day 
Collection Time
1
1
Pre-dose (and pre-infusion durvalumab)
30 minutes post-dose
1 hour post-dose
2 hours post-dose
4 hour post-dose
6 hours post-dose
8 hour post-dose
2
24 hours post-dose
2, 3, 5 7
1
Pre-dose
Table 18
Arm B AZD4635 Sparse PK Sampling Schedule (All Participants)
Cycle 
Day
Collection Time
1, 3, 5, 7
1
Pre-dose


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Table 19
Arm B Cabazitaxel PK Sampling Schedule (First 12 Evaluable
Participants)
Cycle
Day
Collection Time
1
Pre-dose (and pre-infusion durvalumab)
5 minutes before the end of infusion
30 minutes post-dose
1 hour post-dose
2 hours post-dose
4 hour post-dose
6 hours post-dose
8 hour post-dose
2
24-hours post-dose
Note: The first 12 evaluable participants in Arm B will have cabazitaxel PK samples collected only during Cycle 
1.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration (AZD4635 and metabolites, and cabazitaxel)
in plasma will be assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, 
using an appropriately validated bioanalytical method. Full details of the analytical method 
used will be described in a separate bioanalytical report.
8.5.2
Immunogenicity Assessments
Collection of durvalumab pharmacokinetic and anti-drug antibody samples
Venous blood samples for determination of concentrations of durvalumab (3.5 mL) and 
anti-drug antibodies (5 mL) in serum will be taken at the times presented in Table 20 below:
Table 20
Durvalumab PK and Anti-Drug Antibody Sampling Times
Cycle/Day
PK Sample Collection Time
Anti-drug Antibody Sample Collection Time
Cycle 1 Day 1
Pre-infusion and end of infusion
Pre-infusion
Cycle 2 Day 1
Pre-infusion
Pre-infusion
Cycle 4 Day 1
Pre-infusion and end of infusion
Pre-infusion
Cycle 7 Day 1
Pre-infusion
Pre-infusion
Follow-up Visit
90 days post last dose
90 days post last dose
Samples for determination of durvalumab concentration in serum will be analysed by a 
designated third party on behalf of AstraZeneca. Samples will be collected, labelled, 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.


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 1 of 1 9 3
All d ur val u ma b P K sa m ples nee d t o be c ollecte d wit hi n 1 0 % of t he n o mi nal t i me 
( e. g., ± 6 mi n utes f or a 6 0 -mi n ute sa m ple) t o be pr ot oc ol c o m p lia nt. T he ti mi n g of t he P K a n d 
a nt i-dr u g a nt i b o d y sa m ples ma y b e a djuste d d uri n g t he st u d y, de pe n de nt o n e mer gi n g data, i n 
or der t o e ns ure a p pr o priate c haracterisat i on of t he plas ma c o nce ntrati o n -time pr ofiles.
Bl o o d sa m pl es f or deter mi nat i on of a nti-dr u g a nt i b o d y i n s er u m will be assa ye d b y 
bi oa nal yt ical test sites o perate d b y or o n be half of Astra Ze neca, usi n g a n a p pr o priatel y 
vali date d bi oa nal y tical met h o d. F ull details of t he met h o ds use d will be descri be d i n a se parate 
re p ort.
A nt i-dr u g a nt i b o d y sa m ples ma y als o be f urt her teste d f or c haracterisat i on of t he a nti-dr u g 
a nt i b o d y res p o nse.
S a m ples will  be c ollecte d, la belle d, st ore d, a n d s hi p pe d as detaile d i n t he La b orat or y Ma n ual.
8. 5. 3
P h ar m ac o d y n a mics
P har mac o d y na mic bi o mar kers are detaile d i n Sect i o n 8. 6 .
8. 6
H u m a n  Bi ol o gic al S a m ple Bi o m ar kers
Ma n dat or y  c ollecti on of sa m ples f or bi o mar ker researc h is a part of t his st u d y. T he f o ll owi n g 
sa m ples f or bi omar ker researc h are re q uire d a n d will be c o llecte d fr om all part ici pa nts i n t his 
st u d y as s pecifie d i n t he S o A (Ta ble 1 a n d Ta ble 2 ).
 
 
 
 
 
 
 
8. 6. 1. 2
C ollecti o n of Pl as m a S a m ples f or Circ ul ati n g T u m o ur D N A
 
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 2 of 1 9 3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 3 of 1 9 3
8. 7
 
 
 
 
 
 
 
 
 
8. 8
He alt h Ec o n o mic s
Heal t h Ec o n o mics para meters are n ot e val uate d i n t his st u d y.
C CI
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 0 4 of 1 9 3
9
S T A TI S TI C A L C O N SI D E R A TI O N S
9. 1
St atistic al H y p ot heses
T he st u d y  is n o n-c o m parati ve s o t here will be n o f or mal statist ical h y p ot heses. T he a nal ysis 
f or t he st u d y will be descri pti ve.
9. 2
S a m ple Size Deter mi n ati o n
As of N o ve m ber 2 0 2 0, t he S p o ns or st o p pe d e nr ol me nt i n Arm A  foll o wi n g decisi o n s at t he 
pr o gra m le vel .
F or Ar m B, a p pr o xi matel y 8 0 parti ci pa nts will be all ocate d t o A Z D 4 6 3 5 pl us d ur val u ma b pl us 
ca bazita xel at t he rec o m me n de d P hase 2 d ose ( R P 2 D).
T he pri mar y  efficac y e n d p oi nt is r P F S. 
 
 
 
 
 
 
 
 
 
Ei g ht y partici pa nts per ar m  will pr o vi de a n esti mate of t he me dia n P F S. C o nfi de nce i nter vals 
( CI) will be c o nstr ucte d ar o u n d t he me dia n P F S, t o e na ble decisi ons t o be ma de a b o ut t he 
li kel y s uccess of f ut ure st u dies i n t his p o p ulat i on. 
A f utility i nteri m a nal ysis will be carrie d o ut as descri be d i n Sect i on 9. 5 .
9. 3
P o p ul ati o ns f or A n al yses
F or p ur p oses of a nal ysis, t he f oll owi n g p o p ul at i ons are defi ne d:
C CI
C CI


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Table 21
Populations for Analysis
Population/Analysis set
Description
Evaluable for efficacy
Dosed participants with a baseline tumour assessment.
Tumour response
Dosed participants with a baseline tumour assessment, and measurable 
disease at baseline.
Safety analysis set
All participants who received at least 1 dose of study drug
PSA evaluable
Dosed participants with an abnormal baseline PSA (≥1ng/mL) 
Pharmacokinetics
Dosed participants for whom an adequate PK profile has been obtained
9.4
Statistical Analyses
Analyses will be performed by Parexel under the direction of the Oncology Biometrics, 
AstraZeneca. A comprehensive statistical analysis plan will be developed and finalised before 
database lock and will describe the participant 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.
9.4.1
General Considerations
The main aims of the study are to assess the efficacy, safety, and tolerability of multiple study 
drugs in participants with prostate cancer. The two arms (Arm A and Arm B) will be analysed 
separately. Following the decision to stop enrolment in Arm A, data from Arm A will be listed 
only because the number of enrolled participants will be too small for a meaningful analysis.
The analysis for Arm B will be descriptive, including summaries from the Kaplan-Meier 
curve.
If relevant for the study, the following will be included due to the COVID-19 pandemic: 
participants affected by the COVID-19 pandemic will be listed including category for study 
disruption due to the pandemic and details of the disruption. If required, the study disruptions 
due to the pandemic will also be summarised. Participant disposition will be summarised 
including number (%) of participants who discontinued treatment due to the pandemic and 
who withdrew from study due to the pandemic. Important protocol deviations will be 
summarised including number (%) of participants with at least one important protocol 
deviation related to the pandemic.
9.4.1.1
Primary Endpoint
The primary efficacy endpoint is rPFS defined as the time from first dose until radiographic 
progression as assessed by the Investigator per RECIST v1.1 (soft tissue) and PCWG3 (bone) 
or death from any cause, whichever comes first.


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9.4.1.2
Secondary Endpoints
Secondary endpoints include: safety, OS, ORR, DoR, PSA50 response, time to pain 
progression, and PK. The analysis will be descriptive and summaries will be presented for 
Arm B. Data from Arm A will be listed only.
The primary endpoint (ie, rPFS) will be summarised by ADO signalling gene expression in 
high and low subgroups in Arm B.
9.4.2
Efficacy
Radiological progression-free survival (rPFS)
Progression-free survival is defined as the time interval from the first dose of AZD4635 until 
the date of objective disease progression or death (by any cause in the absence of progression) 
regardless of whether the participant withdraws from treatment or receives another anti-cancer 
therapy prior to progression. Participants who have not progressed (defined as CR, PR or SD 
by RECIST v1.1 for soft tissue disease, or non-PD for bone disease) at the time of analysis 
will be censored at the time of the last evaluable RECIST v1.1 assessment or bone scan.
However, if the participant progresses or dies after 2 or more missed radiologic visits the 
participant will be censored at the time of the last evaluable RECIST v1.1 or bone scan 
assessment prior to the 2 missed visits. If a participant has an assessment for soft tissue 
disease (MRI/CT) but not for bone disease (bone scan), or vice versa, then this will count as a 
missed assessment. If the participant has no evaluable post-baseline RECIST v1.1 or bone 
scan assessments they will be censored at Day 1 unless they die within 2 visits of baseline (in 
which case their date of death will be used). 
Progression-free survival will be derived based on scan/assessment dates not the scheduled 
visit dates. If RECIST v1.1 assessments/bone scans contributing toward a particular visit are 
performed on different dates then the date of progression will be determined based on the 
earliest of the dates of the component that triggered the progression. With regard to censoring, 
a participant will be censored at the latest of the dates contributing to a particular overall visit 
assessment. Summaries (number of events, medians, proportion and 95% CI for progression 
free at fixed time points using the Kaplan-Meier estimate) and Kaplan-Meier plots will be 
provided. A 2-sided 95% CI for the median PFS will be produced in addition to the 25th and 
75th percentiles.
Overall survival (OS)
Overall survival is defined as the time from the date of first dose until death due to any cause 
regardless of whether the participant withdraws from study therapy or receives another anti-
cancer therapy. Any participant not known to have died at the time of analysis will be 
censored based on the last recorded date on which the participant was known to be alive.


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Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if participants are confirmed to be alive or if the death date is after the DCO date these 
participants will be censored at the date of DCO.
Overall survival will be analysed in the same manner as PFS if the number of participants 
with events allows.
Tumour response
Tumour response data will be summarised for dosed participants with measurable disease at 
baseline, and separately for dosed participants with measurable or non-measurable disease at 
baseline.
Tumour response data will be listed using the following response categories: CR, PR, SD, 
Non-CR/Non-PD, PD, and not evaluable (NE).
For the secondary endpoint ORR assessed by RECIST 1.1 and PCWG3, only dosed 
participants with measurable disease (target lesions) at baseline will be included in the 
analysis. A responder will be any participant with a confirmed  response of PR or CR in their 
soft tissue disease assessed by RECIST 1.1, in the absence of progression on bone scan 
assessed by PCWG3. A participant will be classified as a responder if the RECIST 1.1 criteria 
for a CR or PR are satisfied (as well as the absence of confirmed progression on bone scan 
assessed by PCWG3).
Best objective response and confirmed ORR will be summarised. The BOR table will be 
presented for the evaluable for efficacy analysis set and separately for the tumour response 
analysis set. The tumour analysis set will be used for ORR. The proportion of participants 
achieving an confirmed objective response (CR or PR) will be presented with a two-sided 
95% CI using the Clopper-Pearson method (Clopper C and Pearson E 1934). Percentage 
change from baseline in tumour size will be determined for participants with measurable 
disease at baseline and is derived at each visit by the percentage change in the sum of the 
diameters of TLs.
Waterfall plots (bar plots), and spider plots (individual line plots of percent change from 
baseline over time) indicating the percentage change from baseline in sum of the diameters of 
TLs will be produced. Specifically, these plots will be based on the sum of diameters as 
entered in the database, including no adjustment as a function of tumour response in the case 
of participants with lymph node regression.
Duration of response will be defined as the time from the date of first documented response 
(which is subsequently confirmed using RECIST v1.1) until date of documented progression 
or death in the absence of disease progression. The end of response should coincide with the 
date of progression or death from any cause used for the PFS endpoint. The time of the initial 


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res p o nse will be defi ne d as t he latest of t he dates c o ntri b ut i n g t o war ds t he first visit t hat was 
P R or C R t hat was s u bse q ue nt l y c o nfir me d.
D urati o n of  res p o nse will be a nal yse d i n t he sa me ma n ner as P F S if t he n u m ber of parti ci pa nt s 
wi t h D O R all o ws. I n a d diti on, S wi m mer pl ots will be pr o d uce d.
If a parti ci pa nt d oes n ot pr o gress f o ll owi n g a res p o nse, t he n t heir d urati o n of res p o nse will use 
t he P F S ce ns ori n g date as t he date at w hic h t hat partici pa nt is ce ns ore d f or D o R.
 
P S A res p o nse
P S A 5 0 res p o nse is defi ne d as t he pr o p orti o n of partici pa nts ac hie vi n g a ≥5 0 % decrease i n P S A 
fr om baseli ne t o t he l o west p ost -baseli ne P S A, c o nfir me d b y a c o nsec ut i ve P S A at least 
3 wee ks later . I g n ore earl y rises ( bef ore 1 2 wee ks) i n deter mi ni n g P S A res p o nse.

A partici pa nt will be re gar de d as ha vi n g a si n gle P S A visit res p o nse if t heir P S A le vel at 
a n y p ost -d ose visit is re d uce d b y 5 0 % or m ore c o m pare d wit h baseli ne

A pa rtici pa nt will be re gar de d as ha vi n g a c o nfir me d P S A res p o nse if t he y ha ve a 
re d uctio n i n P S A le vel of 5 0 % or m ore c o m pare d wit h baseli ne t hat is c o nfir me d at t he 
ne xt assess me nt at least 3 wee ks later (i.e., decrease relati ve t o baseli ne of at least 5 0 % 
d oc u m e nte d o n 2 c o nsec ut i ve occasi o ns at least 3 wee ks a part).
P S A pr o gressi o n
If t here is a P S A decli ne fr om baseli ne, pr o gressi o n is defi ne d as t he date of t he first P S A  
i ncrease t hat is b ot h ≥2 5 % a n d ≥2 n g/ m L  a b o ve t he na dir a n d w hic h is c o nfir me d b y a 
sec o n d val ue ≥3 wee ks later, e ve n if wit hi n 1 2 wee ks.
If t here is n o P S A decli ne fr om baseli ne, pr o gressi o n is defi ne d as a ≥2 5 % i ncrease a n d 
≥2 n g/ m L  increase fr o m baseli ne be y o n d 1 2 wee ks.
T he pr o p orti o n of  p artici pa nts ac hie vi n g a P S A res p o nse a nd partici p a nts wi t h a c o nfir me d 
P S A  res p o nse will be prese nte d wit h 9 5% CI. T he best P S A  perce nta ge c ha n ge fr om baseli ne 
a n d t he perce nt c ha n ge fr o m baseli ne i n P S A le vels at 1 2 wee ks will be s u m marise d a n d 
gra p he d. Wa t erfall plots ( bar pl ots), a n d s pi der pl ots (i n di vi d ual li ne pl ots of perce nt c ha n ge 
fr om baseli ne o ver ti me) will be pr o d uce d.
P atie nt Re p orte d O utc o mes
F or a nal ysis of t he P R O e n d p o i nts, B PI-S F, F A C T -P, t he f o ll owi n g a nal ysis will be 
perf or m e d a n d will be re p orte d i n t he C S R .
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Summary statistics for mean score, standard deviation, median and range will be presented by
treatment group for visits until there are less than one third of participants with evaluable data.
The proportion of participant with best responses of ‘Improved’, ‘No Change’ and 
“Worsened” will be presented with a two-sided 95% CI using the Clopper-Pearson Method 
(Clopper C and Pearson E 1934).
Time to deterioration will be assessed using the same methods as for the primary analysis. 
Kaplan-Meier plots will be presented for each treatment arm.
In addition the time to deterioration for the subscales of the FACT-P (TOI, FAPSI-6, PCS and
FWB) will be presented.
9.4.3
Safety
Safety data will not be formally analyzed but appropriate summaries for safety data will be 
produced, as defined below. All participants who received at least 1 dose of study drug will be 
included in the assessment of the safety profile (safety analysis set). 
Data from all cycles of initial treatment will be presented as described in the Statistical 
Analysis Plan. Adverse events will be listed individually by participant and dose group. For 
participants who have a dose modification, all AEs (due to drug or otherwise) will be assigned 
to the initial dose group. The number of participants experiencing each AE will be 
summarised by the Medical Dictionary for Regulatory Activities (MedDRA) system organ 
class, MedDRA preferred term, and CTCAE grade. The number and percentage of participants 
with AEs in different categories (e.g., causally related, CTCAE Grade ≥3, etc.) will be 
summarised by dose group, and events in each category will be further summarised by 
MedDRA system organ class and preferred term, by dose group. Serious AEs will be 
summarised separately if a sufficient number occur.
Any AE occurring before the first dose of IP (i.e., before study Day 1) will be included in the 
data listings, but will not be included in the summary tables of AEs.
Any AE occurring within the defined follow-up period after discontinuation of IP will be 
included in the AE summaries. Any AEs in this period that occur after a participant has 
received further therapy for cancer (following discontinuation of IP) will be flagged in the 
data listings. Adverse events occurring after the 30-day follow-up period after discontinuation 
of IP will be listed separately, but not included in the summaries.
Haematology, clinical chemistry, vital signs, ECG data, ECHO/MUGA, demographic data, 
medical histories, and concomitant medications will be listed individually by participant and 
suitably summarised. For all laboratory variables, which are included in the current version of 
CTCAE, the CTCAE grade will be calculated. Summary statistics of mean, median, standard 
deviation, minimum, maximum and number of observations will be used.


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Details o f a n y deat hs will be liste d f or all part ici pa nts.
9. 4. 4
Ot her A n al yses
 
9. 4. 4. 1
P h ar m ac o ki netic A n al ysis
P har mac o ki net ic a nal ysis of t he plas ma c o nce ntrati o n data f or A Z D 4 6 3 5 a n d its meta b o lite(s), 
a n d ca bazita xel , will be deter mi ne d b y  C o va nce o n be half of t he Cli nical P har mac o ki netic 
Allia nce, Astra Ze neca R & D. T he act ual sa m pli n g ti mes will be use d i n t he para meter 
calc ulat i ons a n d P K para meters will be deri ve d usi n g sta n dar d n o n- c o m part me nt al met h o ds i n
P h oe ni x ® W i n N o nli n ® Versio n  8. 1 or hig her. D ur val u ma b P K para meters deri vat i on is n ot 
pl a n ne d d ue t o a s parse sa m ple c ollecti on sc he d ule. D ur val u ma b pre d ose a n d e n d of i nf usi o n 
c o nce ntrati o ns will be s u m maris e d o nl y.
W here p ossi ble t he f o ll owi n g si n gle d o se P K para meters will be deter mi ne d f or A Z D 4 6 3 5 , its 
meta b o lites ( S S P -0 0 5 1 7 3 a n d S S P -0 0 5 1 7 4) a n d ca bazita xel.

Ma xi m u m o bser ve d plas ma c o nce ntrati o n ( C
ma x) a n d ti me t o Cma x (tma x )

Ti me o f t he last meas ura ble c o nce ntrati o n (t last)

Ter mi nal eli mi nat i on rate c o nsta nt ( λz)

Ter mi nal half -life (t 1/ 2 λz)

Area u n der t he plas ma c o nce ntrati o n ti me c ur ve fr o m zer o t o 2 4 h o urs [ A U C ( 0-2 4)], fr o m 
zer o t o 8 h o urs [ A U C ( 0-8)], fr om zer o t o t he ti me of t he last meas ura ble c o nce ntrati o n 
( A U Clast), a n d fr o m zer o e xtra p olate d t o i nfi nity ( A U C i nf).

A p pare nt plas ma cleara nce ( C L/ F f or A Z D 4 6 3 5, C L f or ca bazita xel)

A p pare nt v ol u me o f di stri b uti on d uri n g t he ter mi nal p hase ( Vz/ F f or A Z D 4 6 3 5, Vz f or 
ca bazita xel)

Mea n resi de nce ti me ( M R T)
C ma x, tma x , a n d tlast will be deter mi ne d directl y b y i ns pecti on of t he c o nce ntrati o n -ti me pr ofiles.
W here p ossi ble, λ z will be calc ulate d b y lo g -li near re gressi o n of t he ter mi nal p orti o n of t he 
c o nce ntrati o n-ti me pr ofiles w here t here are s ufficie nt data a n d t ½ λz will be calc ulate d as l n 
2/ λ z. A U C ( 0-8), A U C ( 0-2 4), a n d A U C last will be calc ul ate d usi n g t he li near u p/l o g d o w n 
tra pez oidal r ul e. W here a p pr o priate, A U C last will be e xtra p ol ate d t o i nfi nit y usi n g λ z t o o btai n 
A U C i nf. C L/ F a n d C L will be deter mi ne d as t he rati o of d ose/ A U C i nf. Vz/ F a n d Vz will be
deter mi ne d fr o m t he ratio of  C L/ F or C L t o λz.
A d dit i onal P K para meters, i ncl u di n g para meters f or A Z D 4 6 3 5 meta b o lites, ma y be 
C CI


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deter mi ne d w here a p pr o priate .
 
9. 5
I nteri m A n al yses
Gi ve n t he li mite d data a vaila ble wit h t he tri pl et c o m bi nat i on, a f utility i nteri m a nal ysis is 
pl a n ne d f or Ar m B base d o n P S A 5 0 res p o nse a n d will be tri g gere d acc or di n g t o t he f oll owi n g:
after a p pr o xi matel y n = 3 0 d ose d pa rtici pa nts f or t he ar m ha ve ha d t he o p p ort u nit y f or sa mple 
c ollect i on f or P S A res p o nse at t he start of We e k 1 3 . It will be base d o n a deci sio n  fra me w or k 
(Fre wer et al. 2 0 1 6 ) usi n g pre di ct i ve pr o ba bility of a g o o d si g nal bei n g o bser ve d at t he fi nal 
a nal ysis. F urt her details will be pr o vi de d i n t he S A P . Ot her data a vaila ble at t he ti me will als o 
be c o nsi dere d. T his is pla n ne d f or t he assess me nt of f ut ility,  s uc h t hat f urt her recr uit me nt i nt o 
t he ar m ma y be st o p pe d. H o we ver, partici pa nts alrea d y recr uite d w o ul d c o nti n ue t o be 
f oll owe d. Parti ci pa nt recr uit me nt will be pa use d d uri n g t he ti me of t he i nteri m a nal ysis o nce
t he n u m ber of d ose d partici pa nts i n Ar m B reac hes a p pr o xi matel y 3 5 t o e ns ure 3 0 e val ua ble 
parti ci pa nts f or t he P S A 5 0 res p o nse. Of t hese part ici pa nts, a p pr o xi matel y 1 5 partici pa nts are t o 
ha ve R E CI S T v 1. 1 meas ura ble disease at baseli ne a n d t he re mai n der of t he partici pa nts ma y 
ha ve b o ne -o nl y  disease or meas ura ble disease.
9. 6
D at a M o nit ori n g C o m mittee
Data m o ni t ori n g c o m mittee will n ot be use d.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organisations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator 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 amendments to the 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 participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators.

For all studies except those utilizing 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.

An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [Investigator’s Brochure or state other documents] and will 
notify the IRB/IEC, if appropriate according to local requirements.


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A 2
Fi n a nci al Discl os ure
In vest i gat ors a n d s u b-I n vesti gat ors will pr o vi de t he s p o ns or wit h s ufficie nt, acc urate fi na ncial 
i nf or mat i on as re q ueste d t o all o w t he s p o ns or t o s u b mit c o m pl ete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ulat or y  a ut h orities. I n vestigat ors 
are res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
a n d f or 1 year after c o mpleti o n of  t he st u d y.
A 3
I nfor me d C o nse nt Pr ocess
T he I n vesti gat or or his re prese ntati ve will e x plai n t he nat ure of t he st u d y  t o t he partici pa nt or 
his le gall y  a ut h orize d re prese ntati ve a n d a ns wer all q uest i ons re gar di n g t he st u d y .
P arti cipa nt s m ust be i nf or me d t hat t heir parti ci pat i o n is v ol unt ar y. Partici pa nt s or t heir le gall y 
a ut h orize d re prese ntati ve will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat meets 
t he re q uire me nts of 2 1 C F R 5 0 , lo c al  re g ulat i ons, I C H g ui deli nes, Heal t h I ns ura nce P orta bility 
a n d Acc o u nta bilit y Act ( HI P A A) re q uire me nts, w here a p plica ble, a n d t he I R B/I E C or st u d y 
ce nter.
T he m e dical rec or d must i ncl u de a state m e nt t hat writte n i nf or me d c o nse nt was o btai ne d 
bef ore t he partici pa nt was e nr olle d i n t he st u d y  a n d t he date t he writte n c o nse nt was o btai ne d.
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.
P arti cipa nt s m ust be re-c o nse nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
parti ci pat i on i n t he st u d y.
A c o p y  of t he I C F(s) must be pr o vi de d t o t he pa rtici pa nt le gall y a ut h orize d re prese ntati ve.
 
 
If a parti ci pa nt ’s part ner bec ome s pre g na nt d uri n g or wit hi n 3 m o nt hs ( or as i n dicates i n 
m o d ule -s pecific) after t he st u d y, t he part ner is as ke d t o si g n t he " A d ult St u d y I C F f or 
Pre g na nt Part ners of St u d y  P atie nts" a n d pr o vi de i nf or mat i on a b o ut t he pre g na nc y  
acc or di n gl y.
 
 
 
 
 
C CI
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A 4
D at a Pr otecti o n

P arti cipa nt s will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt rec or ds or 
datasets t hat are tra nsferre d t o t he s p o ns or will c o ntai n t he i de nt ifier o nl y; partici pa nt 
na mes or a n y  inf or m at i on w hic h w o ul d ma ke t he partici pa nt i de nt ifia ble will n ot be 
tra nsferre d.

T he parti ci pa nt m ust be i nf or me d t hat his pers o nal st u d y-relate d data will be use d b y t he 
s p o ns or i n acc or da nce with l ocal data pr otectio n la w. T he l e v el of dis clos ure a n d use of 
t heir data m ust als o b e e x plai ne d t o t he partici pa nt i n t he i nf or me d c o nse nt 

T he parti ci pa nt m ust be i nf or me d t hat his me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h or ised pers o n nel  a p p oi nte d b y t he s p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y  a ut h orities.
A 5
C o m mittees Str uct ure
T he safet y of  all Astra Ze neca cli nical st u dies is cl osel y mo ni t ore d o n a n o n-g oi n g basis b y  
Astra Ze neca re prese ntati ves i n c o ns ultat i on wi t h Parti ci pa nt Safet y. Iss ues i de ntifie d will be 
a d dresse d; f or i nsta nce t his c o ul d i n v o l ve a me n d me nts t o t he Cli nical St u d y Pr ot oc ol a n d 
letters t o I n vesti gat ors.
A 6
Disse mi n ati o n of Cli nic al St u d y D at a
A descri pt i on of t his cli nical trial will be a vaila ble o n 
ht t p://astraze negr o u p trials. p har m a c m.c o m a n d htt p:// w w w.cli nicaltrials. g o v as will t he 
s u m mar y of t he mai n st u d y res ults w he n t he y are a vaila ble. T he cli nical trial a n d/ or s u m mar y  
of  mai n st u d y res ults m a y als o be a vaila ble o n ot her we bsites acc or di n g t o t he re g ulati ons o f 
t he c o u ntries i n w hic h t he st u d y is c o n d ucte d.
A 7
D at a Q u alit y Ass ur a nce

All partici pa nt data relat i n g t o t he st u d y will be rec or de d o n eC R F u nless tra ns mitte d t o 
t he s p o ns or or desi g nee electr o nicall y ( e g, la b orat or y data). T he I n vesti gat or is 
res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or 
ele ctr o nicall y si g ni n g t he eC R F.

T he I n vestig at or m u st mai ntai n acc urate d oc u me ntati o n (s o urce data) t hat s u p p orts t he 
i nf or mat i on e ntere d i n t he eC R F.
C CI


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
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 (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg,
Contract Research Organisations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that
the study is being conducted in accordance with the currently approved 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 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the clinical trial agreement.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.


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The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(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 participants
and should assure appropriate participants therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a 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 Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the 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 is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when they become aware of it.
Adverse Events (AEs) for new malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 


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routine treatment that does not require hospitalisation, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy.
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (i.e., it is not the tumour for which entry into the study is a criterion and that 
is being treated by the IP under study and is not the development of new or progression of 
existing metastasis to the tumour under study). Malignant tumours that – as part of normal, if 
rare, progression – undergo transformation (e.g., Richter’s transformation of B cell chronic 
lymphocytic leukaemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumour.
Life threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important medical event or medical treatment
Medical and scientific 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, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
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


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
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
The grading scales found in the revised CTCAE latest version will be utilised 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 can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable version of 
CTCAE should be described clearly.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, 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 recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 


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‘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 no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route 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 IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:


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
Errors related to or resulting from IVRS/IWRS - 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

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
B 5
Adverse Events of Special Interest
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product 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 this 
investigational product. 
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 steroids, immunosuppressants and/or hormone replacement therapy. 
These AESIs are being closely monitored in clinical studies with durvalumab monotherapy 
and combination therapy. An immune-mediated adverse event (imAE) is defined as an AESI 
that is associated with drug exposure and is consistent with an immune-mediated mechanism 
of action 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 regard to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESI/imAEs observed with anti PD-L/PD-1 agents such as durvalumab include pneumonitis, 
hepatitis, diarrhoea/colitis, intestinal perforation, endocrinopathies (hypo- and hyper-
thyroidism, adrenal insufficiency, hypophysitis/hypopituitarism and Type 1 diabetes mellitus), 
nephritis, rash/dermatitis, myocarditis, myositis/polymyositis, pancreatitis and rare/less 
frequent imAEs including neuromuscular toxicities such as myasthenia gravis and 
Guillain-Barre syndrome.
Other inflammatory responses that are rare/less frequent with a potential immune-mediated 


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etiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and other events 
involving the eye, skin, haematological, 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, infusion-related reactions and hypersensitivity/anaphylactic reactions with a 
different underlying pharmacological etiology are also considered AESIs.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire 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 AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample 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 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The Investigator:

Ensures participant’s’ withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 


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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A pathogens are e.g., Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900:
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, C, D, and E viruses. 
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 - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 2 6 of 1 9 3
A p pe n di x D
O pti o n al Ge n o mics I niti ati ve S a m ple
D 1
Use/ a n al ysis of D N A

 
 
 
 
 

 
 


 

 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI


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1 2 7 of 1 9 3

 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 2 8 of 1 9 3

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C CI


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A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 2 9 of 1 9 3
 
 
 
 
 
 
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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
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. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets 
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 data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (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 Adverse Events (AEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 


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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 (i.e., 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 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
Local laboratories being used:
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative 

Determine whether the participant meets PHL criteria (see Section E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 


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treatment (See Section E 6).

Notify the AstraZeneca representative who will then inform the central Study Team.

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 participants that 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 participant’s 
condition.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the Investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete the three Liver eCRF Modules as information becomes available 
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) 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 Physician 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 
Physician 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 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate. 


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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 a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the 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 participants with liver metastases who meet PHL criteria on study 


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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 participants’ condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in
Section E 4.2.
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant 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 participant meet PHL criteria prior to starting study treatment 
and at their first on study treatment visit?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) 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 Physician if there is any uncertainty.


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E 8
Laboratory tests
Hy’s Law lab kit for central laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) b
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 9
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


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Appendix F
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST v1.1 in Soft Tissue 
INTRODUCTION
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumors) v1.1 guidelines (Eisenhauer et al. 2009) and PCWG3 guidelines (Appendix H, Scher 
et al. 2016) for the D8731C00002 study with regards to Investigator assessment of tumour 
burden including protocol-specific requirements for this study.  
ASSESSMENT OF SOFT TISSUE DISEASE USING RECIST 1.1
CRITERIA
Definition of measurable, non-measurable, target and non-target lesions
Participants with at least one lesion (measurable and/or non-measurable) that can be 
accurately assessed at baseline by computed tomography (CT), magnetic resonance imaging 
(MRI) or plain X-ray should be included in this study.  
Measurable:
A lesion, not previously irradiated, that can be accurately measured at baseline as ≥ 10 mm in 
the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with 
computed tomography (CT) or magnetic resonance imaging (MRI) and which is suitable for 
accurate repeated measurements.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 to <15mm short axis at baseline*).

Truly non-measurable lesions include the following: leptomeningeal disease, ascites, 
pleural / pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, abdominal masses/abdominal organomegaly identified by physical 
examination that is not measurable by CT or MRI.

Previously irradiated lesions**.

Skin lesions

Brain metastasis
*Nodes with <10mm short axis are considered non-pathological and should not be recorded or 
followed as NTL.


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**Localized post-radiation changes which affect lesion sizes may occur. Therefore, lesions 
that have been previously irradiated will not be considered measurable and must be selected as 
Non-Target Lesions (NTL) at baseline and followed up as part of the NTL assessment.
Special Cases:
Lytic bone lesions or mixed lytic blastic lesions, with identifiable soft tissue components, can 
be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered non-measurable.
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same participant, these should be selected as target lesions.
Target lesions:
A maximum of 5 measurable lesions (with a maximum of 2 lesions per organ), representative 
of all lesions involved suitable for accurate repeated measurement, should be identified as 
target lesions (TL) at baseline.
Non-Target lesions:
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline (except bone lesions which will be assessed as defined in bone lesion section of this 
appendix).
Methods of assessment
The same method of assessment and the same technique should be used to characterize 
each identified and recorded lesion at baseline and during follow-up visits.
A summary of the methods to be used for RECIST assessment is provided below and those 
excluded from tumour assessments for this study are highlighted, with the rationale provided.
Table 22
Summary of Methods of Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI 
X-ray, Chest x-ray
CT (preferred)
MRI 
X-ray, Chest x-ray
Ultrasound
FDG-PET


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CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TL selected for response assessment and to assess NTL and identification 
of any new lesions. 
In the D8731C00002 study it is recommended that CT examinations of the chest, abdomen 
and pelvis will be used to assess tumour burden at baseline and follow-up visits. CT 
examination with intravenous (i.v.) contrast media administration is the preferred method.
MRI should be used where CT is not feasible or it is medically contra-indicated.  
Every effort should be made to maintain the radiologic imaging modality used at baseline 
throughout subsequent assessments. 
X-rays
Plain X-rays
Plain X-rays may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Chest X-ray
In the D8731C00002 study, chest x-ray assessment will not be used for assessment of TL as 
they will be assessed by CT examination or MRI examination.  Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Ultrasound 
In the D8731C00002 study, ultrasound examination will not be used for assessment of TL and 
NTL as it is not a reproducible method, does not provide an accurate assessment of tumour 
size and it is subjective and operator dependent. Ultrasound examination can, however, be 
used to identify the presence of new lesions. If new clinical symptoms occur and an 
ultrasound is performed then new lesions should be confirmed by CT or MRI examination.
Endoscopy and laparoscopy 
In the D8731C00002 study, endoscopy and laparoscopy will not be used for tumour 
assessments as they are not validated in the context of tumour assessment.
Tumour markers 
In the D8731C00002 study tumour markers will not be used for tumour response assessments 
as per RECIST 1.1.


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In this study the following marker (PSA) are being collected for separate analysis. However, 
the results will not contribute to tumour response based on RECIST 1.1 assessment.
Cytology and histology 
In the D8731C00002 study histology will not be used for tumour response assessments as per 
RECIST 1.1 and tumour response assessments will be performed on radiological criteria only. 
FDG-PET scan 
In the D8731C00002 study FDG-PET scans may be used as a method for identifying new 
lesions, according with the following algorithm: New lesions will be recorded where there is 
positive FDG uptake* not present on baseline FDG-PET scan or in a location corresponding 
to a new lesion on CT/MRI at the same follow-up visit. If there is no baseline FDG-PET scan 
available, and no evidence of new lesions on CT/MRI scans then follow-up CT/MRI 
assessments should be continued, scheduled as per protocol or clinical indicated, in order to 
confirm new lesions.
* A positive FDG-PET scan lesion should be reported only when an uptake greater than twice 
that of the surrounding tissue is observed.
Tumour response evaluation 
Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual participants and should be performed no more than 28 
days before allocation. The first follow-up assessment for should be at Week 8 (Arm A) or 
Week 9 (Arm B). In Arm A follow-up assessments should be every 8 weeks ±1 week, from 
the start of dosing, for the first 24 weeks and then every 12 weeks (±1 week) thereafter. In 
Arm B follow-up assessments should be performed every 9 weeks ±1 week, from the start of 
dosing, for the first 27 weeks and then every 12 weeks (±1 week). Any other sites at which 
new disease is suspected should also be adequately imaged at follow-up.
If an unscheduled assessment was performed and the participant has not progressed, every 
attempt should be made to perform the subsequent assessments at their originally scheduled 
visits. This schedule is to be followed in order to minimize any unintentional bias caused by 
some participants being assessed at a different frequency than other participants.
Target lesions (TL)
Documentation of target lesions


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A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes), representative of all lesions involved should be identified as TL at baseline.
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis 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 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. 

If the CT/MRI slice thickness used is > 5mm, the minimum size of measurable 
disease at baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the longest diameter should be recorded as 0 
mm.

If a TL splits into 2 or more parts, then record the sum of the diameters of those parts. 

If 2 or more TL merge then the sum of the diameters of the combined lesion should 
be recorded for one of the lesions and 0 mm recorded for the other lesion(s).  

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate 
of the size of the lesion. 

When a TL has had any intervention e.g., radiotherapy, embolisation, surgery etc., 
during the study, the size of the TL should still be provided where possible.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL.


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Table 23
Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions since baseline. Any 
pathological lymph nodes selected as target lesions must have a 
reduction in short axis 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 shrinkage to qualify for PR nor sufficient 
increase to qualify for PD
Progressive Disease (PD)
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.
Not Evaluable (NE)
Only relevant if any of the target lesions were not assessed or not 
evaluable or had a lesion intervention at this visit. Note: If the sum 
of diameters meets the progressive disease criteria, progressive 
disease overrides not evaluable as a target lesion response


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Appendix H
PCWG3 Criteria (Scher et al. 2016)
Baseline/Study Entry
PSA progression requirements for study entry
A sequence of rising PSA values should be obtained at least 1 week apart, with a minimum 
starting level of 2.0 ng/mL for trial entry. 1.0 ng/mL is acceptable as the minimum starting 
level for trial entry if the confirmed rise is the only indication of progression (excluding small 
cell carcinoma). It is recommended to estimate a pretreatment PSA doubling time (PSA-DT) 
if at least three values are available ≥4 weeks apart. 
Baseline Imaging
Imaging of the chest, abdomen, and pelvis using a contrast-enhanced CT scan with ≤5 mm 
axial slices is advised for all participants. For participants that are intolerant of contrast, a 
cross-sectional MRI scan of the abdomen and pelvis with a noncontrast CT scan of the chest is 
acceptable. For Phase I and II trials, it is recommended to report whether progression on entry 
was in the growth of pre-existing lesions, the development of new lesions, or both. RECIST 
v1.1 (Eisenhauer et al. 2009) should be followed for extraskeletal disease; however, in 
contrast to RECIST v1.1, up to 5 lesions per site of metastatic spread can be recorded. Bone 
lesions should be recorded separately.  

Prostate/prostate bed- If there is a question of locally persistent or recurrent disease, 
an MRI of the prostate or prostate bed and/or biopsy of the site is recommended.  

Nodes or viscera- Nodal disease should be measured in the short axis and recorded by 
location: pelvic disease should be classified as locoregional, and extrapelvic disease 
(retroperitoneal, mediastinal, thoracic, or other) as metastatic. Nodes ≥1.5 cm in the
short axis are considered pathologic and measurable. As per RECIST v1.1, lymph 
nodes ≥1.0 and less than 1.5 cm in the short axis may be pathologic and should be 
recorded as non-target lesions. Nodes less than 1.0 cm in the short axis are considered 
nonpathologic. Visceral disease in metastatic participants should be designated 
separately as lung, liver, adrenal, or CNS and must be ≥1.0 cm in the longest 
dimension per RECIST v1.1 to be included as a target lesion.
To establish non-metastatic status in the non-metastatic castration-resistant prostate 
cancer (nmCRPC) population, nodes ˂1.0 cm in the short axis are considered 
nonpathologic; nodes 1.0 to less than 1.5 cm may be considered pathologic but with 
clinical discretion; and nodes ≥1.5 cm are both pathologic and measurable. Trial entry 
should be based on PSA-DT, and standard imaging modalities (bone scan, CT, and/or 
MRI) should be used.  


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
Bone- The use of 99mTc-methylene diphosphonate radionuclide bone scintigraphy 
should be used, with the presence or absence of metastasis recorded. A quantitative 
measure of disease burden, such as lesion number, the bone scan index, or lesion area, 
is recommended. Changes in lesions considered metastatic on bone scintigraphy 
should be followed, assessed, and recorded. Areas/lesions on bone scans that are 
suggestive can be assessed further with CT or MRI and followed separately, but this 
supplemental imaging should not be used to establish lesions for the purposes of the 
trial.

Neurologic- It is recommended to perform an MRI or CT of the brain for participants 
with small cell/neuroendocrine tumours and to maintain a low threshold for 
performing an MRI of the base of the skull or spine to diagnose and/or detect 
impending neurologic compromise. Routine imaging of the brain for adenocarcinoma 
is not recommended.
Imaging progression requirements for study entry

Measurable lymph nodes/lesions are not required

Nodal progression or visceral progression independent of PSA is sufficient

Previously normal (˂1 cm) lymph nodes must have grown by ≥5 mm in the short axis 
from baseline or nadir and be ≥1.0 cm in the short axis to be considered to have 
progressed. If the node progresses to ≥1.5 cm in the short axis, it is measurable; nodes 
that have progressed to 1.0 to less than 1.5 cm are pathologic, subject to clinical 
decision, and nonmeasurable.  

For existing pathologic adenopathy, progression is defined per RECIST v1.1

For bone involvement, there must be two new lesions. Ambiguous results should be 
confirmed by other imaging modalities (CT or MRI). Note: only positivity on the bone 
scan defines metastatic disease to bone.
On-Study Disease Assessments
Throughout the trial, on-treatment evaluations should include physical examinations, 
symptom assessments, and laboratory studies to assess safety (appropriately attributing to the 
disease or therapy).
Clinical symptoms, performance status, participant reported outcomes, and blood based 
biomarkers (PSA, alkaline phosphatase [ALP], lactate dehydrogenase [LDH], serum 
chemistry, complete blood count, and circulating tumour cells) should be assessed at every 
cycle.  
Changes over time should be reported for the following blood-based biomarkers: LDH, total 
ALP, bone-specific ALP, urine N-telopeptide, hemoglobin, and neutrophil/lymphocyte ratio 
(NLR). The reported changes may include the proportion showing normalisation of a given 


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biomarker and/or waterfall plots of percent change from baseline in a given biomarker.
Institutional normal ranges should be reported to determine normalisation of a given 
biomarker.
PSA
PSA should be monitored by cycle, but treatment should continue through early rises for a 
minimum of 12 weeks unless there is other evidence of progression, as a favorable effect on 
PSA may be delayed for ≥12 weeks. When determining PSA response, ignore early rises 
(before 12 weeks).
For control/relieve/eliminate end points:

Record the percentage change from baseline (rise or fall) at 8-9 or 12 weeks, and 
separately, the maximal change (rise or fall) at any time using a waterfall plot

Describe absolute changes in PSA over time from baseline to best response
For delay/prevent end points:

After decline from baseline: record time from start of therapy to first PSA increase that 
is ≥25% and ≥2 ng/mL above the nadir, and which is confirmed by a second value 
≥3 weeks later.

If no decline from baseline: 
In participants who show evidence of benefit, treatment should be continued in the case of an 
isolated PSA rise after an initial decline until radiographic or clinical progression is manifest.
Circulating tumour cells (CTC)
Circulating tumour cell counts should be enumerated at the start of treatment and recorded as 
favorable (four or fewer cells per 7.5 mL of blood) or unfavorable (five or more cells per 7.5 
mL of blood). If the result was unfavorable, changes after treatment should be monitored.
For control/relieve/eliminate end points:
Report as change from unfavorable to favorable, and separately, the percent change from 
baseline using a waterfall plot. 
For delay/prevent end points:
No validated definition exists; however, rising CTC counts are associated with a poor 
prognosis. 


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Imaging
Imaging should include cross-sectional imaging of the chest, abdomen, and pelvis, as well as 
bone scintigraphy, regardless of whether participants have involvement of those sites at 
baseline. Disease progression at new sites may be missed if imaging is restricted to known 
sites of disease. Imaging should be performed at fixed intervals. An 8- to 9-week assessment 
interval is advised for the first 24 weeks and every 12 weeks thereafter; however, there may be 
exceptions to these suggestions: in nmCRPC trials, for example, imaging assessment intervals 
of 16 weeks are advised. Likewise, in long-term responders (˃2 to 3 years of clinical benefit 
and no signs of clinical biomarker progression), reduced frequency of imaging is reasonable, 
such as every 16 to 24 weeks (4 to 6 months). A favorable change noted by imaging should be 
confirmed with a second scan.
For control/relieve/eliminate end points:
RECIST v1.1 criteria should be followed; however, up to five lesions per site of disease can 
be recorded. Record changes in lymph nodes, lung, liver, adrenal, and CNS sites separately.
Favorable changes should be confirmed with a second scan. Complete elimination of disease 
at any site should be recorded separately.  

Lymph nodes: Only report changes in lymph nodes that were measureable at baseline 
(≥1.5 cm in the short axis). Changes in pelvic and extrapelvic nodes should be reported 
separately.

Visceral: Only report changes in lesions that were measureable at baseline (≥1.0 cm in 
the longest dimension). Changes in liver, lung, adrenal, and CNS should be reported 
separately.

Bone: Changes should be recorded as improved, stable (no new lesions), worse (new 
lesions), or resolved. Changes in intensity of uptake alone do not constitute 
progression or regression. If there are no new lesions, therapy should be continued in 
the absence of other signs of progression.  
For delay/prevent end points:
RECIST v1.1 criteria should be followed; however, up to five lesions per site of spread can be 
recorded. Record changes in lymph nodes, lung, liver, adrenal, and CNS sites separately. The 
type of progression (growth of existing lesions versus development of new lesions) should be 
recorded separately by site. The proportion of participants who have not progressed at fixed 
time points (6 or 12 months) should be reported. 

Note that for some treatments, a lesion may increase in size before it decreases.

Lymph nodes: Previously normal (˂1.0 cm) lymph nodes must have grown by ≥5 mm 
in the short axis from baseline or nadir and be ≥1.0 cm in the short axis to be 
considered to have progressed. Nodes that have progressed to 1.0 to less than 1.5 cm 


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are pathologic, subject to clinical discretion, and nonmeasureable. For existing 
pathologic adenopathy (≥1.5 cm), progression is defined per RECIST v1.1.

Bone: For progression, pseudoprogression should be excluded in the absence of 
symptoms or other signs of progression. The 2+2 rule (at least two new lesions on the 
first post-treatment scan, with at least two additional lesions on the next scan) should 
be used to distinguish flare from true progression. If at least two additional new lesions 
are seen on the next (confirmatory) scan, the date of progression is the date of the first 
post-treatment scan (i.e. when the first two new lesions were documented). For scans 
after the first post-treatment scan, at least two new lesions relative to the first post-
treatment scan should be confirmed on a subsequent scan. The date of progression will 
be the date of the scan that first documents the second lesion. Changes in intensity of 
uptake alone do not constitute either progression or regression. The proportion of 
participants who have not progressed at fixed time points (6 or 12 months) should be 
reported.

.
Radiographic Progression-Free Survival (rPFS)
rPFS, defined as the time from first dose until radiographic progression, assessed by the 
Investigator per PCWG3 criteria (bone) or death from any cause, whichever occurs first by 
gene expression subgroup. 
PCWG3 advises the date of progression in all specific sites be reported independently whether 
it is bone, nodes (pelvic or extrapelvic), visceral (lung, liver, adrenal, or CNS), or other.
Reporting the proportion of patients who remain radiographic progression free at fixed time 
points (e.g., 6 and 12 months) is also advised.


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Appendix I
Disallowed Medications
The following interventions listed are restricted or prohibited and are to be used with caution 
or not at all as described. Exceptions may be agreed, but the circumstances must be reviewed 
by the Medical Monitor/AstraZeneca Study Physician in advance. 
Information on any treatment in the 4 weeks prior to starting study treatment and all 
concomitant treatments given during the study with reasons for the treatment should be 
recorded.
Prohibited medications with AZD4635
Contribution of CYP1A2 to AZD4635 metabolism appears to be >80%.  CYP1A2 is readily 
inducible by medications.  The following CYP1A2 strong and moderate inducers and 
inhibitors (Table 24) are not permitted from 2 weeks prior to the first dose of AZD4635 until 
at least 2 weeks after the last dose of AZD4635.
Table 24
Examples of CYP1A2 Inhibitors and Inducers
CYP1A2
Strong inhibitors
Moderate inhibitors
ciprofloxacin, clinafloxacin, enoxacin, 
fluvoxamine, oltipraz, zafirlukast, 
rofecoxib, Angelica root - Bai Zhi 
(Angelica dahurica radix)
methoxsalen, mexiletine ,oral 
contraceptives,3,4-methylene-
dioxymethamphetamine (MDMA), 
etintidine, genistein, idrocilamide, 
osilodrostat, phenylpropanolamine, 
pipemidic acid, propafenone, propranolol, 
troleandomycin, vemurafenib, 
grepafloxacin, piperine, zileuton 
Strong Inducers
Moderate Inducers
Phenytoin, rifampin, ritonavir, smoking, 
teriflunomide
Based on the potential risks for DDI, sensitive substrates of OATP1B1/3, OAT1, OCT1, 
OCT2, MATE1 and P-gp are prohibited.  If medically feasible, patients taking regular 
medication, with the exception of examples of known substrates of transporters listed in 
Table 25, should be maintained on it throughout the study period. 


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Table 25
Examples of Substrates of Transporters
Substrate category
Examples of drugs in the category
Substrates of:
BCRP
methotrexate, mitoxantrone, imatinib, lapatinib, sulfasalazine, 
topotecan, daunorubicin, doxorubicin, SN-38, irinotecan, prazosin, 
pantoprazole, atorvastatin, fluvastatin, rosuvastatin, and 
simvastatin.
OAT1
adefovir, captopril, furosemide, lamivudine, methotrexate, 
oseltamivir, tenofovir, zalcitabine, zidovudine, ciprofloxacin, 
cephaloridine, methotrexate, pravastatin
OATP1B1, OATP1B3
asunaprevir, atorvastatin, bosentan, danoprevir, docetaxel, 
fexofenadine, glyburide, nateglinide, paclitaxel, pitavastatin, 
pravastatin, repaglinide, rosuvastatin, simvastatin acid
OCT1
metformin, oxaliplatin, aciclovir, ganciclovir
OCT2
metformin, pindolol, procainamide, ranitidine
amantadine, amiloride, oxaliplatin, varenicline, cisplastin, 
debrisoquine, propranolol, guanidine, D-tubocurarine, 
pancuronium,
memantine, picoplatin, ifosfamide, cimetidine, famotidine, 
zalcitabine, lamivudine, berberine
MATE1
metformin
P-gp
dabigatran etexilate, digoxin, fexofenadine
Herbal Preparations
Herbal preparations/medications are not allowed throughout the study, starting 7 days prior to 
first dose of AZD4635. These herbal medications include but are not limited to St. John’s 
wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, and ginseng. 
Prohibited medications with Cabazitaxel
Avoid concomitant administration of strong CYP3A4 inhibitors/inducers (see Table 26) with 
cabazitaxel administration (Arm B). In addition, live attenuated vaccines should not be given 
through 3 months after the last dose of cabazitaxel.
Table 26
Examples of Strong CYP3A4 Inducers and Inhibitors
Examples of drugs in the category
CYP3A4 inducers
phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, St. John's wort
CYP3A4 inhibitors
ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, 
voriconazole


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Table 27
Prohibited Medications with Durvalumab
Prohibited medication/class of drug:
Additional information
mAbs against CTLA-4, PD-1, or PD-L1 other than 
those under investigation in this study
Should not be given concomitantly while the participant is 
on study intervention
Live attenuated vaccines 
Should not be given through 30 days after the last dose of 
durvalumab
Immunosuppressive medications including, but not 
limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumour necrosis 
factor-α blockers
Should not be given concomitantly, or used for 
premedication prior to the I-O infusions.  The following 
are allowed exceptions:
Use of immunosuppressive medications for the 
management of IP-related AEs 
Use in participants with contrast allergies. 
In addition, use of inhaled, topical, and intranasal 
corticosteroids is permitted.
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the participant (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc.).
Epithelial growth factor receptor tyrosine kinase 
inhibitors (EGFR TKIs) 
Should not be given concomitantly. 
Should be used with caution in the 90 days post-last dose 
of durvalumab. 
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with first-generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly.


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Appendix J
Brief Pain Inventory (short form) Example – Not for 
Participant Use


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Appendix K
FACT-P (Version 4) Example - Not for Participant Use 


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Appendix L
COVID-19 Specifics
L 1
Background to COVID-19
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the WHO to declare a pandemic situation on 
12 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden including new outbreaks, locally or globally, 
will impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect participants, 
site staff, and society as a whole.
Both EMA and FDA as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at high pace. 
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in future, special attention will be paid to protect participants 
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline.
L 2
Risk Assessment in view of the COVID-19 Pandemic 
There are 3 study drugs with different mechanisms of action that are unlikely to impact on the 
course of infection with SARS-CoV-2. 
It is possible that respiratory symptoms of pneumonitis could arise due to durvalumab or 
cabazitaxel that may be difficult to distinguish clinically from COVID-19. It is recommended 
that evaluation be done including imaging and infectious disease testing to try to understand 
the causality of such events to the extent that is possible.
AZD4635 alone has not resulted in significant immune-mediated toxicity although close 
monitoring will be done including monitoring of adverse events. It is not anticipated that 
AZD4635 should worsen infection with COVID-19 but there is no clinical data available at 
this time.
Durvalumab therapy may lead to AEs including, 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 steroids, immunosuppressants and/or hormone 
replacement therapy. Adverse events of special interest (AESIs) for durvalumab also include 
pneumonitis. It is possible, albeit rare, that events with an inflammatory or immune-mediated 


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mechanism could occur in nearly all organs.
While, this poses a theoretical risk of adversely influencing the antiviral response, this is 
judged to be unlikely. Therefore, risk of the participants exposed to SARS-CoV-2 or to suffer 
from COVID-19 is expected to be similar to the background population with the same 
co-morbidities as those in the study. The risk of exposure to infected people cannot be 
completely excluded as the participants may need to expose themselves to public areas (e.g., 
commute to the site) and have additional human contact (eg, with site staff and other 
participants of the clinical study).
Measures to mitigate the additional risks caused by COVID-19 are:

This study is going to start enrolling only when the Sponsor and CRO in collaboration
deem it is safe to start the study. In addition, the study will not start until the local
confinement measures or other safety restrictions linked to the COVID-19 pandemic
imposed by the local authorities are compatible with safe conduct of the study. Current 
national laws and local recommendations for prevention of pandemic will be strictly 
adhered to.

During the study, COVID-19 tests may be prescribed, if required, and in accordance 
with local guidance. If a participant tests positive, his continued participation in the 
study and his treatment with the study drugs will be discussed with the Parexel and 
AstraZeneca Medical Monitors for this study.

The probability of virus transmission will be controlled as much as possible by:
o
Advice for participant to adhere to local requirements for reduction of the 
public exposure while ambulatory.
o
Confirmation of COVID-19 infection by optional laboratory assessment will be
conducted based on availability (test capacity and turnaround time) of 
approved tests and on Investigator’s discretion. If applicable, participants will 
be referred to the local health care system for further follow-up and treatment.
o
Physical distancing and person-to-person contact restrictions will be applied 
during site visits and in-house confinement.
o
Where physical distancing is not possible, PPE will be used by study 
participants (surgical face mask, gloves) and staff (for example but not limited 
to masks, gloves, protectors, medical suits) if deemed appropriate by the 
Investigators and site staff and guided by local requirements.
o
Logistical improvements of the site and structural measures of the study site 


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building will be implemented to further improve physical distancing.
o
Home or remote visit to replace on-site visit (where applicable): A qualified 
Health Care Professional (HCP) from the study site or third-party vendor 
service may visit the patient’s home or other remote location as per local 
standard operating procedures, as applicable. Supplies will be provided for a 
safe and efficient visit. The qualified HCP will be expected to collect 
information per the Clinical Study.
o
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. Having a telemedicine contact with the patients 
will allow AEs, concomitant medication, patient report outcomes 
questionnaires, and health economic data to be reported and documented.
o
Remote location Investigational Product administration instructions: If a site 
visit is not possible, administration of Investigational Product may be 
performed at a remote location by a qualified HCP from the study site or third 
party vendor service (eg, infusion centers, external non-hospital medical 
settings, alternate clinical site locations), if appropriate per local regulatory 
requirements. The remote location must have immediate access to emergency 
resuscitation teams and equipment in addition to the ability to admit 
participants to an intensive care unit if necessary.  The option of Investigational 
Product administration at a remote location ensures patient’s safety in cases of 
a pandemic where patients may be at increased risk by traveling to the 
site/clinic. This will also minimize interruption of Investigational Product 
administration during other study disruptions, e.g., site closures due to natural 
disaster.

Investigational Product administration at a remote location: Prior to 
remote location Investigational Product administration, the investigator 
must confirm whether administration of Investigational Product at the 
considered remote location is appropriate for the participant. All 
necessary supplies and instructions for administration and 
documentation of Investigational Product administration will be 
provided. More information related to the visit can be obtained via a 
telemedicine or home/remote visit.


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L 3
Restrictions Related to COVID-19
During the COVID-19 pandemic, participants are advised to adhere to local requirements for
reduction of the public SARS-CoV-2 exposure while ambulatory. If appropriate, participants 
will be referred to the local health care system. Physical distancing and person-to-person 
contact restrictions will be applied and explained to participants while staying at the study site. 
Where physical distancing is not possible, study participants will be asked to use surgical face 
masks and/or gloves if deemed appropriate by the Investigator and site staff and guided by 
local requirements.
L 4
Data Quality Assurance Related to COVID-19
Monitoring visits at site will be limited to a minimum required as deemed appropriate during
COVID-19 pandemic, per local regulations. All AEs/SAEs should be reported in line with 
instructions for safety reporting documented in the CSP. For patients experiencing signs and 
symptoms indicating an infection, an attempt will be made to determine whether the 
COVID-19 virus is the infectious organism and the AE will be recorded accordingly. If 
COVID test results are available to the site staff, they will be recorded as either “COVID-19 
positive” or “COVID-19 negative” in the Adverse Event Field, along with the AE/SAE signs 
and symptoms and/or other diagnosis.
If a test has not been performed or result is not available and signs and symptoms, as judged 
by the Investigator, are highly suggestive of COVID-19 infection, record “COVID-19 
suspected” in the Adverse Event Field. If the Investigator has other concurrent diagnoses for 
the patient’s signs and symptoms (eg, pneumonia), these will be recorded as separate AEs.
In addition, where possible, other measures for carrying out protocol related activities, such as
but not limited to home nursing, may be employed as required. Data collected during 
telemedicine or home/remote visits will be captured by the qualified HCP from the study site 
or third-party vendor service in the source documents, or by the patient themselves.
L 5
References
1. Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus)
pandemic, EMA, Version 3 (28/04/2020).
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf.
2. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, March 2020, Updated on April 16, 2020 https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/fdaguidance-conduct-clinical-trials-medical-
products-during-covid-19-public-healthemergency.


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 6 8 of 1 9 3
A p pe n di x M
A b bre vi ati o ns
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
A 2 AR
A de n osi ne 2 A rece pt or
A A R D V A R C
A 2 AR i n hi bit or a n d D ur V al u ma b A ssess me nt of R es p o nse i n C R P C
A D A
A de n osi ne dea mi nase
A D O
A de n osi ne
A E
A d verse e ve nt (see defi niti o n i n A p pe n di x B )
A E SI
A d verse e ve nt of s pecial i nterest
A L P
Al kali ne p h os p hatase
A L T
Ala ni ne a mi n otra nsferase
A S T
As partate a mi n otra nsferase
A U C
Area u n der t he c o nce ntrati o n -ti me c ur ve
BI D
T wice dail y
B PI -S F
Br ief Pai n I n ve nt or y ( S h ort F or m)
C D 7 3
Cl uster of differe ntiati o n 7 3: 5' -n ucle oti dase ( 5' -N T) or ect o - 5'-n ucle oti dase
CI
C o nfi de nce i nter val
C L
Cleara nce
C L/ F
A p pare nt plas ma cleara nce
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n
C N S
Ce ntral ner v o us s yste m
C O VI D - 1 9
C or o na vir us disease of 2 0 1 9
C R
C o m plete res p o nse
C R C
C ol orectal carci n o ma
C S P
Cli nical st u d y pr ot oc ol
C S R
Cli nical st u d y re p ort
C T
C o m p ute d t o m o gra p h y
C T C A E
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts
C Y P
C y t oc hr o me P 4 5 0
D C O
Data c ut -off
D DI
Dr u g -dr u g i nteracti o n
D L T
D ose -li miti n g t o xicit y
E C G
Electr ocar di o gra m
e C R F
Electr o nic case re p ort f or m
E S -S C L C
E xte nsi ve -sta ge s mall cell l u n g ca ncer 
C CI


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A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 6 9 of 1 9 3
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
F A C T - P
F u ncti o nal Assess me nt of Ca ncer T hera p y -Pr ostate
F D A
F o o d a n d Dr u g A d mi nistrati o n
G- C S F
Gra n ul oc yte -c ol o n y sti m ulati n g fact or
G C P
G o o d Cli nical Practice
G G T
Ga m ma -gl uta m yltra nsferase
G L P
G o o d La b orat or y Practice
G R H
G o na d otr o pi n -releasi n g h or m o ne
I A T A
I nter nati o nal Air Tra ns p ort Ass ociati o n
I B
I n vesti gat or’s Br oc h ure
I C5 0
C o nce ntrati o n gi vi n g 5 0 % of t he dr u g -i n d uce d i n hi bit or y effect
I C F
I nf or me d c o nse nt f or m
I C H
I nter nati o nal C o u ncil f or Har m o nisati o n
I F Nγ
I nterfer o n ga m ma
I g
I m m u n o gl o b uli n
I H C
I m m u n ohis t oc he mistr y
I L D
I nterstitial l u n g disease
i m A E
I m m u ne-me diate d a d verse e ve nts
I M P
I n vesti gati o nal me dici nal pr o d uct
I O
I m m u n ot hera p y
I P
I n vesti gati o nal pr o d uct
I R B
I nstit uti onal Re vie w B oar d 
I V
I ntra ve n o us
m A b
M o n ocl o nal a nti b o d y
m C R P C
Metastatic castrate-resista nt pr ostate carci n o ma
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities
M O A
Mec ha nis m of acti o n
M RI
Ma g netic res o na nce i ma gi n g
M T D
Ma xi m u m -t olerate d d ose
M U G A 
M ulti ple- gate d ac q uisiti o n
n A b
Ne utralizi n g a nti b o d y
N E
N ot e val ua ble
N H A
Ne w h or m o nal a ge nt(s)
NI M P
N o n -i n vesti gati o nal me dici nal pr o d uct
N K
Nat ural killer (cells)
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 0 of 1 9 3
A b bre vi ati o n or 
s peci al ter m
E x pl a n ati o n
N O A E L
N o -o bser ve d -a d verse-effect le vel
N T L
N o n -tar get lesi o n
O A E
Ot her si g nifica nt a d verse e ve nt
O R R
O bjecti ve res p o nse rate
O S
O verall s ur vi val
P D
Pr o gressi o n of disease
P D - 1
Pr o gra m me d cell deat h pr otei n 1 (e. g., ni v ol u ma b [ O p di v o ® ])
P D -L 1
Pr o gra m me d deat h li ga n d 1
P E T
P ositr o n e missi o n t o m o gra p h y
PI
Prescri bi n g i nf or mati o n
P K
P har mac o ki netics
P O
Per os ( orall y)
P R
Partial res p o nse
P R O
Patie nt re p orte d o utc o me
P R E D
Pre d nis o ne
P S A
Pr ostate -s pecific a nti ge n
Q 3 W
E ver y 3 wee ks
Q 4 W
E ver y 4 wee ks
Q D
O nce dail y
Q T
E C G i nter val meas ure d fr o m t he o nset of t he Q R S c o m ple x t o t he e n d of t he T wa ve
Q Tc
Q T i nter val c orrecte d f or heart rate
Qtc F
Q T i nter val c orrecte d f or heart rate usi n g Fri dericia’s f or m ula
R E CI S T
Res p o nse E val uati o n Criteria i n S oli d T u m o urs
r P F S
Ra di o gra p hic pr o gressi o n -free s ur vi val
S A E
Seri o us a d verse e ve nt (see defi niti o n i n Secti o n 8. 3 )
S C C H N
S q ua m o us cell carci n o ma hea d a n d nec k
S D
Sta ble disease
S o A
Sc he d ule of acti vities
S R C
Safet y Re vie w C o m mittee
S T D 1 0
1/ 1 0 t h of t he se verel y t o xic d ose i n r o de nt st u dies
S m P C
S u m mar y of Pr o d uct C haracteristics
T B N K
C o m plete i m m u ne pa nel ( T -, B-, a n d N K l y m p h oc yte s u bsets)
T E A E
Treat me nt -e mer ge nt a d verse e ve nt
C CI
C CI


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Abbreviation or 
special term
Explanation
TID
Three times a day
TL
Target lesion
tmax
Time to reach Cmax
TME
Tumour microenvironment
TMGs
Toxicity Management Guidelines
TNα
Tumour necrosis factor-α
TNBC
Triple-negative breast cancer
Treg
Regulatory T cells
ULN
Upper limit of normal
USPI
United States Prescribing Information
WHO
World health organisation (performance status)


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Appendix N
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1, 07-September-2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the council of the European Union.
Overall Rationale for the Amendment:
The global protocol was amended to address comments received from various health 
authorities in the EU. A summary of changes and the rationale for each change are tabulated 
below.


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
1.1 Synopsis and 2.1 
Study Rationale
Edited with updated data from AZD4635 Investigator’s Brochure (IB) 
Ed 6.1, dated 12 Aug 2020
Information from new 
data cut-off date (02 Dec 
2019) was available
Substantial
1.1 Synopsis and 3 
Objectives and 
Endpoints
The list of parameters for which laboratory values will be recorded to 
evaluate safety of each treatment regimen was clarified
Added to the endpoints 
column for clarity
Non-substantial
1.1 Synopsis and 3 
Objectives and 
Endpoints
It was clarified that the Pharmacokinetic (PK) parameters for the study 
drugs will be derived, where deemed appropriate.
Added to clarify that 
derived PK parameters 
for all study drugs may 
be presented, only where 
deemed appropriate –
given the sparse and 
intense PK sampling. 
Non-substantial
1.1 Synopsis and 3 
Objectives and 
Endpoints
The following was added to the objectives and endpoints table “Time to 
pain progression based on BPI-SF Item 3 ‘pain at its worst in the last 
24 hours’ will be additionally summarised for the high and low gene 
expression subgroups for ADO and ADA in each arm separately.
Added per input from 
study team.
Substantial
1.1 Synopsis and 3 
Objectives and 
Endpoints
The secondary objective “To explore the effects of AZD4635 on pain 
and other prostate cancer-related symptoms.” was edited to “To 
determine the effects….”.
Edited to ensure that it is 
not perceived as an 
exploratory objective
Non-substantial
1.1 Synopsis and 3 
Objectives and 
Endpoints 8.2.9 Clinical 
outcome assessments
Endpoint for the secondary objective “To determine the effects of 
AZD4635 on pain and other prostate cancer-related symptoms.” was 
edited to clarify that change from baseline in average pain would be 
recorded instead of general pain, and that time to pain progression 
based on Item 3 - “pain at its worst in the last 24 hours” - of the Brief 
Pain Inventory (Short Form) (BPI-SF) would be measured. The worst 
bone pain item of the BPI-SF was omitted.
Revised per input from 
study team.
Substantial
1.1 Synopsis, 
3 Objectives and 
Endpoints, and 8.2.9 
Clinical outcome 
measures
Endpoint for the secondary objective “To determine the effects of 
AZD4635 on pain and other prostate cancer-related symptoms.” was 
edited to add “FAPSI–6 as derived from 6 items” of the Functional 
Assessment of Cancer Therapy-Prostate (FACT-P) scale. FACT 
Advanced Prostate Symptom Index-6 (FAPSI-6) was also added to the 
clinical outcome measures under FACT-P, in Section 8.2.9 Clinical 
Revised per input from 
study team.
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
outcome measures. FAPSI-6 is a subset of FAPSI-8 which was already 
in the protocol.
1.1 Synopsis, 2 
Introduction, and 4.1 
Overall design
The following instruction was added: Participants in Arm B will 
receive cabazitaxel chemotherapy as per the local label. This will start 
approximately 1 hour (or up to a maximum of 2 hours) after the end of 
the durvalumab infusion. Cabazitaxel will be administered as per the 
local prescribing guidelines for a maximum of 10 cycles. After cycle 
10 durvalumab + AZD4635 will be administered Q4W to harmonise 
with the Arm A treatment cycle length.
Revised per input from 
study team.
Substantial
1.1 Synopsis and 4.1 
Overall Design
During the study, tests for active Coronavirus disease of 2019 
(COVID-19) infection may be conducted, if required, and in 
accordance with local guidance.
In the overall design section, it was further clarified that “If a 
participant is symptomatic for active COVID-19 infection during a site 
visit, he may be prescribed a COVID-19 test. Dosing may continue 
while results are awaited, per the Investigator’s discretion and local 
guidelines, and the Medical Monitor/AstraZeneca Study Physician 
should be consulted. For participants who test positive (for COVID-19) 
the study drugs may be temporarily interrupted and later resumed, per 
the Investigator’s discretion and local guidelines, and this should be 
discussed with the Medical Monitor/AstraZeneca Study Physician. 
Where applicable, home or remote visits may be conducted for study 
assessments and study drug administration (see Appendix L).”
Added in view of
ongoing COVID-19 
pandemic
Substantial
1.1 Synopsis and 6 
Study intervention
The following statement was added: In this protocol AZD4635, 
durvalumab and cabazitaxel are all referred to as either study drugs, 
study interventions, investigational products, or investigational 
medicinal products, and these terms are used interchangeably.
Revised to add clarity 
regarding terminology 
used in protocol
Non-substantial
1.1 Synopsis and 9.5 
Interim analysis
The term “Bayesian predictive probability” was changed to “predictive 
probability”. It was also clarified that participant recruitment will 
Revised per input from 
study team.
Substantial


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 5 of 1 9 3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
c o nti n ue w hile t he i nteri m a nal ysis is o n g oi n g, b ut ma y be pa use d if t he 
n u m ber of partici pa nts i n Ar m A reac hes a p pr o xi matel y 5 0.
1. 3 Sc he d ule of 
Acti vities
Visit wi n d o ws f or t he f oll o w -u p visits were clarifie d i n t he hea der f or 
Ta bles 1 a n d 2 a n d a f o ot n ote is a d de d t o descri be t he ti mi n g of t he first 
pr o gressi o n -free f oll o w- u p
Re vise d f or clarit y
N o n -s u bsta ntial
1. 3 Sc he d ule of 
Acti vities
Ne w acti vities a d de d t o b ot h Ta bles 1 a n d 2 f or Ec h ocar di o gra m
( E C G)/ m ulti ple-gate d ac q uisiti o n ( M U G A) assess me nt at scree ni n g. 
Rele va nt f o ot n otes ha ve als o bee n a d de d t o i n dicate a d diti o nal 
assess me nts f or ec h ocar di o gra m/ M U G A d uri n g t he st u d y.  
Re g ulat or y re q uest t o a d d 
ec h ocar di o gra m/ M U G A 
assess me nt at scree ni n g 
in or der t o e xcl u de 
partici pa nts wit h ejecti o n 
fractio n < 5 5 %.
S u bsta ntial
1. 3 Sc he d ule of 
Acti vities
Ne w acti vities a d de d t o b ot h Ta bles 1 a n d 2 t o all o w f or a test f or 
C O VI D -1 9, if re q uire d. A rele va nt f o ot n ote was als o a d de d t o clarif y 
t hat “ D uri n g t he st u d y, tests f or acti ve C O VI D-1 9 i nfecti o n ma y be 
prescri be d, if re q uire d, a n d i n acc or da nce wit h l ocal g ui deli nes.”
A d de d i n vie w of 
o n g oi n g C O VI D -1 9 
pa n de mic
S u bsta ntial
1. 3 Sc h e d ule of 
Acti vities a n d 8. 2. 6 
C o nc o mita nt 
me dicati o ns
It was clarifie d i n b ot h Ta bles 1 a n d 2 t hat c o nc o mita nt me dicati o ns at 
t he 9 0-da y f oll o w -u p a n d pr o gressi o n -free f oll o w-u p visits w o ul d o nl y 
be t o gat her data o n ca ncer t hera p y. Secti o n 8. 2. 6 was als o u p date d 
acc or di n gl y.
Re vise d per st u d y tea m 
i n p ut t o ca pt ure 
s u bse q ue nt ca ncer 
t hera p y
S u bsta ntial
1. 3 Sc he d ule of 
Acti vities
It as clarifie d i n b ot h Ta bles 1 a n d 2 t hat A de n osi ne ( A D O) bi o mar ker 
assess me nts were “ A D O si g nalli n g ge ne e x pressi o n”. T his was als o 
casca de d i n t he pr ot oc ol.
Re vise d per st u d y tea m 
i n p ut
N o n -s u bsta ntial
 
 
 
 
1. 3 Sc he d ule of 
Acti vities
Ne w acti vit y a d de d t o Ta ble 2 f or ca bazita xel p ost -d ose P K sa m pli n g, 
a n d ti me p oi nts f or A Z D 4 6 3 5 a n d d ur val u ma b sa m pli n g were e dite d
T hese e dits were ma de 
f or c o nsiste nc y wit h 
N o n -s u bsta ntial
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 6 of 1 9 3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
pla n ne d a nal yses i n 
pr ot o c ol b o d y.
1. 3 Sc he d ule of 
Acti vities
I ma gi n g efficac y assess me nts were e dite d t o a d d p ositr o n e missi o n 
t o m o gra p h y ( P E T) sca ns t o t u m o ur i ma gi n g per Res p o nse E val uati o n 
Criteria i n S oli d T u m o urs ( R E CI S T) criteria, a n d t o a d d a ± 1 wee k visit 
wi n d o w d uri n g t he treat me nt peri o d i n b ot h Ta bles 1 a n d 2 f or 
c o nsiste nc y wit h else w here i n t he pr ot oc ol.
Re vise d per st u d y tea m 
i n p ut
S u bsta ntial
1. 3 Sc he d ule of 
Acti vities
F o ot n otes were a d de d t o eac h, Ta bles 1 a n d 2, all o wi n g t hat r o uti ne 
cli nical a n d safet y assess me nts ma y be d o ne 1 da y pri or t o eac h visit, if 
re q uire d, a n d t hat t he patie nt re p orte d o utc o me ( P R O) i nstr u me nts will 
be a d mi nistere d a n d c o m plete d at t he start of eac h visit.
Re vise d per st u d y tea m 
i n p ut
S u bsta ntial
 
 
 
 
1. 3 Sc he d ule of 
Acti vities
A f o ot n ote was a d de d t o Ta ble 2, wit h refere nce t o t he hae mat ol o g y 
assess me nt, t o c o nfir m t hat t he hae mat ol o g y assess me nt will i ncl u de 
f ull bl o o d c o u nt
Re g ulat or y re q uest t o 
i nclu de f ull bl o o d c o u nt 
at Wee k 2 as wee kl y 
meas ure me nts are 
rec o m me n de d d uri n g 
C y cle 1 f or ca bazita xel.
S u bsta ntial
1. 3 Sc he d ule of 
Acti vities
A f o ot n ote was a d de d t o Ta ble 2, t o pr o vi de refere nce t o Secti o n 6. 7. 3 
a n d Ta ble 1 2 w hic h i ncl u des i nstr ucti o n o n h y perse nsiti vit y m o nit ori n g 
d uri n g ca bazita xel i nf usi o n, a n d d ose m o dificati o ns i n t he e ve nt of 
t o xicities.
Re vise d per st u d y tea m 
i n p ut
N o n -s u bsta ntial
1. 3 Sc he d ule of 
Acti vities
F or Ta bles 1 a n d 2, t he Sc he d ule d assess me nts f or e P R Os were u p date d 
t o ma ke c o nsiste nt wit h pr ot oc ol b o d y a n d statistical a nal ysis pla n 
( S A P).
Re vise d per u p date t o 
S A P a n d per st u d y tea m 
i n p ut
S u bsta ntial
C CI


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 7 7 of 1 9 3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
2 I ntr o d ucti o n, 4. 3 
J ustificati o n of d ose, 
a n d 6. 2. 3 Ca bazita xel
A d de d t he U nite d States ( U S) prescri bi n g i nf or mati o n as o n e of t he 
refere nce safet y d oc u me nts f or ca bazita xel.
Re vise d per st u d y tea m 
i n p ut
S u bsta ntial
2. 2 Bac k gr o u n d
E xte nsi ve -sta ge s mall cell l u n g ca ncer ( E S-S C L C) was a d de d t o t he 
d ur val u ma b i n dicati o ns i n t he U S.
U p date d per Marc h 2 0 2 0 
u p date t o t he U S 
prescri bi n g i nf or mati o n
N o n -s u bsta ntial
2. 2. 1 Be nefit/ris k 
Assess me nt
T his secti o n was u p date d wit h a n u p date d data -c ut -off of 0 2 Dece m ber 
2 0 1 9.
Re vise d wit h ne w data 
a vaila ble i n t he I B
S u bsta ntial
2. 2. 1 Be nefit/ris k 
Assess me nt
T his secti o n was u p date d t o i ncl u de a li n k t o A p pe n di x L descri bi n g 
ris k c o nsi derati o ns f or C O VI D-1 9. 
A d de d i n vie w of 
o n g oi n g C O VI D -1 9 
pa n de mic
S u bsta ntial
3 O bjecti ves a n d 
e n d p oi nts
 
Re vise d per st u d y tea m 
i n p ut
N o n -s u bsta ntial
3 O bjecti ves a n d 
e n d p oi nts
 
 
 
Re vise d f or clarit y per 
st u d y tea m i n p ut
S u bsta ntial
4. 1. 1 Safet y Re vie w 
C o m m ittee
It was clarifie d t hat t he st u d y tea m will c o nsi der halti n g recr uit me nt at 
a n y p oi nt d uri n g t he Safet y Re vie w C o m mittee ( S R C)’s re vie w, u ntil 
f ull a nal ysis a n d re vie w b y t he S R C is a vaila ble.
Re vise d f or clarit y 
re gar di n g partici pa nt 
recr uit me nt d uri n g S R C 
re vie w per st u d y tea m 
i n p ut
S u bsta ntial
5. 1. I ncl usi o n Criteria 
a n d 8. 3. 9. 1 Pater nal 
e x p os ure
I ncl usi o n criteri o n n u m ber 7 u p date d t o re place “ barrier met h o ds” wit h 
“ male c o n d o m” a n d t o e xte n d c o ntrace pti o n re q uire me nt t o 6 m o nt hs
after last d ose of ca bazita xel.
Re g ulat or y re q uest t o 
u p date as t he ca bazita xel 
S u m mar y of Pr o d uct 
C haracteristics ( S m P C) 
o bser ves t hat e x p os ure of 
a n ot her pers o n t o st u d y 
S u bsta ntial
C CI
C CI


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Brief Rationale
Substantial/Non-
substantial
drug via ejaculate must 
be prevented.
5.1. Inclusion Criteria 
and 8.3.9.1 Paternal 
exposure
The timeline for reporting of the outcome of a pregnancy for a female 
partner of a participant was updated in Section 8.3.9.1 (Pregnancy): 
“However, the outcome of all pregnancies (spontaneous miscarriage, 
elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) occurring any time from the first date of dosing for 
AZD4635, durvalumab and cabazitaxel until 3 months (Arm A) or 6 
months (Arm B) after the last dose of the study drugs should, if 
possible, be followed up and documented until 30 days after birth. As 
deemed appropriate, the pregnancies will be followed up per local 
guidance and regulatory requirements.” A reference to Section 8.3.9.1 
was added to inclusion criterion 7 in Section 5.1
Updated per input from 
ethics committees
Substantial
5.1. Inclusion Criteria
Update of inclusion criterion 8 to clarify the haemoglobin level for Arm 
B:
“Haemoglobin ≥9.0 g/dL (≥10.0 g/dL for Arm B)”
Regulatory request to be 
accordance with the 
SmPC of cabazitaxel.
Substantial
5.1 Inclusion criteria
Update of inclusion criterion 10 to add that “Patients who were eligible 
for both Arm A and Arm B will be preferentially allocated to Arm B, 
until enrollment of Arm B is completed.”
Revised for clarity per 
study team input
Substantial
5.2. Exclusion Criteria
Exclusion criterion number 2 has been expanded to include:
For current or prior use of immunosuppressive medication within 
14 days before the first dose the following will be exceptions to this:
Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 
intra-articular injection)
Systemic corticosteroids at physiologic doses not to exceed 
10 mg/day of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (eg, CT 
scan premedication)
Regulatory request to 
expand this exclusion 
criterion to account for 
the immune system 
profiles of the study 
drugs.
Substantial
5.2. Exclusion Criteria
Exclusion criterion number 3 was updated to delete the text “requiring 
corticosteroids”:
Regulatory request to 
update since more than 
Substantial


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Substantial/Non-
substantial
Participant with a history of pneumonitis requiring corticosteroids.
one study drug in this 
study may cause 
pneumonitis and the risk 
in combination therapy to 
participants with any 
history of pneumonitis 
without qualification is 
therefore sufficient to 
exclude the participant.
5.2. Exclusion Criteria
Exclusion criterion number 5 has been expanded to include additional 
systemic diseases that would require exclusion from the study.
“As judged by the Investigator, any evidence of severe or uncontrolled 
systemic diseases, including uncontrolled hypertension, active bleeding 
diatheses, active infection including hepatitis B, hepatitis C, and human 
immunodeficiency virus, chronic gastrointestinal diseases (eg, 
Crohn's disease, chronic colitis), ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, 
unstable angina pectoris, uncontrolled cardiac arrhythmia, or 
active interstitial lung disease (ILD).”
Regulatory request to 
expand this exclusion 
criterion to account for 
information in the 
AZD4635 IB (chronic 
gastrointestinal diseases) 
and toxicity profiles of 
the study drugs.
Substantial
5.2. Exclusion Criteria
Addition of exclusion criteria numbers 8, 9, and 10:
8. History of allogeneic organ transplantation.
9. Active or prior documented autoimmune or inflammatory 
disorders (including inflammatory bowel disease [eg, colitis or 
Crohn's disease], diverticulitis [with the exception of 
diverticulosis], systemic lupus erythematosus, Sarcoidosis 
syndrome, or Wegener syndrome [granulomatosis with 
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, 
uveitis, etc]). The following are exceptions to this criterion:
Participants with vitiligo or alopecia
Participants with hypothyroidism (eg, following Hashimoto 
syndrome) stable on hormone replacement 
Any chronic skin condition that does not require systemic therapy
Regulatory request to add 
these exclusion criteria 
since the study drugs 
modify the immune 
system.
Substantial


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substantial
Participants without active disease in the last 5 years may be 
included but only after consultation with the Study Physician
Participants with coeliac disease controlled by diet alone
10. History of active primary immunodeficiency.
5.2. Exclusion Criteria
Addition of exclusion criterion number 11:
Active infection including tuberculosis (clinical evaluation that 
includes clinical history, physical examination and radiographic 
findings, and tuberculosis testing in line with local practice).
Regulatory request to 
include since the 
durvalumab SmPC 
specifies that participants 
with tuberculosis were 
excluded from clinical 
trials of durvalumab, the 
clinical implications in 
this study of combination 
therapies are unknown, 
and therefore, 
participants with 
tuberculosis need to be 
specified as excluded.
Substantial
5.2. Exclusion Criteria
Previous exclusion criterion number 16 has been moved up to 
exclusion criterion 12
Exclusion criterion for 
vaccines should be 
included for all 
participants and not just 
for those in Arm B.
Substantial
5.2. Exclusion Criteria
Update of exclusion criterion number 16 to clarify hypersensitivity to 
study drugs and excipients:
“History of hypersensitivity to any of the study drugs or any of the 
study drug excipients including hypersensitivity to polysorbate-80 if 
allocated to cabazitaxel.”
Regulatory request to 
update the criterion to 
specify hypersensitivity 
to all study drugs and 
study drug excipients.
Substantial


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Description of Change
Brief Rationale
Substantial/Non-
substantial
5.2. Exclusion Criteria 
and 6.5 concomitant 
medication
Exclusion criteria 18, 19 and 20, and the concomitant medication 
section, were updated to include updated instruction for disallowed 
medication. 
Revised per study team 
input
Substantial
5.2. Exclusion Criteria
Exclusion criterion 25 was updated with detail “History of allogeneic 
organ, or other transplant, such as bone marrow transplant
Revised per study team 
input
Substantial
5.2. Exclusion Criteria
A correction was made to exclusion criterion 28 to exclude participants 
with concomitant treatment with another adenosine 1 receptor (A1R)
antagonist
Revised per study team 
input
Substantial
5.2 Exclusion criteria
Clarity was added to exclusion criterion 29 regarding cardiac criteria: 
Ejection  fraction <55% or the lower limit of normal of the institutional 
standard, ascertained by an echocardiogram or MUGA that has 
been obtained in the 6 months prior to screening. If there has been 
a change in the participant’s cardiac status, or if there has not be 
an echocardiogram or MUGA within the 6 months prior to study 
enrollment, this should be performed as part of the screening 
assessments
Revised per study team 
input
Substantial
5.3.1 Meals and dietary 
restrictions
Dietary restrictions for participants in Arm B were clarified
Revised per study team 
input
Substantial
6.1.1 Investigational 
products
Text regarding packaging and labelling was revised
Revised per input from 
clinical logistics team
Non-substantial
6.2.1 AZD4635
Broadened language that states that AZD4635 can be taken with food.
Revised per input from 
study team
Non-substantial
6.5.2. Prohibited or 
Restricted Medications
Addition of a new sub-heading “Prohibited or Restricted 
Medications”
Regulatory request to 
clarify appropriate sub-
heading to match the 
contents of text and 
Tables 5, 6, 7, and 8.
Substantial


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Description of Change
Brief Rationale
Substantial/Non-
substantial
6.5.3 Drug-drug 
interactions
Drug-drug interactions with AZD4635 were updated
Revised per updated IB 
Version 6.1, dated 12 
Aug 2020
Substantial
6.6.1. Definition of 
Dose-Limiting Toxicity 
for Arm B
Text has been added to clarify haematological dose limiting toxicities 
as below:
“Haematological toxicities CTCAE ≥ Grade 3 not attributed to 
cabazitaxel alone, except for neutropenia, which is addressed as:
Neutropenia ≥ CTCAE Grade 4 or febrile neutropenia present for more 
than 7 days. For AZD4635/cabazitaxel/durvalumab it will not be 
considered a DLT if attributed to cabazitaxel only.”
Regulatory request to 
update to specify 
“haematological 
toxicities…” as the text 
was limited to one 
specified event 
suggesting that every 
other significant 
haematological toxicity 
is excluded from 
consideration as 
drug-limiting toxicity 
(DLT).
Non-substantial
6.7.2 Management of 
Toxicities Related to 
Durvalumab Therapy
The following text was deleted, as it is not intended, and for 
consistency with the rest of the protocol: “If medically appropriate, 
dose modifications are permitted after discussion with the Medical 
Monitor/AZ Study Physician. All dose modifications should be 
documented with clear reasoning and documentation of the approach 
taken.”
Revised per input from 
study team
Substantial
6.7.2.1. Specific 
Toxicity Management 
Guidelines and Dose 
Modification 
Information for 
Durvalumab
Clarification was provided that specific toxicity management guidelines 
and dose modification information is for durvalumab and so 
“tremelimumab” has been deleted from the text pertaining to the 
guidelines. All related text deleted.
Also, the following hyperlink was deleted as it was not active:
Regulatory request to 
remove description of 
tremelimumab as it is not 
a study drug for this 
study.
Regulatory request to 
check inactive hyperlink.
Substantial


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substantial
“In addition, a current version of TMGs is available through the 
following link: https://tmg.azirae.com. Please contact the clinical study 
associate for information on how to gain access to this website”
6.7.2.1. Specific 
Toxicity Management 
Guidelines and Dose 
Modification 
Information for 
Durvalumab
Addition of text to clarify the risks associated with durvalumab:
“Risks with durvalumab include, but are not limited to, 
diarrhoea/colitis, pneumonitis/ILD, endocrinopathies (i.e., events of 
hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypo-thyroidism, type I diabetes mellitus and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in 
creatinine, rash/dermatitis, myocarditis, myositis/polymyositis, 
infusion-related reactions, hypersensitivity reactions, pancreatitis, 
serious infections, and other rare or less frequent inflammatory 
events including neuromuscular toxicities (e.g. Guillain-Barre 
syndrome, myasthenia gravis)”
Regulatory request to 
indicate toxicities for 
durvalumab.
Substantial
6.7.3. Management of 
Toxicities Related to 
Cabazitaxel Therapy
Addition of peripheral neuropathy dose modification actions to 
Table 12.
Regulatory request to add 
neurological toxicity and 
potential dose 
modifications.
Substantial
6.7.3. Management of 
Toxicities Related to 
Cabazitaxel Therapy
Addition of text to describe close monitoring for hypersensitivity 
reactions:
“Participants should be observed closely for hypersensitivity 
reactions especially during the first and second infusions, as per the 
local cabazitaxel label. Hypersensitivity reactions may occur within 
a few minutes following the initiation of the infusion of cabazitaxel, 
thus facilities and equipment for the treatment of hypotension and 
bronchospasm should be available. Severe reactions can occur and 
may include generalised rash/erythema, hypotension and 
bronchospasm. Severe hypersensitivity reactions require 
immediate discontinuation of cabazitaxel and appropriate 
therapy.”
Regulatory request to 
include close monitoring 
as indicated in the 
cabazitaxel SmPC for the 
first and second infusions 
due to the risk of 
hypersensitivity 
reactions.
Substantial


Cli nical St u d y Pr ot oc ol – 3. 0
Astra Ze neca
A Z D 4 6 3 5 - D 8 7 3 1 C 0 0 0 0 2
C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 8 4 of 1 9 3
Secti o n # a n d N a me
Descri pti o n of C h a n ge
Brief R ati o n ale
S u bst a nti al/ N o n -
s u bst a nti al
7. 2 Partici pa nt 
wit h dra wal fr o m t he 
st u d y
Te xt was a d de d t o pr o vi de g ui da nce: “ D uri n g t he st u d y, C O VI D - 1 9 
tests ma y be prescri be d, if re q uire d, a n d i n acc or da nce wit h l ocal 
g ui da nce. If a partici pa nt tests p ositi ve, his c o nti n ue d partici pati o n i n 
t he st ud y a n d his treat me nt wit h t he st u d y dr u gs will be disc usse d wit h 
t he Pare xel a n d Astra Ze neca Me dical M o nit ors f or t his st u d y.”
A d de d i n vie w of 
o n g oi n g C O VI D -1 9 
pa n de mic
S u bsta ntial
8. 1. 2 P C W G 3 B o ne 
Lesi o n Assess me nt
P E T sca n was re m o ve d fr o m t his secti o n as it is n ot i nte n de d f or t his 
assess me nt
Re vise d per st u d y tea m 
i n p ut
S u bsta ntial
8. 2. 1. P h ysical 
E xa mi nati o ns a n d 
Wei g ht
P h y sical e xa mi nati o n descri pti o n has bee n u p date d t o clarif y t hat:
“P h ysic al e x a mi n ati o ns will i ncl u de assess me nts of t he he a d, e ye s, 
e ars, n ose, a n d t hr o at a n d t he res pir at or y, c ar di o v asc ul ar, 
g astr oi ntesti n al, ur o ge nit al, m usc ul os kelet al, ne ur ol o gic al, 
der m at ol o gic al, he m at ol o gic/l y m p h atic, a n d e n d ocri ne s yste ms. 
Hei g ht will be me as ure d at scree ni n g o nl y. ”
Re g ulat or y re q uest t o a d d 
ne ur ol o gical e xa mi nati o n 
t o re mi n d I n vesti gat ors 
of t he i m p orta nce of 
ne ur o pat hic t o xicit y wit h 
d ur val u ma b a n d 
ca bazita xel.
N o n -s u bsta ntial
8. 2. 4 
Electr ocar di o gra ms
T he refere nce t o st u d y s pecific E C G ma n ual was delete d as r o uti ne 
e val uati o n of t he E C Gs is i nte n de d
Re vise d per st u d y tea m 
i n p ut
S u bsta ntial
8. 2. 5. 
Ec h ocar di o gra m/ M U G A
Ne w secti o n has bee n i ncl u de d t o descri be ec h ocar di o gra m/ M U G A 
re q uire me nts.
A ne w secti o n f or 
ec h ocar di o gra m/ M U G A 
has bee n a d de d si nce 
ec h ocar di o gra m/ M U G A 
assess me nts ha ve bee n 
i ncl u de d i n t he sc he d ule 
of acti vities.
S u bsta ntial
8. 2. 8 Ot her assess me nts
Ne w secti o n a d de d a n d a d diti o nal te xt a d de d t o clarif y t hat t he pr ostate -
s pecific a nti ge n ( P S A) 
 sa m ples 
will be a nal yse d b y a l ocal la b orat or y a n d a ce ntral la b orat or y, 
res pecti vel y
Re vise d per st u d y tea m 
i n p ut
N o n -s u bsta ntial
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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
8.2.8 Other assessments
Text was added to provide guidance around COVID-19 testing in the 
study: “COVID-19 testing
During the study, tests for active COVID-19 infection may be 
prescribed, where appropriate, and in accordance with local procedures. 
If a participant tests positive, his continued participation in the study 
and his treatment with the study drugs will be discussed with the 
Parexel and AstraZeneca Medical Monitors for this study.”
Added in view of 
ongoing COVID-19 
pandemic
Substantial
8.2.9 Clinical outcome 
measures
Revised to clarify that the PRO questionnaires should be completed at 
the start of each visit.
Revised per study team 
input
Non-substantial
8.2.10 Survival follow-
up
The following text was added “Note: when required survival calls will 
be made in the week following the date of DCO for the analysis, and if 
participants are confirmed to be alive or if the death date is after the 
DCO date these participants will be censored at the date of DCO. When 
required the status of ongoing, withdrawn (from the study) and “lost to 
follow-up” participants at the time of the OS analysis should be 
obtained by the site personnel by checking the participant’s notes, 
hospital records, contacting the participant’s general practitioner and 
checking publicly-available death registries. In the event that the 
participant has actively withdrawn consent to the processing of their 
personal data, the vital status of the participant can be obtained by site 
personnel from publicly available resources where it is possible to do 
so under applicable local laws.”
Revised per study team 
input
Non-substantial
8.3.3 Causality 
collection
It was clarified that AZD4635, durvalumab and cabazitaxel are all 
investigational products that will be considered for causality 
assessment
Revised for clarity per 
study team input
Substantial
8.3.9.1. Paternal 
Exposure
Addition of text regarding the storage of sperm in Arm B:
“Participants in Arm B will be advised on storage of sperm prior to 
receiving cabazitaxel due to the possibility of irreversible 
infertility/testicular damage due to cabazitaxel therapy.”
Regulatory request to 
instruct Investigators to 
provide advice to 
participants on the 
conservation of sperm 
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
prior to treatment 
because of the possibility 
of irreversible 
infertility/testicular 
damage due to therapy 
with cabazitaxel as noted 
in SmPC.
8.3.9.1. Paternal 
Exposure
The period for follow-up of pregnancy outcomes was clarified for each 
treatment arm: “However, the outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring any time from the first date of 
dosing for AZD4635, durvalumab and cabazitaxel until 3 months (Arm 
A) or 6 months (Arm B) after the last dose of the study drugs should, if 
possible, be followed up and documented until 30 days after birth. As 
deemed appropriate, the pregnancies will be followed up per local 
guidance and regulatory requirements”
Revised for clarity, per 
team input
Substantial
8.4 Overdose
Text in this section was rephrased to clarify that “If associated with an 
AE, any dose in excess of the dose specified according to the protocol 
will constitute an overdose.”
Revised for clarity, per 
team input
Non-substantial
8.5.1 Pharmacokinetics
This section was updated to provide clarity on the schedule for PK 
assessments, and to add a note to Table 17 that The SRC will review 
the data from the first 6 evaluable participants receiving Cycle 1 of 
Arm B and if agreed after the data review subsequent participants 
entering the study will follow the PK sampling schedule in Table 
18. Recruitment in Arm B may continue until the SRC complete 
their review and their decision is made. Intense PK sampling per 
Table 17 may be performed for > 6 participants until the SRC 
decision is made
Revised for flexibility 
and clarity, per team 
input
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
8.5.1. Pharmacokinetics, 
Table 19
Text added as footnote to Table 19 to clarify that the first 6 participants 
in Arm B will have cabazitaxel PK samples collected during Cycle 1.
Clarification that PK data 
is required from only the 
first 6 participants.
Substantial
8.5.2 Immunogenicity 
Assessments 
The following text was added: Samples for determination of 
durvalumab concentration in serum will be analysed by a designated 
third party on behalf of AstraZeneca. Samples will be collected, 
labelled, 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.
Revised per team input
Substantial
9.4.1. General 
considerations
The following text was added: “If relevant for the study, the following 
will be included due to the COVID-19 pandemic: participants affected 
by the COVID-19 pandemic will be listed including category for study 
disruption due to the pandemic and details of the disruption. If required, 
the study disruptions due to the pandemic will also be summarised. 
Participant disposition will be summarised including number (%) of 
participants who discontinued treatment due to the pandemic and who 
withdrew from study due to the pandemic. Important protocol 
deviations will be summarised including number (%) of participants 
with at least one important protocol deviation related to the pandemic.”
Added in view of 
ongoing COVID-19 
pandemic
Substantial
9.4.2 Efficacy
The following text was added for clarity under the sub-heading 
“Tumour response”:
“For the secondary endpoint ORR assessed by RECIST 1.1 and 
PCWG3, only dosed participants with measurable disease (target 
lesions) at baseline will be included in the analysis. A responder will be 
any participant with a confirmed  response of PR or CR in their soft 
tissue disease assessed by RECIST 1.1, in the absence of progression 
on bone scan assessed by PCWG3. A participant will be classified as a 
responder if the RECIST 1.1 criteria for a CR or PR are satisfied (as 
well as the absence of confirmed progression on bone scan assessed by 
PCWG3).”
Revised for clarity, per 
team input
Non-substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
9.4.2 Efficacy
The text for analysis of PROs was updated to omit the bone pain item, 
FAPSI-8 and box plot presentations, and to changed “time to 
worsening” to “time to deterioration”
The following text was also omitted “Graphical presentations of safety 
data will be presented as is deemed appropriate. This may include, but 
is not restricted to, presentation of parameters against time, 
concentration or shift plots. Appropriate scatter plots will also be 
considered to investigate trends in parameters compared to baseline.”
Revised per study team 
input
Substantial
9.4.4.1 Pharmacokinetic 
analysis
It was clarified that AZD4635’s metabolites will be analyzed, and that 
durvalumab PK derivations are not planned. A note was added that 
“The PK parameter data may also be used to explore the relationship 
with other endpoints such as pharmacodynamics.”
Updated per revisions 
made to the SAP
Substantial
Appendix B, B2. 
Definitions of serious 
adverse event
Clarification of reporting period for SAEs:
“If any SAE occurs in the course of the study, then Investigators or 
other site personnel inform the appropriate AstraZeneca 
representatives within one day i.e., immediately but no later than 
24 hours of when they become aware of it.”
Regulatory request to 
repeat in Appendix B the 
specific time-frame for 
reporting SAE.
Non-substantial
Appendix B, B2. 
Definitions of serious 
adverse event
Update to Appendix B2 to include text that was missing previously for 
tumour AEs:
“Adverse Events (AEs) for new malignant tumours reported 
during a study should generally be assessed as Serious AEs. If no 
other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical 
judgement on an individual event basis should be applied to clarify 
that the malignant tumour event should be assessed and reported 
as a Non-Serious AE. For example, if the tumour is included as 
medical history and progression occurs during the study, but the 
progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being 
Regulatory request to 
check text and include 
description of new 
malignancies. 
Substantial


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Section # and Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
assessed as serious, although reporting of the progression of the 
malignant tumour as an AE is valid and should occur. Also, some 
types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be 
assessed as Non-Serious; examples include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone 
biopsy.”
Appendix B, B5. 
Adverse Events of 
Special Interest
Section was added to include specific details of adverse events of 
special interest (AESI).
Regulatory request to 
update Appendix B with 
AESI details that were 
missing.
Substantial
Appendix H, PCWG3 
Criteria
Text for Progression from nmCRPC to metastatic CRPC was omitted 
as it was not directly relevant to the study population.
Revised per team input
Non-substantial
Appendix I. Disallowed 
Medications
Clarifications have been made to describe the correct CYP3A inhibitors 
and inducers and remove redundant information/. 
Updated to remove 
information which is not 
relevant to AZD4635 or 
cabazitaxel. 
Substantial
Appendix L
Appendix L was added to the protocol, containing specifics regarding 
COVID, including a background to COVID-19, risk assessment in view 
of the COVID-19 pandemic, risk mitigation measures restrictions 
related to COVID-19 and data quality assurance considerations. 
References to the EMA and FDA guidances on the management and 
conduct of clinical trials during this pandemic were also provided.
Added in view of 
ongoing COVID-19 
pandemic
Substantial
General
Minor updates throughout to correct typographical errors and for 
consistency in terminology.
Minor updates to correct 
typographical errors.
Non-substantial


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11
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
1 9 2 of 1 9 3
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Cabazitaxel. Drugs. 2011;71:1251-1258.


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: 
D oc u me nt Title:
D 8 7 3 1 C 0 0 0 0 2 Cli nical St u d y Pr ot oc ol versi o n 3
D oc u me nt I D:
Versi o n L a bel:
3. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
3 0- N o v- 2 0 2 0 1 6: 5 4 U T C
C o nte nt A p pr o val
3 0- N o v- 2 0 2 0 0 9: 5 7 U T C
C o nte nt A p pr o val
3 0- N o v- 2 0 2 0 1 3: 1 9 U T C
C o nte nt A p pr o val
N otes: ( 1) D oc u me nt details as st ore d i n  
, a n Astra Ze neca d oc u me nt ma na ge me nt s yste m.
P P D
P P D
C CI
C CI
P P D
C CI

SAP_001.pdf: 
Protocol number: D8731C00002
Document title: A Phase II, Open-label Study to Assess the 
Efficacy, Safety, and Tolerability of AZD4635 in Combination 
with Durvalumab and in Combination with Cabazitaxel and 
Durvalumab in Patients Who Have Progressive Metastatic 
Castrate-Resistant Prostate Cancer (AARDVARC)
NCT number: NCT04495179
Version number: 4.0
Date of the document: 20 Apr 2022 


Pare xel I nter nati o nal
Astra Ze neca
D 8 7 3 1 C 0 0 0 0 2
Statistical A nal ysis Pla n
C O N FI D E N TI A L
Pr oject D oc u me nt Versi o n N o . 4. 0
Effecti ve Date:  2 6 N o v 1 9
Pr oject D oc u me nt Effecti ve D ate : 2 0 A pr. 2 2
Relate d t o:  
Pa ge 1 of 8 6
P are xel I nter n ati o n al
Astra Ze neca
D 8 7 3 1 C 0 0 0 0 2
A P hase II, O pe n -label St u d y  t o Assess t he Efficac y, S af et y, a n d T olera bilit y o f A Z D 4 6 3 5 i n 
C o m bi nat i on wi t h D ur val u ma b a n d i n C o m bi nati o n wit h Ca bazita xel a n d D ur val u ma b i n Pat ient s 
W h o Ha ve Pr o gressi ve Metastatic Castrate -Resista nt Pr ostate Ca ncer ( A A R D V A R C)
St atistic al A n al ysis Pl a n
Versi o n: 4. 0
P are xel Pr oject N u m ber: 
C CI
C CI
C CI