Conditions: Prostate Cancer Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Keywords: Prostate cancer AZD4635 oleclumab durvalumab MEDI9447 Adenosine 2A Receptor Antagonist A2AR
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 59
Healthy volunteers: no

Brief summary:
This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arms (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

Detailed description:
This is an open-label Phase II modular study in participants with prostate cancer which will assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in different treatment arm (referred to as modules).

Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2: AZD4635 plus oleclumab.

All participants will be allocated into a module using an Interactive Web Response System (IWRS). Randomization will occur when patients meet eligibility criteria for two or more modules that are currently recruiting. If participants only meet the criteria for one currently recruiting module, they will be allocated to that module without randomization taking place.

The primary objective of the clinical study is to evaluate the efficacy of each combination therapy by: 1) assessing the objective response rate (ORR) of participants with measurable disease (response will be determined by Response Evaluation Criteria in Solid Tumours \[RECIST 1.1\]); 2) assessing the prostate-specific antiget (PSA) confirmed response rate of each combination therapy (PSA confirmed response rate is defined as the proportion of participants with a reduction in the PSA level of ≥50% measured from baseline to the lowest post-baseline PSA result measured twice, at least 3 weeks apart by the Prostate Cancer Working Group 3 criteria \[PCWG3\]).

The safety endpoints include assessment of adverse events and serious adverse events, physical examinations, vital signs, and collection of clinical chemistry/hematology parameters

There will be approximately 30 PSA evaluable participants in each module, and approximately 20 participants will have RECIST measurable disease at baseline in each module. If any of the required participants for PSA and/or ORR are not evaluable for PSA response or tumor response, respectively, they may be replaced at the sponsor's discretion.

Arms:
arm 1: Participants will receive monotherapy of AZD4635 75 mg orally once daily (QD) for first 14 days and thereafter will continue to receive 75 mg orally QD in combination with durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) until will derive clinical benefit as judged by the investigator, confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. arm 2: Participants will receive combination therapy of AZD4635 (50 mg / 75 mg orally QD) and oleclumab 1500 mg IV (every 2 weeks of 28-day cycle for the first 4 doses and Q4W thereafter) until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Interventions: intervention 1: AZD4635 intervention 2: Oleclumab intervention 3: Durvalumab
Intervention descriptions: intervention 1: In Module 1, participants will receive AZD4635 75 mg capsule orally QD for first 14 days and thereafter will continue to receive 75 mg orally QD Q4W.

In Module 2, participants will receive AZD4635 50 mg / 75 mg capsule orally QD Q2W of 28-day cycle for the first 4 doses and Q4W thereafter.

In both modules, participants will receive treatment until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. intervention 2: In Module 2, participants will receive oleclumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q2W of 28-day cycle for the first 4 doses and Q4W thereafter until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first. intervention 3: In Module 1 after monotherapy of AZD4635, participants will receive durvalumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q4W until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.

Protocol document:
SAP_006.pdf: 
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Statistical Analysis Plan
Study Code
D8731C00001
Edition Number
2.0
Date
08/November/2021
An Open-label, Multi-drug, Multi-center Phase II Combination 
Study of AZD4635 in Patients with Prostate Cancer


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 5
AMENDMENT HISTORY................................................................................................... 8
1
STUDY DETAILS ........................................................................................... 14
1.1
Study objectives................................................................................................ 14
1.2
Study design ..................................................................................................... 15
1.3
Number of subjects........................................................................................... 16
2
ANALYSIS SETS ............................................................................................ 16
2.1
Definition of analysis sets................................................................................. 16
2.2
Violations and deviations.................................................................................. 18
3
PRIMARY AND SECONDARY VARIABLES ............................................... 20
3.1
General principles............................................................................................. 20
3.2
Primary outcome variables................................................................................ 23
3.2.1
Calculation of derivation of tumor response variables....................................... 23
3.2.1.1
RECIST visit responses .................................................................................... 23
3.2.1.2
Objective response rate/Best objective response rate......................................... 30
3.2.1.3
Change in tumor size ........................................................................................ 32
3.2.2
PSA response rate............................................................................................. 33
3.3
Secondary outcome variables............................................................................ 33
3.3.1
Duration of response (DOR) ............................................................................. 33
3.3.2
Radiological Progression-Free Survival (rPFS)................................................. 34
3.3.3
Overall survival (OS)........................................................................................ 35
3.3.4
Calculation or derivation of pharmacokinetic variables..................................... 36
3.3.5
3.4
Safety outcome variables .................................................................................. 36
3.4.1
Duration of exposure ........................................................................................ 36
3.4.2
Dose intensity................................................................................................... 38
3.4.3
Adverse events.................................................................................................. 38
3.4.4
ECG changes .................................................................................................... 39
3.4.5
Echocardiography or muli-gated acquisition scan (ECHO/ MUGA).................. 39
3.4.6
Vital sign changes............................................................................................. 39
3.4.7
Laboratory data................................................................................................. 39
3.4.8
Creatinine clearance.......................................................................................... 40
4
ANALYSIS METHODS................................................................................... 40
4.1
General principles............................................................................................. 40
4.2
Analysis methods.............................................................................................. 41
4.2.1
Randomization.................................................................................................. 41
4.2.2
Disposition, demography, and baseline characteristics ...................................... 41
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4.2.2.1
Patient disposition............................................................................................. 41
4.2.2.2
Analysis sets..................................................................................................... 41
4.2.2.3
Protocol deviations ........................................................................................... 42
4.2.2.4
Demography and baseline characteristics .......................................................... 42
4.2.2.5
Disease diagnosis and staging ........................................................................... 42
4.2.2.6
Prior therapies................................................................................................... 43
4.2.2.7
Concomitant medications.................................................................................. 43
4.2.2.8
Medical History................................................................................................ 43
4.2.3
Tumor response and efficacy ............................................................................ 44
4.2.3.1
Best objective response and Objective response rate ......................................... 44
4.2.3.2
Change in tumor size ........................................................................................ 44
4.2.3.3
Radiological Progression-free survival.............................................................. 45
4.2.3.4
Duration of response......................................................................................... 45
4.2.3.5
Overall survival ................................................................................................ 45
4.2.3.6
Overall Survival will be analyzed in the same manner as PFS if patient 
numbers allow. 
.................................................................................. 45
4.2.4
PSA response.................................................................................................... 45
4.2.5
Safety analyses ................................................................................................. 46
4.2.5.1
Exposure........................................................................................................... 46
4.2.5.2
Adverse events/ Serious adverse events ............................................................ 46
4.2.5.3
Laboratory results ............................................................................................. 47
4.2.5.4
Monitoring for drug-induced liver injury........................................................... 48
4.2.5.5
Electrocardiographic (ECG).............................................................................. 48
4.2.5.6
Echocardiography or Multi-gated acquisition scan (ECHO/ MUGA) ................ 48
4.2.5.7
Vital signs assessments..................................................................................... 48
4.2.6
Pharmacokinetics data ...................................................................................... 48
4.2.7
Immunogenicity................................................................................................ 50
4.2.8
Exploratory research variables .......................................................................... 50
5
INTERIM ANALYSES.................................................................................... 50
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 50
7
REFERENCES................................................................................................. 50
LIST OF TABLES
Table 1
Study objectives....................................................................................... 14
Table 2
Analysis Set............................................................................................. 17
Table 3
Summary of outcome variables and analysis sets ..................................... 17
Table 4
TL visit responses.................................................................................... 25
Table 5
NTL Visit Responses............................................................................... 29
Table 6
Overall visit responses............................................................................. 30
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LIST OF FIGURES
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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
A2AR
Adenosine 2A receptor
Ae
Amount of drug excreted unchanged
AE
Adverse event
AESI
Adverse Event of Special Interest
BoR
Best objective response
BP
Blood pressure
CLR
Renal clearance
CRF
Case Report Form
CR
Complete response
CSP
Clinical Study Protocol
CSR 
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DCO
Data cut-off
DLT
Dose-limiting toxicity
DOR
Duration of Response
ECG
Electrocardiogram
ECHO
Echocardiograph
ECOG
Eastern Cooperative Oncology Group
EWOC
Escalation with Overdose Control
gmean
Geometric mean
GPS 
Global Product Statistician
imAE
Immune mediated adverse events
IV
Intravenous
LD
Longest diameter
LOQ
Limit of quantification
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Abbreviation or special 
term
Explanation
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary for Regulatory Activities
MDSC
Myeloid-derived suppressor cells
MRI
Magnetic resonance imaging
MRT
Mean residence time
MUGA
Multi-gated acquisition scan
NA
Not applicable
NC
Not calculable
NCI
National Cancer Institute
NE
Not evaluable
NK
Natural killer (cells)
NPD
Non progressive disease
NQ
Non-quantifiable
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAE
Other significant adverse events
ORR
Objective response rate
OS
Overall survival
PCWG
Prostate Cancer Working Group
PD
Progressive disease
PFS
Progression free survival
PID
Percentage intended dose
PK
Pharmacokinetics
PO
Per os (orally)
PR
Partial response
PSA
Prostate Specific Antigen
PT
Preferred term
Rac
Extent of accumulation on multiple dosing
RDI 
Relative dose intensity
RECIST
Response Evaluation Criteria in Solid Tumors
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Abbreviation or special 
term
Explanation
rPFS
Radiological progression-free survival
QTc
QT interval corrected for heart rate
sd
Standard deviation
SAE
Serious adverse event
SAP 
Statistical Analysis Plan
SD
Stable disease
SOC
System organ class
TCP
Temporal change parameter
TL
Target lesion
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AMENDMENT HISTORY
Date
Description of change
In line 
with the 
CSP?
Rationale
15 March 2021
Changed to use US English convention 
throughout the document.
Yes
Current protocol uses the same convention.
15 March 2021
Updated the list of abbreviations
Yes
Added a few abbreviations that were missing but being 
used in the SAP text.
15 March 2021
Changed the edition number.
Yes
 
 
15 March 2021
Updated the CSP version.
Yes
To reflect the latest approved version of the CSP.
18 December 2020
Section 1.1: Updated the endpoint/ variables.
Yes
Details about radiological progression free survival 
variable were missing. To align with the protocol.
18 December 2020
Section 1.1: Added PK related study objective.
Yes
To align with the protocol.
18 December 2020
Section 1.1: Updated the study objectives and 
added 
evaluation.
Yes
To align with the protocol.
15 December 2020
Section 1.2: Added language in the study design 
section, to indicate that the analyses for module 
3 will not be conducted 
Yes
As per CSP version 5.0 dated 23 February 2021, overall 
design was amended which refers to a decision made by 
the sponsor not to open Module 3 to recruitment after a 
comprehensive strategy review of the AZD4635 
program.
18 December 2020
Section 1.3: Updated section 1.3 and added 
‘approximately’ for the number of subjects 
needed with measurable disease at baseline.
Yes
To align with the protocol update.
18 December 2020
Section 2.1: Updated the definition of PK 
analysis set in Table 2.
Yes
Discussions with PK group.
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18 December 2020
Section 2.1: Changed the name of analysis set 
from PSA evaluable response to PSA response
Yes
To match with protocol section 9.3.
18 December 2020
Section 2.1: Updated Table 3 and added OS as 
one of the outcome variables.
Yes
It was missing from this table.
18 December 2020
Section 2.1: Added immunogenicity section in 
table 3.
Yes
To align with the protocol.
15 March 2021
Section 2.1: Updated the analysis set for PSA 
response in Table 3.
Yes
To be consistent with Table 2.
18 December 2020
Updated section 2.2, 4.2.2.1, and 4.2.2.3 to 
include Covid-19 related violations/ deviations.
Yes
The protocol was updated to capture any deviations due 
to Covid-19 pandemic.
10 February 2021
Section 3.1: Added description about handling of 
missing/ partial date for adverse events, in 
section 3.1, 
Yes
To provide clear guidance for programming.
10 February 2021
Section 3.1: Added definition for on-treatment.
Yes
For clarity for programming.
12 February 2021
Section 3.1: Added description of handling 
missing AE start/ end dates.
Yes
Provide clarity to programming.
12 February 2021
Section 3.1 updated to describe visit windowing 
for efficacy analyses.
Yes
To provide guidance for programming of efficacy 
analyses.
15 March 2021
Updated the description of time windows for 
efficacy, in section 3.1.
Yes
To add clarity to the description of efficacy analyses.
19 March 2021
Section 3.1: Updated the description of time 
windows and changed the order to describe 
efficacy analyses first and then safety outcomes.
Yes
For better flow and clarity.
09 June 2021
Section 3.1: Removed reference to PhUSE from 
the subsection of ‘Missing dates’. .
Yes
The guidance for handling of partial dates is aligned 
with available guidance. 
09 June 2021
Section 3.1: For the imputation rules for missing 
AE and concomitant dates, the scenarios in a, b, 
Yes
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and c were updated to add the condition about 
end date not before first dose date.
15 June 2021
Section 3.1: Added the definition of treatment 
emergent adverse event.
Yes
For completeness and clear guidance for programming.
10 February2021
Updated section 3.2.1.3 and added more details 
on derivation of change in tumor size.
Yes
To provide clear guidance to programming and also to 
make sure all scenarios are included in the derivation.
15 March 2021
Updated the names of the CRF modules for 
‘Missed or forgotten doses’ and ‘Patients who 
permanently  discontinue during a dose 
interruption’, in section 3.4.1.
Yes
To align with the study CRF module names. 
12 February 2021
Section 3.4.1 updated : clarification on 
calculation of total treatment duration for 
Oleclumab added; calculation of duration of 
treatment starting dose added. 
Yes
To align with the AZ standard summary for duration of 
exposure.
12 February 2021
Section 3.4.1: Description for missed or 
forgotten doses updated . 
Yes
Align with the current CRFs and the CRF completion 
guidelines.
10 February 2021
Added clarification about the use of snapshot
date and/ or DCO date in section 3.4.1.
Yes
For clearer guidance to programming.
15 March 2021Section 
Details added in Section 3.4.2 about different 
doses administered for AZD4635, for module 2.. 
Yes
To add clarity and align with the CSP.
10 February 2021
Added description for handling of immune 
mediated adverse events, in section 3.4.3.
Yes
As per the prevailing guidance.
18 December 2020
Added description for reporting of AESIs in 
section 3.4.3.
Yes
To align with the protocol.
16 July 2021
Section 3.4.4: Updated the description for ECG 
schedule and programming instructions.
Yes
Better reflect the details in the protocol.
16 July 2021
Section 3.4.5: Added this section about ECHO/ 
MUGA.
Yes
To align with the protocol.


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16 July 2021
Section 3.4.6: Added the description for the vital 
signs collection routine.
Yes
To align with protocol.
16 July 2021
Section 4.2.2: Added the description for the 
summary of study disruptions due to COVID-19 
pandemic.
Yes
To align with the mandated outputs per AZ guidance on 
reporting Covid-19 related disruptions.
12 February 2021
Section 4.2.2.7 was updated to remove the 
description of handling of partial dates.
Yes
To adhere to the PhUse language for the imputation of 
missing/ partial dates for AEs and concomitant 
medications.
15 March 2021
Section 4.2.2.7, removed the post treatment 
medication definition with start date of 30 days 
after the last dose pf AZD4635.
Yes
This information was conflicting with the other 
definition of post-treatment medication.
30 June 2021
Section 4.2.2.8: Added details about the listing 
for medical history.
Yes
The listing was missing and was requested to be added 
by the medical writing team.
15 December2020
Section 4.2.3.1: Added calculation of 80% CI 
based on Clopper-Pearson method, for ORR
Yes
To better match with decision criteria 
15 March 2021
In section 4.2.3.2, removed the description of the 
spider plots when patients have lymph node 
regression. 
Yes
Not needed for creating the spider plots.
June 30 2021
Section 4.2.3.2: Clarified about imputation for 
change in tumor size calculation.
Yes
For  clarity.
June 30 2021
Section 4.2.3.3: Listing of progression details 
added.
Yes
Required as per AZ guidance.
18 December 2020
Section 4.2.3.5 updated to add that OS will be 
analyzed if sufficient number of patients are 
available. 
Yes
For clarity about the basis for OS analysis.
15 March 2021
Updated section 4.2.3.6 to indicate the analysis 
maybe performed, if required.
Yes
To add clarity that this is not a required analysis.


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12 February 2021
Section 4.2.4 updated and handling of patients 
who receive subsequent anti-cancer therapy, 
described.
Yes
To align with the protocol and provide guidance to 
programming.
30 June 2021
Section 4.2.4: Added description for waterfall 
and spider plots for more clarity on the purpose 
of the plots.
Yes
To better explain the purpose of the graphs.
16 July 2021
Section 4.2.5.1: Added the description for the 
graph for the duration of exposure for the study 
treatment.
Yes
It was missing.
18 December 2020
Section 4.2.5.2: Updated this section to clarify 
the definition of Treatment emergent AE.
Yes
To make sure that all treatment emergent AEs are 
properly identified.
15 March 2021
Removed the description of imputation of dates 
in section 4.2.5.2.
Yes
Redundant information. The same details are provided 
in ‘Missing dates’ in section 3.1.
15 March 2021
Section 4.2.5.2 updated to change the 
responsible function for AESI definition.
Yes
AZ patient safety responsible for this task and not the 
representatives from SCDI.
19 April 2021
Clarified the AE follow up time period, in 
section 4.2.5.2.
Yes
To better align with the CRF completion guidelines.
30 June 2021
Section 4.2.5.5: Added description of the 
summary tables.
Yes
To clarify the summaries produced for the ECG data.
16 July 2021
Section 4.2.5.6: This section was added.
YEs
To align with the protocol.
16 July 2021
Section 4.2.5.7: Added further clarification on 
handling of the vital signs data.
Yes
To align with the protocol.
18 December 2020
Updated section 4.2.6 and removed the graphical 
presentation of plasma concentrations. Added to 
clarify handling of non quantifiable plasma 
concentration.
Yes
As per the input from the PK group.
18 October 2021
Added description for box plots in section 4.2.6.
Yes
To align with the TFL shells.


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15 March 2021
Added clarification to section 4.2.7.
Yes
 
18 October 2021
Modified the imAE section to include only one 
approach for identification of imAEs.
Yes
To align with the latest guidance on adjudication of 
imAEs.
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1
STUDY DETAILS
1.1
Study objectives
Table 1
Study objectives
Primary Objective:
Endpoint/Variable:
To evaluate efficacy of each combination therapy on 
objective response rate (ORR) for patients with 
measurable disease
Proportion of patients with measurable disease at 
baseline who have a confirmed ORR per Response 
Evaluation Criteria in Solid Tumors (RECIST 1.1)
To evaluate efficacy of each combination therapy on 
PSA response rate 
PSA confirmed response is defined as the proportion 
of participants with a reduction in the PSA level of 
≥50% from baseline to the lowest post-baseline PSA 
results, measured twice, at least 3 weeks apart by the 
Prostate Cancer Working Group 3 criteria (PCWG3)
Secondary Objectives:
Endpoint/Variable:
To evaluate the efficacy of each combination therapy 
on the proportion of patients alive and progression 
free at 6 months
Summaries of the Kaplan-Meier curve for 
radiological progression-free survival including the 
proportion of patients alive and radiological 
progression free at 6 months using RECIST 1.1 (soft 
tissue lesions) and PCWG3 (bone lesions)
To evaluate efficacy of each combination therapy on 
duration of response (DoR) 
Duration of Response (DoR) is defined as the time 
from the date of first documented response until date 
of documented progression or death in the absence of 
disease progression
To evaluate efficacy of each combination therapy on 
overall survival (OS).
Overall survival is length of time from date of first 
dose until the date of death due to any cause.
To evaluate the pharmacokinetics (PK) of AZD4635 
and its metabolites and other combination agent(s).
Steady state trough
To evaluate the immunogenicity of mAB study 
drug(s) in combination with AZD4635.
The proportion of patients with the presence of anti-
drug antibody (ADA)
Safety Objective:
Endpoint/Variable:
To assess the safety and tolerability of each treatment 
regimen.
AEs/SAEs
Physical exam and vital signs 
Collection of clinical chemistry/hematology 
parameters 
Exploratory Objectives
Endpoint/Variable:
 
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Table 1
Study objectives
1.2
Study design
This is an open-label Phase II modular study in patients with prostate cancer to assess safety, 
efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in 
different treatment modules.  Patients will be randomized for inclusion in the initial 2 or 3 
modules of AZD4635 plus durvalumab, AZD4635 plus oleclumab and AZD4635 plus 
durvalumab plus oleclumab. Patients will be dosed with the capsule formulation of AZD4635.  
The decision was made by the Sponsor not to open Module 3 (AZD4635 plus durvalumab 
plus oleclumab) to recruitment after a comprehensive strategy review of the AZD4635 
program. Thus any reference to module 3 in this SAP shall not be taken into consideration 
from all analyses perspective. 
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1.3
Number of subjects
The study is a Phase 2a signal searching study and consists of multiple single arm cohorts 
under a modular protocol. There are no plans to formally compare between the cohorts and 
this is not part of the study objectives. The aim is to identify treatment(s) to take forward into 
further trial(s), as such there are no formal statistical hypothesis tests associated with the study 
objectives; statistical analysis of all study endpoints is descriptive. 
The primary efficacy endpoint is PSA decline from baseline ≥50% (PSA50) and overall 
response rate (ORR) per RECIST v1.1 for patients with measurable disease at baseline.   In 
Module 1, 2 and 3 there will be approximately 30 PSA evaluable patients in each module, and 
approximately 20 patients will have RECIST measurable disease at baseline in each module. 
In Module 1, 2 and 3 , approximately 30 patients with and without measurable disease at 
baseline will be assessed for PSA50 in each module.  
 
 
 
 
 
 
In Module 1, 2 and 3 , approximately 20 patients with measurable disease at baseline will be 
assess for ORR in each module.  
 
 
 
 
 
 
If any of the required patients for PSA and/or ORR are not evaluable for PSA response or 
tumor response, respectively, they may be replaced at the sponsor’s discretion.
2
ANALYSIS SETS
2.1
Definition of analysis sets
All patients who received at least one dose of study medication will be included in the safety 
analysis set.  For the safety analysis, patients will be classified according to the dose schedule 
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they actually received.  For the efficacy analysis (including OS), patients will be classified 
according to the planned dose schedule. 
Details of the analysis sets are presented in Table 2 and Table 3.
Table 2
Analysis Set
Analysis Set
Definition
Enrolled
All patients who signed informed consent
Safety
All patients who received at least 1 dose of study drug.
DLT (Module 2)
The first 6 patients who complete 28 days AND receive all planned doses of 
oleclumab and at least 80% of AZD4635 during this time OR experience a 
DLT during this time.
Pharmacokinetics (PK)
All participants who received at least 1 dose of study drug with at least 1 
reportable concentration.
Tumor response
Dosed patients with a baseline tumor assessment, and measurable disease at 
baseline.
Evaluable for Efficacy
Dosed patients with a baseline tumor assessment.
PSA response
Dosed patients with an abnormal baseline PSA  (≥1ng/mL).
*
Summaries of PK data will consider the subset of the PK analysis set with reportable plasma concentrations 
at that visit for which there are no important adverse events or protocol deviations that may impact PK at that 
visit.
Table 3
Summary of outcome variables and analysis sets
Outcome variable
Analysis Sets
Demography and baseline characteristics
Safety
Safety data
Exposure
Safety
Adverse Events
Safety
Laboratory measurements
Safety
Vital Signs/ECG/Physical examination (ECOG)
Safety
ECHO/MUGA
Safety
Concomitant medications
Safety
Efficacy Data
Best Objective Response
Tumor response and Evaluable for Efficacy
Objective Response Rate (ORR)
Tumor response 
Change in tumor size      
Tumor response
Duration of Response
Tumor response
Overall survival (OS)
Safety
Radiological progression-free survival (rPFS)
Evaluable for Efficacy


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Outcome variable
Analysis Sets
PSA response
PSA Response
Pharmacokinetics
Plasma Pharmacokinetic variables
PK
Immunogenicity
Anti-Drug Antibody Response 
Safety
2.2
Violations and deviations
The following general categories will be considered important protocol deviations: 
Patients who deviate from key entry criteria per the CSP (Deviation 1) as below: 

Patients must have prostate cancer with histological or cytological confirmation 
[Inclusion criteria 4 of core CSP]

For module 1, 2 and 3 :  
o
Histologically or cytologically confirmed metastatic CRPC [Inclusion criteria  
K-1, L-1 or M-1]
o
Patients must have had either orchiectomy OR be on luteinizing hormone-
releasing hormone (LHRH) agonist or antagonist therapy with serum 
testosterone <50 ng/dL AND agree to stay on LHRH agonist or antagonist 
therapy during the study [Inclusion criteria K-1, L-1 or M-1 ]
o
Patients must have previously received and progressed on >2 lines of approved 
systemic therapy for mCRPC, including a second generation hormonal agent (eg, 
abiraterone, enzalutamide, apalutamide). [Inclusion criteria K-1, L-1 or M-1]

Patients must have evidence of mCRPC that progressed within 6 months prior to 
screening [Inclusion criteria K-1, L-1 or M-1]

Previously received and progressed on SOC [Inclusion criteria 5 of core CSP]

Patients must have not received prohibited anti-cancer therapy prior the first dose of 
study treatment as defined in the exclusion criteria in CSP

Patients with measurable diseases must have 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 patients 
with 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) [Inclusion criteria 8 of core CSP]


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
Patients assigned to treatment who received their assigned study treatment at an incorrect 
dose at more than 1 occasion or received an alternative study treatment to that which they 
were assigned (Deviation 2)  

Persistently missing important protocol required safety assessments (haematology, liver 
function test, chemistry panel and/or as per medical monitor discretion) and potentially 
having major impact to patient safety (clinical review on a case by case base) (Deviation 
3).  

Baseline RECIST or Bone scan >28 days before start of assigned treatment (unless agreed 
with medical team), or no baseline RECIST 1.1 assessment on or before start of treatment  
and/or no baseline bone scan assessment on or before start of treatment  or no baseline 
PSA (Deviation 4)  

Patient received study treatment but post-baseline tumor assessment scans not performed 
at all or major issues with scans not being performed in accordance with the protocol, or 
Patient met PSA baseline criteria and received study treatment but no post-baseline PSA 
data collection (Deviation 5) 

Patient received prohibited other anti-cancer therapy during study treatment period 
(Deviation 6)

Changes to the procedures that impact the quality of the data or any circumstances that 
can alter the evaluation of the PK (Deviation 7).  

Met study treatment discontinuation criteria but continued study treatment and potentially 
had major impact to patients’ safety according to clinical judgement (Deviation 8).

Patients affected by the COVID-19 pandemic.
The categorization of these as IPDs is not automatic and will depend on duration and the 
perceived effect on efficacy and safety. In addition to the programmatic determination (where 
possible) of the deviations above, monitoring notes or summaries will be reviewed to 
determine any important post entry deviations that are not identifiable via programming, and 
to check that those identified via programming are correctly classified. For example, details of 
disallowed concomitant medication use will be reviewed and may be determined as important.
Patients who enrolled but did not receive study treatment will be excluded from the safety, PK 
and efficacy analysis sets.  Missing baseline tumor assessment or missing baseline PSA, or 
having neither measurable disease at baseline nor meeting baseline PSA criteria will lead to 
exclusion from some of the efficacy analysis sets. None of the other deviations will lead to 
patients being excluded from the analysis sets (except for the PK analysis set, if the deviation 
is considered to impact upon PK). However, the impact on the primary endpoint will be 
assessed, and if considered necessary sensitivity analysis may be considered. 
A list of all protocol deviations, including those reported by monitors, will be reviewed and 
decisions regarding how to handle these deviations will be documented by the study team 
physician, clinical pharmacology scientist and statistician prior to database lock. The final 
classification will be made prior to database lock.


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The important protocol deviations will be listed and summarized by treatment group.
3
PRIMARY AND SECONDARY VARIABLES
3.1
General principles
Baseline measurements and change from baseline variables 
Baseline will be the last non-missing value obtained prior to the first dose/administration of 
study medication and any information taken after first dose/administration of study medication 
will be regarded as post baseline information. If two visits are equally eligible to assess patient 
status at baseline (e.g., screening and baseline assessments both on the same date prior to first 
dose/administration with no washout or other intervention in the screening period), the 
average should be taken as the baseline value.  For non-numeric laboratory tests (i.e., some of 
the urinalysis parameters) where taking an average is not possible, then the clinical favourite 
value would be taken as baseline (i.e., normal and abnormal were observed on the same date 
prior to first dose/administration, then normal is considered as baseline value).  In the scenario 
where there are two assessments on Day 1, one with time recorded and the other without time 
recorded, the one with time recorded would be selected as baseline. Where safety data are 
summarized over time, study day will be calculated in relation to date of first treatment.  If no 
value exists before the first dose/administration, then the baseline value will be treated as 
missing. 
In all summaries, change from baseline variables will be calculated as the post treatment value 
minus the value at baseline. For % change from baseline, calculate:
100× (Post baseline value – Baseline value)/Baseline value 
Study day will be calculated as:
Date of assessment – Date of first dose/administration of study medication +1 
Study day prior to Date of first dose/administration of study medication will be calculated as 
follows:
Date of assessment – Date of first dose/administration of study medication
Time Windows 
Time windows are defined for any presentations that summarize values by visit. 

For efficacy, the visit specific analyses such as change from baseline in target lesion size 
at week x, PSA response at week x, a windowing rule will be applied and will follow the 
protocol allowed visit window; therefore any RECIST scan performed within ± 7 days of 
the protocol scheduled visit will be used for that visit. The same +/- 7 days window will 


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be used for PSA. That is, only assessments closest to the protocolled visit day are selected 
for this summary, therefore unscheduled visits may be excluded.
The following conventions should apply to safety outcomes, where applicable

The time windows should be exhaustive so that data recorded at any time point has the 
potential to be summarized.  Inclusion within the time window should be based on the 
actual date and not the intended date of the visit.

All unscheduled visit data should have the potential to be included in the summaries.

The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the first 
post-baseline visit will be Day 2). If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the midpoint value minus 1 day.

For example, the visit windows with 2 weeks between scheduled assessments are:

Day 15, visit window 2 – 21

Day 29, visit window 22 – 35

Day 43, visit window 36 – 49

Day 57, visit window 50 – 63

Day 71, visit window 64 – 77

Day 85, visit window 78 – 91

For summaries showing the maximum or minimum values at a visit, the 
maximum/minimum value recorded on treatment at that visit (including within the 
corresponding window) will be used (regardless of where it falls in a window).

Listings should display all values contributing to a time point for a patient.

For visit based summaries, if there is more than one value per patient within a time 
window then the closest value to the scheduled visit date should be summarized, or the 
earlier, in the event the values are equidistant from the nominal visit date. 

The listings should highlight the value for the patient that contributed to the summary 
table, wherever feasible. 

Note: in summaries of extreme values all post baseline values collected are used including 
those collected at unscheduled visits regardless of whether or not the value is closest to 
the scheduled visit date.  

For summaries at a patient level, all values should be included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic 
such as a maximum.
Missing Dates
In situations when the whole date is missing, it is more difficult to follow a general principle 
and these should be reviewed within the study and decided how to be handled.


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Generally, the imputation of dates is used to decide if an observation is treatment emergent for 
adverse events or concomitant medications. The imputed dates are not advised to be used to 
calculate durations where the results would be less accurate.
Furthermore:-

For missing diagnostic dates (e.g. disease diagnosis), if day and/or month are missing use 
01 and/or Jan. If year is missing, put the complete date to missing.

For missing AE and concomitant medication start dates, the following will be applied:
a.
Missing day - impute the 1st of the month unless month is the same as month of 
the first dose of study drug, and end date is not definitely before first dose date
then impute first dose date.
b. Missing day and month - impute 1st January unless year is the same as first dose, 
and end date is not definitely before first dosedate then impute first dose date.
c.
Completely missing - impute first dose date unless the end date indicates it ended 
prior to first dose,  in which case impute the 1st January of the same year as the 
end date.
d. Ensure that the new start date is sensible and should is no later than the end date.

For missing AE and concomitant medication end dates, the following will be applied:
a.
Missing day - impute the last day of the month unless both the month and the 
year are the same as the End of Study Date or the primary analysis data cut-off 
date then impute the End of Study Date or the primary analysis data cut-off 
date. 
b. Missing day and month - impute 31st December unless the year is the same as 
the End of Study Date or the primary analysis data cut-off date then impute the 
End of Study Date or the primary analysis data cut-off date. Flags will be 
retained in the database indicating where any programmatic imputation has 
been applied, and in such cases, any durations would not be calculated.
c.
Completely Missing – need to look at whether the AE/medication is still 
ongoing before imputing a date and also when it started in relation to study 
drug. If the ongoing flag is missing then assume that AE is still present / 
medication is still being taken (i.e. do not impute a date).

If a participant is known to have died where only a partial death date is available then the 
date of death will be imputed as the latest of the last date known to be alive +1 from the 
database and the death date using the available information provided:-

For Missing day only – using the 1st of the month. 


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
For Missing day and Month – using the 1st of January.
a.
Imputed end date should be no earlier than end date. 
On treatment definition
Post-dose assessments are considered on treatment if the assessment occurred after first dose 
and up to and including the last dose.
Treatment emergent adverse event definition
Adverse events will be defined as treatment emergent if they begin, or worsen (by investigator 
report of a change in intensity), during the treatment period, i.e., starting after the first dose of 
therapy or within 30 days after the end of the last investigational product (90 days for the 
durvalumab and oleclumab.
3.2
Primary outcome variables
The primary outcome variables, which evaluate the efficacy of each combination therapy, are 
described in Table 3 of the Clinical Study Protocol.
3.2.1
Calculation of derivation of tumor response variables
3.2.1.1
RECIST visit responses
For all patients with measurable and non-measurable disease at baseline, the RECIST tumor
response data will be used to determine each patient’s visit response according to RECIST 
version 1.1.  It will also be used to determine if and when a patient has progressed in 
accordance with RECIST and also their best objective response to study treatment.  
Baseline radiological tumor assessments are to be performed no more than 28 days before the 
start of study treatment and ideally as close as possible to the start of study treatment.  Tumor
assessments are then performed at 6 weeks (post Cycle 1) and every 8 weeks thereafter 
following the start of study treatment until disease progression. 
If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits.  This 
schedule is to be followed in order to minimise any unintentional bias caused by some patients 
being assessed at a different frequency than other patients.
From the investigator’s review of the imaging scans, the RECIST tumor response data will be 
used to determine each patient’s visit response according to RECIST version 1.1. At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of CR, PR, SD 
or PD, using the information from TLs, NTLs and new lesions and depending on the status of 


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their disease compared with baseline and previous assessments.  If a patient has had a tumor
assessment, which cannot be evaluated, then the patient will be assigned a visit response of 
not evaluable (NE) (unless there is evidence of progression in which case the response will be 
assigned as PD).
Please refer to Table 6 below for the definitions of CR, PR, SD and PD. 
RECIST outcomes (i.e. PFS, ORR etc.) will be calculated programmatically for the site 
investigator data from the overall visit responses.
Target lesions (TLs)
Measurable disease is defined as having at least one measurable lesion, not previously 
irradiated, which is ≥ 10 mm in the longest diameter (LD) (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. A patient can have a 
maximum of 5 measurable lesions recorded at baseline with a maximum of 2 lesions per organ 
(representative of all lesions involved and suitable for accurate repeated measurement) and 
these are referred to as target lesions (TLs).  If more than one baseline scan is recorded then 
measurements from the one that is closest and prior to first dose/administration of study 
medication will be used to define the baseline sum of TLs. 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.
All other lesions (or sites of disease) not recorded as TL should be identified as NTLs at 
baseline.  Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL 
assessment and/or the absence/presence of new lesions (see Table 4 for further details). If a 
patient does not have measurable disease at baseline then the TL visit response will be not 
applicable (NA).
For patients with no disease at baseline (i.e. no TLs and no NTLs), evaluation of overall visit 
responses will be based on absence/presence of new lesions.  If no TLs and no NTLs are 
recorded at a visit, both the TL and NTL visit response will be recorded as NA and the overall 
visit response will be no evidence of disease (NED). If a new lesion is observed then the 
overall visit response will be PD.


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Table 4
TL visit responses
Visit Reponses
Description
Complete Response (CR)
Disappearance of all TLs.  Any pathological lymph nodes selected as 
TLs must have a reduction in short axis to <10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters as long as criteria for PD are 
not met.
Progressive disease (PD)
A ≥ 20% increase in the sum of diameters of TLs and an absolute 
increase of ≥5mm, taking as reference the smallest sum of diameters 
since treatment started including the baseline sum of diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD
Not Evaluable (NE)
Only relevant in certain situations (i.e. if any of the target lesions were 
not assessed or not evaluable or had a lesion intervention at this visit; 
and scaling up could not be performed for lesions with interventions). 
Note: If the sum of diameters meets the progressive disease criteria, 
progressive disease overrides not evaluable as a target lesion response
Not applicable (NA)
No TLs are recorded at baseline
Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous 
minimum should be rounded to 1 d.p. before assigning a TL response.  For example 19.95% 
should be rounded to 20.0% but 19.94% should be rounded to 19.9%  
Missing TL data 
If all TL measurements are missing then the TL visit response is not evaluable (NE).  Overall 
visit response will also be NE, unless there is a progression of non-TLs or new lesions, in 
which case the response will be PD.
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However a size will still be given and this size should still be used to determine the TL visit 
response as normal.  In the special case where all lymph nodes are < 10mm and all other TLs
are 0mm then although the sum may be >0mm the calculation of TL response should be over-
written as a CR. 


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TL visit responses subsequent to CR
A CR can only be followed by CR, PD or NE.  If a CR has occurred then the following rules 
at the subsequent visits must be applied:
1
Step 1:  If all lesions meet the CR criteria (i.e. 0mm or < 10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met i.e. 
if a lymph node short axis increases by 20% but remains < 10mm.
2
Step 2:  If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE 
irrespective of whether the criteria for PD of TL is also met i.e. if a lymph node short axis
increases by 20% but remains < 10mm. 
3
Step 3:  If not all lesions are missing, and those that are non-missing do not meet the CR 
criteria (i.e. a pathological lymph node selected as TL has short axis >= 10mm or the 
reappearance of previously disappeared lesion), then response will be set to PD.
4
Step 4:  If all lesions are missing the response will be set to NE.
TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded.  If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team blinded to treatment assignment.  It is expected that a 
visit response of PD will remain in the vast majority of cases.  
TL too small to measure
If a TL becomes too small to measure then this will be indicated as such on the case report 
form and a value of 5mm will be entered into the database and used in TL calculations. 
However a smaller value may be used if the radiologist has not indicated ‘too small to 
measure’ on the case report form and has entered a smaller value that can be reliably 
measured.  If a TL response of PD results then this will be reviewed by the study team.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolization), should be handled in the following way and 
once a lesion has had intervention then it should be treated as having intervention for the 
remainder of the study noting that an intervention will most likely shrink the size of tumors:


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1
Step 1: the diameters of the TLs (including the lesions that have had intervention) will be 
summed and the calculation will be performed in the usual manner. If the visit response is 
PD, this will remain as a valid response category. 
2
Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for 
those lesions with intervention) as missing and if 
1/3 of the TLs have missing 
measurements then scale up as described in the ‘Scaling’ section below.  If the scaling 
results in a visit response of PD then the patient would be assigned a TL response of PD.  
3
Step 3: If, after both steps, PD has not been assigned, then, if appropriate (i.e. if 
1/3 of 
the TLs have missing measurements), the scaled sum of diameters calculated in step 2 
should be used, and PR or SD then assigned as the visit response.  Patients with 
intervention are evaluable for CR as long as all non-intervened lesions are 0 (or <10mm 
for lymph nodes) and the lesions that have been subject to intervention also have a value 
of 0 (or <10mm for lymph nodes) recorded.  If scaling up is not appropriate due to too 
few non-missing measurements then the visit response will be set as NE.
At subsequent visits, the above steps will be repeated to determine the TL and overall visit 
response.  When calculating the previous minimum, lesions with intervention should be 
treated as missing and scaled up (as per step 2 above).
Scaling
If > 1/3 of TL measurements are missing then TL response will be NE, unless the sum of 
diameters of non-missing TL would result in PD (i.e. if using a value of 0 for missing lesions, 
the sum of diameters has still increased by 20% or more compared to nadir and the sum of 
TLs has increased by ≥5mm from nadir).  
If ≤1/3 of the TL measurements are missing then the results will be scaled up (based on the 
sizes at the nadir visit) to give an estimated sum of diameters and this will be used in 
calculations; this is equivalent to comparing the visit sum of diameters of the non-missing 
lesions to the nadir sum of diameters excluding the lesions with missing measurements.
Example of scaling
Lesion 5 is missing at the follow-up visit; the nadir TL sum including lesions 1-5 was 74 mm.  
The sum of lesions 1-4 at the follow-up is 68 mm.  The sum of the corresponding lesions at 
nadir visit is 62 mm.
Scale up as follows to give an estimated TL sum of 81mm:
68 x 74 / 62 = 81 mm


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CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases.  However, for visits 
with ≤1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0 cm.
Change in method of assessment of TLs
CT, MRI and clinical examination are the only methods of assessment that can be used within 
a trial, with CT and MRI being the preferred methods and clinical examination only used in 
special cases.  If a change in method of assessment occurs between CT and MRI this will be 
considered acceptable and no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing.  The TL visit response may 
still be evaluable if the number of missing TL measurements at a visit is ≤1/3 of the total 
number of TLs.  
Non-Target Lesions (NTLs) and new lesions
At each visit, an overall assessment of the NTL response should be recorded by the 
investigator. This section provides the definitions of the criteria used to determine and record 
overall response for NTL at the investigational site at each visit.
NTL response will be derived based on the Investigator’s overall assessment of NTLs as 
described in Table 5.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumor burden has increased sufficiently to merit a determination of disease 
progression. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.  


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A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
Table 5
NTL Visit Responses
Visit Responses
Description
Complete Response (CR)
Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10 mm short axis).
Progressive Disease (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one 
lesion only or in several lesions. In all cases, the progression 
MUST be clinically significant for the physician to consider 
changing (or stopping) therapy.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of 
progression.
Not Evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the investigator's opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit.
Note: For patients without TLs at baseline, this is relevant if any 
of the NTLs were not assessed at this visit and the progression 
criteria have not been met.
Not Applicable (NA)
Only relevant if there are no NTLs at baseline
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present, but should 
not overtly affect the derivation.  
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.


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Patients with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumor
assessments where possible until objective disease progression is observed.
Overall visit response
Table 6 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 6
Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR or NA
No (or NE)
CR
CR
Non-CR/Non-PD or NE
No (or NE)
PR
PR
Non-PD or NE or NA
No (or NE)
PR
SD
Non-PD or NE or NA
No (or NE)
SD
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non-PD or NE or NA
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non-CR/Non-PD
No (or NE)
SD
NA
NE
No (or NE)
NE
NA
NA
No (or NE)
NED
3.2.1.2
Objective response rate/Best objective response rate
Objective response rate
ORR is defined as the percentage of patients with a confirmed, programmatically determined 
CR or PR and will be based on a subset of all dosed patients evaluable for response with 
measurable disease at baseline per the site investigator. 
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR.  Patients who discontinue study treatment without 
progression, receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy 
is not considered a subsequent anti-cancer therapy) and then responder will not be included as 


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responders in the ORR (i.e. both visits contributing to a response must be prior to subsequent 
therapy for the patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder.  Similarly, if a patient has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment, described in Section 4.2.3.1.  It is the best response a patient has had 
following first dose but prior to starting any subsequent cancer therapy and up to and 
including RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. Categorisation of BoR will be based on RECIST using the following response 
categories: CR, PR, SD, PD and NE.
CR or PR must be confirmed.  For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used.  SD should be 
recorded at least 6 weeks minus 7 days, i.e. at least 35 days (to allow for an early assessment 
within the assessment window), after first dose/administration of study medication.  For 
CR/PR, the initial overall visit assessment which showed a response will use the latest of the 
dates contributing towards a particular overall visit assessment.
It will be determined programmatically based on RECIST using all site investigator data up 
until the first progression event.  The denominator will be consistent with that used in the 
ORR analysis.
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤ 79 days 
(i.e., 6 weeks + 8 weeks + 7 days to allow for a late assessment within the assessment 
window) after first dose/ administration of study medication, then BoR will be assigned to the 
progression (PD) category.  For patients who die with no evaluable RECIST assessments, if 
the death occurs >  79 days after start of treatment then BoR will be assigned to the NE 
category.
A patient will be classified as a responder if the RECIST criteria for a confirmed CR or PR is 
satisfied at any time following first dose/administration of study medication, prior to RECIST 
progression or prior to starting any subsequent cancer therapy.


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3.2.1.3
Change in tumor size
The best percentage change in tumour size from baseline will be reported, i.e. the maximum 
reduction from baseline or the minimum increase from baseline in the absence of a reduction
from baseline based on all post baseline assessments:
•
up to and including the first visit at which the overall visit response is PD,
•
prior to death in the absence of progression, 
•
prior to the start of subsequent anti-cancer therapy (note: this should not include 
radiotherapy) 
•
or up to and including the last evaluable RECIST assessment if the participant has not 
died, progressed or started subsequent anti-cancer therapy.
Tumor size is the sum of the diameters of the target lesions.  Target lesions are measurable 
tumor lesions.  Baseline for RECIST is defined to be the last evaluable assessment prior to 
starting treatment, including the measurement occurring on the date of first 
dose/administration.  The percentage change in target lesion tumor size at each visit for which 
data are available will be obtained for each patient taking the difference between the sum of 
the target lesions at each visit and the sum of the target lesions at baseline divided by the sum 
of the target lesions at baseline multiplied by 100 (i.e. (week x - baseline)/baseline * 100).
Only patients with measurable disease at baseline should be included in summaries of best 
percentage change in tumor size (measurable disease is as denoted on the CRF by the 
investigator).
If following the scaling up rules, best percentage change cannot be calculated due to missing 
data, and a patient has no post baseline assessments, then the following imputation rules 
should be applied:
1
If there is no observed TL tumor size measurement data post progression but there is 
evidence of progression for the individual during their time on study, where evidence of 
progression is defined as progression of NTLs, the appearance of new lesions or as 
determined by an investigator (i.e. investigator’s opinion of response recorded on the 
RECIST CRF is PD at that assessment or study treatment was discontinued for 
progression in the assessment time window), and there are at least 5 patients with non-
missing TL tumor size who have also progressed then impute a best percentage change 
from baseline as the median best percentage change from patients with non-missing TL 
tumor size who also have progressed.  However if there are less than 5 patients with non-
missing TL tumor size who have also progressed then impute a best percentage change 
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2
If there is no evidence of progression, assume that the data is missing completely at 
random, the patient will be excluded from the analysis.
3
If it is known that the patient has died, impute a best percentage change from baseline as 
the maximum (i.e. corresponding to the biggest increase in TL tumor size) best 
percentage change reported on the study.
3.2.2
PSA response rate
PSA response rate is defined as the proportion of patients achieving a ≥50% decline from 
baseline to the lowest post-baseline PSA results, confirmed by a second consecutive PSA 
assessment at least 3 weeks later. Ignore early rises (before 12 weeks) in determining PSA 
response

A patient will be regarded as having a single PSA visit response if their PSA level at any 
post-dose visit is reduced by 50% or more compared with baseline

A patient will be regarded as having a confirmed PSA response if they have a reduction in 
PSA level of 50% or more compared with baseline that is confirmed at the next 
assessment at least 3 weeks later (i.e., decrease relative to baseline of at least 50% 
documented on 2 consecutive occasions at least 3 weeks apart).
PSA progression
If there is a PSA decline from baseline, progression is defined as the date of the first PSA 
increase that is both ≥25% and ≥2 ng/mL above the nadir and which is confirmed by a second 
value ≥3 weeks later, even if within 12 weeks.
If there is no PSA decline from baseline, progression is defined as a ≥25% increase and ≥2 
ng/mL increase from baseline beyond 12 weeks.
The proportion of patients achieving a PSA response and patients with a confirmed PSA 
response will be presented with both 95% CI and 80% CI. The best PSA percentage change 
from baseline and the percent change from baseline in PSA levels at 12 weeks will be 
summarized and graphed.  Waterfall plots (bar plots), and spider plots (individual line plots of 
percent change from baseline over time) will be produced.
3.3
Secondary outcome variables
3.3.1
Duration of response (DOR)
Duration of response will be defined as the time from the date of first documented response 
(which is subsequently confirmed) until date of documented progression or death in the 
absence of disease progression (ie, date of PFS event or censoring – date of first response + 1). 
The end of response should coincide with the date of progression or death from any cause 


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used for the PFS endpoint.  The time of the initial response will be defined as the latest of the 
dates contributing towards the first visit that was PR or CR that was subsequently confirmed.
If a patient does not progress following a response, then their duration of response will use the 
PFS censoring time.
3.3.2
Radiological Progression-Free Survival (rPFS)
rPFS is defined as the time from 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 
patient withdraws from study therapy or receives another anti-cancer therapy prior to 
progression (i.e. date of event or censoring – date of first dose + 1).  
Patients who have not progressed (defined as CR, PR or SD by RECIST v1.1 for soft tissue 
disease, or non-PD for bone disease) or died at the time of analysis will be censored at the 
time of the latest date of assessment from their last evaluable RECIST assessment or bone 
scan.  However, if the patient progresses or dies after two or more missed radiologic visits, the 
patient will be censored at the time of the latest evaluable RECIST 1.1 or bone scan 
assessment prior to the two missed visits. Given the scheduled visit assessment scheme (i.e. 
six-weekly for the first 6 weeks and then eight-weekly thereafter) the definition of 2 missed 
visits will change. 
1
If the two missed visits occur over the period when the scheduled frequency of 
assessments changes from six-weekly to eight-weekly this will equate to 15 weeks or 105 
days (i.e. take the average of 6 and 8 weeks which gives 7 weeks and then 2 x 7 weeks + 
1 week for a late assessment = 15 weeks). The time period for the previous assessment 
will be until study day 35 (i.e. up to week 5). 
2
If the previous assessment is from week 5 (day 36) onwards (when the scheduling 
changes to eight weekly assessments), two missing visits will equate to 18 weeks or 126 
days (i.e. 2 x 8 weeks + 1 week for an early assessment + 1 week for a late assessment = 
18 weeks).
Progression-free follow-up are scheduled every 3 months (±1 week) for those patients without 
objective PD at the time of the study drug discontinuation. 3 months is approximately 13 
weeks. 
1
If the two missed visits occur over the period when the scheduled frequency of 
assessments changes from eight-weekly to 3-monthly this will equate to 23 weeks or 161 
days (i.e. take the average of 8 and 13 weeks which gives 10.5 weeks and then 2 x 10.5 
weeks + 1 week for an early assessment + 1 week for a late assessment = 23 weeks). 


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2
If the two missing visits occur when the scheduling changes to 3-monthly assessment, 
two missing visits will equate to 28 weeks or 196 days (i.e. 2 x 13 weeks + 1 week for an 
early assessment + 1 week for a late assessment = 28 weeks).
If a patient 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 patient has no evaluable post-baseline RECIST v1.1 or bone scan assessment, they will 
be censored at 1 day unless they die within 2 visits of baseline (in which case their date of 
death will be used).
The PFS time will always be derived based on scan/assessment dates not visit dates. RECIST 
assessments/bone scans contributing towards a particular visit may be performed on different 
dates.  The following rules will be applied:
1
For investigational assessments, the date of progression will be determined based on the 
earliest of the dates of the component that triggered the progression
2
When censoring a patient for PFS the patient will be censored at the latest of the dates 
contributing to a particular overall visit assessment.
3.3.3
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 patient withdraws from study therapy or receives another anti-cancer 
therapy (i.e. date of death or censoring – date of first dose + 1).  Any patient not known to 
have died at the time of analysis will be censored according to the following rules.
1
If the patient is lost to follow-up immediately after 1st dose of study drug, the patient will 
be censored at the date of 1st dose of study drug.
2
If the patient is not known to have died at or after the analysis cutoff date, the patient will 
be censored at the date last known alive before data analysis cutoff.
3
If the patient is known to have died after the analysis cutoff date, the patient will be 
censored at the date of analysis cutoff.
Note: Survival calls will be made in the week following the date of data cut-off (DCO) for the 
analysis, and if patients are confirmed to be alive or if the death date is post the DCO date 
these patients will be censored at the date of DCO.  The status of ongoing, withdrawn (from 
the study) and “lost to follow-up” patients at the time of the final OS analysis should be 
obtained by the site personnel by checking the patient’s notes, hospital records, contacting the 
patient’s general practitioner and checking publicly-available death registries. In the event that 
the patient has actively withdrawn consent to the processing of their personal data, the vital 


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status of the patient can be obtained by site personnel from publicly available resources where 
it is possible to do so under applicable local laws.
Note that for any OS analysis performed prior to the final OS analysis, in the absence of 
survival calls being made, it may be necessary to use all relevant CRF fields to determine the 
last recorded date on which the patient was known to be alive for those patients still on 
treatment.  The last date for each individual patient is defined as the latest among the 
following dates recorded on the case report forms (CRFs):
1
AE start and stop dates
2
Admission and discharge dates of hospitalization
3
Study treatment date
4
End of treatment date
5
Laboratory test dates
6
Date of vital signs
7
Disease assessment dates
8
Start and stop dates of alternative anticancer treatment
9
Date last known alive on survival status CRF
10 End of study date
3.3.4
Calculation or derivation of pharmacokinetic variables
Pharmacokinetic samples for steady state trough of the plasma concentration for AZD4635 
and serum concentration for durvalumab and oleclumab will be summarized in the CSR.  No 
parameters will be calculated.  
 
 
3.3.5
 
3.4
Safety outcome variables
3.4.1
Duration of exposure
Duration of exposure is defined as:
CCI
CCI
CCI


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1
Total treatment duration of AZD4635 (in months) = min((last dose date where dose > 0 
[units], date of death, date of DCO) – first dose date +1) / (365.25/12) 
Total treatment duration of durvalumab = min ((last dose date where dose > 0 +27, date 
of death, date of DCO) − date of first dose +1) / (365.25/12)
Total treatment duration of oleclumab = min ((last dose date where dose > 0 +27, date of 
death, date of DCO) − date of first dose +1) / (365.25/12)       
**** it should be noted that for cycle 0, 13 should be added, instead of 27. This only 
applies to oleclumab.
2
Actual treatment duration of AZD4635 = total treatment duration – total duration of dose 
interruptions, where total treatment duration will be calculated as above and a dose 
interruption is defined as any length of time where the patient has not taken any of the 
planned daily dose.
3
Duration of therapy at starting dose = actual treatment duration for the dose assigned.
It should be noted that a snapshot date might be used instead of the date of DCO, as 
applicable. 
The actual treatment duration calculation makes no adjustment for any dose reductions that 
may have occurred.
Exposure will also be measured by the number of cycles received for IV administered 
treatment (durvalumab and oleclumab).  A cycle corresponds to a period of 14 days for Cycle 
0 (oleclumab) and 28 days for Cycle 1 and beyond. If the last dose is in Cycle 0, the number 
of cycles received will be 1.  If a cycle is prolonged due to toxicity, this should still be counted 
as one cycle.  A cycle will be counted if treatment is started even if the full dose is not 
delivered.
For handling exposure and dose interruptions, the following rules will be considered. 
Missed or forgotten doses
Missed and forgotten doses should be recorded on the TREATMENT – AZD4635/ 
TREATMENT – Oleclumab/ TREATMENT - Durvalumab module as ‘drug interrupted’. 
These missed or forgotten doses will not be included as dose interruptions in the summary 
tables but the information will appear in the listing for dosing.  However, these missed and 
forgotten doses will be considered in the derivation of actual exposure.
Patients who permanently discontinue during a dose interruption
If a patient permanently discontinues study treatment during a dose interruption, then the date 
of last administration of study medication and other assessment data recorded on END OF 


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TREATMENT – AZD4635/ END OF TREATMENT – Oleclumab/ END OF TREATMENT/ 
Durvalumb (as applicable), will be used in the programming.
3.4.2
Dose intensity
Dose intensity of each individual therapy will be addressed by considering relative dose 
intensity (RDI), and will be derived as detailed below. 

Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation.  The RDI is equal to 100% * d/D, 
where d is the actual cumulative dose delivered up to the earlier of progression (or a 
censoring event) or actual last day of dosing, and D is the intended cumulative dose up to 
the earlier of progression (or a censoring event) or the actual last day of dosing plus the 
protocol-defined post-dose rest period.
It should be noted for Module 2 that the initial patients received a dose of AZD4635 50 mg 
PO QD and oleclumab 1500 mg Q2W for the first 4 doses and Q4W thereafter. Following the 
SRC meeting and the protocol amendment being implemented at sites, subsequent patients 
began treatment at the AZD4635 75 mg dose, and continued with that dose.
3.4.3
Adverse events
AEs and SAEs will be collected throughout the study, from date of informed consent until 30 
days after the end of the last investigational product administration (90 days for 
the durvalumab and oleclumab) .  Events will be defined as treatment emergent if they begin, 
or worsen (by investigator report of a change in intensity), during the treatment period, 
i.e., starting after the first dose of therapy or within 30 days after the end of the last 
investigational product (90 days for the durvalumab and oleclumab; see further details in 
section 4.2.5.2).   The Medical Dictionary for Regulatory Activities (MedDRA) (version 21.1 
or higher) will be used to code the AEs.  AEs will be graded according to the National Cancer 
Institute Common Terminology Criteria for AEs (CTCAE Version 5.0).
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the IP and may require close monitoring and rapid communication by the 
investigator to the sponsor. More information regarding AESIs can be found in the module 
specific appendices to the clinical study protocol. Other categories may be added or existing 
terms may be modified as necessary. Further reviews may take place prior to database lock 
(DBL) to ensure any further terms not already included are captured within the categories. 
Preferred terms used to identify AESI will be listed before DBL.
Immune Mediated Adverse Events (imAE) are defined as a subset of AESI that consider 
interventions of corticosteroids, immunosuppressants, and/or endocrine therapy; are deemed 
consistent with having an immune-mediated mechanism of action and where there was no 


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clear alternative etiology.   Automated adjudication approach via programming will be used to 
identify the imAEs, and will be reported outside of the CSR. 
Other significant adverse events (OAE)
During the evaluation of the AE data, Medical Monitor will review the list of AEs that were 
not reported as SAEs and AEs leading to discontinuation of investigational product.  Based on 
the expert’s judgement, adverse events of particular clinical importance may, after 
consultation with the Medical Science Director, be considered other significant adverse events 
(OAEs) and reported as such in the Clinical Study Report.  A similar review of laboratory 
values, vital signs, ECGs and other safety assessments will be performed for identification of 
other significant adverse events.  This review will take place prior to database lock, and any 
AEs identified will be fully documented in meeting minutes.  Further review following 
database lock may result in ad-hoc OAEs being identified, in this case, the OAEs and resulting 
summaries will be fully documented in the CSR.
3.4.4
ECG changes
ECG will be obtained at screening, end of treatment and when clinically indicated. QTc 
intervals will be collected in msec.  For numeric ECG parameters, change from baseline in 
ECG variables will be calculated for each post-dose visit (if available) on treatment, and at the 
end of treatment. . It should be noted that the  ECGs are to be performed in triplicates. As 
such, the ECG parameters shall be averaged and then summarized, as applicable  .
3.4.5
Echocardiography or muli-gated acquisition scan (ECHO/ MUGA)
Echocardiogram or multi-gated acquisition scan will be performed at screening and within 14 
days after a clinically significant ECG finding. ECHO/ MUGA may also be repeated at the 
end of treatment visit to address recovery during off-treatment period. 
3.4.6
Vital sign changes
Change from baseline in vital signs variables will be calculated for each post-dose visit on 
treatment. Vital signs including blood pressure (BP), pulse, respiration, temperature and 
weight will be collected at module specific timepoints. Blood Pressure and pulse will be 
collected before, during and after the first infusion visit, including 2 or more readings of BP 
pre-infusion. For the subsequent visits, all vital signs will be recorded prior to start of infusion 
and also during, post infusion as per institutional standard and as clinically indicated.
3.4.7
Laboratory data
Change from baseline in haematology, clinical chemistry and urinalysis variables will be 
calculated for each post-dose visit on treatment. CTCAE (version 5.0) grade will be 


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calculated at each visit.  Maximum post-baseline CTC will also be calculated.  Absolute 
values will be compared to local laboratory reference ranges and classified as low (below 
range), normal (within range or on limits of range) and high (above range).  All values 
classified as high or low will be flagged on the listings.
3.4.8
Creatinine clearance
Estimated creatinine clearance will be calculated using the Cockcroft and Gault formula as 
follows:
(140 – age [years]) x weight [kg] x 1.23
creatinine [μmol/L]
4
ANALYSIS METHODS
4.1
General principles
The local laboratory reference ranges will be used for laboratory data.  The below mentioned 
general principles will be followed throughout the study:

Descriptive statistics will be used for all variables, as appropriate. Continuous variables 
will be summarized by the number of observations, mean, standard deviation, median, 
minimum, and maximum. For log-transformed data, it is more appropriate to present 
geometric mean, geometric standard deviation, coefficient of variation (CV), median, 
minimum and maximum. Categorical variables will be summarized by frequency counts 
and percentages for each category.

If data are available for less than 3 patients, no summary statistics other than minimum, 
maximum and number of observations will be presented.

Unless otherwise stated, percentages will be calculated out of the analysis set total and for 
each module.  

For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data.

For categorical data, percentages will be rounded to 1 decimal place.

For PK data, various significant figures will be used as standard.

SAS Institute 2001® version 9.4 or higher will be used for all analyses.

It is acceptable to present large numerical values in more appropriate units. For example, 
an AUC value of 123,000 ng·h/mL may be reported as 123 µg·h/mL instead of 123,000 
ng·h/mL. It is, however, important to keep the units consistent within the report and the 
precision consistent with that prior to conversion.


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4.2
Analysis methods
Summaries will be presented separately by module.  There is no formal statistical analysis 
required for this study.
4.2.1
Randomization
Randomization will occur when patients meet eligibility criteria for 2 or more modules that 
are currently recruiting.  If patients only meet the criteria for 1 currently recruiting module, 
they will be allocated to that module without randomization taking place.  All patients 
allocated or randomized will be stratified by patients with either bone only metastasis or 
measurable soft tissue metastasis to ensure there is sufficient number of patients in each group 
as specified in the module sample size.
4.2.2
Disposition, demography, and baseline characteristics
Disposition, demography, baseline characteristics (including disease characteristics), protocol 
deviations, concomitant medications and medical history will be listed and summarized by 
module. Any study disruptions due to COVID-19 pandemic will be summarized by module.
4.2.2.1
Patient disposition
The reasons for each study treatment discontinuation and study discontinuation will be 
summarized with the number and percentage of patients. This will include patients who 
discontinued treatment due to the pandemic and who withdrew from study due to the 
pandemic. Percentages are calculated from number of patients who received treatment in each 
module.

Enrolled

Treated 

Ongoing treatment

Discontinued treatment

Reasons for treatment discontinuation (including the reason due to COVID-19 pandemic)

Ongoing study

Discontinued study

Reasons for study discontinuation (including the reason due to COVID-19 pandemic)
4.2.2.2
Analysis sets

Enrolled

Safety

DLT (Module 2)

Pharmacokinetics (PK)

Tumor response


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
Evaluable for Efficacy

PSA Reponse
4.2.2.3
Protocol deviations
The number and percentage of patients with important protocol deviations in each deviation 
category will be summarized, including number and percentage of participants with at least 
one important protocol deviation related to the pandemic.  Important protocol deviations will 
be listed. Patients affected by the COVID-19 pandemic will be listed including category for 
study disruption due to the pandemic and details of the disruption. The examples of the 
categories are shown in Section 2.2.
4.2.2.4
Demography and baseline characteristics
The non-missing numerical values will be summarized as mean, median, standard deviation, 
minimum and maximum; while the categorical values will be summarized as frequency and 
percentage. 

Demographic characteristics include age, sex, race, ethnicity, and age group (<50, ≥ 50 -
< 65, ≥ 65 - < 75 and ≥ 75 years)  

Baseline characteristics include height, weight, weight group (< 70, 70 to 90, > 90), BMI 
and BMI group (Normal (< 25), Overweight (25-30), Obese (>30)).
4.2.2.5
Disease diagnosis and staging
The number and percentage of patients with the corresponding categorical values in disease 
diagnosis and staging will be summarized including:  

Eastern Cooperative Oncology Group (ECOG) performance status

Primary Diagnosis

Histology and histological grade 

Stage: TNM stage at diagnosis, stage classification

Gleason Score

Metastatic site at study entry

No of metastatic sites at study entry

Time from diagnosis to enrolment
For the missing diagnostic dates, if day and/ or month are missing, use 01 and/ or Jan. IF year 
is missing, put the complete date to missing.


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4.2.2.6
Prior therapies
The number and percentage of patients with prior systemic therapy, prior radiation, and prior 
surgery will be summarized by category (e.g. chemotherapy, radiotherapy, etc.) and the 
number of regimens.

Number of each therapy type (0, 1, 2, 3, 4, 5, 6, >6)

Percentage of patients receiving one or more courses of prior therapy by type.

Best overall response, if applicable

Summary of prior systemic therapy drugs by WHO preferred name and disease setting

Summary of prior surgery by MedDRA system organ class and preferred term
4.2.2.7
Concomitant medications
World Health Organization (WHO) Drug Dictionary March 2016 will be used for coding 
medication terms.  

Prior medications are those taken prior to study treatment with a stop date prior to the first 
dose of study treatment.

Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment).

Post-treatment medications are those with a start date after the last dose date of study 
treatment.
Imputed dates are not to be used to calculate durations.
Concomitant medications will be summarized (frequency and percentage of patients) by WHO 
drug preferred name.  Each unique drug will be counted once per patient.  The summary will 
be ordered by decreasing total frequency of use. Disallowed concomitant medications will be 
summarized and listed.   
Appendix J of the Core Clinical Study Protocol lists the disallowed medications for 
AZD4635.  Details for other study treatments are provided in the modular-specific appendix. 
A separate summary of any disallowed concomitant medications taken by a patient will be 
tabulated.
4.2.2.8
Medical History
Medical will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
21.1 or higher.  The frequency and percentage of patients with each condition will be 
summarized by System Organ Class (SOC) and preferred term (PT).  Patients with multiple 
unique terms will be counted once per each unique PT and unique SOC.  Each summary will 
be ordered by decreases frequency of PT within SOC. A listing of medical history will be 
provided as well.


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4.2.3
Tumor response and efficacy
Objective response rate (ORR) will be summarized for dosed patients with measurable disease 
at baseline.   BOR will be summarized for dosed patients with measurable disease at baseline 
and separately for dosed patients evaluable for efficacy.
Tumor response data will be summarized by module, if appropriate, using the following 
response categories: CR, PR, SD, PD, and not evaluable (NE).
Details of tumor assessment and response will be listed for each patient.  This listing will 
include information on lesion site, the method of assessment, diameter of lesion, sum of 
diameters of lesions, percent change from baseline, the calculated visit response, non-target 
lesions, new lesions, best objective response.
4.2.3.1
Best objective response and Objective response rate
The proportion of patients achieving an objective response (CR or PR) will be presented with 
a two-sided 95% CI, as well as 80% CI,using the Clopper-Pearson method (Clopper and 
Pearson 1934).  The Objective response rate (ORR) will be presented separately for each 
module.  The number and percentage of patients in each RECIST response category (CR, PR, 
SD, PD, and NE) will be summarized for each module.
4.2.3.2
Change in tumor size
Target lesion size at each tumor assessment time point will be summarized, along with 
percentage change from baseline.imputation will not be used for the calculation of percent 
change in tumor size)Also, the best percentage change in tumor size from baseline over all 
tumor assessment time points will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum).
Waterfall plots indicating the best percentage change from baseline in sum of the diameters of 
target lesions will be produced.  The plot will present each patient’s best percentage change 
from baseline in TL tumor size as a separate bar, with the bars ordered from the largest 
increase to the largest decrease.  A reference line at the –30% change in TL tumor size level 
will be added to the plots, which corresponds with the definition of ‘partial’ response.  Best 
overall response will be color coded.  The scale in these plots will be fixed to be from -100 to 
100 to avoid presenting extreme values.  Values that are capped as a result of this restriction to 
the scale are marked with ‘#’.  Values will be ordered in descending order with the 
imputations due to death appearing first followed by a gap followed by all other patients. 
Imputed values will be clearly marked with ‘*’ and patients with imputation where there was a 
death or evidence of progression have different shading to each other and the other patients to 
make it clear that these are different.  


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Additionally, ‘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 by dose level.  This depicts each patient’s percentage change in TL tumor size as a 
line over time and progression due to non- target and/or new lesions will be indicated.  
(Imputation will not be used for spider plots.)
4.2.3.3
Radiological Progression-free survival
Summaries (number of events, medians, proportion and 95% confidence interval for 
progression free at 3, 6, 9 months and 12 months using the Kaplan-Meier estimate) and 
Kaplan Meier plots will be provided.  A 2-sided 95% confidence interval for the median PFS 
will be produced in addition to the 25th and 75th percentiles. A listing of progression details 
will be provided.
4.2.3.4
Duration of response
Duration of Response will be analysed in the same manner as PFS, if patient numbers allow.
A swimmer plot will be presented with the duration of response over time. The bars in the 
swimmer plots indicate the duration of response for each subject, the y-axis will indicate the 
subject ID.
4.2.3.5
Overall survival
4.2.3.6
Overall Survival will be analyzed in the same manner as PFS if patient 
numbers allow.
 
 
4.2.4
PSA response
The proportion of patients achieving a PSA response and patients with a confirmed PSA 
response will be presented with both 95% CI and 80% CI.  The best PSA percentage change 
from baseline and the percent change from baseline in PSA levels at 12 weeks will be 
summarized and graphed. For patients who receive a subsequent anti-cancer therapy (note that 
for this analysis radiotherapy is not considered a subsequent anti-cancer therapy), data will 
only be included until the start date of the subsequent anti-cancer therapy.
Waterfall plots (bar plots) for the best percent change from baseline in PSA levels will be 
presented with each bar corresponding to the best percent change from baseline in PSA level 
for each patient, with the bars ordered from the largest increase to the largest decrease. The 
scale in these plots will be fixed to be from -100 to 100 to avoid presenting extreme values.  
Values that are capped as a result of this restriction to the scale are marked with ‘#’.
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Additionally spider plots (individual line plots of percent change from baseline over time)
depicting the percent change from baseline in PSA levels, at different dose levels over time,
for each patient will be produced.
4.2.5
Safety analyses
Safety data will not be formally analyzed.  At the end of the study, appropriate summaries for 
all safety data will be produced, as defined below.  All patients who received at least 1 dose of 
study drug will be included in the assessment of the safety profile (safety analysis set).
4.2.5.1
Exposure
Exposure to investigational product i.e., total amount of study drug received, will be listed for 
all patients.
Reasons for discontinuation of investigational product will be listed including the study day of 
treatment discontinuation and will be summarized by dose level if appropriate.
Total exposure, number of infusion cycles (where applicable), total treatment duration (as 
defined in Section 3.4.1), and the amount delivered relative to the intended amount (dose 
intensity: RDI) will be summarized by the following: mean, standard deviation, minimum, 
maximum, median and number of observations.  In addition, the number and percentage of 
patients with at least one dose interruption and at least one dose reduction will be presented 
separately for the initial period of DLT evaluability (Module 2 only) and for total treatment 
duration.
A swimmer plot will be produced for duration of exposure of study treatment. For each 
patient (indicated on the Y-axis) , the corresponding bar represents over time - the best 
response (CR, PR, SD, PD, NE) or no measurable disease, the beginning of RECIST and PSA 
response, time of RECIST and/or PSA progression, and whether the treatment is still ongoing 
or not.
4.2.5.2
Adverse events/ Serious adverse events
Adverse events (including laboratory-related adverse events) will be coded with System 
Organ Class (SOC) and Preferred Term (PT) using MedDRA version 21.1 or higher.  
Adverse events occurring on (could be on the same day as the first dose of IP, but at an earlier 
time) or before the first dose of IP (pre-treatment adverse events) or >30 days post the last 
dose i.e within 30 days after the end of the last investigational product (90 days for  
durvalumab and oleclumab) will be listed separately.  For module 1, adverse events onsetting 
or worsening on/after the first dose of study treatment up until the defined 30 day follow up 
period following end of AZD4635 or 90 days following end of durvalumab – whichever is 
later; and for module 2, adverse events onsetting or worsening on/after the first dose of study 
treatment up until 90 days following end of treatment  will be summarized by MedDRA 


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system organ class (SOC) and MedDRA preferred term (PT), with further splits by maximum 
CTCAE grade, possibly related to study medication as assessed by investigator, dose 
interruption or modification, and adverse events classed as CTCAE Grade 3 or higher. 
Additional tables will summarize AEs with outcome of death.
Generally, the imputation of dates is used to decide if an observation is treatment emergent for 
adverse events or concomitant medications.  The imputed dates are not advised to be used to 
calculate durations where the results would be less accurate.  After querying, dates will be 
imputed as described in the “Missing dates” part in section 3.1 of this SAP.
Flags will be retained in the database indicating where any programmatic imputation has been 
applied, and in such cases, any durations would not be calculated.
Separate tables will present adverse events leading to discontinuation, serious adverse events 
and other significant adverse events.  All AE data will be listed appropriately.  
Cause of death will be summarized and the details of any deaths will be listed for all patients.
In addition, adverse events of special interest will be summarized in a similar manner as 
TEAEs.  The listing of preferred terms and categories will be provided by AZ patient safety 
lead based on Medical Review at end of study, prior to database lock (DBL).
For Module 2, a DLT table will be generated showing the number of patients experiencing a 
DLT together with the total number of DLTs by patient. This table will use the DLT Analysis 
set.
4.2.5.3
Laboratory results
Clinical laboratory assessments for this study include: haematology, clinical chemistry, 
coagulation, and urinalysis.  
Haematology, clinical chemistry, and coagulation parameters will be summarized as follows:

Change and percentage change from baseline by module and visit (including mean, 
median, standard deviation, maximum, and minimum) (unscheduled assessments will not 
be included)

Shift from baseline to maximum post-baseline CTCAE grade (unscheduled assessments 
will be included) if applicable
.For urinalysis, the number and percentage of patients shifting from baseline to maximum 
abnormal results through treatment discontinuation will also be summarized .  For 
electrolytes, CTCAE grade change from baseline to maximum on treatment high and low will 
be summarized.


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4.2.5.4
Monitoring for drug-induced liver injury
The patients who had ALT ≥3xULN or AST ≥3xULN together with total bilirubin ≥2xULN 
will be listed for the safety analysis set.  The listing will include absolute values along with a 
function of the upper limit of normal (ULN) ALT, AST, total bilirubin and ALP.  Any 
potential Hy’s law case will be listed.
4.2.5.5
Electrocardiographic (ECG)
The ECG parameters will be summarized numerically and categorically for the safety analysis 
set 

Change and percentage change of ECG parameters from baseline by visit and module 
(including mean, median, standard deviation, maximum, and minimum)

The number and percentage of patients with maximum on-treatment QTcF values  >450, 
>480, >500 msec by module

The number and percentage of patients with the QTcF maximum changes as  >30, >60, 
>90 msec by module.
ECG data will also be listed.
4.2.5.6
Echocardiography or Multi-gated acquisition scan (ECHO/ MUGA)
All available data for ECHO/ MUGA, if performed to assess the ejection fraction, will be 
listed.
4.2.5.7
Vital signs assessments
Vital signs (e.g. weight, heart rate, respiratory rate, systolic blood pressure, diastolic blood 
pressure, and body temperature) will be summarized and listed for the safety analysis set.  As 
per the protocol specified requirements, the baseline vital signs parameters of systolic and 
diastolic blood pressure were recorded 2 or more times. These values will be averaged and 
summarized. Result and percentage change from baseline by visit and module (including 
mean, median, standard deviation, maximum, and minimum). On the day of the first infusion, 
the vital signs were collected pre, during, and post infusion, and this will be reflected in the 
summary, 

From baseline at each visit through treatment discontinuation
4.2.6
Pharmacokinetics data
PK concentrations of AZD4635, Durvalumab and Oleclumab will be analyzed descriptively 
by summarizing data at each scheduled time point (pre-dose and/or  post dose) based on 
observed data. Additionally, the PK concentrations will be presented in box plots separately, 


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one each for AZD4635, Durvalumab and Oleclumab. PK concentrations not assigned to a 
scheduled time point will be listed only. Plasma/serum concentrations below the lower limit of 
quantification (LLOQ) will be reported as not quantifiable (NQ) with LLOQ defined in the 
TFLs. 
 
  
 
Plasma concentrations will be summarized by module, cycle, day and nominal sample time.  
Plasma concentrations of AZD4635 and its metabolites will be summarized by nominal 
sample time. Parameters concentrations will be summarized by the following summary 
statistics:

The geometric mean (gmean, calculated as exp [μ], where μ is the mean of the data on a 
logarithmic scale)

Coefficient of variation (CV, calculated as 100 √ [exp(s2)-1], where s is the standard 
deviation of the data on a loge scale)

Gmean + geo standard deviation(geoSD) (calculated as exp[μ +s])

Gmean – geo standard deviation (geoSD) (calculated as exp[μ-s])

Arithmetic mean calculated using untransformed data

Standard deviation calculated using untransformed data

Median

Minimum

Maximum

Number of observations

Number of observations above the lower limit of quantification (LLOQ) 
Handling of non-quantifiable plasma concentrations (at a given time point) 
Non-quantifiable (NQ) values of plasma concentrations (at a given time point) will be handled 
as follows:

For timepoints prior to first measurable concentration, substitute 0.

If 50% or less of the values are NQ, the gmean, CV, gmean + geo standard deviation, 
gmean – geo standard deviation, arithmetic mean and standard deviation will be 
calculated by substituting the limit of quantification (LOQ) for values which are NQ. 

If more than 50%, but not all, of the values are NQ, the gmean, CV, gmean + standard 
deviation, gmean - standard deviation, arithmetic mean and standard deviation will be 
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reported as not calculable (NC). The maximum value will be reported from the individual 
data, and the minimum and median will be set to NQ.

If all the values are NQ, no summary statistics will be calculated. The gmean, arithmetic 
mean, minimum, median, and maximum will be reported as NQ. The CV, gmean + 
standard deviation, gmean - standard deviation, and standard deviation will be set to NC.
At least 3 observations are required for concentrations to be summarized. If data are available 
for less than 3 observations, no summary statistics other than minimum, maximum and n will 
be presented.
For any gmean plasma concentration-time plots where a gmean was unable to be calculated as 
there were fewer than 3 patients for that dose group, the individual patient profile(s) for that 
dose group could be included instead of the gmean.
4.2.7
Immunogenicity
 
 
Presence of ADAs to study drug(s) in combination with AZD4635 (confirmatory results: 
positive or negative) will be listed for each time point, and included in the CSR.
4.2.8
Exploratory research variables
 
5
INTERIM ANALYSES
No formal interim analysis is planned.
6
CHANGES OF ANALYSIS FROM PROTOCOL
There are no changes of analysis from the protocol.
7
REFERENCES
Clopper and Pearson 1934
Clopper, C. and Pearson, E. S.  The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika 26: 404-413, 1934
SAS Institute 2001
SAS Institute Inc. (2001): The SAS System, Version 8.2. Cary, NC. SAS Institute Inc.
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d8731c00001-sap-ed-2
Document Title:
Statistical Analysis Plan Edition 2
Document ID:
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
12-Nov-2021 08:36 UTC
Qualified Person Approval
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PPD

Prot_005.pdf: 
Clinical Study Protocol – 8.0 
AZD4635 - D8731C00001
AstraZeneca 
Core Clinical Study Protocol
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Clinical Study Protocol
Drug Substance
AZD4635 
Study Code
D8731C00001
Version
8.0
Date
28 September, 2022
An Open-label, Multi-drug, Multi-center Phase II Combination Study of 
AZD4635 in Patients with Prostate Cancer
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Redacted 
da ed
An
An Open
Open-lab
D4635 in Pa
D4635 in P
Zeneca
Zeneca A
for 
B, 15
15
Public Disclosure


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Changes to the protocol are summarized below in response to comments from the FDA 
received on the 20th May 2019.
!
Section 5.2 Exclusion criteria:
o
Updating of exclusion criteria 2 from “History of seizures, CNS tumors or 
metastasis” to “Previously untreated brain metastases. Patients who have 
received radiation or surgery for brain metastases are eligible if therapy was 
completed at least 21 days previously and there is no evidence of CNS disease 
progression or mild neurologic symptoms”;
o
Removal of exclusion criteria 6: “Symptoms of a significant mental illness in 
the 4-week period preceding drug administration”.
!
Section 4.3 Justification for dose: updated to add summary of food effect data.
Version 2.0, 22 May 2019
Initial creation
Version 1.0, 10 April 2019
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.
o
Updated exclusion criterion 10 to clarify the interval between the end of the 
prior treatment and first dose of study drug for chemotherapy: ≥21 days or 5 
half-lives (whichever is shorter longer) of the first dose of study drug.
!
Section 8.1 Efficacy assessments was updated to clarify: All CT/bone scans and all 
imaging assessments performed for RECIST 1.1 tumour assessment will be reviewed at 
site. Duplicates must be available at the site in readiness to be sent for retrospective 
independent central RECIST 1.1 review, if deemed appropriate. More information on 
this procedure is available in the Image Acquisition Guideline for this study.
Version 3.0, 01 July 2019


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY ........................................................................................................... 2
TABLE OF CONTENTS ....................................................................................................... 9
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis............................................................................................................ 14
1.2
Schema ............................................................................................................. 18
1.3
Schedule of Activities (SoA) - Screening........................................................... 19
2
INTRODUCTION ............................................................................................ 21
2.1
Study rationale .................................................................................................. 21
2.2
Background....................................................................................................... 22
2.3
Benefit/risk assessment ..................................................................................... 23
3
OBJECTIVES AND ENDPOINTS................................................................... 24
4
STUDY DESIGN ............................................................................................. 26
4.1
Overall design................................................................................................... 26
4.1.1
Modular protocol structure................................................................................ 27
4.1.1.1
List of modules ................................................................................................. 28
4.1.2
Clinical screening procedures............................................................................ 28
4.1.3
COVID-19 testing (if applicable)....................................................................... 29
4.2
Scientific rationale for study design................................................................... 30
4.3
Justification for AZD4635 dose......................................................................... 30
4.4
End of study definition...................................................................................... 31
5
STUDY POPULATION.................................................................................... 32
5.1
Inclusion criteria ............................................................................................... 32
5.2
Exclusion criteria .............................................................................................. 34
5.3
Lifestyle restrictions.......................................................................................... 38
5.3.1
Meals and dietary restrictions............................................................................ 38
5.3.2
Reproduction..................................................................................................... 38
5.4
Screen failures................................................................................................... 39
6
STUDY TREATMENTS .................................................................................. 40
6.1
Treatments administered.................................................................................... 40
6.1.1
Investigational products .................................................................................... 40
6.2
Preparation/handling/storage/accountability ....................................................... 41
6.3
Measures to minimize bias ................................................................................ 41
6.4
Treatment compliance ....................................................................................... 42
6.5
Treatment assignment........................................................................................ 43
6.5.1
Methods for assigning treatment groups............................................................ 43
6.5.2
Procedures for handling incorrectly allocated patients....................................... 43


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6.6
Concomitant therapy......................................................................................... 44
6.6.1
COVD-19 Vaccination Guidance ...................................................................... 45
6.6.2
Additional concomitant treatment...................................................................... 45
6.6.3
Other concomitant treatment ............................................................................. 46
6.7
Dose modification............................................................................................. 46
6.8
Treatment after the end of the study.................................................................. 46
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 47
7.1
Discontinuation of study treatment .................................................................... 47
7.1.1
Procedures for discontinuation of study treatment.............................................. 47
7.1.2
Procedures for patients who test positive for COVID-19.................................... 48
7.2
Lost to follow-up............................................................................................... 48
7.3
Withdrawal from the study................................................................................ 48
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 49
8.1
Efficacy assessments......................................................................................... 50
8.1.1
Tumor assessments with RECIST v1.1.............................................................. 51
8.1.2
PCWG3 bone lesions assessment ...................................................................... 53
8.1.4
PWCG3 PSA criteria ......................................................................................... 54
8.2
Safety assessments ............................................................................................ 54
8.2.1
Clinical safety laboratory assessments............................................................... 54
8.2.2
Physical examinations....................................................................................... 57
8.2.3
Performance status............................................................................................ 57
8.2.4
Vital signs......................................................................................................... 58
8.2.5
Electrocardiograms............................................................................................ 58
8.2.6
Echocardiography or multi-gated acquisition scan ............................................. 59
8.2.7
End-of-treatment visit........................................................................................ 59
8.2.8
Follow-up visits ................................................................................................ 59
8.2.8.1
30-day follow-up visit ....................................................................................... 59
8.2.8.2
Progression-free follow-up visits....................................................................... 60
8.2.8.3
Survival follow-up ............................................................................................ 60
8.2.9
COVID-19 Testing ............................................................................................ 60
8.3
Collection of adverse events.............................................................................. 60
8.3.1
Method of detecting AEs and SAEs................................................................... 61
8.3.2
Time period and frequency for collecting AE and SAE information .................. 61
8.3.3
Follow-up of AEs and SAEs.............................................................................. 61
8.3.4
Adverse event data collection............................................................................. 61
8.3.5
Causality collection........................................................................................... 62
8.3.6
Adverse events based on signs and symptoms ................................................... 62
8.3.7
Adverse events based on examinations and tests................................................ 63
8.3.8
Hy’s law ........................................................................................................... 63
8.3.9
Disease progression........................................................................................... 63
8.3.10
New cancers ...................................................................................................... 64
8.3.11
Deaths............................................................................................................... 64
8.3.12
Adverse events of special interest...................................................................... 64
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LIST OF TABLES
Table 1
Study objectives....................................................................................... 14
Table 2
Schedule of Activities - Screening............................................................ 19
Table 3
Study objectives....................................................................................... 24
Table 4
Highly effective methods of contraception (<1% failure rate)................... 39
Table 5
Restricted medications ............................................................................. 44
Table 6
Prohibited medications............................................................................. 44
Table 7
Requirements for documentation of progression....................................... 54
Table 8
Laboratory safety variables ...................................................................... 56
Table 9
AZD4635 dose modifications and discontinuation criteria for non-
hematologic toxicities (except hypertension)............................................ 68
Table 10
AZD4635 dose modifications and discontinuation criteria for
management of hypertension.................................................................... 69
Table 11
Summary of Methods of Assessment...................................................... 109
Table 12
Evaluation of target lesions .................................................................... 112
Table 13
Evaluation of Non-Target Lesions.......................................................... 113
Table 14
Overall Visit Soft Tissue Response ........................................................ 114
Table 15
Bone progression status.......................................................................... 119
Table 16
Overall radiological visit response.......................................................... 119
Table 17
Best overall response when confirmation of CR and PR required............ 120
Table 19
Examples of CYP1A2 inhibitors and inducers of.................................... 125
Table 20
Examples of substrates of transporters.................................................... 126
LIST OF FIGURES
Figure 1
Study design ............................................................................................ 18
Figure 2
Modular study designa ...............................................................................................................................27
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations ............................. 83
Appendix B
Adverse event definitions and additional safety information..................... 89
Appendix C
Handling of Human Biological Samples................................................... 93
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Appendix E
Actions required in cases of increases in liver biochemistry and
evaluation of Hy’s Law............................................................................. 99
Appendix F
Abreviations........................................................................................... 105
Appendix G
Guidelines for Evaluation of Objective Tumor Response Using RECIST
Version 1.1 (Response Evaluation Criteria in Solid Tumors) in Soft
Tissue and PCWG3 (Prostate Cancer Working Group Criteria 3) in Bone
Lesions .................................................................................................. 108
Appendix I
PCWG3 PSA Criteria............................................................................. 124
Appendix J
Disallowed medications .......................................................................... 125
Appendix K
Module 1: AZD4635 plus Durvalumab
Appendix L
Module 2: AZD4635 plus Oleclumab
Appendix M
Module 3: AZD4635 plus Durvalumab plus Oleclumab
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1
PROTOCOL SUMMARY
1.1
Synopsis
Coordinating Principle Investigator
Columbia University Medical Center/Herbert Irving Pavilion 
161 Fort Washington Avenue
New York, NY 10032 
United States
Protocol Title:
An Open-label, Multi-drug, Multi-center Phase II Combination Study of AZD4635 in Patients 
with Prostate Cancer
Rationale:
AZD4635 appears to have increased efficacy in combination with anti-programmed death 
ligand 1 in prostate cancer due to increased immune activation compared to single agent 
AZD4635. On study D8730C00001 in the Phase 1A dose escalation portion, 12 patients with 
metastatic castrate-resistant prostate cancer were dosed with AZD4635, and prostate-specific 
antigen (PSA) responses were seen in 4 patients (2 in monotherapy and 2 in combination 
therapy). Three Response Evaluation Criteria in Solid Tumours responses were seen among 
these same patients with 1 complete response and 2 partial responses, all of which persisted 
for >6 months. Data from the ongoing Phase 1b portion of this study so far support the 
development of AZD4635 in combination in prostate cancer. Therefore, this open-label 
multi-center, modular Phase II study in patients with prostate cancer consists of a number of
treatment cohorts, allowing evaluation of the efficacy, safety and tolerability of the study drug 
in multiple treatment arms.
Table 1
Study objectives
Primary Objective:
Endpoint/Variable:
To evaluate efficacy of each combination therapy on 
objective response rate (ORR) for patients with 
measurable disease
Proportion of patients with measurable disease at 
baseline who have a confirmed ORR per Response 
Evaluation Criteria in Solid Tumours (RECIST 1.1)
To evaluate efficacy of each combination therapy on 
PSA response rate
PSA confirmed response is defined as the proportion 
of participants with a reduction in the PSA level of
≥50% from baseline to the lowest post-baseline PSA 
results, measured twice, at least 3 weeks apart by the 
Prostate Cancer Working Group 3 criteria (PCWG3)
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Study objectives
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Secondary Objectives:
Endpoint/Variable:
To evaluate the efficacy of each combination therapy 
on the proportion of patients alive and
progression-free at 6 months
Summaries of the Kaplan-Meier curve for 
radiological progression-free survival including the 
proportion of patients alive and radiological 
progression-free at 6 months using RECIST 1.1 (soft 
tissue lesions) and PCWG3 (bone lesions)
To evaluate efficacy of each combination therapy on 
duration of response (DoR)
Duration of Response (DoR) is defined as the time 
from the date of first documented response until date 
of documented progression or death in the absence of 
disease progression
To evaluate efficacy of each combination therapy on 
overall survival (OS).
Overall survival is length of time from date of first 
dose until the date of death due to any cause.
To evaluate the pharmacokinetics (PK) of AZD4635 
and its metabolites and other combination agent(s).
Steady state trough
To evaluate the immunogenicity of mAB study 
drug(s) in combination with AZD4635.
Patients with the presence or absence of anti-drug 
antibody (ADA)
Safety Objective:
Endpoint/Variable:
To assess the safety and tolerability of each treatment 
regimen.
Adverse events (AEs)/serious adverse events (SAEs) 
Physical exam and vital signs
Collection of clinical chemistry/hematology 
parameters
 
 
 
 
 
 
 
 
 
 
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Study objectives
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Overall design:
This is an open-label Phase II modular study in patients with prostate cancer which will assess 
safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in 
different treatment arms. The details of the study design, including identification of the 
combination agents, will be described in appendices to the core protocol. Three appendices 
are included in Study D8731C00001 as specified below. The decision was made by the 
Sponsor not to open Module 3 to recruitment after a comprehensive strategy review of the 
AZD4635 program and not due to new dose-limiting toxicities or concerning safety signals 
observed with AZD4635. Other combination agents may be identified and included in the 
study appendices under the auspices of appropriate IND or CTA amendments.
Appendix K
Module 1: AZD4635 plus durvalumab 
Appendix L
Module 2: AZD4635 plus oleclumab
Appendix M
Module 3: AZD4635 plus durvalumab plus oleclumab
All patients will be allocated into a module using the Interactive Web Response System 
(IWRS). Randomization will occur when patients meet eligibility criteria for 2 or more 
modules that are currently recruiting. If patients only meet the criteria for 1 currently 
recruiting module, they will be allocated to that module without randomization taking place.
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Study Period:
Estimated date of first patient enrolled: Q3 2019 
Estimated date of last patient completed: Q2 2021
Administrative Structure:
Sarah Cannon Development Innovations has been contracted by AstraZeneca to serve as the 
Contract Research Organization for this study up to the implementation of Clinical Study 
Protocol (CSP) version 7.
Parexel has been contracted to take over the management of the patients from Sarah Cannon 
Development Innovations from implementation of CSP version 7.
Study site(s) and number of patients planned:
There will be approximately 30 patients with prostate cancer in each module. The intent is to 
conduct the study in multiple sites.
Treatments and treatment duration:
This protocol has a modular design, with the potential for future treatment arms to be added 
via protocol amendment. The core protocol has information about AZD4635 and refers to the 
following modules and study drugs. For specific information on each of the study drugs, 
please refer to the relevant module.
!
Module 1: AZD4635 in combination with durvalumab
!
Module 2: AZD4635 in combination with oleclumab
!
Module 3: AZD4635 in combination with durvalumab and oleclumab
Additional modules and agents may be added as part of this multi-drug protocol as decisions 
on the most appropriate combinations to use become available. A substantial protocol 
amendment with relevant nonclinical and clinical data will be put in place before starting a 
new combination module.
Patients will continue to receive study treatment until one of the discontinuation criteria is met 
or withdrawal from study, whichever occurs first.
Statistical methods
The primary efficacy endpoint is PSA decline from baseline ≥50% (PSA50) and overall 
response rate (ORR) per RECIST v1.1 for patients with measurable disease at baseline. In 
Modules 1, 2, and 3 (if conducted) there will be approximately 30 PSA evaluable patients in 
each module, and approximately 20 patients will have RECIST measurable disease at baseline 
in each module. Approximately 30 patients with and without measurable disease at baseline




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1.3
Schedule of Activities (SoA) - Screening
The Schedule of Activities (SoA) for the pre-screening and screening visits is shown in Table
2 below. For the SoA to be performed during the on-treatment period, please refer to the 
relevant module.
Table 2
Schedule of Activities - Screening
Screening
Details in Section
Informed consenta
X
5.1
Inclusion/exclusion
X
5
Medical history and demographicsb
X
4.1.2
Physical examinationb
X
8.2.2
ECOG performance statusb
X
8.2.3
Vital signsb
X
8.2.4
Height and weightb
X
8.2.4
12-lead ECG (triplicate) b
X
8.2.5
ECHO/ MUGA scanb
X
8.2.6
Hematologyb
X
8.2.1
Clinical chemistry (including LDH, thyroid panel, and 
CRP) b
X
8.2.1
Testosterone sampleb
X
8.2.1
Prostate-specific antigen (PSA)d
 
X
8.1.4
Urinalysisb
X
8.2.1
Coagulation test (PT/INR/aPTT)b
X
8.2.1
Hepatitis A, B, C; HIV-1b
X
8.2.1
Archival tumor samplee
X
8.8.2
Concomitant medication
X
6.6
Adverse event (AE) evaluation
X
8.3
Fresh tumor biopsyf
X
8.8.1.1
Tumor assessments CT/MRI/PET and Bone scansc
X
8.1.1
a
Informed consent must be obtained ≤28 days prior to the initiation of treatment and before any study-
specific procedures are performed.
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b
Assessments should be done ≤14 days prior to initiation of treatment. If these assessments are performed 
within 72 hours of initiation of treatment, they do not need to be repeated, with the exception of the ECOG 
performance status, abbreviated physical examination, vital signs (including respiration assessment) weight, 
and triplicate ECGs required prior to first study dose. The testosterone sample may be taken within 28 days 
of screening. Urinalysis should be repeated on Day 1 of every cycle, at the end-of-treatment (EOT) visit, 
and if clinically indicated. The Hepatitis A laboratory test should only be performed if the patient is 
considered symptomatic per the Investigator.
c
Baseline tumor 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. Baseline tumor 
assessments should encompass all areas of known disease under evaluation and should additionally 
investigate areas that may be involved based on signs and symptoms of individual patients as per 
Investigator discretion. The methods of assessment used at baseline should be used at each subsequent 
follow-up assessment.
d
Patients 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 pure small cell carcinoma). It is 
recommended to estimate a pre-treatment PSA doubling time (PSADT) if at least 3 values are available ≥4 
weeks apart. Treatment or enrollment onto a trial should not be delayed to estimate PSADT.
e
All patients will be required to provide a sample of their archival tumor, if available (tissue from the 
primary lesion or a metastatic site is acceptable). The archived tumor samples will preferably be in the 
form of a formalin fixed paraffin embedded (FFPE) block. If archival tumor tissue is not available, then 
tissue from a fresh tumor biopsy is required.
f
All patients will be required to have a site of disease that is safely accessible for biopsy (paired) upon 
enrollment unless there are sufficient paired samples for the analysis as determined by the Sponsor. The 
initial predose biopsy should be taken within 30 days of screening (at least 1 day prior to the first 
administration of AZD4635) and 2 weeks after the initiation of AZD4635 therapy. A 5-day window is 
permitted to facilitate on-treatment biopsy collection (Days 12 - 16 post first dose of AZD4635). The time 
and site of the biopsy must be clearly documented. Instructions for processing of biopsies are in the 
Laboratory Manual.
g
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2
INTRODUCTION
Prostate cancer is the second most frequently diagnosed cancer in men and was estimated to
be responsible for over 300,000 deaths worldwide in 2018 (Bray et al. 2018). For patients 
who require systemic therapy, the mainstay of treatment is hormonal therapy but patients
often develop resistance to this therapy (castrate-resistant prostate cancer). Treatment for both 
metastatic and non-metastatic prostate cancer is rapidly evolving. Since the development of a 
docetaxel regimen for the treatment of metastatic castration-resistant prostate cancer
(mCRPC) in 2004 (Tannock et al. 2014), the outcomes of this condition have improved 
dramatically. However, many of the treatments for prostate cancer, including docetaxel and 
cabazitaxel for mCRPC, may not be suitable for all patients and some patients are refractory
to these treatments, thus there remains a need for additional therapies for this disease.
Current standard of care (SOC) therapies for mCRPC include enzalutamide, and abiraterone 
plus prednisone. Enzalutamide, a targeted androgen-receptor inhibitor that blocks binding of 
androgen to the androgen-receptor, translocation to the nucleus, and DNA binding (Tran et al.
2009), was approved for the first-line treatment of patients with mCRPC and metastatic 
castration-sensitive prostate cancer (mCSPC). Abiraterone, a selective inhibitor of 17 α-
hydroxylase/C17,20-lyase (CYP17) was also approved in combination with prednisone for the 
treatment of mCRPC in the first-line setting (Ryan et al. 2013a, Ryan et al. 2013b) and for 
metastatic high-risk castration-sensitive prostate cancer.
2.1
Study rationale
Although there are now standard of care (SOC) treatments for mCRPC, better treatments are 
needed for patients after the SOC options have been exhausted.
AZD4635 is being developed as monotherapy and in combination with other agents to 
augment the anti-tumor immune response. Ongoing studies D8730C00001 and D6070C00004 
include the combination of AZD4635 with durvalumab (anti-PDL1 monoclonal antibody) as 
well as in combination with oleclumab (CD73 mAb), respectively. On study D8730C00001
in the Phase 1A dose escalation portion, 12 patients with metastatic CRPC were dosed with 
AZD4635, and PSA responses were seen in 4 patients (2 in monotherapy and 2 in
combination therapy). Three RECIST responses were seen among these same patients with
1 CR and 2 PRs, all of which persisted for >6 months. Data for the ongoing Phase 1b portion 
of the study so far support the development of AZD4635 in combination in prostate cancer. 
Therefore, this open-label multi-center, modular Phase II study in patients with prostate 
cancer consists of a number of treatment cohorts, allowing evaluation of the efficacy, safety 
and tolerability of the study drug in multiple treatment arms.
Study rationale for each module is provided in the modular-specific appendix.


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2.2
Background
T-cell-mediated immune responses to treatment with immune checkpoint inhibitors have been 
shown to induce durable responses in several cancers (Larkin et al. 2015, Robert et al. 2015,
Brahmer et al. 2015, McDermott et al. 2015, Le et al. 2015, Antonia et al. 2017). However, 
immune suppression in the tumor microenvironment (TME) can lead to immune evasion, 
decrease effectiveness of T cells, and impact primary resistance or acquired resistance to 
immunotherapy. Extracellular adenosine signaling through adenosine 2a receptor (A2AR) is 
one such mediator of immune suppression which leads to decreases in antigen presentation 
and T-cell activation, as well as an increase in suppressive cells. Modulation of the TME with 
drugs that decrease adenosine or inhibit the A2AR may reverse these effects and enable the 
host to mount an effective anti-tumor immune response, even in tumor types that are not 
typically responsive to immune checkpoint inhibitors.
AZD4635 is a potent, highly selective inhibitor of A2AR. In preclinical mechanistic, efficacy 
and pharmacodynamic (PDx) studies, AZD4635 demonstrates activity consistent with 
enhancement of anti-tumor immunity.
 
 
 
 
 
 
AZD4635 appears to have increased efficacy in combination with anti-programmed death 
ligand 1 in prostate cancer due to increased immune activation compared to single agent 
AZD4635. As of October 4, 2018, in the ongoing study D8730C00001, prostate-specific 
antigen (PSA) responses were seen in 4 of 10 patients with advanced prostate cancer (2 
patients in AZD4635 monotherapy [Phase 1a], and 2 patients receiving AZD4635 in 
combination with durvalumab [Phase 1a]). In Phase 1a, 8 patients had disease measurable by 
Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and were observed 
to have 2 partial responses (1 in a monotherapy cohort, 1 in AZD4635 + durvalumab 
combination cohorts) and 1 complete response (in an AZD4635 + durvalumab combination 
cohort). All of these responses persisted for >6 months (11-16 months). Data from this 
ongoing study appear to suggest a higher response rate in prostate cancer following 
combination therapy with AZD4635 + durvalumab over AZD4635 monotherapy. Although 
the combination of anti-CD73 (oleclumab) with AZD4635 has not been studied specifically in
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prostate cancer, there is an ongoing study of oleclumab with AZD4635 in refractory epidermal 
growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) post-tyrosine 
kinase inhibitor (TKI) progression. This combination provides inhibition of the adenosine 
axis by both reduction of adenosine production plus A2AR blockade and is hypothesized to 
increase the response seen with either single agent alone by further diminishing the
adenosine-mediated immunosuppression. This hypothesis is also applicable to patients with 
prostate cancer.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD4635 is 
provided in the Investigator’s Brochure (IB).
2.3
Benefit/risk assessment
AZD4635 is a novel A2AR antagonist agent that acts against cancer by blocking 
adenosine-mediated A2AR signaling in tumor infiltrating cells. AZD4635 blockade is
hypothesized to modulate the TME so that an active anti-tumor immune response will be more 
effective. Therefore, AZD4635 may have the potential to provide benefit in terms of 
increased efficacy in patients with a variety of advanced solid malignancies and for patients 
who are refractory to SOC treatments.
As of December 2019, approximately 300 patients with advanced cancer had been treated 
with AZD4635 alone or in combination with another cancer drug. Between 30 August 2016 
and 20 June 2019 (date of data cut-off) in the ongoing study D8730C00001, 94 mCRPC 
patients were treated with AZD4635 (125 mg BID, 75 mg QD, or 100 mg QD oral 
nanosuspension Q3W monotherapy [n=49]) or in combination (75 or 100 mg QD) with 
durvalumab 1.5g IV Q4W (n=45).
As of December 17, 2018, 17 healthy volunteers had received AZD4635 nanosuspension or 
AZD4635 capsule formulation in study D8730C00002. As of October 05, 2018 in study 
D6070C00004, 8 patients had received AZD4635 at 2 dose levels in combination with 
oleclumab.
Based on the available safety data, nausea and vomiting are identified risks for AZD4635 
when it is used as monotherapy or given in combination with durvalumab or oleclumab. In 
study D8730C00001, 2 serious adverse events (SAEs) were reported for AZD4635 (at various 
dose levels) in combination with durvalumab which were considered related to study 
treatment by the Investigators: diabetes mellitus type 1 (Grade 4) and hypertension (Grade 3). 
In Study D6070C00004, 1 SAE of pulmonary embolism (Grade 3) was considered related to 
the combination of AZD4635 and oleclumab by the Investigator. Although, thrombosis is 
considered to be an important potential risk for oleclumab based on known mechanism of 
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The most common treatment-emergent AEs (TEAEs) seen in patients treated with AZD4635 
as monotherapy or in combination across all studies were mainly nausea, vomiting and 
fatigue. These AEs were mostly Grade 1 or 2 and were clinically manageable. One patient in 
study D8730C00001, in the Phase 1a dose escalation cohort of the combination
(75 mg AZD4635 + 1500 mg durvalumab), experienced Grade 2 dose-limiting toxicities 
(DLTs) of nausea and fatigue which required dose reduction of AZD4635 to 50 mg.
In study D8730C00001, 70 patients were evaluable for tumor 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% confidence interval [CI], 7.1-15.3) and
14.9 weeks (95% CI, 13.3-29.3) for the combination cohort. PSA response (defined as ≥50% 
decrease from baseline) was observed in monotherapy=6.4% (3/47 patients; 95% CI, 1.3-
17.5%) and combination=20% (9/45 participants; 95% CI, 9.6 34.6%).
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of each study drug may be found in their drug-specific IBs and the relevant 
modules. Appendix A in Modules 1 and 2 describes risk considerations for COVID-19.
3
OBJECTIVES AND ENDPOINTS
Table 3
Study objectives
Primary Objective:
Endpoint/Variable:
To evaluate efficacy of each combination therapy on 
objective response rate (ORR) for patients with 
measurable disease
Proportion of patients with measurable disease at 
baseline who have a confirmed ORR per Response 
Evaluation Criteria in Solid Tumours (RECIST 1.1)
To evaluate efficacy of each combination therapy on 
PSA response rate
PSA confirmed response is defined as the proportion 
of participants with a reduction in the PSA level of
≥50% from baseline to the lowest post-baseline PSA 
results, measured twice, at least 3 weeks apart by the 
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Secondary Objectives:
Endpoint/Variable:
To evaluate the efficacy of each combination therapy 
on the proportion of patients alive and
progression-free at 6 months
Summaries of the Kaplan-Meier curve for 
radiological progression-free survival including the 
proportion of patients alive and radiological 
progression-free at 6 months using RECIST 1.1 (soft 
tissue lesions) and PCWG3 (bone lesions)
To evaluate efficacy of each combination therapyon 
duration of response (DoR)
Duration of Response (DoR) is defined as the time 
from the date of first documented response until date 
of documented progression or death in the absence of 
disease progression
To evaluate efficacy of each combination therapy on 
overall survival (OS).
Overall survival is length of time from date of first
dose until the date of death due to any cause.
To evaluate the pharmacokinetics (PK) of AZD4635 
and its metabolites and other combination agent(s).
Steady state trough
To evaluate the immunogenicity of mAB study 
drug(s) in combination with AZD4635.
Patients with the presence or absence of anti-drug 
antibody (ADA)
Safety Objective:
Endpoint/Variable:
To assess the safety and tolerability of each treatment 
regimen.
AEs/SAEs
Physical exam and vital signs
Collection of clinical chemistry/hematology 
parameters


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4
STUDY DESIGN
4.1
Overall design
This is an open-label Phase II modular study in patients with prostate cancer to assess safety, 
efficacy, and tolerability of AZD4635 in combination with other therapeutic agents in 
different treatment modules. Patients will be randomized for inclusion in the initial 3 modules
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a
The decision was made by the Sponsor not to open Module 3 to recruitment after a comprehensive strategy 
review of the AZD4635 program and not due to new dose-limiting toxicities or concerning safety signals 
observed with AZD4635.
Study drug-specific information including doses and justifications, toxicity management, dose 
modifications and concomitant medications for AZD4635 can be found in the core protocol. 
Study drug-specific information including doses and justifications, toxicity management, dose 
modifications and concomitant medications for additional study agents can be found in the 
relevant module.
4.1.1.1
List of modules
The following modules for the study are included with this protocol. The structure of the 
protocol allows for further modules to be added to the core study via protocol amendment as 
required.
!
Module 1: AZD4635 in combination with durvalumab (Appendix K)
!
Module 2: AZD4635 in combination with oleclumab (Appendix L)
!
Module 3: AZD4635 in combination with durvalumab and oleclumab (Appendix M)
As stated above, the modules contain study drug-specific information. Specific rationales for 
these cohorts are provided in the modules.
4.1.2
Clinical screening procedures
Each potential patient will provide informed consent ≤28 days prior to the initiation of 
treatment and before starting any study-specific procedures.
Following patient consent, data obtained prior to consent may be used for screening provided 
the assessments fall within the protocol-specified period prior to the first dose of study drug.
The following screening procedures, which are common to each of the modules, should be 
performed (please also refer to Table 2):
!
Demographic data and other characteristics will be recorded and will include date of birth 
or age, gender, and race and/or ethnicity per local regulations.
!
A standard medical, medication and surgical history, including prior cancer treatments, 
response, and duration of prior therapy, will be obtained.
!
The following clinical assessments will be required:
o
Physical examination and ECOG performance status evaluation
o
Vital signs + weight and height
o
ECG
o
ECHO/MUGA scan
o
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o
Urine sample collection
o
Tumor assessments: CT/MRI/PET and Bone scans per RECIST v.1.1 and 
PCWG3
!
All patients will be required to provide an archival tumor block (if available) or a new 
fresh tumor biopsy if an archival sample is not available (this biopsy sample is not to 
replace the fresh paired biopsy collection described below).
!
A fresh biopsy will be required within 30 days of screening, prior to the first dose of 
AZD4635, and at week 2 of AZD4635 study treatment, prior to the administration of 
Cycle 1 Day 1 combinational agent, for all patients for each module until there are 
sufficient paired samples for the analysis as determined by the Sponsor. In the case that 
the second sample is not taken, the patient will remain in the study, and there will be no 
penalty or loss of benefit to the patient, and they will not be excluded from other aspects 
of the study. The requirement for biopsies must be made clear to each patient at the time 
of initial approach by the Investigator.
!
At screening, consenting patients are assessed to ensure that they meet the core and 
module-specific eligibility criteria for one or more modules.
!
All eligible patients will then be assigned into a module via IWRS system. 
Randomization will occur when patients meet eligibility criteria for 2 or more modules 
that are currently recruiting. If patients only meet the criteria for 1 currently 
recruiting module, they will be allocated to that module without randomization 
taking place.
!
All patients, after being assigned into a module, will need to consent for a 
module-specific ICF prior to the 1st dose on study.
Samples for laboratory tests for the assessment of safety will be sent to a local laboratory and 
assessed locally. All other samples such as those for the assessment of molecular aberrations 
 will be assessed centrally. The tumor sample(s) taken as part of 
the screening procedures will be sent to a central laboratory(ies) for analysis of molecular 
alterations using tests verified and validated in line with local regulations e.g., Clinical 
Laboratory Improvement Amendments/College of American Pathologists (CLIA/CAP) for US 
laboratories, Good Clinical Practice (GCP), and local accreditation for other territories.
4.1.3
COVID-19 testing (if applicable)
During the study, tests for active coronavirus disease of 2019 (COVID-19) infection may be 
conducted, if required, and in accordance with local guidance.
If a patient is symptomatic for active COVID-19 infection during a site visit, they 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/Study Physician 
should be consulted. If a patient tests 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/Study Physician. Where
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applicable, home, or remote visits may be conducted for study assessments and study drug 
administration (refer to Appendix A in Modules 1 and 2).
4.2
Scientific rationale for study design
Although there are now SOC treatments for prostate cancer, better treatments are needed for 
patients after the SOC options have been exhausted. AZD4635 is being developed as 
monotherapy and as an immuno-oncology agent in combination with durvalumab 
(MEDI4736, PD-L1 monoclonal antibody [mAb]) and in combination with oleclumab 
(MEDI9447, CD73 mAb), exploiting complementary immune-related mechanisms to broaden 
and deepen clinical responses in prostate cancer.
AZD4635 had been studied clinically in 3 other investigational trials prior to initiation of this 
protocol:
!
D8730C00001 (NCT02740985): This first-time-in-human (FTIH) study of AZD4635 is a 
Phase 1 study that dosed AZD4635 at the maximum-tolerated dose (MTD) of 100 mg 
orally (PO) daily (QD) both as monotherapy and in combination with durvalumab in 
patients with advanced solid tumors.
!
D8730C00002 (NCT02740985): A bioavailability study in healthy volunteers was 
undertaken in order to facilitate a change in formulation and compare the performance of 
a capsule formulation to the existing nanosuspension to assess the 2 formulation variants.
!
D6070C00004 (NCT03381274): AZD4635 is also being studied at 75 and 50 mg PO QD 
in combination with oleclumab (MEDI9447) 1500 mg intravenously (IV) every 2 weeks 
(Q2W) in patients with refractory EGFRm lung cancer. Patients developed significant 
nausea and vomiting at the starting dose of AZD4635 75 mg QD + oleclumab 1500 mg. 
However, dose reduction to 50 mg AZD4635 nanosuspension daily in combination with 
oleclumab 1500 mg IV is still under evaluation.
Please see the AZD4635 IB for more information.
4.3
Justification for AZD4635 dose
 
 
 
 
 
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A preliminary food effect assessment was conducted as part of the relative bioavailability 
study (Study D8730C00002) in healthy volunteers to assess the impact of a high-fat meal on a 
single dose of capsule formulation of AZD4635. Interim PK data from 18 subjects suggest 
co-administration of AZD4635 capsule with a high-fat meal decreased AZD4635 geometric 
mean AUC0-48 by 15%, decreased geometric mean Cmax by approximately 50%, and delayed
tmax by 2.5 hours, compared with AZD4635 administered under fasted condition. Food had no 
obvious effect on PK variability of the primary exposure parameters. Given the fact that food 
can mitigate gastrointestinal toxicities and there was a lack of significant effect on AUC, the 
current fasting restrictions will be relaxed to allow patients to receive AZD4635 with or 
without food.
Information on dose justification for other study drugs is provided in the respective modules.
4.4
End of study definition
The end of study is defined as the last scheduled visit or contact of the last patient undergoing 
the study. There will be a primary analysis data cut-off (DCO) for the study (Modules 1 and 
2) at approximately 6 months after the last patient starts investigational product (IP) or
90 days after the final patient discontinues IP if this is earlier. The clinical study database will 
be closed to new data after the DCO (16 June 2022) for the primary analysis.
The study may be terminated at individual centers if the study procedures are not being 
performed according to Good Clinical Practice (GCP) or if the site is unable to recruit 
sufficient numbers of patients into the study.
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The AstraZeneca Study Team may also terminate the entire study or individual modules 
prematurely if concerns for safety arise within this study or in any other study with any agent 
used in any of the study treatments.
Any patients still receiving IP at the time of the primary study DCO can either choose to 
discontinue from the study or keep receiving IP while deriving clinical benefit as per 
Investigator discretion, following discussion with and approval from the AstraZeneca Study 
Team. See section 6.8 of this protocol for more information on treatment after the end of this 
study.
See Appendix A 6 for a description of where protocol information and study results will be 
made publicly available.
5
STUDY POPULATION
Prospective approval of a protocol deviation from recruitment and enrollment criteria, also 
known as a protocol waiver or exemption, is not permitted.
Each patient must meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study module. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures (refer to Section 5.4).
Where there are differences in stringency or cut-off values between the core protocol and 
specific module, the specific module takes precedence. For example, if hematological or 
medication parameters are stricter in the module than in the core protocol, the Investigator 
should adhere to the module criteria.
In this protocol, “enrolled” patients are defined as those who sign informed consent forms 
(ICFs). “Randomized” patients are defined as those who undergo randomization and receive a 
randomization number or are assigned to a module.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
The inclusion criteria that are applicable to all patients in the study are described in this 
section. Please also refer to the relevant module protocol for specific criteria applicable to 
each module.
Inclusion Criteria for all patients in all modules
Patients are eligible to be included in the study only if all of the following inclusion criteria 
are met and none of the exclusion criteria apply:


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Informed consent
1
Ability to provide signed informed consent, which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
protocol.
2
Provision of signed and dated, written informed consent form prior to any mandatory 
study-specific procedures, sampling, and analyses.
 
 
 
The ICF process is described in Appendix A 3.
 
Age
3
Patient must be ≥18 years of age at the time of signing the ICF.
Type of patient and disease characteristics
4
Patients must have prostate cancer with histological or cytological confirmation.
5
Patients must have previously received and progressed on standard of care therapy(ies).
6
Patients must be able to provide an archival tumor tissue. If archival tumor tissue is not 
available, then tissue from a fresh tumor biopsy is required.
7
All patients will be required to have a site of disease that is safely accessible for biopsy 
(paired) upon enrollment unless there are sufficient paired samples for the analysis as 
determined by the Sponsor. Accessible lesions are defined as those which are biopsiable 
(at screening) and amenable to repeat biopsy (after 2 weeks of AZD4635 therapy), unless 
clinically contraindicated.
The provision of paired biopsies will be closely monitored to ensure the desired number 
of biopsiable patients are enrolled and Investigators are aware of this requirement at all 
times.
8
Patients with measurable diseases must have:
!
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 and is suitable 
for repeated measurement (see Appendix G).
Or
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!
Patients with 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).
9
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 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.
10 Ability to swallow and retain oral medication.
11 Must have a life expectancy of at least 12 weeks
Sex
12 Male
Weight
13 Body weight ≥35 kg at screening
Reproduction
14 Willingness to adhere to the study treatment-specific contraception requirements: Male 
patients must be surgically sterile or using an acceptable method of contraception
(defined as barrier methods in conjunction with spermicides) for the duration of the study 
(from the time they sign ICF) and for 3 months after the last dose of AZD4635 to prevent 
pregnancy in a female partner. Male patients must not donate or bank sperm for 24 weeks 
after treatment.
A more detailed description of the required lifestyle restrictions relating to reproduction is 
provided in Section 5.3.2.
5.2
Exclusion criteria
The exclusion criteria that are applicable to all patients in the study are described in this 
section. Please also refer to each specific module protocol for specific criteria applicable to 
each module.
Exclusion Criteria for all patients in all modules
Patients must not enter the study if any of the following exclusion criteria apply:
Medical conditions
1
History or presence of another primary invasive malignancy except for:


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∀
Malignancy treated with curative intent and with no known active disease ≥2 years 
before the first dose of study drug and of low potential risk for recurrence.
∀
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease.
∀
Adequately treated carcinoma in situ without evidence of disease.
∀
Localized non-invasive primary carcinoma under surveillance.
2
Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant 
small bowel resection that would preclude adequate absorption of AZD4635.
3
Previously untreated brain metastases. Patients who have received radiation or surgery 
for brain metastases are eligible if therapy was completed at least 21 days previously and 
there is no evidence of CNS disease progression or mild neurologic symptoms
4
With the exception of alopecia, lymphopenia, and hypothyroidism, any unresolved 
toxicities from prior therapy greater than National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE v5.0) Grade 1 at the time of starting study 
treatment.
5
Patients with prior ≥Grade 3, serious, or life-threatening immune-mediated reactions 
following prior anti-PD-1, anti-PD-L1, or other immuno-oncology therapies.
6
Prior history of myocardial infarction, transient ischemic attack, or stroke in the last 
3 months.
7
Patients must have normotensive or well controlled BP (<150/90), with or without current 
antihypertensive treatment. If there is a diagnosis or history of hypertension, patient must 
have adequately controlled BP on antihypertensive medications, as demonstrated by 2 BP 
measurements taken in the clinical setting by a medical professional within 1 week prior 
to enrollment. Patients on a hypertensive medication must be willing and able to measure 
and record BP readings twice-daily for a minimum of 3 weeks.
8
As judged by the Investigator or Medical Monitor, any evidence of severe or uncontrolled 
systemic diseases, including active bleeding diatheses, or active infection including 
tuberculosis (clinical evaluation that includes clinical history, physical examination and 
radiographic findings, and tuberculosis testing in line with local practice), hepatitis B 
virus (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human 
immunodeficiency virus (positive HIV 1/2 antibodies). Active hepatitis A as judged by 
the Investigator. Patients with a past or resolved HBV infection (defined as the presence 
of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients 
positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. Screening for chronic conditions is not required.
9
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac disease, 
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rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune 
nephritis or nephropathy, etc.) within the past 3 years prior to the start of treatment. The 
following are exceptions to this criterion:
∀
Vitiligo or alopecia
∀
Hypothyroidism (e.g., following Hashimoto's disease) stable on hormone 
replacement
∀
Psoriasis or eczema not requiring systemic therapy for disease control
∀
Celiac disease controlled by diet alone.
Prior/concomitant therapy
10 Prior therapy with AZD4635 or any other A2AR antagonist.
11 Ongoing corticosteroid use, at doses above physiologic replacement therapy. The 
following are exceptions to this criterion:
∀
Use of intranasal, inhaled, topical corticosteroids, local steroid injections (e.g. 
intra-articular injections)
∀
Steroids as pre-medication for hypersensitivity reactions (e.g. CT scan 
pre-medication) are permitted
∀
Systemic corticosteroids at physiologic doses below 10 mg/day of prednisone or 
equivalent.
12 The following intervals between the end of the prior treatment and first dose of study drug 
must be observed:
∀
Anti-cancer therapy: ≥21 days or 5 half-lives (whichever is shorter) of the first dose 
of study drug. At least 7 days must have elapsed between the last dose of such agent 
and the first dose of study drug. Exception: Androgen-deprivation therapy is 
required to maintain castrate levels of testosterone (<50 ng/dL).
∀
Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for 
diabetes and hormone replacement therapy) is acceptable.
13 Major surgery (as defined by the Medical Monitor, excluding placement of vascular 
access) within 4 weeks of the first dose of study treatment.
14 Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the first 
dose of study treatment
15 Patient is receiving medications or other products known to be sensitive breast cancer 
resistance protein (BCRP) or organic anion transporter polypeptide 1 ( OATP1B1), 
OATP1B3, OAT1, organic cation transporter 1 (OCT1), OCT2, multi-drug and toxin 
extrusion protein 1 (MATE1) and P-glycoprotein (P-gp) substrates or potent or moderate 
inhibitors/inducers of CYP1A2, 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 AZD4635.


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See Appendix J for the list of BCRP, OATP1B1, OATP1B3, OAT1, OCT1, OCT2, 
MATE1 and P-gp substrates, and CYP1A2 inhibitors and inducers.
16 Concomitant medications with another A1R antagonist that would increase risk of seizure 
(e.g., theophylline, aminophylline).
17 Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.
18 Ongoing treatment with Coumadin.
19 Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug.
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), 
ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients 
should stop using these herbal medications 7 days prior to the first dose of AZD4635. 
Exceptions may be agreed upon, but the circumstances must be reviewed by the Medical 
Monitor in advance.
21 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 treatment.
22 Enrollment into another therapeutic clinical trial. Exception: Patients are allowed to 
participate in investigational imaging or non-interventional studies.
23 History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or 
class to AZD4635.
Diagnostic assessments
24 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 concomitant medication with known risk of QT interval prolongation. Patients 
receiving a medication(s) known to prolong the QT interval may be discussed with 
the Medical Monitor or Sponsor for study approval.
∀
Ejection fraction <55% or the lower limit of normal of the institutional standard.
25 Inadequate bone marrow reserve or organ function as demonstrated by any of the 
following laboratory values:
∀
Absolute neutrophil count <1.5 x 109/L
∀
Platelet count <100 x 109/L
∀
Hemoglobin <9.0 g/dL
∀
Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no 
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∀
Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver 
metastases or >5 times ULN in the presence of liver metastases
∀
Total bilirubin (TBL) >1.5 times ULN
∀
Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min 
(measured or calculated by Cockcroft and Gault equation); confirmation of creatinine 
clearance is only required when creatinine is >1.5 times ULN.
Other exclusions
26 Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and 
its representatives and/or staff at the study site).
27 Judgment by the Investigator or Medical Monitor that the patient should not participate in 
the study if the patient is unlikely to comply with study procedures, restrictions and 
requirements.
28 Participation in another clinical interventional study or if patient has already received at 
least one dose of study drug in the present study.
 
5.3
Lifestyle restrictions
Please refer to the relevant modules. Where restrictions are more stringent in the module 
rather than the core protocol, the Investigator should adhere to the module criteria.
5.3.1
Meals and dietary restrictions
Whenever possible, all doses of AZD4635 should be taken at approximately the same times 
each day with or without food.
5.3.2
Reproduction
The following restrictions apply while the patient is receiving AZD4635 study treatment and 
for the specified times before and after:
!
Male patients should be asked to avoid unprotected sex with women of childbearing 
potential during the study and for a washout period of 3 months after discontinuing study 
treatment. Patients should refrain from donating sperm from the start of dosing until 24 
weeks after discontinuing study treatment. If male patients wish to father children they
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should be advised to arrange for freezing of sperm samples prior to the start of study 
treatment.
!
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period.
Highly effective methods of contraception, defined as those that result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly, are described in Table 4.
Note that some contraception methods are not considered highly effective (e.g., male or 
female condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).
Table 4
Highly effective methods of contraception (<1% failure rate)
Barrier/intrauterine methods
Hormonal methods
!
Copper T intrauterine device
!
Levonorgestrel-releasing intrauterine 
system (e.g., Mirena®)a
a
This is also considered a hormonal method
!
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
!
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)
!
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®)
!
Combined Pill: Normal and low dose 
combined oral contraceptive pill
!
Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (eg, Ortho 
Evra®)
!
Minipill: Progesterone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone based pill
Please follow module-specific guidance for reproduction information on other study 
treatment.
5.4
Screen failures
Screen failures are defined as patients who sign the ICF to participate in the clinical study but 
are not subsequently randomly assigned to study treatment or do not meet the criteria for 
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A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from Regulatory Authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.
Patients defined as screen failures may be rescreened under certain circumstances. 
Consideration will be given, for example, to the following:
!
Patients 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.
!
Patients for whom Screening procedures are not completed within the 28-day window.
!
Patients 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.
Patients may not be rescreened if they had previously concluded screening and had already 
been allocated to a module. However, 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.
6
STUDY TREATMENTS
Please refer to each modular-specific appendix for details of the investigational products (IPs) 
that are applicable to each module of the study. Details for AZD4635 capsule (which will be 
used in each module) are described in this section.
6.1
Treatments administered
6.1.1
Investigational products
AZD4635
Study treatment name:
AZD4635
Dosage formulation:
Capsule
Route of administration
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AZD4635
Dosing instructions:
Whenever possible, all doses of AZD4635 should be taken at 
approximately the same times each day with or without food. 
Should a patient miss a scheduled dose, the patient 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, the missed dose should not be taken, and the patient 
should take the allotted dose at the next scheduled time. If a 
patient needs to take the dose earlier for any reason, the patient 
can take the dose up to 4 hours earlier than the scheduled dose 
time. The patient should make every reasonable effort to take 
the study drugs on time.
Packaging and labeling
Study treatment will be provided in high-density polyethylene 
(HDPE) bottles induction-sealed with desiccant. Each bottle 
will be labeled in accordance with Good Manufacturing Practice 
(GMP) Annex 13 and per country regulatory requirements.
6.2
Preparation/handling/storage/accountability
AZD4635 capsule should be stored in the pack provided according to the storage conditions 
on the label.
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the module-specific pharmacy manual.
6.3
Measures to minimize bias
This is an open-label study. Recruitment to each module will be centrally assigned using 
IWRS. Before the study is initiated, the log-in information and directions for the IWRS will 
be provided to each site. Potential bias will be reduced by central randomization, whenever 2 
or more modules are currently recruiting as follows:


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All patients will be assigned into a module via IWRS system. Randomization will only occur 
when patients meet eligibility criteria for 2 or more modules that are currently recruiting. If 
patients only meet the criteria for 1 currently recruiting module, they will be allocated to 
that module without randomization taking place.
If a patient withdraws from the study, then his enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced; however, any patient that is withdrawn and 
is not evaluable may be replaced to ensure a minimum number of evaluable patients.
6.4
Treatment compliance
Treatment compliance will be assured by site reconciliation of study treatment dispensed.
It is the Investigator’s/institution’s responsibility to establish a system for handling study 
treatments, including investigational products, to ensure that:
!
Deliveries of such products from AstraZeneca or its representative are correctly received 
by a responsible person.
!
Such deliveries are recorded.
!
Study treatments are handled and stored safely and properly as stated on the label.
!
Study treatments are only dispensed to study patients in accordance with the protocol.
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock.
Any change from the dosing schedule, dose interruptions, dose reductions, and dose 
discontinuations should be recorded in the electronic case report form (eCRF).
Patients should return all used and unused AZD4635 and empty containers. The Investigator 
or pharmacy must retain records of all study drugs administered.
The study personnel at the investigational site will account for all drugs dispensed and for 
appropriate destruction. Certificates of delivery and destruction should be signed. The study 
monitor will check these records to confirm the compliance with the protocol administration 
schedule.
Please refer to the module describing the patient’s study treatment for more information on 
treatment compliance.


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6.5
Treatment assignment
6.5.1
Methods for assigning treatment groups
An IWRS will be used to allocate patients to a module. Randomization will occur when 
patients meet eligibility criteria for 2 or more modules that are currently recruiting. If 
patients only meet the criteria for 1 currently recruiting module, they will be allocated to 
that module without randomization taking place. All patients allocated or randomized will 
be stratified by patients with either bone only metastasis or measurable soft tissue metastasis 
to ensure there is sufficient number of patients in each group as specified in the sample size.
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening.
The Investigator(s) will:
1
Obtain signed informed consent from the potential subject before any study-specific 
procedures are performed.
2
Assign potential subject a unique enrollment number (i.e., E-code) using IWRS. The E-
code is sequentially issued and will be used to identify the subject on all study-related 
documents including the eCRF.
3
Determine subject eligibility. See Sections 5.1 and 5.2.
4
Declare if subject has soft tissue measurable disease by RECIST v1.1 or bone only 
disease using the IWRS.
5
Assign eligible subject to a module.
When feasible, allocation or randomization will be done centrally via IWRS after subject 
eligibility is established and prior to treatment. Every effort should be made to minimize the 
time between allocation or randomization and starting the study drug. It is recommended that 
subjects commence study drug as soon as possible after allocation or randomization.
If the subject is found to be ineligible during screening, the subject 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 subject withdraws from participation in the study, then his assigned codes cannot 
be reused.
6.5.2
Procedures for handling incorrectly allocated patients
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Subjects who 
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into a module or initiated on treatment, and must be withdrawn from the study. Where a 
subject does not meet all the eligibility criteria but is assigned into a module in error, or 
incorrectly started on treatment, the Investigator should inform the Medical Monitor 
immediately, and a discussion should occur between the Medical Monitor and the Investigator 
regarding whether to continue or discontinue the subject from treatment. All decisions must 
be appropriately documented.
6.6
Concomitant therapy
The following treatments and the medications listed in Appendix J are prohibited or are to be 
used with caution while patients are receiving AZD4635. Details for other study treatments 
are provided in the modular-specific appendix.
Table 5
Restricted medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ):
CYP1A2 inhibitors or inducers.
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 J for a list of the prohibited 
medications.
Table 6
Prohibited medications
Prohibited medication/class of drug:
Additional Information
No other investigational therapy should be given to 
patients. No anti-cancer agents other than the study 
medications should be given to patients.
If such agents are required for a patient, then the patient 
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 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.
Use of potent inhibitors or inducers of BCRP and sensitive 
substrates of OATP1B1/3, OAT1, OCT1, OCT2, MATE1 
and P-gp is therefore prohibited in the current study (see 
Appendix J).
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), ginkgo biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.
Patients 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 
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6.6.1
COVD-19 Vaccination Guidance
Authorized/approved COVID-19 vaccines can be given to patients in this study. Investigators 
should follow the Clinical Study Protocol and their local prescribing information and policies 
when considering if vaccination against COVID-19 is appropriate for their patients.
If you are considering vaccinating your patient against COVID-19, please consider the 
following:
!
For a specific vaccine, consider the potential impact of its relevant labeling information 
(i.e., “Indications,” “Contraindications,” “Warnings and Precautions,” “Adverse 
Reactions”) on its use in the study population and individual subject.
!
Please contact the manufacturer of theCOVID-19 vaccine if you have any questions 
concerning their product.
To better assess the overall impact of COVID-19 vaccination on a particular study and study 
population, ensure that both the COVID-19 vaccination details (including brand name and 
manufacturer) is captured in eCRF as concomitant medication, and adverse reactions are 
reported.
6.6.2
Additional concomitant treatment
!
Pre-medication will not be required, but may be utilized following the first doses of the 
investigational products. This includes management of nausea, diarrhea, and vomiting. If 
a patient has a known history of nausea and vomiting with prior therapy, it is strongly 
recommended that prophylactic anti-emetics be initiated at the start of treatment (see 
Section 8.4.5.2).
!
Blood and blood product transfusions, including platelet infusions, are allowed at any 
time during the study, except to meet inclusion criteria.
!
Patients already taking erythropoietin at the time of screening for the study may continue 
it provided they have been taking it for more than one month at the time study treatment 
is started.
!
Granulocyte colony stimulating factors (GCSFs) are permitted for use at the discretion of 
the Investigator.
!
Patients should avoid corticosteroids during the study. If treatment with corticosteroids is 
indicated, the Investigator should discuss with the Medical Monitor. If in the interest of 
patient safety the Investigator must treat the patient immediately and a discussion is not 
feasible, the Medical Monitor should be notified in writing.
!
Patients may receive treatment with bisphosphonates or denosumab for the treatment of 
bone metastases.
!
Patients should avoid medications or drugs that increase risk for seizure (e.g., tricyclic 
antidepressants, pseudoephedrine, anesthetics, amphetamines, cocaine).
!
Patients may receive treatment with megestrol acetate when prescribed for appetite 
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!
Patients may take low molecular weight heparin. It is recommended that patients treated 
with an anticoagulant should have their anticoagulation monitored carefully and dose
adjusted accordingly.
6.6.3
Other concomitant treatment
Other medication than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
6.7
Dose modification
Please refer to each modular-specific appendix for details on dose reduction.
Management of AZD4635-related toxicities and related dose modifications can be found in 
Section 8.4.5.
6.8
Treatment after the end of the study
After this study primary DCO, the clinical study database will be closed to the entry of new 
data. Patients receiving their assigned study treatment at the time of the primary DCO will be 
able to continue to receive study treatment if, in the opinion of the Investigator, they are still 
deriving clinical benefit and not fulfilling discontinuation criteria.
Patients who remain on study treatment after the primary DCO will be managed by the 
Investigator according to routine clinical practice if not specified differently in the study 
modules. It is generally recommended to continue observing ongoing patients at the 
frequency indicated within the study plans as described in the SoA, however the assessments 
are at the Investigators' discretion based on the individual case. Restrictions regarding 
concomitant medications (Section 6.6) will be followed while the patient is receiving the
IP(s). Study treatment will be supplied to sites outside of the IWRS. Drug dispensation and 
reconciliation will be performed by the site on each patient visit. Serious adverse events, 
overdose and pregnancy will be reported after the last dose of study treatment, for the duration 
stated in the relevant module, using a paper form.
Study will be open until last patient treated. Final Last Subject Last Visit will be defined as 
last patient’s treatment discontinuation.
If study drug is approved on market for use in disease under study indication, patients may be 
discontinued and switched to marketed product. Drug supply options can be available 
depending on the country and will be proposed to patient when found as best way to continue 
treatment by both AZ and Investigator.


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7
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL
7.1
Discontinuation of study treatment
Patients that discontinue 1 study drug may remain on the study and receive other study drug(s) 
as long as they are continuing to derive clinical benefit (see Section 8.4.6). Patients may be 
discontinued from study drug(s) in the following situations:
!
Patient decision. The patient is at any time free to discontinue treatment, 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 drug(s).
!
Investigator decision or severe non-compliance with the Clinical Study Protocol
!
Confirmed disease progression unless, in the opinion of the Investigator, the patient is still 
receiving clinical benefit. Patients will continue study treatment until objective disease 
progression, or beyond RECIST 1.1 defined progression if patient is receiving clinical 
benefit, as judged by the Investigator and in the absence of discontinuation criteria.
Tumor assessment must continue while patient continues to receive study treatment as per 
Section 8.1.1.
!
Patients incorrectly initiated on study drug(s) (e.g., patient is determined to have met one 
or more of the exclusion criteria for study participation at study entry and continuing 
investigational therapy might constitute a safety risk)
!
Patient started alternative anti-cancer therapy including another investigational agent
!
Patient lost to follow-up
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study.
See the SoA of the assigned module for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that need to be completed. The 
reason for study drug and combinational agent discontinuation will be recorded in the eCRF.
7.1.1
Procedures for discontinuation of study treatment
The Investigator should instruct the patient to contact the site before or at the time if study 
treatment is stopped. Discontinuation of study treatment, for any reason, does not impact the 
patient´s participation in the study. A patient that decides to discontinue study treatment will 
always be asked about the reason(s) and the presence of any AEs. The date of last intake of 
study treatment and the combinational agent should be documented in the eCRF. All study 
treatment should be returned by the patient at his next on-site study visit or unscheduled visit.


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Patients permanently discontinuing study treatment should be given locally available standard 
of care therapy, at the discretion of the Investigator.
The patient should continue attending subsequent study visits and data collection should 
continue according to the study protocol. If the patient does not agree to continue in-person 
study visits, a modified follow-up must be arranged to ensure the collection of endpoints and 
safety information. This could be a telephone contact with the patient, a contact with a 
relative or treating physician, and/or information from medical records. The approach taken 
should be recorded in the medical records. A patient who agrees to modified follow-up is not 
considered to have withdrawn consent or to have withdrawn from the study.
7.1.2
Procedures for patients who test positive for COVID-19
During the study, COVID-19 tests may be prescribed, if required, and in accordance with 
local guidance. If a patient tests positive, their continued participation in the study and their 
treatment with the study drugs will be discussed with the Medical Monitor.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he fails to return for scheduled 
visits and does not reply to contact attempts by site personnel.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
!
Site personnel must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.
!
Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin (e.g. repeat telephone calls, 
certified letter to the patient’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the patient’s medical record.
!
Efforts to reach the patient should continue until the end of the study. Should the patient 
be unreachable at the end of the study, the patient should be considered to be lost to 
follow-up with unknown vital status at end of study and censored at latest follow-up 
contact.
7.3
Withdrawal from the study
A patient may withdraw from the study (e.g., withdraw consent) at any time (study drug(s) 
and assessments) at his own request, without prejudice to further treatment. The reason for 
patient withdrawal will be recorded in the eCRF.


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If a patient decides to withdraw from the study, including study treatment, the Investigator 
needs to confirm whether the patient:
!
Withdraws consent to all further participation in the study including any further follow-up 
(e.g., survival contact telephone calls)
OR
!
Withdraws consent from study treatment, but agrees to follow-up procedures (as defined 
in Section 7.1).
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g., telephone contact, contact with a relative or treating 
physician, or information from medical records).
If the patient withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws consent to the use of mandatory biological samples, the samples will be 
disposed of/destroyed if possible and the action documented. If samples have already been 
analyzed, the Sponsor is not required to destroy the results of this research.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The Investigator will follow-up with patients as medically indicated.
In the event that the patient has actively withdrawn consent to the processing of his personal 
data, the vital status of the patient can be obtained by site personnel from publicly available 
resources where it is possible to do so under applicable local laws
See the SoA in the relevant module for data to be collected at the time of study drug 
discontinuation and follow-up and for any further evaluations that need to be completed. All 
study drug should be returned by the patient.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the core SoA. For all assessments after 
screening, see the module-specific SoA.
The Investigator will ensure that data are recorded on the eCRF as specified in this Clinical 
Study Protocol and in accordance with the instructions provided. The Medidata Rave 
electronic data capture (EDC) system will be used for data collection and query handling.
The Investigator will ensure the accuracy, completeness, and timeliness of the data recorded 
and the provision of answers to data queries according to the Clinical Study Agreement. The


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Investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) 
and obtained before signing of the ICF may be utilized for screening or baseline purposes, 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
The number of samples taken, as well as the volume required for each analysis, may be 
changed during the study as emerging data become available. However, the estimated total 
volume of blood that will be drawn from each patient in this study during screening and the 
first cycle of treatment will not exceed 300 mL (over a 1-month period). Any additional 
requirements are specified within the module.
8.1
Efficacy assessments
All patients are expected to have both CT/MRI/PET and bone scans at each scheduled disease 
assessment. Evaluation of objective tumor response in this study will be done using RECIST 
v1.1 Criteria in evaluable soft tissue disease (see Appendix G). Tumors will be assessed at
screening according to the module-specific SoA. Reassessment of tumors will be done by the 
same methods used to establish baseline tumor measurements.
PCWG3 PSA criteria (Appendix I) will also be used to evaluate response and progression. 
These criteria will be followed for determining the change in PSA levels. Prostate-specific 
antigen (PSA) levels in this study will be measured at screening, at the start of each new 
treatment cycle, at the end of study visit, at any other timepoints 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:


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!
Soft tissue disease progression as defined by RECIST v1.1
!
Bone lesion progression by PCWG-3 (Table 7)
!
Death
Patients with PSA progression are permitted and encouraged to continue treatment until 
symptomatic or 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.
All CT/bone scans and all imaging assessments performed for RECIST 1.1 tumour assessment 
will be reviewed at site. Duplicates must be available at the site in readiness to be sent for 
retrospective independent central RECIST 1.1 review, if deemed appropriate. More 
information on this procedure is available in the Image Acquisition Guideline for this study.
8.1.1
Tumor assessments with RECIST v1.1
RECIST version 1.1 guidelines for measurable and non-measurable target lesions (TLs) and 
non-target lesions (NTLs) and the objective tumor response criteria are presented in 
Appendix G.
Baseline tumor 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 patients. 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.
The first follow-up assessment should be initially at 6 weeks (±1 week) following the start of 
AZD4635 dosing and subsequent assessments will be performed every 2 cycles (every 8 
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 patient has not 
progressed, every attempt should be made to perform subsequent assessments at the scheduled 
visits.
Categorization of objective tumor response assessment will be based on the RECIST Version
1.1 guidelines for response of soft tissue lesions: CR (complete response), PR (partial 
response), SD (stable disease), and PD (progression of disease). For patients who only have 
non-measurable TLs at baseline, categorization of objective tumor response assessment will 
be based on the RECIST Version 1.1 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 patient’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 in target disease, the overall tumor 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 tumor response variables
At each visit, patients will be programmatically assigned a RECIST visit response of CR, PR, 
SD 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 tumor burden was at a 
minimum (i.e., smallest sum of diameters previously recorded on study, nadir). In the absence 
of progression, tumor response (CR, PR, SD) will be calculated in comparison to the baseline 
tumor measurements obtained before starting treatment.
If a patient has had a tumor assessment that cannot be evaluated, then the patient will be 
assigned a visit response of NE, unless there is evidence of progression in which case the 
response will be assigned as PD.
For TL measurements, if ≤1/3 of the TL sizes are missing then a scaling-up rule will be 
applied as follows:
1
If ≤1/3 of lesions recorded at baseline are missing then the results will be scaled up (based 
on the nadir sizes) to give an estimated sum of diameters and this will be used in 
calculations (this is equivalent to comparing the visit sum of diameters of the non-missing 
lesions to the nadir sum of diameters excluding the lesions that are missing and 
determining at what rate the lesions are changing).
2
If >1/3 of lesions recorded at baseline are missing then the TL response will be NE. 
However, if the sum of non-missing TL diameters would result in PD (i.e., if using a 
value of 0 for missing lesions the sum of diameters has still increased by >20% or more 
compared to the smallest sum of diameters on study), PD takes precedence over NE.
3
A visit response of CR will not be allowed if any of the TL data are missing.
Objective response rate is defined as the proportion of patients with measurable disease at 
baseline who have a confirmed ORR per RECIST v1.1. For the analysis of objective response 
rate an “evaluable-for-response” population will be derived and will exclude patients who do 
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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 <10mm 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 (patients 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 
patient at a later date, the date of the initial scan should be declared as the date of progression 
if the repeat scans confirm progression.
Percentage change from baseline in tumor size will be determined for patients with
measurable disease at baseline and is derived at each visit by the percentage change in the sum 
of the diameters of TLs.
For further details see Appendix G of this CSP.
 
 
 
It is important to follow the assessment schedule as closely as possible. Please refer to the 
Study Plan in each module and Appendix G.
8.1.2
PCWG3 bone lesions assessment
Categorization of tumor progression of bone lesions will be based on the PCWG-3 criteria. 
Bone lesions will be assessed by bone scintigraphy commonly performed with Technetium-99 
(bone scans) or PET scan. Positive hot spots on the bone scan should be considered 
significant and unequivocal sites of malignant disease to be recorded as metastatic bone 
lesions (see Appendix G).
The requirements for determination and confirmation of radiographic progression by either 
bone scan (bone progression) or CT/MRI (soft tissue progression) are summarized in Table 7.
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Table 7
Requirements for documentation of progression
Visit Date
Criteria for Bone Progression
Criteria for Soft Tissue 
Progression
First visit after baseline (expected 
at week 6 after the start of 
AZD4635 study treatment)
!
2 or more new lesions 
compared to baseline bone 
scan.
!
Requires confirmation at 
least 6 weeks later with >2 
additional lesions compared 
to the first scan after baseline
!
Progressive disease on CT or 
MRI by RECIST v1.1
!
Requires confirmation at 
least 4 weeks (but no more 
than 8 weeks).
From the 2nd visit onwards post-
baseline
!
2 or more new lesions 
compared to the first bone 
scan after baseline.
!
Progressive disease on CT or 
MRI by RECIST v1.1
!
No confirmation required.
!
Requires confirmation at 
least 6 weeks later for 
persistence or increase in 
number of lesions
CT, Computed tomography; MRI, Magnetic resonance imaging; RECIST, Response Evaluation Criteria in Solid 
tumours.
 
8.1.4
PWCG3 PSA criteria
All patients should have PSA collected 
 at 
screening, at the start of each new treatment cycle, at the end of study treatment, and as 
indicated in the SoA of each module. PSA
should also be collected when clinically 
indicated as per Investigator discretion.
PWCG3 PSA criteria are located in Appendix I.
8.2
Safety assessments
Planned time points for all safety assessments are provided in the module-specific SoA.
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and the screening and 
module-specific SoA 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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The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at the 
study center as source data for laboratory variables.
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
Safety laboratory assessments will be performed locally at each study site laboratory by means 
of their established methods. Therefore, the number of samples/blood volumes is subject to 
site-specific change.
Laboratory values that meet the criteria for CTCAE Grade 3 or have changed significantly 
from baseline and are considered to be of clinical concern will be repeated/confirmed within 
7 days and followed up as appropriate.


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Table 8
Laboratory safety variables
Hematology
Clinical chemistry
Blood (B)-Hemoglobin
Albumin
B-Leukocyte
Alkaline phosphataseb
B-Absolute leukocyte differential count:
ALTb
!
Neutrophilsa
Amylasec
!
Lymphocytesa
ASTb
!
Monocytes
Bicarbonate HCO3d
!
Basophils
Calcium, total
!
Eosinophils
Chlorided
B-Platelet count
Creatinined,e
Gamma glutamyltransferase (GGT)d
Coagulation
Glucose
Prothrombin Time
Lactate dehydrogenase (LDH)
Or
Lipasec
International normalization ratio (INR) and activated 
partial thromboplastin time (aPTT)
Magnesiumd
Phosphate
Urinalysis
Potassium
Bilirubin, blood, color and appearance, glucose, ketones, 
pH, protein, and specific gravity
Sodium
Total bilirubinb
Additional Tests
Total protein
Testosterone
Thyroid stimulating hormonef
Prostate-specific antigen (PSA)
Free T4g
Hepatitis A, hepatitis B surface antigen, hepatitis C 
antibody, and HIV antibodyh, i, j,k
Free T3g
Urea nitrogen
Uric acid
C-reactive protein (CRP)
a  Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data 
Management if entered as percentage. Total white cell count therefore has to be provided.
b  Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin.
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c
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these 
parameters is routinely measured, either lipase or amylase is acceptable.
d
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, magnesium, 
testing are to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry 
assessments are performed within 3 days prior to Day 1), and if clinically indicated.
e
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body 
weight).
f
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 
1.
g
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE 
related to the endocrine system.
h
Hepatitis A testing will only be performed if the patient is considered symptomatic per the Investigator.
i
Hepatitis B testing: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, IgM 
hepatitis B core antibody. If hepatitis B core (total) antibody testing is unavailable, then the hepatitis B core 
IgG and IgM should both be obtained instead. If a test is not locally available, then standard local practice 
for assessing hepatitis B status should be utilized. If screening tests are positive, a HBV-DNA test should
be obtained to assess infection status.
j
Hepatitis C antibody. If screening antibody is positive, an HCV RNA test should be performed to assess 
infection status.
k
Human immunodeficiency virus-1 antibody.
Note: In case a patient shows an AST or ALT ≥3xULN together with TBL ≥2xULN please 
refer to Appendix E “Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law” for further instructions.
8.2.2
Physical examinations
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems.
Physical examination will be performed at visits as specified in the module-specific SoA. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
New or worsening abnormalities may qualify as AEs (see Section 8.3.7 for details).
Significant abnormal findings will be recorded in the Medical History or as an AE. 
Abbreviated symptom-directed physical examinations will be conducted at subsequent visits 
post-dosing.
8.2.3
Performance status
Performance status will be assessed as indicated in the Study Plan figures according to ECOG 
criteria as follows:
0 =
Fully active, able to carry out all pre-disease activities without restrictions


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1 =
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature e.g., light housework, 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 self-care, totally confined to bed or chair.
8.2.4
Vital signs
Vital signs (pulse rate, systolic and diastolic BP, respiration rate, and temperature) will be 
assessed according to the screening and module-specific SoA. Body weight is also recorded 
at each visit and height is recorded at screening.
!
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
!
Blood pressure and pulse measurements should be preceded by at least 10 minutes of rest 
for the patient in a quiet setting without distractions (e.g., television, cell phones).
!
For the baseline BP measurement, 2 or more readings should be taken at 2-minute 
intervals and averaged. If the first 2 diastolic readings differ by more than 5 mmHg, then 
an additional reading should be obtained. For all other subsequent measurements, 
institutional standards for measuring vital signs should be followed.
If antihypertensive management is initiated during the study, more frequent BP monitoring 
should be initiated until a stable antihypertensive regimen has been established.
Additional assessments may be performed at the discretion of the Investigator, if clinically 
indicated.
8.2.5
Electrocardiograms
Electrocardiograms (ECGs) will be obtained at screening, end of treatment, and when 
clinically indicated.
Resting 12-lead ECG
Twelve-lead ECGs will be obtained after the patient has been resting supine for at least 10 
minutes prior at times indicated in the screening and module-specific SoA. All ECGs should 
be recorded with the patient in the same physical position.


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For each time point 3 ECG recordings should be taken about a minute apart within a 5-minute 
window per timepoint. A standardized ECG machine should be used and the patient should 
be examined using the same machine throughout the study, when feasible.
The ECG traces will be recorded and reviewed as per the study-specific ECG manual. The 
Investigator or designated physician will review each of the ECGs and may refer the patient 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 an AE (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 on the eCRF.
8.2.6
Echocardiography or multi-gated acquisition scan
An echocardiogram (ECHO) should be performed at screening (≤14 days prior to Cycle 1 Day 
1) and within 14 days after a clinically significant ECG finding (T wave inversion/flattening). 
If an ECHO cannot be taken, a cardiac MRI or multi-gated acquisition (MUGA) scan to assess 
left ventricular ejection fraction will be conducted. In case of any T wave abnormality, the 
ECHO, MRI, or MUGA should be repeated at the end of treatment (EOT) visit to address the 
question of recovery during the off-treatment period.
8.2.7
End-of-treatment visit
Patients will return to the clinic for an EOT visit that is to be performed as soon after the study 
drug is stopped as possible, preferably within 2 days of stopping drug. For patients who have 
had drug held prior to the decision for discontinuation, the EOT visit should be performed 
within 7 days of the decision. Tumor assessments will be done at this visit, if they have not 
been performed within the past 2 months. Other assessments to be performed are presented in 
the SoA in the modular-specific appendix.
8.2.8
Follow-up visits
8.2.8.1
30-day follow-up visit
A safety follow-up visit will be performed approximately 30 (±7) days after the study drug(s) 
is (are) permanently discontinued, unless the patient withdraws consent. The primary purpose 
of this visit is to follow-up on any AEs ongoing at the time of study treatment discontinuation 
and to assess any new AEs that may have occurred since discontinuation. In addition, any 
new medications will be recorded. This information can be collected by phone. Any AE, 
SAE, or abnormal laboratory findings that are ongoing at the time of study treatment 
discontinuation, or any new events within 30 days of last study treatment unless otherwise 
indicated in the specific module, must be followed up to resolution or until the event becomes


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stable (or returns to baseline) or is unlikely to resolve further in the opinion of the 
Investigator.
8.2.8.2
Progression-free follow-up visits
Patients who discontinue study treatment prior to the occurrence of objective PD will be 
followed with PSA samples and CT/MRI/PET and bone scans every 3 months (±1 week) from 
the last date of the last tumor response assessment until either: objective PD has been 
confirmed, withdrawal of consent, until the primary analysis DCO, or until the study or 
module is terminated by the Sponsor.
8.2.8.3
Survival follow-up
Patients will be followed every 3 months after the last dose of study drug for survival until 
withdrawal of consent, or until the primary DCO for the study. The survival and subsequent 
cancer therapy follow-up can be done by a medical record review or telephone call at the 
Investigator’s discretion.
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.
8.2.9
COVID-19 Testing
Tests for active COVID-19 infection may be prescribed, where appropriate, and in accordance 
with local procedures. If a patient tests positive, their continued participation in the study and 
treatment with the study drugs will be discussed with the Medical Monitor
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of AEs and SAEs can be found in Appendix B.
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).


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The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow-up AEs 
see Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about
AE occurrences.
8.3.2
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 follow-up period, unless specified differently in 
each module (see module-specific guidance).
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients. 
However, if the Investigator learns of any SAE, including a death, at any time after a patient’s 
last visit and he/she considers the event to be reasonably related to the study treatment or 
study participation, the Investigator may notify the Sponsor.
The methods of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs/non-serious AEs/AEs of special interest (AESIs) (see 
module-specific guidance) will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up
Any AEs that are unresolved at the patient’s last AE assessment or visit in the study will be 
followed up by the Investigator for as long as medically indicated, but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
patient with ongoing AEs/SAEs at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim)


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!
The date when the AE started and stopped
!
CTCAE 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 which criterion
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication
8.3.5
Causality collection
The Investigator will 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 related to the IP?”
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit?”, 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


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symptoms. However, if a diagnosis is known and there are other signs or symptoms that are 
not generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately.
8.3.7
Adverse events based on examinations and tests
The results from the protocol mandated laboratory tests and vital signs will be summarized in 
the clinical study report (CSR). Deterioration as compared to baseline in protocol mandated 
laboratory values, vital signs, ECGs, or other safety assessments should therefore only be 
reported as AEs if they fulfil any of the SAE criteria or are the reason for discontinuation of 
treatment with the IP.
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 
will use the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin 
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 (see Sections 8.3.9 and 8.3.10).
8.3.8
Hy’s law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥3xULN together with TBL ≥2xULN 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.
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’s condition attributable to 
the disease for which the IP is being studied. It may be an increase in the severity of the 
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.


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8.3.10
New cancers
The development of a new cancer should be regarded as an SAE. New cancers are those that 
are not the primary reason for the administration of the study treatment and have been 
identified after the patient’s inclusion in this study. They do not include metastases of the 
original cancer.
8.3.11
Deaths
All deaths that occur during the study, or within the follow-up period after the administration 
of the last dose of study drug, should be reported as follows:
!
Death clearly resulting from disease progression should be communicated to the study 
monitor at the next monitoring visit and should be documented in the eCRF on the Death 
page. It should not be reported as an SAE.
!
When death is not clearly due to PD of the disease under study, the AE causing the death 
should be reported to the study monitor as an SAE within 24 hours. It should also be 
documented on the Death page in the eCRF. The report should contain a comment 
regarding the co-involvement of PD, if appropriate, and should assign a single primary 
cause of death together with any contributory causes.
!
Deaths with an unknown cause should always be reported as SAEs, but every effort 
should be made to establish a cause of death. It should also be documented in the 
Statement of Death page in the eCRF. A post-mortem may be helpful in the assessment 
of the cause of death, and if performed a copy of the post-mortem results (with translation 
of important parts into English) should be forwarded to an AstraZeneca representative 
within the usual time frames.
Deaths occurring after the protocol defined safety follow-up period after the administration of 
the last dose of study drug should be documented on the Death page. If the death occurred as 
a result of an event that started after the defined safety follow-up period and the event is 
considered to be due to a late onset toxicity to study drug, then it should also be reported as an 
SAE.
8.3.12
Adverse events of special interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and rapid communication by the Investigator to the Sponsor, or 
delegate. 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 IP.
Please refer to the modular-specific appendices for AESIs to be followed.


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8.3.13
Safety data to be collected following the primary DCO of the study
For patients continuing to receive treatment after primary DCO and database closure, it is 
recommended that the patients continue the scheduled site visits and Investigators monitor the 
patient’s safety laboratory results prior to and periodically during treatment in order to manage 
AEs in accordance with the Dose Modification and Toxicity Management Guidelines (see 
Section 8.4.5). All data after the primary DCO and database closure will be recorded in the 
patient notes but, with the exception of SAEs, overdose and pregnancy, will not otherwise be 
reported for the purposes of this study.
All SAEs that occur in patients still receiving treatment (or within the 90 days following the 
last dose of treatment) after the primary DCO and database closure must be reported as 
detailed in Section 8.4.1.
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF and on paper forms after the final 
analysis DCO (16 June 2022).
If any SAE occurs in the course of the study, then Investigators or other site personnel will 
inform the appropriate AstraZeneca representatives within one day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The detailed SAE reporting process will be provided to the sites in the SAE reporting 
guidelines contained in the study reference manual. The designated AstraZeneca 
representative will work 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 of the information for fatal and life-threatening events and within 5 calendar days of 
initial receipt of the information for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Investigators must report SAEs and follow-up information to their responsible IRB according 
to the policies of the responsible IRB. For fatal or life-threatening AEs for which important or 
relevant information is missing, active follow-up is undertaken immediately.


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AstraZeneca, or their representatives, will provide Regulatory Authorities, Ethics Committees, 
and Principal Investigators with clinical safety updates/reports according to local
requirements.
Full details of the AE reporting process are provided in the Safety Handling Plan for the study.
For further guidance on the definition of a SAE, see Appendix B of the core Clinical Study 
Protocol.
8.4.2
Pregnancy
Conception must be avoided during paternal exposure to AZD4635. If a pregnancy in the 
female partner of a male patient is reported, the Investigator should inform AstraZeneca 
within 24 hours of learning of the pregnancy. Exception to this is if the pregnancy is 
discovered before the study subject has received any study drug. Abnormal pregnancy 
outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered SAEs. All pregnancies occurring after the final analysis DCO will 
be recorded on paper forms.
8.4.2.1
Paternal exposure to AZD4635
Information on the pregnancy of a patient’s partner must be obtained directly from the 
patient’s partner. Therefore, prior to obtaining information on the pregnancy, the Investigator 
must obtain the consent of the patient’s partner.
Pregnancy of a patient’s partner is not considered to be an AE. However, outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) occurring from the first date of dosing until 3 months (unless 
specified differently in relevant module) after dosing should, if possible, be followed up and 
documented.
Male patients should use condoms with female partners during the study and for 12 weeks (3 
months or as specified in relevant module) after the last dose of AZD4635, 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 patients with a desire to have children. See relevant module for module-
specific information.
It is not currently known whether AZD4635 affects fertility in humans.
AstraZeneca should be notified of any pregnancy that occurs in partners of male patients 
during participation in studies of AZD4635.


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8.4.3
Overdose
Any dose of AZD4635 in excess of 110% of the dose per cycle of treatment specified 
according to the protocol will constitute an overdose, unless associated with an AE, in which 
case 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. Please refer to relevant module to see 
module-specific overdose guidance. All overdoses as specified above, occurring after the 
final analysis DCO will be recorded on paper forms.
If an overdose of an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel will inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
!
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 
8.3.2). For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error
If an medication error occurs in the course of the study, then the Investigator or other site 
personnel will inform the appropriate AstraZeneca representatives within 1 day i.e., 
immediately but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 calendar day (initial fatal/life-threatening or 
follow-up fatal/life-threatening) or 5 calendar days (other serious initial and follow-up) if 
there is an SAE associated with the medication error (see Section 8.3.2) and within 30 days 
for all other medication errors.
The definition of a medication error can be found in Appendix B.
8.4.5
Management of AZD4635-related toxicities
AZD4635 management and discontinuation guidelines for non-hematologic toxicities (except 
hypertension) are shown in Table 9. Intrapatient dose re-escalation is not permitted.
AZD4635 dose reduction guidelines are in Section 6 of the study-specific modules.
If a patient experiences a clinically significant and/or unacceptable toxicity not attributable to 
the disease or disease-related processes under investigation, dosing will be interrupted or the 
dose reduced and supportive therapy administered, as required. If the toxicity resolves or 
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benefit per the Investigator, treatment with AZD4635 may be restarted. If the toxicity does 
not resolve to ≤ CTCAE Grade 2 after 2 weeks of treatment then the patient should be 
withdrawn from the study and observed until resolution of the toxicity. Maximum drug 
holiday allowed is 2 weeks for non-immune-mediated toxicity.
Table 9
AZD4635 dose modifications and discontinuation criteria for non-
hematologic toxicities (except hypertension)
NCI CTCAE Toxicity Grade
Action
Grade 1 or 2
None required
Grade 3 or 4 and/or clinically significanta
Hold AZD4635
Toxicity resolved to Grade 1, Grade 2, or baseline
<14 days
Toxicity remains Grade 3 to 4 or is clinically 
significanta >14 days
Restart AZD4635 at 1 dose level reduction
Discontinue AZD4635
Recurrence of Grade 3
Reduce 1 more dose level if module-specific 
guidance allows 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%), increases 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), QTc 
prolongation >500 ms.
8.4.5.1
Hypertension
Treatment of hypertension and goal BP will be in accordance with international guidelines. 
AZD4635 dose reduction and discontinuation guidelines for the management of hypertension 
are shown in Table 10. Details on daily management of BP are provided in Section 8.2.4.
Patients taking antihypertensive medications will take and record BP readings twice-daily 
while at home (recommended 1 hour post-dose) for at least the first 3 weeks after starting 
study drug. Twice-daily monitoring should be re-implemented after any AZD4635 
hold/dosing delay for 2 weeks or until the patient is re-established on a stable antihypertensive 
regimen, whichever takes longer. Patient BP readings should be reviewed with the study team 
on a weekly basis for the first 3 weeks of study treatment to ensure that BP guidelines are 
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Table 10
AZD4635 dose modifications and discontinuation criteria for 
management of hypertension
Event severity
Antihypertensive 
therapy
BP monitoring
AZD4635 dose modification
Systolic BP 150 to 159 mm 
Hg or diastolic BP
90 to 99 mm Hg; 
medical intervention 
indicated;
recurrent or persistent (≥24 
hrs); symptomatic increase 
by >20 mm Hg (diastolic) or 
to >150/90 mm Hg if 
previously within normal 
limits
Initiate/escalate 
antihypertensive 
medication as per local 
guidelines.
BP goal and the choice 
of the antihypertensive 
drug will be 
individualized for each 
patient.
Increase 
frequency of 
monitoring until 
stabilized to BP
<150/90 mmHg
None
Grade 3
(systolic BP >=160 mm Hg 
or diastolic BP >=100 mm 
Hg); medical intervention 
indicated; more than one 
drug or more intensive 
therapythan previouslyused 
indicated
Initiate or maximize BP 
therapy as per local 
guidelines.
Consider consult with a 
BP management 
specialist
Increase 
frequency of 
monitoring until 
stabilized to BP
<150/90 mmHg
May continue AZD4635 with 
optimization of 
antihypertensive management 
unless persistent BP-related 
clinical symptoms.
Hold AZD4635 if BP is not 
decreased to grade 2 within 48 
hours after optimum therapy is 
instituted.
If BP is reduced to baseline or 
Grade 1 within 14 days and 
considered stable, AZD4635 
may be resumed at original
dose.
Discontinue AZD4635 if BP 
does not resolve to Grade 1 
within 14 days.
Discontinue AZD4635 if BP 
systolic ≥180 mmHg and/or 
diastolic ≥110 mmHg)
Recurrence of Grade 3: 
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Table 10
AZD4635 dose modifications and discontinuation criteria for 
management of hypertension
Event severity
Antihypertensive 
therapy
BP monitoring
AZD4635 dose modification
Grade 4
Life-threatening 
consequences
(e.g., malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis); urgent 
intervention indicated
Initiate treatment per 
local guidelines, 
including 
hospitalization, ICU 
management, and IV 
therapy as necessary
Discontinue AZD4635
8.4.5.2
Nausea and vomiting
If a patient has a known history of nausea and vomiting with prior therapy, it is strongly 
recommended that prophylactic anti-emetics be initiated at the start of treatment. They should 
continue as required thereafter, in accordance with local treatment practice guidelines.
Additionally, AZD4635 capsules can be taken with a light meal/snack which may improve 
tolerability (i.e., 2 pieces of toast or a couple of biscuits).
As per international guidance on anti-emetic use in cancer subjects (ESMO, NCCN), 
generally a single agent anti-emetic should be considered (e.g., dopamine receptor antagonist, 
antihistamines or dexamethasone).
8.4.6
Duration of therapy
Patients may continue to receive AZD4635 and/or other combination therapeutic agent as long 
as they are continuing to show clinical benefit, as judged by the Investigator, and in the 
absence of discontinuation criteria.
8.5
Pharmacokinetics
Venous blood samples (2mL each) for determination of concentrations of AZD4635 and its 
metabolites in plasma will be taken in this study for all modules.
Please refer to the module-specific appendix for AZD4635 collection time points.
8.5.1
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analyzed by analytical test 
sites on behalf of AstraZeneca, using an appropriate bioanalytical method. Full details of the 
analytical method used will be described in a separate bioanalytical report.


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All samples still within the known stability of the analytes of interest at the time of receipt by 
the bioanalytical laboratory will be analyzed.
In addition, the PK samples may be subjected to further analyses in order to further investigate 
the presence and/or identity of drug metabolites. Any results from such analyses will be 
reported separately from the CSR, but known metabolites will be reported in the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.
8.5.2
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the bioanalytical report finalization or 
6 months after issuance of the draft bioanalytical report (whichever is earlier), unless 
requested for future analyses.
Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled PK samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from the CSR.
8.6
8.7
8.7.1
 
 
 
 
 
8.7.2
 
 
 
 
 
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8.8.2
 
 
 
 
 
 
 
8.8.3
 
 
 
 
8.8.4
 
 
 
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8.8.5
 
 
 
 
8.9
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics are not evaluated in this study.
9
STATISTICAL CONSIDERATIONS
A comprehensive Statistical Analysis Plan will be developed and finalized before database 
lock and will describe the patient populations to be included in the analyses (performed by 
AstraZeneca and/or a third party), 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 clinical study 
report. Final analysis of all endpoints specified in this protocol will use all data up to and 
including the date of final analysis DCO.
The primary aim of the study is to assess the efficacy, safety, and tolerability of multiple study 
drugs in patients with prostate cancer.
9.1
Statistical hypotheses
Not applicable
9.2
Sample size determination
The study is a Phase 2a signal searching study and consists of multiple single arm cohorts 
under a modular protocol. There are no plans to formally compare between the cohorts and 
this is not part of the study objectives. The aim is to identify treatment(s) to take forward into 
further trial(s). As such, there are no formal statistical hypothesis tests associated with the 
study objectives; statistical analysis of all study endpoints is descriptive.
The primary efficacy endpoint is PSA decline from baseline measure ≥50% (PSA50) and 
overall response rate (ORR) per RECIST v1.1. The PSA endpoint will be used to define the 
sample size for patients with and without measurable disease at baseline.
In Module 1, 2, and 3 (if conducted) there will be approximately 30 PSA evaluable patients in 
each module, and approximately 20 patients will have RECIST measurable disease at baseline 
in each module.
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In Module 1, 2, and 3 (if conducted) approximately 30 patients with and without measurable 
disease at baseline will be assessed for PSA50 in each module.
 
 
 
In Module 1, 2, and 3 (if conducted), approximately 20 patients with measurable disease at 
baseline will be assessed for ORR in each module.
 
 
 
 
 
 
 
If any of the required patients for PSA and/or ORR are not evaluable for PSA response or 
tumor response, respectively, they may be replaced at the Sponsor's discretion.
9.3
Populations for analyses
For purposes of analysis, the following populations are defined:
Population
Description
Pharmacokinetics
Dosed patients with at least 1 reportable PK concentration
Tumor response
Dosed patients with a baseline tumor assessment, and measurable disease at 
baseline.
PSA response
Dosed patients with an abnormal baseline PSA data (≥1ng/mL)
Evaluable for efficacy
Dosed patients with a baseline tumor assessment.
Safety analysis set
All patients who received at least 1 dose of study drug
Summaries of PK data for AZD4635 will consider the subset of the PK analysis set with 
evaluable PK data at that visit for which there are no important AEs or protocol deviations 
that may impact PK at that visit.
In the case of an important protocol deviation that affects the evaluability of the PK analysis, 
affected PK data collected will be excluded from the summaries, but will still be reported in 
the study result listings. Important deviations will be listed and summarized in the CSR.
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9.4
Statistical analyses
All analyses will be reported per module.
9.4.1
Definition of endpoints
To meet the objectives for this study, data for the following endpoints will be collected:
!
PSA response (Primary)
!
Overall Response Rate (Primary)
!
AZD4635 and metabolites PK concentrations (Secondary)
!
Durvalumab and oleclumab PK concentrations (Secondary)Tumor response (Secondary)
∀
DOR
!
Overall survival (OS) (Secondary)
!
Radiological progression-free survival (rPFS) (Secondary)
!
!
!
Immunogenicity (ADA) (Secondary)
!
Safety and Tolerability
∀
AEs/SAEs
∀
Physical exam and vitals
∀
Clinical chemistry/hematology parameters
!
!
9.4.2
Demographic data
Characteristics of the patients, including medical history and disease characteristics at 
baseline, will be listed for each patient and summarized by module where appropriate.
9.4.3
Exposure
Exposure to IPs, i.e., total amount of study drug received, will be listed for all patients.
Reasons for discontinuation of IP will be listed including the study day of treatment 
discontinuation and will be summarized by dose level if appropriate.
Total exposure and total time on study (date of last dose minus date of first dose) will be 
summarized by the following: mean, standard deviation, minimum, maximum, median and 
number of observations. In addition, the number and percentage of patients with at least one 
dose interruption and at least one dose reduction will be presented separately for the initial
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period of evaluability (defined as 21 days) and for any time following this initial period of the 
study.
Relative Dose Intensity (RDI) will be calculated, and is defined as follows:
!
RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the earlier of 
progression (or a censoring event) or the actual last day of dosing and D is the intended 
cumulative dose up to the earlier of progression (or a censoring event) or the actual last 
day of dosing plus the protocol defined post-dose rest period.
9.4.4
Efficacy analyses
PSA response
PSA response is defined as the proportion of patients achieving a ≥50% decline from baseline 
to the lowest post-baseline PSA results, confirmed by a second consecutive PSA assessment at 
least 3 weeks later. Ignore early rises (before 12 weeks) in determining PSA response.
∀
A patient will be regarded as having a single PSA visit response if their PSA level at 
any post-dose visit is reduced by 50% or more compared with baseline
∀
A patient will be regarded as having a confirmed PSA response if they have a 
reduction in PSA level of 50% or more compared with baseline that is confirmed at 
the next assessment at least 3 weeks later (i.e., decrease relative to baseline of at least 
50% documented on 2 consecutive occasions at least 3 weeks apart).
PSA progression
If there is a PSA decline from baseline, progression is defined as the date of the first PSA 
increase that is both ≥25% and ≥2 ng/mL above the nadir and which is confirmed by a second 
value ≥3 weeks later, even if within 12 weeks.
If there is no PSA decline from baseline, progression is defined as a ≥25% increase and ≥2 
ng/mL increase from baseline beyond 12 weeks.
The proportion of patients achieving a PSA response and patients with a confirmed PSA 
response will be presented with 95% CI. The best PSA percentage change from baseline and 
the percent change from baseline in PSA levels at 12 weeks will be summarized and graphed. 
Waterfall plots (bar plots), and spider plots (individual line plots of percent change from 
baseline over time) will be produced.
Tumor response
Tumor response data will be summarized for dosed patients with measurable disease at 
baseline and separately for dosed patients that had measurable or non-measurable disease at 
baseline.


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Tumor response data will be listed and summarized by dose, if appropriate, using the 
following response categories: CR, PR, SD, PD, and not evaluable (NE).
Best objective response and ORR will be summarized. Percentage change from baseline in 
tumor size will be determined for patients 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 by dose level.
Duration of response (DoR) 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 response will be defined as the latest of the dates contributing towards the 
first visit that was PR or CR that was subsequently confirmed.
If a patient does not progress following a response, then their duration of response will use the 
PFS censoring date as the date at which that subject is censored for DoR.
 
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 patient withdraws from treatment or receives another anti-cancer 
therapy prior to progression. Patients who have not progressed (defined as CR, PR or SD by 
RECIST v1.1 for soft tissue disease, or non-PD for bone disease, see Appendix G) at the time 
of analysis will be censored at the time of the last evaluable RECIST assessment or bone scan.
However, if the patient progresses or dies after 2 or more missed radiologic visits the patient 
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 patients 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 
patient has no evaluable post-baseline RECIST v1.1 or bone scan assessment they will be 
censored at 1 day 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
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earliest of the dates of the component that triggered the progression. With regard to 
censoring, a patient will be censored at the latest of the dates contributing to a particular 
overall visit assessment.
Overall survival
Overall survival is defined as the time from the first dose of AZD4635 until death due to any 
cause regardless of whether the patient withdraws from study therapy or receives another anti-
cancer therapy. Any patient not known to have died at the time of analysis will be censored 
based on the last recorded date on which the subject was known to be alive.
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if subjects are confirmed to be alive or if the death date is after the DCO date these subjects 
will be censored at the date of DCO. See Section 7 for methods that can be used to determine 
status of subjects who withdraw consent or are lost to follow-up.
9.4.5
Safety analyses
Safety data will not be formally analyzed but appropriate summaries for safety data will be 
produced, as defined below. All patients 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 patient and dose group. For 
patients who have a dose modification, all AEs (due to drug or otherwise) will be assigned to 
the initial dose group. The number of patients experiencing each AE will be summarized by 
the Medical Dictionary for Regulatory Activities (MedDRA) system organ class, MedDRA 
preferred term, and CTCAE grade. The number and percentage of patients with AEs in 
different categories (e.g., causally related, CTCAE Grade ≥3, etc.) will be summarized by 
dose group, and events in each category will be further summarized by MedDRA system 
organ class and preferred term, by dose group. Serious AEs will be summarized 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 (see modules for specific time period) 
after discontinuation of IP will be included in the AE summaries. Any AEs in this period that 
occur after a patient has received further therapy for cancer (following discontinuation of IP) 
will be flagged in the data listings. Adverse events occurring after the 30-day or 90-day 
follow-up period after discontinuation of IP will be listed separately, but not included in the 
summaries.
Hematology, clinical chemistry, vital signs, ECG data, ECHO/MUGA, demographic data, 
medical histories, and concomitant medications will be listed individually by patient and 
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CTCAE, the CTCAE grade will be calculated. Summary statistics of mean, median, standard 
deviation, minimum, maximum and number of observations will be used.
Details of any deaths will be listed for all patients.
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.
9.4.6
Other analyses
The analysis of the secondary endpoints PK, known metabolites and immunogenicity will be 
reported in the CSR.
 
9.4.7
COVID-19 analyses
Refer to the Statistical Analysis Plan for details regarding COVID-19.
9.5
Interim analyses
No formal interim analysis is planned.
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10
REFERENCES
Antonia et al. 2017
Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after 
chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-
29.
Brahmer et al. 2015
Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab 
versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015 
Jul 9; 373(2):123-35.
Bray et al. 2018
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin. 2018;68:394-424.
Eisenhauer et al. 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (Version 1.1). Euro J Cancer.
2009;45:228-47.
Larkin et al. 2015
Larkin J, Hodi FS, Wolchok JD. Combined nivolumab and ipilimumab or monotherapy in 
untreated melanoma. N Engl J Med. 2015 Sept;373(13):1270-1.
Le et al. 2015
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in 
tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-20.
McDermott et al. 2015
McDermott DF, Drake CG, Sznol M, Choueiri RK, Powderly JD, Smith DC, et al. Survival, 
durable response, and long-term safety in patients with previously treated advanced renal cell 
carcinoma receiving nivolumab. J Clin Oncol. 2015;33(18):2013-20.
Robert et al. 2015
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus 
ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521-32.
Ryan et al. 2013a
Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in 
metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138-48.




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11
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
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 Organizations 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 
(e.g., 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 approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.
The Investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC
!
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
!
Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the Investigator to 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 
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investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs, 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 (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB, if 
appropriate according to local requirements.
A 2
Financial disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate Regulatory Authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed consent process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative.


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If a patient’s partner becomes pregnant during or within 3 months (or as indicated in module-
specific appendix) after the study, the partner is asked to sign the "Adult Study ICF for 
Pregnant Partners of Study Patients" and provide information about the pregnancy 
accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
A 4
Data protection
Each patient will be assigned a unique identifier by the Sponsor. Any patient records or data 
sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the patient.
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from Regulatory Authorities.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
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A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or eCRF unless transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the eCRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 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 patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on 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.


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Definitions of what constitutes source data can be found in the clinical trial agreement.
A 9
Study and site closure
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. The study may be stopped if, in the 
judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that:
!
meet individual stopping criteria or are otherwise considered significant
!
are assessed as causally related to study drug,
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests
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
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.


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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 event definitions and additional safety information
B 1
Definition of adverse events
An adverse event (AE) is the development of any untoward medical occurrence in a patient or 
clinical study patient administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization
!
Results in persistent or significant disability or incapacity.
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardize the patient or may require medical 
treatment to prevent one of the outcomes listed above.
B 3
Life-threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.


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B 5
Important medical event or medical treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (e.g., neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse
B 6
Intensity rating scale:
The grading scales found in the revised National Cancer Institute CTCAE latest version will 
be utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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!
Time Course. Exposure to suspect drug. Has the patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug 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.


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Medication error includes situations where an error.
!
occurred
!
was identified and intercepted before the participant received the drug
!
did not occur, but circumstances were recognize that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error e.g. 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 e.g. tablet dissolved in water when it should be taken as a 
solid tablet
!
Drug not stored as instructed e.g. 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:
!
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) e.g. 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 AZ product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research.
The Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the organization(s) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed, the action documented 
and the signed document returned to the study site
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.


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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever 
virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations
!
Clinical trial samples will routinely be packed and transported at ambient
!
Temperature in IATA 650 compliant packaging
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)
!
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable
!
Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


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Appendix D
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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CCI


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CCI


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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 patient meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated total 
bilirubin (TBL) from a local laboratory.
The Investigator will also review Adverse Event (AE) data (for example, for AEs that may 
indicate elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. 
HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the investigational 
product (IP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and AEs according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of 
normal (ULN) together with TBL ≥2×ULN at any point during the study following the start 
of study medication irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 ×ULN, where no other reason, other than the 
IP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.


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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 time frame 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 patient 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:
!
Determine whether the patient 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 patient does not meet PHL criteria the Investigator will:
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
E 4.2    Potential Hy’s Law criteria met
If the patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section 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 patients who met PHL criteria prior to starting IP, the Investigator is not required to 
submit a PHL SAE unless there is a significant change# in the participant’s condition


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!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree on 
an approach for the study patients’ follow-up (including any further laboratory testing) 
and the continuous review of data.
!
Subsequent to this contact the Investigator will:
∀
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated
∀
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the Hy’s Law lab kit should be used
∀
Complete the 3 Liver eCRF Modules as information becomes available
#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or 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 IP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from date 
PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 
Physician will also be involved in this review together with other subject matter experts as 
appropriate.
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for 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.


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If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IP:
!
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:
!
Provide 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 IP 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 met. Update the previously submitted PHL SAE report following 
CSP process for SAE reporting, according to the outcome of the review amending the 
reported term if an alternative explanation for the liver biochemistry elevations is 
determined.
E 6
Actions required when potential Hy’s Law criteria are met before 
and after starting study treatment
This section is applicable to patients with liver metastases who meet PHL criteria on study 
treatment having previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ 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 patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit.


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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 (e.g., chronic or progressing malignant disease, severe 
infection or liver disease), or did the patient meet PHL criteria prior to starting study 
treatment and at first on-study treatment visit, as described in Section E 6 of this 
Appendix?
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 patient’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Section E 4.2 for reporting 
PHL as an SAE.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or 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 8
Laboratory tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory and it may be modified based on clinical judgment. If 
required, additional assistance on which tests could be used to evaluate other potential causes 
of liver dysfunction consult with the Hepatic Safety Knowledge Group. Any test results need 
to be recorded.
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT 
LDH
Prothrombin time
INR
Viral hepatitis
Immunoglobulin M (IgM) anti-HAV


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IgM and Immunoglobulin G (IgG) anti-
HBc
HBsAg 
HBV DNAa
IgG anti-HCV 
HCV RNAa
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV 
IgM & IgG anti-HSV
IgM & IgG anti-EBV
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 
Transferrinb
Transferrin saturation
a HCV RNA is 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 GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al 2011. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharm Ther.
2011;89(6):806-15.
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
Abreviations
Abbreviation
Explanation
A2AR
Adenosine 2a receptor
ADA
Anti-drug antibody
AE
Adverse event (see definition in Appendix B)
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
BCRP
Breast cancer resistance protein
BP
Blood pressure
CD73
Cluster of differentiation 73: 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase
CI
Confidence interval
Cmax
Maximum observed concentration
CNS
Central nervous system
CR
Complete response
CRP
C-reactive protein
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCO
Data cut-off
DILI
Drug induced liver injury
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EOT
End of treatment (visit)
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
FTIH
First-time-in-human
GCP
Good Clinical Practice
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Abbreviation
Explanation
GGT
Gamma glutamyltransferase
HL
Hy’s Law
IATA
International Air Transport Association
IB
Investigator’s brochure
IC50
Concentration giving 50% of the drug-induced inhibitory effect
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent ethics committee
ILD
Interstitial lung disease
imAE
Immune-mediated adverse event
IP
Investigational product
IRB
Institutional Review Board
IV
Intravenous
IWRS
Interactive web response system
LDH
Lactate dehydrogenase
mAb
Monoclonal antibody
MATE1
Multi-drug and toxin extrusion protein 1
mCRPC
Metastatic castration-resistant prostate carcinoma
MDSC
Myeloid-derived suppressor cells
MOA
Mechanism of action
MRI
Magnetic resonance imaging
MTD
Maximum-tolerated dose
MUGA
Multi-gated acquisition scan
NCI
National Cancer Institute
NE
Not evaluable
NHA
New hormonal agent(s)
NSCLC
Non-small cell lung cancer
NTL
Non-target lesion
OAT1
Organic anion transporter 1
OATP
Organic anion transporter polypeptide
OCT
Organic cation transporter
ORR
Overall response rate
CCI
CCI
CCI


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Abbreviation
Explanation
PBMC
Peripheral blood mononuclear cells
PCWG3
Prostate Cancer Working Group 3
PD
Progression of disease
PD-1
Programmed cell death protein 1 (e.g., nivolumab [Opdivo®])
PD-L1
Programmed death ligand 1
PDx
Pharmacodynamics
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PHL
Potential Hy’s Law
PK
Pharmacokinetics
PO
Per os (orally)
PR
Partial response
PSA
Prostate-specific antigen
Q2W
Every 2 weeks
Q4W
Every 4 weeks
QD
Once daily
QRS
QRS complex; the main spike on an ECG line
QT
ECG interval measured from the onset of the QRS complex to the end of the T wave
QTc
QT interval corrected for heart rate
QtcF
QT interval corrected for heart rate using Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended Phase 2 dose
rPFS
Radiographic progression-free survival
SAE
Serious adverse event (see definition in Appendix B)
SD
Stable disease
SoA
Schedule of activities
SRC
Safety Review Committee
TBL
Total bilirubin
TBNK
Complete immune panel (T-, B-, and natural killer [NK] lymphocyte subsets)
TL
Target lesion
tmax
Time to reach Cmax
TME
Tumor microenvironment
ULN
Upper limit of normal
CCI


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Appendix G
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST Version 1.1 (Response Evaluation Criteria in 
Solid Tumors) in Soft Tissue and PCWG3 (Prostate Cancer 
Working Group Criteria 3) in Bone Lesions
INTRODUCTION
This appendix details the implementation of RECIST (Response Evaluation Criteria in Solid 
Tumors) 1.1 guidelines (Eisenhauer et al. 2009) and PCWG3 guidelines (Scher et al. 2016) for 
the D8731C00001 study with regards to Investigator assessment of tumor 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
Patients 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 subject, 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 tumor assessments for this study are highlighted, with the rationale provided.
Table 11
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 D8731C00001 study it is recommended that CT examinations of the chest, abdomen 
and pelvis will be used to assess tumor 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 D8731C00001 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 D8731C00001 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 tumor 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 D8731C00001 study, endoscopy and laparoscopy will not be used for tumor 
assessments as they are not validated in the context of tumor assessment.
 
CCI


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Cytology and histology
In the D8731C00001 study histology will not be used for tumor response assessments as per 
RECIST 1.1 and tumor response assessments will be performed on radiological criteria only.
FDG-PET scan
In the D8731C00001 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.
Tumor 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 subjects and should be performed no more than 28 days 
before allocation/randomization. The first follow-up assessment for Modules 1, 2, and 3 
should be initially at 6 weeks (±1 week) following the start of AZD4635 dosing and 
subsequent assessments will be performed every 2 cycles (8 weeks, ±1 week) thereafter. 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 subject 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 subjects being assessed at a different frequency than other subjects.
Target lesions (TL) 
Documentation of target lesions
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.
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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, embolization, 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 tumor visit 
response for TL.
Table 12
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
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Table 12
Evaluation of target lesions
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
Non-Target lesions (NTL) 
Evaluation of non-target lesions
All other lesions (or sites of disease), except for bone lesions, not recorded as TL should be 
identified as NTL at baseline. Measurements are not required for these lesions, but their status 
should be followed at subsequent visits. At each visit an overall assessment of the NTL 
response should be recorded by the Investigator. This section provides the definitions of the 
criteria used to determine and record overall response for NTL at the investigational site at 
each visit.
Table 13
Evaluation of Non-Target Lesions
Complete Response (CR)
Disappearance of all non-target lesions since baseline. All lymph nodes
must be non-pathological in size (< 10 mm short axis).
Non CR/Non PD
Persistence of one or more NTL
Progression (PD)
Unequivocal progression of existing non-target lesions. Unequivocal
progression may be due to an important progression in one lesion only or 
in several lesions. In all cases the progression MUST be clinically 
significant for the physician to consider changing (or stopping) therapy.
Not Evaluable (NE)
Only relevant when one or some of the non-target lesions were not
assessed and, in the Investigator's opinion, they are not able to provide 
an evaluable overall non-target lesion assessment at this visit.
Note: For subjects without target lesions at baseline, this is relevant if 
any of the non-target lesions were not assessed at this visit and the 
progression criteria have not been met.
To achieve ‘unequivocal progression’ on the basis of non-target lesions, there must be an 
overall level of substantial worsening in non-target disease such that, even in presence of SD 
or PR in target lesions, the overall tumor burden has increased sufficiently to merit


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discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions 
is usually not sufficient to qualify for unequivocal progression status.
New Lesions
Details of any new soft tissue lesions will also be recorded with the date of assessment. The 
presence of one or more new lesions is assessed as progression.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumor.
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of 
the initial scan.
Symptomatic deterioration
Symptomatic deterioration is not a descriptor of an objective response; it is a reason for 
stopping study therapy.
Evaluation of Overall Visit Soft Tissue Response
The overall visit response will be derived using the algorithm shown in Table 14.
Table 14
Overall Visit Soft Tissue Response
Target lesions
Non-Target lesions
New Lesions
Overall soft tissue response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non CR/Non PD
No
PR
CR
NE
No
PR
PR
Non PD or NE
No
PR
SD
Non PD or NE
No
SD
NA
Non CR/Non PD
No
SD (Non CR/Non PD)
NA
NA
No
NED
NE
Non PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD


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CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NA = not applicable (only relevant if there were no TL and/or NTLs at baseline), NED = No Evidence 
of Disease (only relevant when there is no TL and NTL from baseline).
Specifications for radiological imaging
These notes are recommendations for use in clinical studies. The use of standardized 
protocols for CT and MRI allows comparability both within and between different studies, 
irrespective of where the examination has been undertaken.
CT scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the 
anatomical regions of interest.
The most critical CT image acquisition parameters for optimal tumor evaluation using 
RECIST Version 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
Anatomic coverage
Optimal anatomic coverage for most solid tumors is the chest, abdomen and pelvis. Coverage 
should encompass all areas of known predilection for metastases in the disease under 
evaluation and should additionally investigate areas that may be involved based on signs and 
symptoms of individual patients. Because a lesion later identified in a body part not scanned 
at baseline would be considered as a new lesion representing PD, careful consideration should 
be given to the extent of imaging coverage at baseline and at subsequent follow-up time 
points. This will enable better consistency not only of tumor measurements but also 
identification of new disease.
Intravenous contrast administration
Optimal visualization and measurement of metastases in solid tumors requires consistent 
administration (dose and rate) of intravenous contrast as well as timing of scanning.
Typically, most abdominal imaging is performed during the portal venous phase and 
(optimally) about the same time frame after injection on each examination. An adequate 
volume of a suitable contrast agent should be given so that the metastases are demonstrated to 
best effect and a consistent method is used on subsequent examinations for any given patient. 
It is very important that the same technique be used at baseline and on follow- up 
examinations for a given patient. For patients who develop contraindications to contrast after 
baseline contrast CT is done, the decision as to whether non-contrast CT or MRI (enhanced or 
non-enhanced) should be performed should also be based on the tumor type and anatomic 
location of the disease and should be optimized to allow for comparison to the prior studies if 
possible. Each case should be discussed with the radiologist to determine if substitution of 
these other approaches is possible and, if not, the patient should be considered not evaluable 
from that point forward. Care must be taken in measurement of TLs on a different modality


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and interpretation of non-target disease or new lesions, since the same lesion may appear to 
have a different size using a new modality. Oral contrast is recommended to help visualise 
and differentiate structures in the abdomen.
If iodine contrast media is medically contraindicated at baseline or at any time during the 
course of the study then the recommended methods are CT thoracic examination without 
contrast and abdominal and pelvic MRI with contrast. If MRI cannot be performed, then a CT 
scan without IV contrast is an option for the thorax, abdomen, and pelvic examinations. For 
assessment of brain lesions, MRI is the preferred method.
Slice thickness and reconstruction material
It is recommended that CT scans be performed at 5 mm contiguous slice thickness and this 
guideline presumes a minimum 5 mm thickness in recommendations for the measurable lesion 
definition. Exceptionally, particular institutions may perform medically acceptable scans at 
slice thicknesses greater than 5 mm. If this occurs, the minimum size of measurable lesions at 
baseline should be twice the slice thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered. When measuring lesions, the TLs should 
be measured on the same window setting for repeated examinations throughout the study. All 
images from each examination should be included in the assessment and not “selected” 
images of the apparent lesion.
MRI scan
MRI has excellent contrast, spatial and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity 
and measurement. Furthermore, the availability of MRI is variable globally. The modality 
used at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. Generally, axial imaging of the abdomen and 
pelvis with T1 and T2 weighted imaging along with gadolinium-enhanced imaging should be 
performed. The field of view, matrix, number of excitations, phase encode steps, use of fat 
suppression and fast sequences should be optimized for the specific body part being imaged as 
well as the scanner utilized. It is beyond the scope of this appendix to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts and diseases. Ideally, the same type of 
scanner should be used and the image acquisition protocol should be followed as closely as 
possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques if possible.
For these reasons, CT is the imaging modality of choice.


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FDG-PET scans
FDG-PET has gained acceptance as a valuable tool for detecting, staging and restaging several 
malignancies. If FDG-PET scans are included in a protocol, an FDG uptake period of 60 
minutes prior to imaging has been decided as the most appropriate for imaging of patients
with malignancy. Whole-body acquisition is important since this allows for sampling of all 
areas of interest and assessment if new lesions have appeared thus determining the possibility 
of interval progression of disease. Images from the base of the skull to the level of the mid-
thigh should be obtained 60 minutes post injection. PET camera specifications are variable 
and manufacturer specific, so every attempt should be made to use the same scanner, or the 
same model scanner, for serial scans on the same patient. Whole-body acquisitions can be 
performed in either 2- or 3-dimensional mode with attenuation correction, but the method 
chosen should be consistent across all patients and serial scans in the clinical study.
PET/CT scans
At present, low dose or attenuation correction CT portions of a combined PET/CT are of 
limited use in anatomically based efficacy assessments and it is therefore suggested that they 
should not be substituted for dedicated diagnostic contrast enhanced CT scans for tumor 
measurements by RECIST Version 1.1. In exceptional situations, if a site can document that 
the CT performed as part of a PET/CT is of identical diagnostic quality to a diagnostic CT 
(with IV and oral contrast) then the CT portion of the PET/CT can be used for RECIST 
measurements. However, this is not recommended because the PET portion of the CT 
introduces additional data that may bias an Investigator if it is not routinely or serially 
performed.
ASSESSMENT OF BONE LESION PROGRESSION USING PCWG3 
CRITERIA
Bone lesions will be assessed by bone scan in addition to being part of the RECIST v1.1 
malignant soft tissue assessment.
Method of assessment
Bone lesions identified on a whole-body isotopic bone scan at baseline should be recorded and 
followed by the same method as per baseline assessment.
In the D8731C00001 study isotopic bone scans will be used as a method of assessment to 
identify the presence of new bone lesions at follow-up visits. New lesions will be recorded 
where a positive and unequivocal hot-spot that was not present on the baseline bone scan 
assessment is identified on a bone scan performed at any time during the study. The 
Investigator should consider the positive hot-spot to be a significant new site of malignant 
disease and represent true disease progression in order to record the new lesion.


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Tumor progression evaluation
Schedule of the evaluation
Baseline assessments should be performed no more than 28 days before the start of study 
treatment. The first follow-up assessment for Modules 1, 2, and 3 should be initially at 6 
weeks (±1 week) following the start of AZD4635 dosing and subsequent assessments will be 
performed every 2 cycles (8 weeks, ±1 week) thereafter.
If an unscheduled assessment was performed and the subject 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 subjects being assessed at a different frequency than other subjects.
Documentation of lesions
All bone lesions (or sites of disease) should be identified by a bone scan at baseline. Their 
status should be followed at subsequent visits. At each visit an overall assessment of the bone 
lesion progression should be recorded by the Investigator. This section provides the 
definitions of the criteria used to determine and record bone progression at the investigational 
site at each visit.
Progression on a bone scan is identified using PCWG3 as follows:
!
At the first bone scan post-baseline (6 weeks):
2 or more new metastatic bone lesions are observed on the first 6-week scan compared to 
the baseline assessment. The confirmatory scan performed at least 6 weeks later and 
preferably no later than the next scheduled visit for a bone scan (i.e., Week 12), must 
show 2 or more additional new metastatic bone lesions (for a total of 4 or more new 
metastatic bone lesions since the baseline assessment) for progression to be documented.
Note - The first bone scan completed after baseline will be considered the ‘6-week scan’ 
regardless if taken at week 6 or at an unscheduled assessment.
!
After the first bone scan post-baseline (6 weeks):
2 or more new metastatic bone lesions are observed compared to the 6‑week assessment. 
The confirmatory scan, performed at least 6 weeks later and preferably at the next 
scheduled visit for a bone scan, must show the persistence of or an increase in the number 
of metastatic bone lesions compared to the prior scan for progression to be documented.
The date of progression is the date of the scan that first documents the second lesion.
Evaluation of bone progression status
Table 15 provides the definitions for the visit bone progression status for bone lesions.


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Table 15
Bone progression status
Non Progressive Disease (Non-PD)
No evidence of progression, or appearance of one new bone lesion, or
non-fulfillment of the progression criteria including new lesions without 
confirmation of progression.
Progressive Disease (PD)
Bone lesions fulfilling the requirements for at least 2 new lesions and 
confirmation of progression.
Not Evaluable (NE)
Only relevant if a follow-up bone scan is not performed
OVERALL RADIOLOGICAL VISIT ASSESSMENT
Table 16 provides the definitions how the visit responses for soft tissue (according to 
RECIST1.1 criteria) and bone progression status (according to PCWG3 criteria) are combined 
to give an overall radiological objective visit response.
Table 16
Overall radiological visit response
Overall visit soft tissue 
response (RECIST 1.1)
Bone progression status 
(PCWG3)
Bone lesions at visit 
Present/Absent
Overall radiological 
visit response
CR
Non-PD
Absent
CR
CR
Non-PD
Present
PR
CR
NE
-
PR
PR
Non-PD or NE
Any
PR
SD
Non-PD or NE
Any
SD
NED
Non-PD or NE
Any
Non-PD
NE
Non-PD or NE
Any
NE
PD
Any
Any
PD
Any
PD
Any
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable, NED = No Evidence of Disease (only relevant when there is no TL and NTL from baseline).
CONFIRMATION OF RESPONSE
In the D8731C00001 study, imaging for confirmation of response (CR or PR) should be 
performed at the next scheduled RECIST and PCWG3 assessment, i.e., 8 weeks (and must not 
be less than 4 weeks later) following the date the criteria for response were first met.


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Table 17
Best overall response when confirmation of CR and PR required.
Overall radiological 
response First time point
Overall radiological response 
subsequent time point
Best Overall response
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD or PD
CR
PD
SD or PD
CR
NE
SD or NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD or PD
PR
NE
SD or NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, NE = not 
evaluable.
a
If a CR is truly met at first time point, then any disease seen at subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes 
‘CR’ may be claimed when subsequent scan suggest small lesions were likely still present and in fact the 
subject had PR, not CR at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR.








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Appendix I
PCWG3 PSA Criteria
Baseline/Study Entry
PSA progression requirements for study entry
Patients 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 pure small cell 
carcinoma). It is recommended to estimate a pre-treatment PSA doubling time (PSADT) if at 
least 3 values are available ≥4 weeks apart. Treatment or enrollment onto a trial should not be 
delayed to estimate PSADT.
On-Study Disease Assessments
!
PSA results are to be collected on Day 1 of each treatment cycle
∀
Continue through early rises for a minimum of 12 weeks unless there is other 
evidence of progression, as a favorable effects on PSA may be delayed for ≥12 weeks
∀
Ignore PSA rises before 12 weeks in determining PSA response
Patients with PSA progression are allowed and encouraged to continue treatment until 
symptomatic or radiographic progression.
Reference: Scher et al. 2016


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Appendix J
Disallowed medications
Contribution of CYP1A2 to AZD4635 metabolism appears to be >80%. The following 
CYP1A2 strong and moderate inducers and inhibitors (Table 19) 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 19
Examples of CYP1A2 inhibitors and inducers of
CYP1A2
Strong inhibitors
Moderate inhibitors
Ciprofloxacin, clinafloxacin, enoxacin, 
fluvoxamine(a), 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
a
Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A.
Use of inhibitors or inducers of BCRP and sensitive substrates of OATP1B1/3, OAT1, OCT1, 
OCT2, MATE1 and P-gp is not permitted from 2 weeks before the first dose of AZD4635 
until at least 2 weeks after the last dose of AZD4635.
Examples of sensitive substrates of these substrates above are presented in Table 20.
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. If medically feasible, patients taking regular medication, with the exception of 
examples of known substrates of transporters listed in Table 20, should be maintained on it 
throughout the study period.


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Table 20
Examples of substrates of transporters
Substrate category
Examples of drugs in the category
Sensitive substrates of:
BCRP
Methotrexate, mitoxantrone, imatinib, lapatinib, sulfasalazine, 
topotecan, daunorubicin, doxorubicin, SN-38, irinotecan, prazosin, 
pantoprazole, atorvastatin, fluvastatin, rosuvastatin, 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


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D8731C00001 Clinical Study Protocol version 8
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