A Phase I/IIa, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Ascending Doses of AZD7648 Monotherapy or in Combination With Either Cytotoxic Chemotherapies or Novel Anti-Cancer Agents in Patients With Advanced Malignancies
Phase: PHASE1
Conditions: Advanced Malignancies
Sponsor: AstraZeneca

 
 
 
 
 
 
 
 
 
A Phase I/IIa, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Preliminary Efficacy of Ascending Doses of AZD7648 Monotherapy or in Combination with 
either Cytotoxic Chemotherapies or Novel Anti-Cancer Agents in Patients with Advanced 
Malignancies 
 
ClinicalTrials.gov Identifier: NCT03907969 
 
 
Date of Protocol: 01 October 2021 

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Clinical Study Protocol
Drug Substance
AZD7648
Study Code
D9170C00001
Version
5.0
Date
01 October 2021
A Phase I/IIa, Open-Label Study to Assess the Safety, Tolerability, 
Pharmacokinetics and Preliminary Efficacy of Ascending Doses of 
AZD7648 Monotherapy or in Combination with either Cytotoxic 
Chemotherapies or Novel Anti-Cancer Agents in Patients with Advanced 
Malignancies
Sponsor: AstraZeneca AB, 151 85, Södertälje, Sweden
EudraCT number: 2018-003688-73
This document contains trade secrets and confidential commercial information, disclosure of 
which is prohibited without providing advance notice to AstraZeneca and opportunity to 
object.

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Section 8.5 has been modified to remove details of plasma volumes used for analysis of PK 
blood samples.  Text has also been added to clarify that intra-patient dose escalation is only 
allowed in the Core Module.
Section 8.5.1 has been modified to clarify that for the determination of PK pegylated 
liposomal doxorubicin (PLD) concentrations total doxorubicin will be reported (updates are 
also made to Section 15.2 and SoA Table 14). 
Section 8.5.2 has been modified to state that Covance will perform the analysis of 
4β-hydroxy cholesterol. 
Section 8.5.3 has been modified to include additional text on incurred sample reproducibly 
analysis. 
Section 8.7.1 has been modified to remove text for a process which is not supported at 
sites/clinics. 
Section 9.4.1 has been modified to clarify tumour lesion measurements (there was an error 
in bullet 2).
Section 9.4.1 has been modified to remove months 3, 6, and 9 from the progression-free 
survival rate (PFS) variable.
Section 9.4.1 has been modified to remove week 16 from the objective response rate (ORR) 
variable. Text has been included to clarify objective disease progression confirmation and 
that a modified RECIST 1.1 criteria will be used.
Section 9.5 has been modified to correct the number of interim analyses from 5 to 3. 
Section 15.2 has been updated to include a table detailing PK sampling times for 
Combination Module 1. A similar table has also been included in Section 22.2 for 
Combination Module 2. 
Section 21.2 has been updated to include details of when olaparib should be taken in 
relation to AZD7648. 

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Synopsis has been updated to revise the number of patients enrolled in the study.  Patients 
have been removed for Combination Module 2 and for Combination Module 1 an additional 
30 patients may be enrolled once maximum tolerate dose (MTD) has been determined. 
Sample size has been updated in Sections 9.2 and 16.1. 
Figure 1 has been revised to remove the triple negative breast cancer (TNBC) arm and 
remove the subset of patients with HRRm-enriched ovarian cancer in treatment arm M1B1
and to remove Module 2. 
Figure 2 has been updated to clarify the title. 
Table 2 Study objectives the title for primary objective has been updated to match 
formatting of other objectives.
Sections 4.1.2, 9.2, 12.1, and 16.1 have been updated to include/clarify the number of 
evaluable patients and make text consistent across all modules. 
Sections 4.1.2 bullet updated to harmonise with the text in Section 6.1.2 (the text in italics 
has been added): The planned next higher dose must be declared tolerated by the SRC 
(based on assessment of 2 to 6 evaluable patients).  Grammatical updates have also been 
made to the 2 other bullets in this list. 
Section 4.1.4 a new section is included which gives guidance on how the study could 
continue in the event of a serious disruption (eg, coronavirus disease 2019 [COVID-19]) 
with details of mitigation that could be employed to ensure study continuity. The new text 
details the measures that may be implemented if a patient is not able to visit a study site to 
ensure that the clinical study can continue whilst minimising risk to the patient, maintaining 
compliance with Good Clinical Practice (GCP), and minimising risks to study integrity. 
These changes will only be initiated at a time of study disruption. Appendix J has also been 
included to provide further details. 
Inclusion Criterion 11 has been updated to revise the definition of post-menopausal based 
on the Clinical Trial Facilitation Group Recommendations Related to Contraception and 
Pregnancy Testing in Clinical Trials (version 1.1, 21 Sep 2020).
Exclusion Criterion 7 has been updated to clarify which steroid treatments are not 
permitted.
Exclusion Criterion 12e has been updated to clarify that for patients with 
documented/suspected Gilbert’s disease bilirubin is ≥2 x upper limit normal (ULN) for 
exclusion.  

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Exclusion Criterion 12f has been updated to clarify that for aspartate aminotransferase or 
alanine aminotransferase the ULN for patients with liver metastases is ≥5 x ULN. 
Exclusion Criterion 18 has been added: For food effect cohort only: insulin-dependent 
diabetes.
Exclusion Criterion 19 has been added for history and/or presence of COVID-19.
Section 5.4 has been updated to clarify that screen failures are patients who sign the 
informed consent but are not subsequently dosed with study treatment. The text has also 
been revised to clarify that the reason for screen failure is recorded in the case report form 
(CRF). 
Tables 3 and 15 have been updated to include a 
mg dosage formulation for AZD7648
and text is added to clarify that the tablets are oral and that intermediate strengths may be 
added at a later date.  
Sections 6.1.2 Dose escalation scheme – Core Module:

Text has been updated to clarify that sentinel dosing is applied 48 hours after Cycle 1, 
Day 1. 

Text has been updated to clarify that if enrolment is halted within a cohort the Safety 
Review Committee (SRC) will review all safety data, but review of the 
pharmacokinetic data was only required for Cohorts 1 to 4. This is also updated in 
Table 4 and elsewhere in this section.  Text in Section 6.1.4 is also updated.

The Illustrative Dose Escalation Schedules in Tables 4 and 16 have been updated to 
reflect revised possible AZD7648 doses; to add Cohort n (escalate to MTD or 
maximum feasible dose [MFD]); to specify maximum 
mg (
mg 
dose levels 
and dosing days; and in Combination Module 1, to specify expected starting cohorts.
Footnotes are also included for further information on maximum dose limit. 

Text has been updated to clarify that for SRC meetings prior to dose escalation where 
3 patients have been enrolled, at least 2 patients will need to be evaluable for 
dose-limiting toxicity. This update is also applied to Section 14.1.2.

Text has been updated to clarify the evaluable patient definition for dose escalation in 
Part A (the text in italics has been added): 
Has completed minimum safety evaluation requirements and has received at least 75% 
of the total amount of planned dose of AZD7648 (and PLD for Combination Module 1) 
during Cycle 1.

The text describing the triggers for starting the additional modules has been updated 
(text struck-through and text in italics has been added): 
•Total drug exposure levels ≥ 50% of that predicted to be required for biological 
activity for a period defined for the specific combination.  It is anticipated that the 
combination module will be triggered after the 
 mg monotherapy cohort is declared 
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Sections 4.1.2, 4.3.1, 6.1.2.1, and 6.1.3.2, and Tables 3, 4, 14, and 15 have been updated.
Following a negative AMES test result which demonstrated that the main impurity did not 
have any mutagenic potential, the text related to mutagenicity testing and reduced dose 
range incorporated in Protocol Version 4 has been removed and the original text and 
AZD7648 dose ranges have been added.
Section 4.1.2 has been updated to correct the evaluable patient numbers in line with the rest 
of the CSP (Section 9.2 has also been updated).
Section 4.4 has been updated to define a data cut-off point for each module or study part. 
Section 6.1.2 has been updated to clarify that at the recommended Phase II dose (RP2D) up 
to 12 patients may be treated to explore chronic toxicity, as described in Section 9.2. The 
sample size and number of patients have also been updated in Sections 9.2 and 1.2 to 
include 6 additional patients. 
Section 6.1.3 confirmed laboratory abnormalities will need to be greater than 72 hours of 
duration to be considered a dose limiting toxicity (DLT); this has been reworded to exclude 
non-significant laboratory abnormalities. 
Section 6.5.2 has been updated to provide advice on the administration of coronavirus 
disease 2019 (COVID-19) vaccinations during the study. 
Section 8.1.2 text has been updated for tumour response data and objective response rate 
(ORR) efficacy analyses based on the SAP. The modified RECIST criteria will not be used 
for the ORR analysis for the Core Module or Combination Module 1 (Section 9.4.1 has also 
updated).
Sections 8.4.2.1 and 8.4.2.2, and Appendix B2 have been revised to reword congenital 
abnormalities/abnormality to congenital anomalies/anomaly. 
Section 8.6.1.1 and Table 12 the timings for the collection of peripheral blood samples for 
 has been changed from 2 to 8 hours post-dose to 2 to 4 hours post-dose for
AZD7648. The footnotes (p and q) in Table 1 have been updated to reflect these changes. 
Section 8.6.1.4 and footnotes in Tables 1 and 13 (Part A and Part B) have been updated 
to include the collection of additional blood samples if immune-related events are 
suspected, to investigate safety signals.
Section 9.3 has been updated to reflect text used in the Statistical Analysis Plan (SAP). Two 
additional analysis sets “Evaluable for objective response” and “DLT evaluable set” have 
been added, and one has been removed (“Tumour biopsy set”). 
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Section 9.4.3.1 the statistical analysis for the assessment of pharmacokinetic food effect has 
been updated based on the SAP. 
Section 9.5 has been moved to Section 16 as the interim analysis applies to Combination 
Module 1 only. It has also been updated to remove text stating that the sample size for the 
interim analysis will be approved AstraZeneca governance.
Table 13 (Part A and Part B) has been updated to add footnotes to the Day Y and Day 8 
columns to add further clarity for these visits. 
Section 12.1 the wording regarding intermittent dosing schedules for the
Combination Module 1 has been updated to clarify that intermittent schedules will be 
required.
Section 14.1.1, Table 14 has been updated to amend the starting dose instructions for 
AZD7648 in relation to PLD dosing for Combination Module 1.
Section 14.1.2 text for sentinel dosing has been added for Combination Module 1. 
Section 15.3, Table 16 PK sampling times have been revised. For Part A Cycle 1, Day 1 
the AZD7648 sample will be collected 2 hours (h) post-dose instead of 1 h to align with 
Tmax. The PLD samples will be taken 4 h after start of PLD infusion. The 10 to 12 h 
AZD7648 samples have been removed and 6 h samples will be taken instead (to reduce 
patient burden/time at site). The PK footnotes in Table 13 (SoAs Part A and Part B) have 
been updated to refer to Table 16 for further details on sampling times. 
Section 15.4 has been added to include details for the collection of blood samples for
 
 in relation to PLD dosing in Combination Module 1 (including addition of 
Table 17). The footnotes in Table 13 (Part A and Part B) have been updated to include 
relevant details.
Appendix D has been updated to correct the visit for collection of the sample for genetic 
research (it was changed from Visit 6 to the Cycle 1, Day 1 Visit).
Appendix H has been updated to state that 
 
 will be used in 
an exploratory analysis.  
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
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TABLE OF CONTENTS
VERSION HISTORY........................................................................................................... 2
TABLE OF CONTENTS.................................................................................................... 13
1
PROTOCOL SUMMARY................................................................................ 19
1.1
Schedule of Assessments – Core Module.......................................................... 19
1.2
Synopsis ........................................................................................................... 23
1.3
Schema............................................................................................................. 25
2
INTRODUCTION............................................................................................ 26
2.1
Study rationale.................................................................................................. 26
2.2
Background ...................................................................................................... 26
2.3
Benefit/risk assessment..................................................................................... 30
3
OBJECTIVES AND ENDPOINTS................................................................... 31
4
STUDY DESIGN ............................................................................................. 33
4.1
Overall design................................................................................................... 33
4.1.1
Modular protocol structure................................................................................ 33
4.1.2
Core module study design: AZD7648 monotherapy.......................................... 34
4.1.3
Regulatory amendment for additional modules ................................................. 36
4.1.3.1
Europe and Rest of World................................................................................. 36
4.1.3.2
United States of America .................................................................................. 36
4.1.4
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 36
4.2
Scientific rationale for study design .................................................................. 37
4.3
Justification for dose......................................................................................... 38
4.3.1
Justification for the dose escalation doses ......................................................... 39
4.4
End of study definition...................................................................................... 39
5
STUDY POPULATION ................................................................................... 40
5.1
Inclusion criteria............................................................................................... 41
5.2
Exclusion criteria.............................................................................................. 42
5.3
Lifestyle restrictions ......................................................................................... 45
5.3.1
Fasting restrictions............................................................................................ 45
5.3.2
Dietary restrictions............................................................................................ 45
5.3.3
Contraception ................................................................................................... 45
5.3.4
Concomitant medication ................................................................................... 46
5.3.5
Blood donation ................................................................................................. 46
5.4
Screen failures .................................................................................................. 46
6
STUDY TREATMENTS.................................................................................. 46
6.1
Treatments administered................................................................................... 47
6.1.1
Investigational products.................................................................................... 47
6.1.2
Dose escalation scheme – Core Module ............................................................ 47

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6.1.2.1
Optional Expansion Cohorts ............................................................................. 52
6.1.3
Definition of dose-limiting toxicity................................................................... 53
6.1.3.1
Definition of Maximum Tolerated Dose and Recommended Phase II Dose....... 54
6.1.3.2
Definition of Maximum Feasible Dose.............................................................. 55
6.1.4
Safety review committee................................................................................... 55
6.2
Preparation/handling/storage/accountability...................................................... 56
6.3
Measures to minimise bias: randomisation and blinding.................................... 56
6.4
Treatment compliance....................................................................................... 57
6.5
Concomitant therapy......................................................................................... 58
6.5.1
Other concomitant treatment............................................................................. 59
6.5.2
Support medication........................................................................................... 59
6.6
Dose modification............................................................................................. 60
6.7
Treatment after the end of the study.................................................................. 61
7
PATIENT DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL .............................................................................................. 62
7.1
Discontinuation of study treatment.................................................................... 62
7.1.1
Temporary discontinuation ............................................................................... 62
7.1.2
Rechallenge ...................................................................................................... 62
7.1.3
Procedures for discontinuation of study treatment............................................. 62
7.2
Lost to follow-up .............................................................................................. 63
7.3
Withdrawal from the study................................................................................ 63
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 64
8.1
Efficacy assessments......................................................................................... 65
8.1.1
Tumour assessments by CT or MRI.................................................................. 65
8.1.2
Tumour evaluation............................................................................................ 66
8.1.3
Survival assessment .......................................................................................... 67
8.2
Safety assessments............................................................................................ 67
8.2.1
Clinical safety laboratory assessments............................................................... 67
8.2.2
Physical examinations....................................................................................... 68
8.2.3
Body weight ..................................................................................................... 69
8.2.4
Vital signs......................................................................................................... 69
8.2.5
Electrocardiograms........................................................................................... 69
8.2.6
Performance status............................................................................................ 69
8.3
Collection of adverse events ............................................................................. 70
8.3.1
Method of detecting AEs and SAEs .................................................................. 70
8.3.2
Time period and frequency for collecting AE and SAE information.................. 70
8.3.3
Follow-up of AEs and SAEs ............................................................................. 71
8.3.4
AE data collection............................................................................................. 71
8.3.5
Causality collection........................................................................................... 72
8.3.6
AEs based on signs and symptoms.................................................................... 72
8.3.7
AEs based on examinations and tests ................................................................ 72
8.3.8
Hy’s law ........................................................................................................... 73
8.3.9
Disease progression .......................................................................................... 73

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11
INTRODUCTION............................................................................................ 99
11.1
Study rationale.................................................................................................. 99
11.2
Background ...................................................................................................... 99
11.2.1
Pegylated liposomal doxorubicin .................................................................... 100
11.2.1.1
Overview of pegylated liposomal doxorubicin ................................................ 100
11.2.1.2
Pegylated liposomal doxorubicin data............................................................. 100
11.3
Benefit/risk assessment................................................................................... 101
12
STUDY DESIGN ........................................................................................... 102
12.1
Overall design................................................................................................. 102
12.2
Scientific rationale for study design ................................................................ 102
12.3
Justification for dose....................................................................................... 103
12.3.1
Justification for AZD7648 dose ...................................................................... 103
12.3.2
Justification for pegylated liposomal doxorubicin dose ................................... 103
13
STUDY POPULATION ................................................................................. 103
13.1
Inclusion criteria............................................................................................. 103
13.2
Exclusion criteria............................................................................................ 104
13.3
Lifestyle restrictions ....................................................................................... 105
14
STUDY TREATMENTS................................................................................ 105
14.1
Treatments administered................................................................................. 106
14.1.1
Investigational products.................................................................................. 106
14.1.2
Dose escalation scheme .................................................................................. 106
14.2
Treatment compliance..................................................................................... 109
14.3
Concomitant therapy....................................................................................... 110
14.3.1
Effect of pegylated liposomal doxorubicin on other drugs............................... 110
14.4
Dose modification........................................................................................... 110
15
STUDY ASSESSMENTS AND PROCEDURES ........................................... 110
15.1
Management of study treatment-related toxicities ........................................... 110
15.2
Echocardiogram.............................................................................................. 111
15.3
Pharmacokinetics............................................................................................ 111
15.4
Pharmacodynamics......................................................................................... 112
15.5
Biomarkers ..................................................................................................... 113
16
STATISTICAL CONSIDERATIONS............................................................. 114
16.1
Interim analysis .............................................................................................. 114
16.2
Sample size determination .............................................................................. 114
17
REFERENCES............................................................................................... 115
18
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 118

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LIST OF TABLES
Table 1
Schedule of assessments – Core Module.................................................. 20
Table 2
Study objectives....................................................................................... 31
Table 3
Study treatments ...................................................................................... 47
Table 4
Example of AZD7648 monotherapy dose escalation scheme.................... 49
Table 5
Prohibited medications............................................................................. 58
Table 6
Management of AZD7648 treatment related toxicity................................ 61
Table 7
Dose modification of study treatment AZD7648 ...................................... 61
Table 8
Laboratory safety variables...................................................................... 68
Table 9
Eastern Cooperative Oncology Group Performance Status....................... 70
Table 10
AZD7648 PK sample collection schedule in monotherapy cohorts........... 77
Table 11
AZD7648 PK sample collection schedule in food effect cohort................ 79
Table 12
PD blood sample collection schedule in monotherapy cohorts.................. 81
Table 13
Schedule of assessments – Combination Module 1................................... 93
Table 14
Study treatments .................................................................................... 106
Table 15
Illustrative AZD7648 dose escalation schedule ...................................... 108
Table 16
AZD7648 and PLD PK sample collection schedule ............................... 111
Table 17
............................... 113
Table 18
Interim analysis ..................................................................................... 114
LIST OF FIGURES
Figure 1
Study design............................................................................................ 25
Figure 2
DNA damage repair pathways including non-homologous end joining 
pathway................................................................................................... 28
Figure 3
Role of DNA-PK in non-homologous end joining repair pathway............ 29
Figure 4
Role of DNA-PK in replication stress response........................................ 29
Figure 5
Modular protocol structure....................................................................... 34
Figure 6
AZD7648 monotherapy study flow chart ................................................. 48
Figure 7
Starting dose and schedule for AZD7648 monotherapy............................ 49
Figure 8
Ovarian cancer xenograft – mean tumour volume .................................. 101
Figure 9
AZD7648 combinations study flow chart............................................... 107
Figure 10
Illustration of starting dose and schedule for AZD7648 in combination 
with PLD............................................................................................... 108
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LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations........................ 118
Appendix B
Adverse Event Definitions and Additional Safety Information............... 123
Appendix C
Handling of Human Biological Samples ................................................ 127
Appendix D
Genetics................................................................................................. 129
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 133
Appendix F
Guidance Regarding Potential Interactions with Concomitant 
Medications ........................................................................................... 138
Appendix G
Acceptable Birth Control Methods......................................................... 140
Appendix H
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 142
Appendix I
Food Effect Cohort Plan ........................................................................ 153
Appendix J
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 157
Appendix K
Abbreviations ........................................................................................ 159

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1
PROTOCOL SUMMARY
The structure of the protocol will follow a modular design.  Sections 1 to 9, 16 and 17 of the 
protocol contain information mainly related to the Core Module and the overall study.  
Sections 10 to 16 of the protocol contain additional information specific to Combination 
Module 1. Further details on study design can be found in Section 4.1.1.
1.1
Schedule of Assessments – Core Module
The SoA for Combination Module 1 can be found in Section 10.1. 

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Table 1
Schedule of assessments – Core Module
Screening
Single Dose
Multiple Dose
IP 
Disc
28-day FU 
After IP 
Disc
Details in 
Section
Cycle 0
Cycle 1a
Weekly Visitb
Cycle 
2a
Cycle 
3a
Cycle 
4a
On
wards
Day
-28 to -1
1
2
3
4
1
Yc
8 
15
22
1
15
1
1
Visit Windowd
-
-
-
-
-
-
-
-
-
±1
±1
±2
±2
-
±7
Informed consent
X
5.1
Demographics and medical 
history, including tumour gene 
mutationse
X
5.1
Physical examination 
X
X
Xf
X
Xf
Xf
X
Xf
Xf
Xf
Xf
8.2.2
Height 
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.3
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.4
ECGg
X
X
X
X
X
X
X
X
X
X
X
X
8.2.5
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
8.3
Pregnancy testi
X
Xi
Xi
X
X
X
X
5.1
Haematology, coagulation, 
chemistry, urinalysis, tumour 
marker, TSHj
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.1
ECOG PS
X
X
X
X
X
X
X
X
X
8.2.6
Archival tumourk
X
8.8
Fresh tumour biopsy with 
biomarker analysesl
X
X
X
X
8.6.3
PK AZD7648 blood m
X
X
X
X
X
X
X
X
X
X
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Screening
Single Dose
Multiple Dose
IP 
Disc
28-day FU 
After IP 
Disc
Details in 
Section
Cycle 0
Cycle 1a
Weekly Visitb
Cycle 
2a
Cycle 
3a
Cycle 
4a
On
wards
Day
-28 to -1
1
2
3
4
1
Yc
8 
15
22
1
15
1
1
Visit Windowd
-
-
-
-
-
-
-
-
-
±1
±1
±2
±2
-
±7
PK AZD7648 urinen
X
X
8.5
4-beta-hydroxy-cholesterol
X
X
X
8.5.2
PD blood biomarkero
X
Xp
Xq
Xq
Xp
Xr,s
8.6.1.1
8.6.1.4
X
Xp
Xq
Xq
Xq
Xp
Xq
Xq,r
Xq,r
Xr
8.6.1.2
X
Xp
Xq
Xq
Xq
Xp
Xq
Xq,r
Xq,r
Xr
8.6.1.3
Tumour assessment
X
Xt
Xt
8.1.1 8.1.2
PGx (optional)
(X)
8.7
Appendix D
X
X
X
X
X
X
X
X
X
X
6.1
Patient diary dispensed
X
6.4
AE=Adverse Events; 
; 
 DNA; ECG=Electrocardiogram; Disc=discontinuation; ECOG PS=Eastern 
Cooperative Oncology Group performance status; FU=Follow-up; IP=Investigational Product; PD=Pharmacodynamics; PGx=pharmacogenetic sample; 
PK=Pharmacokinetics; TSH=Thyroid stimulating hormone.
a
1 cycle = 28 days.  Cycles repeat on a continuous basis with no interval between cycles. 
b
Weekly visit may be omitted if Visit Y is within 2 days of weekly visit.
c
Visit Y is only utilised if the dosing schedule is intermittent.  Visit Y represents the last AZD7648 dosing day in the first block of AZD7648 treatment in a 
cycle eg, 
d
There are no visit windows in Cycle 0 and Cycle 1.
e
With the patient’s consent, as part of the medical history, any available information on known tumour gene mutations will be collected.
f
Targeted physical examinations only required if clinically indicated (indication should be stated).
g
Vital signs then ECG measurements will be collected prior to PK blood draws at all PK sample timepoints.  Timepoints may be modified based on initial 
data obtained. 
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1.2
Synopsis
Principal Investigator:
Dr Timothy Yap
1515 Holcombe Boulevard, Unit 0455
Houston, Texas
77030
United States
Protocol Title:
A Phase I/IIa, Open-Label Study to Assess the Safety, Tolerability, Pharmacokinetics and 
Preliminary Efficacy of Ascending Doses of AZD7648 Monotherapy or in Combination with 
either Cytotoxic Chemotherapies or Novel Anti-Cancer Agents in Patients with Advanced 
Malignancies
Rationale:
In cancer cells, defective DNA damage response (DDR) promotes genomic instability, 
neoplastic transformation and proliferation.  Such instability results in the formation of highly 
destructive double-strand breaks (DSBs) and cell death.  DNA dependent protein kinase 
(DNA-PK) overexpression renders tumours resistant to DNA damage; therefore DNA-PK 
inhibition is an attractive therapeutic strategy.  Preclinical data from both in vitro and in vivo 
systems supports this hypothesis and provides the rationale required to explore the clinical 
potential of the DNA-PK selective inhibitor AZD7648.
Study Design:
This is a modular Phase I/IIa, open-label, multi-centre, study of AZD7648 administered 
orally, either as a monotherapy, or in combination with either cytotoxic chemotherapies or 
novel anti-cancer agents in patients with advanced malignancies.  The modular design allows 
for an escalation of the dose of AZD7648 alone or in combination with either cytotoxic 
chemotherapies or novel anti-cancer agents, with intensive safety monitoring to ensure the 
safety of the patients.
The study consists of 2 modules each evaluating the safety and tolerability of AZD7648 
monotherapy or with a specific combination partner.  The initial components are a Core 
Module of AZD7648 monotherapy and Combination Module 1 (AZD7648 in combination 
with pegylated liposomal doxorubicin [PLD]).  Up to 5 additional combination modules may 
be added via a formal amendment (see Section 4.1.3) to allow further evaluation of AZD7648 
in defined populations or novel combinations.  These may include i) combination with a DDR 
agent eg, ataxia telangiectasia and Rad3-related protein (ATR) inhibitor; ii) combination with 
an immuno-oncology agent eg, a programmed death-ligand 1 (PD-L1) inhibitor; iii) 

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combination with a cytotoxic agent eg, paclitaxel; iv) combination with an antibody-drug 
conjugate; and v) combination with radiotherapy.
Combination Module 1 has 2 study parts: Part A consisting of dose escalation cohorts and 
Part B, a safety and proof of concept (PoC) Phase IIa expansion.  Part A dose escalation and 
de-escalation will follow the principles of the Bayesian adaptive design which combines prior 
expectations about the dose toxicity relationship and applies the data at the end of each cohort 
to recommend a dose for the next cohort.  A Safety Review Committee (SRC) will review 
evaluable patients at each cohort and assess if the study should progress to Part B.  Optional 
expansion cohorts may also be triggered in Part A dose escalations, enrolling additional 
patients at appropriate dose(s) to explore further the safety, tolerability, pharmacodynamics 
(PD), pharmacokinetics (PK), biological activity and effect of food. 
Main Objectives:
The primary objective is to investigate the safety and tolerability of AZD7648 when given 
orally to patients with advanced malignancies, as monotherapy and in combination with 
anti-cancer agents, and to define the doses and schedules for further clinical evaluation.
Secondary objectives are i) to characterise the PK of AZD7648, following a single dose and at 
steady state after multiple doses, when given orally as monotherapy and in combination with 
anti-cancer agents, and to characterise the effect of food on AZD7648 exposure (if 
conducted); ii) to obtain a preliminary assessment of anti-tumour activity of AZD7648 as 
monotherapy and in combination with anti-cancer agents.
Tertiary/exploratory objectives are described in Section 3.
Study Period:
Estimated date of first patient enrolled: Q4 2019
Estimated date of last patient completed: Q2 2024
Number of Patients:
Approximately 192 evaluable patients may be enrolled in the Core Module (95 evaluable 
patients: 46 patients in the dose escalation and up to 49 additional patients in optional 
expansion cohorts) and Combination Module 1 (97 evaluable patients: 30 patients in the dose 
escalation with the potential for an additional 30 patients once maximum tolerate dose [MTD] 
has been determined, and 37 patients in the expansion cohort).

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Treatments and Treatment Duration:
For the Core Module, a single dose of AZD7648 will be administered in the clinic (Cycle 0, 
Day 1) to enable collection of blood samples for PK analyses.  This will be followed by a drug 
washout (no dose) of 3 to 7 days prior to Cycle 1, Day 1 AZD7648 administration.
In cohort 1, at Cycle 1, Day 1, the starting dose of AZD7648 will be mg 
 on a 
continuous 
.  There is no interval between cycles.  Using an accelerated 
titration design, dose escalation may occur with single patient cohorts up to and including 
mg 
.  From 
mg 
, a minimum of 3 patients will be 
enrolled into each dose cohort.  Dose escalation will stop at the MTD, maximum feasible dose 
(MFD), or the recommended Phase II dose (RP2D).  From Cohort 2 onwards, intermittent 
dosing schedules for AZD7648 may be explored.
For Combination Module 1 the starting dose of AZD7648 is dependent on emerging safety 
and tolerability data from the Core Module.  Intermittent dosing schedules for AZD7648 may 
be explored. 
For Combination Module 1 the starting dose of PLD is 40 mg/m2, administered by intravenous 
(IV) infusion once every 4 weeks, for a maximum of 6 cycles.  AZD7648 will be administered 
4 hours from the start of the IV infusion of PLD.  
1.3
Schema
The general study design is shown in Figure 1.
Figure 1
Study design
Lipo.dox=pegylated liposomal doxorubicin.
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2
INTRODUCTION
Study D9170C00001 is a Phase I/IIa, open-label, multi-centre, study of AZD7648 
administered orally, either as monotherapy, or in combination with either cytotoxic 
chemotherapies or novel anti-cancer agents to patients with advanced malignancies.  The 
modular design allows the evaluation of the safety, tolerability, and preliminary efficacy of 
multiple study treatments.  The Core Module will investigate AZD7648 as a monotherapy, 
and Combination Module 1 will investigate AZD7648 administered in combination with 
pegylated liposomal doxorubicin (PLD).
Details related to study rationale, background and benefit/risk assessment for Combination 
Module 1 can be found in Section 11 (see Section 4.1.1 for further details on the modular 
structure).
2.1
Study rationale
The 
.  In 
cancer cells, 
 
.  Such instability results in an accumulation of 
 
  
 
 
.  
 
  Preclinical data from both in 
vitro and in vivo systems 
 
2.2
Background
DNA damage events occur frequently in any living cell and various mechanisms have evolved 
to deal with them.  Different forms of DNA damage trigger responses by different repair 
mechanisms and signalling pathways (Figure 2). 
Among DNA damage lesions, DSBs are the most cytotoxic.  They induce cell cycle arrest and 
cell death if left unrepaired.  NHEJ pathway of DSB repair occurs independently but is 
preferentially used during the early G1/S phases, where no template sister chromatid is 
available (Hartlerode and Scully 2009).  This contrasts with the second major pathway of DSB 
repair, homologous recombination (HR), which occurs primarily in G2/M phases of the cell 
cycle when undamaged sister chromatids are available (San Filippo et al 2008).
DNA-PK is a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family (that 
includes ataxia telangiectasia mutated [ATM] and ATR) and is a key modulator for the NHEJ 
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pathway of DNA repair elicited by DSBs (Jackson et al 1993) and for V(D)J recombination, a 
process that utilises NHEJ to promote immune system diversity (Blunt et al 1995).  
DNA-PK is activated when it is recruited to DSBs by Ku70/80 heterodimer.  
Autophosphorylation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), is 
critical for the regulation of DNA-end processing, enzyme inactivation, and complex 
dissociation (Chan et al 2002).  Activated DNA-PKcs promotes DNA-end tethering 
(Graham et al 2016) which prevents DNA degradation by exonucleases 
(Yoo and Dynan 1999) and alters the activity of a wide range of substrates that mediate 
DNA-end processing and resolution (Figure 3) (Neal and Meek 2011).
DNA-PK has also been implicated in a range of other biological processes, including 
modulation of chromatin structure, telomere maintenance, transcriptional regulation, and the 
response to replication stress (Figure 4) (Goodwin and Knudsen 2014). 

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Figure 2
DNA damage repair pathways including non-homologous end joining pathway
DNA-dependent protein kinase (DNA-PK) adds non-homologous end joining (NHEJ) repair targeting to the DNA damage response agent (DDR) portfolio.
APE1=apurinic/apyrimidinic endonuclease; ATM=ataxia telangiectasia mutated; ATR=ataxia telangiectasia and Rad3-related protein; PARP=poly ADP ribose 
polymerase; RTx=treatment; UV=ultraviolet; XP=xeroderma pigmentosum. 

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Figure 3
Role of DNA-PK in non-homologous end joining repair pathway
Phosphorylation of H2AX at DNA double-strand breaks (DSB) and auto-phosphorylation of DNA-dependent 
protein kinase catalytic subunit (DNA-PKcs) S2056 during non-homologous end joining (NHEJ) repair.
Figure 4
Role of DNA-PK in replication stress response
Phosphorylation of RPA32 by DNA-dependent protein kinase (DNA-PK) during replication stress response.  
Adapted from O’Connor 2015.

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Upregulation of DNA-PK has been reported in various tumour types, correlates with poor 
clinical prognosis, and has been shown to correlate with decreased response to DNA 
damaging agents and therapeutic resistance in multiple cancers, such as colorectal cancer, 
oesophageal cancer, oral squamous cell carcinoma, and neuroblastoma 
(Goodwin and Knudsen 2014, Shintani et al 2003, Hosoi et al 2004, Shintani et al 2003, 
Tonotsuka et al 2006, Dolman et al 2015, Beskow et al 2009).
The concept of targeting DNA-PK as an anti-cancer strategy is based on exploiting tumour 
dependence on NHEJ repair.  Synthetic lethal interactions have been identified between 
DNA-PK and multiple damage response factors including ATM and HR proteins suggesting 
that a DNA-PK inhibitor may show efficacy as monotherapy in specifically selected genetic 
backgrounds (Gurley et al 2001, Oken et al 1982, Riabinska et al 2013, Dietlein et al 201).  
Furthermore, combining a DNA-PK inhibitor with agents that increase levels of DNA DSBs 
in cells – such as radiation, topoisomerase 2 inhibitors (eg, doxorubicin) represents another 
rational strategy for clinical development of DNA-PK inhibitor.  
There is currently one other DNA-PK selective inhibitor, M3814, known to be undergoing 
clinical trials.  A Phase I study (NCT02316197) of M3814 showed that the drug was safe and 
tolerable at doses up to 400 mg BID with limited single-agent activity (Van Bussel et al 2017) 
and a Phase Ia/b study is now being conducted in combination with radiation and 
chemoradiation (NCT02516813).  Preliminary results from 16 patients dosed across 3 cohorts 
(100 mg, 200 mg, and 400 mg once daily [QD]) in combination with radiation have shown 
that the combination was well tolerated, although some Grade 3 events of mucositis and 
odynophagia were observed.  Two dose-limiting toxicities (DLTs) were observed at 400 mg 
QD therefore 300 mg QD is being explored.  Initial efficacy data from 12 evaluable patients 
was reported to have 1 complete response (CR), 4 partial responses (PR) and 7 stable disease 
(SD) (Van Triest et al 2018).  Two additional studies are also recruiting patients: a Phase I 
study (NCT03724890) to evaluate RP2D and/or MTD of M3814 in combination with 
avelumab with and without radiotherapy in solid tumours; and a Phase Ib/2 study 
(NCT03770689) to first define RP2D of M3814 in combination with capecitabine and 
radiotherapy followed by evaluation of the combination efficacy in patients with locally 
advanced rectal cancer.  There are 2 other DNA-PK drugs, SF-1126 and CC-115, in Phase I 
clinical trials but, unlike AZD7648 and M3814, they are known to be multi-kinase inhibitor 
and dual-kinase inhibitor respectively.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD7648 is 
provided in the Investigator’s Brochure (IB).
2.3
Benefit/risk assessment
The Core Module of the study is a first time in human (FTIH) Phase I/IIa dose escalation 
study with the DNA-PK inhibitor AZD7648.  Detailed information about the known and 

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expected benefits and risks of AZD7648 may be found in the IB.  The study design aims to 
minimise potential risks and although the potential benefits in patients are unknown at this 
time, non-clinical data demonstrates evidence of anti-tumour activity.  Thus, the benefit/risk 
assessment for this Phase I/IIa study appears acceptable based on the lack of effective 
alternative treatments, the limited life expectancy due to malignant disease, and the strength of 
the scientific hypothesis under evaluation.
3
OBJECTIVES AND ENDPOINTS
Table 2
Study objectives
Primary objective:
Endpoint/Variable:
To investigate the safety and tolerability of AZD7648 
when given orally to patients with advanced 
malignancies, as monotherapy and in combination 
with anti-cancer agents, and define the doses and 
schedules for further clinical evaluation
Adverse events (AEs)/serious adverse events (SAEs)
DLTs
Physical examination
Eastern Cooperative Oncology Group performance 
status (ECOG PS)
Vital signs
Electrocardiogram (ECG) and Echocardiogram 
(ECHO; Combination Module 1 only)
Laboratory data
Secondary objectives:
Endpoint/Variable:
To characterise the PK of AZD7648, following a 
single dose and at steady state after multiple dosing, 
when given orally as monotherapy and in 
combination with anti-cancer agents. 
To characterise the effect of food on AZD7648 
exposure (if conducted)
Area under the curve (AUC) and/or AUC0-t after a 
single dose and AUCtau after multiple doses.
Maximum plasma concentration (Cmax) after a single 
dose and Cmax,ss after multiple doses
Time to reach maximum plasma concentration (tmax)
Minimum plasma concentration at steady state 
(Cmin,ss)
Half-life (t1/2)
Accumulation ratio
Dose proportionality 
AUC0-t and Cmax ratio for food effect
To understand the cytochrome P450 3A4 (CYP3A4) 
induction potential of AZD7648
Post-dose to pre-dose 4-β-hydroxy cholesterol ratio
To obtain a preliminary assessment of anti-tumour 
activity of AZD7648 as monotherapy and in 
combination with anti-cancer agents
Radiological response evaluated using response 
evaluation criteria in solid tumours (RECIST) 1.1

Percentage best change in target lesion (TL)

Duration of response

Objective response rate (ORR)

Progression-free survival (PFS)

Overall Survival (OS) (Part B only) 

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4
STUDY DESIGN
4.1
Overall design
This is a modular Phase I/IIa, open-label, multi-centre, study of AZD7648 administered 
orally, either as monotherapy, or in combination with either cytotoxic chemotherapies or 
novel anti-cancer agents to patients with advanced malignancies.  The modular design allows 
for an escalation of the dose of AZD7648 alone or in combination with either cytotoxic 
chemotherapies or novel anti-cancer agents, with intensive safety monitoring to ensure the 
safety of the patients.
For an overview of the study design see Figure 1, Section 1.3.  For study flow charts and 
details of treatments given during the Core Module and Combination Module 1 see 
Sections 6.1, and 14.1, respectively.
For details on what is included in the safety, efficacy and exploratory endpoints, see Section 3
Objectives and Endpoints (applicable to the Core Module and Combination Module 1).
4.1.1
Modular protocol structure
The structure of the protocol will follow a modular design.  
The initial module will be a Core Module relating to AZD7648 monotherapy.  Additional 
combination modules may be added as described below, via a formal amendment, based on 
emerging supportive preclinical data and study rationale.  The decision to initiate a 
combination module once regulatory approvals have been obtained will be made by the SRC.  
The starting dose/schedule of AZD7648 in further combination modules will not exceed the 
equivalent maximum exposure of AZD7648 found to be tolerated in the core module or from 
other studies in the clinical programme at that point.
List of Modules
The following starting modules for the study are included within this protocol.  
1
Core Module: AZD7648 Monotherapy. Part A, dose escalation (which may include a 
food effect cohort)
2
Combination Module 1: AZD7648 + PLD.  Part A, dose escalation and Part B, safety 
and PoC Phase IIa expansions
3
Up to 5 additional combination modules may be added as follows:

Combination with a DDR agent eg, ATR inhibitor

Combination with an immuno-oncology agent eg, PD-L1 inhibitor

Combination with a cytotoxic agent eg, paclitaxel

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
Combination with radiotherapy/radiation therapy 
The maximum number of modules in this protocol will be eight, inclusive of the Core Module. 
The modular protocol structure is shown in Figure 5.
Figure 5
Modular protocol structure
AE=adverse event; PK=pharmacokinetic; PLD=pegylated liposomal doxorubicin.
4.1.2
Core module study design: AZD7648 monotherapy
This part of the study is dose escalation (Part A) of AZD7648 monotherapy, administered 
orally, in approximately 46 evaluable patients with advanced solid tumours. Further details of 
the study design for Combination Module 1 can be found in Section 12. 
The starting dose of AZD7648 is mg 
.  A single dose of AZD7648 will be administered 
during 
.  From Cycle 1, Day 1, the initial 
schedule will be AZD7648 dosed on a continuous basis in a 
.  There will be no 
interval between cycles.  Using an accelerated titration design (see Table 4), dose escalation 
may occur with single patient cohorts up to and including 
mg 
  From 
mg 
 
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onwards, a minimum of 3 patients will be enrolled into each dose cohort.  Dose escalation will 
stop at the maximum tolerated dose (MTD), maximum feasible dose (MFD), or the RP2D.  
Dose escalations with single patient cohorts may proceed up to and including 
mg 
 
following SRC recommendation (informed by real-time PK analysis) and provided no 
CTCAE Grade ≥2 drug-related toxicity is observed.  If either of these conditions is not met, 
the cohort will be expanded to recruit a minimum of 3 patients (maximum of 6 patients) in all 
subsequent cohorts.  At this point, the decision to dose escalate AZD7648 will follow the 
principles of the Bayesian adaptive design, using all of the available data and considering the 
PK from a minimum of 2 out of the 3 patients enrolled into each dose cohort (data from all 
evaluable patients will be used to make the dose escalation decision).  The DLT period is from 
the first dose until the end of Cycle 1 (inclusive of any non-dosing days).  This DLT 
assessment period was selected as the major potential toxicities would be anticipated to 
present within this duration.  Doses and/or schedules of AZD7648 will be defined by the SRC 
by taking the Bayesian adaptive design and PK into consideration.
Part A cohorts may be expanded at doses at or above the monotherapy Minimum Biologically 
Active Dose (MBAD) in parallel to continuing the dose escalation cohorts provided the dose 
has already been declared as tolerated.  Further recruitment to such an expansion cohort will 
stop if the dose in that cohort is subsequently evaluated to be non-tolerated.  The optional 
expansion cohort(s) are described in Section 6.1.2.1. 
Escalation will stop at the MTD, MFD, or the RP2D. 
To account for the dose range between starting dose and target dose level, intra-patient dose 
escalation is permitted as part of the monotherapy dose escalation to maximise patient benefit 
and minimise exposure to non-efficacious doses.  However, the following criteria must be 
fulfilled before a patient is permitted to proceed with an intra-patient dose escalation:

The planned next higher dose must be declared tolerated by the SRC (based on 
assessment of 2 to 6 evaluable patients).

Agreement by the SRC that the patient is permitted to have an intra-patient dose 
escalation.

Intra-patient dose escalation occurs on Day 1 following a scheduled scan assessment.
Whilst a patient is being considered for an intra-patient dose escalation, they should continue 
treatment at their allocated dose level.  In the event of an intra-patient dose escalation, such 
patients will not be evaluable for DLT at the escalated dose.
No Part B expansion is planned in the Core Module but there are optional expansion options 
as described in Section 6.1.2.1.
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4.1.3
Regulatory amendment for additional modules
To support amendment of the protocol for additional combination modules, AstraZeneca will 
provide a summary of all non-clinical and clinical data to support the proposed new 
combination and dosing schedule, this will include updating the following:

Study objectives

Background information providing rationale for the proposed patient population(s) and 
the proposed treatment plan(s)

Specific study eligibility criteria

A detailed description of the proposed study treatment plans

A revised schedule of patient assessments

A summary of safety data from the completed or ongoing cohort(s)/modules(s) and the 
proposed toxicity management plans for the proposed new combination

A description of any dose modifications and the data (clinical safety information, clinical 
PK data, and non-clinical data) that support the safety of the proposed dose modifications 
for the combination regimen in question

A clearly stated justification for the proposed sample size based on the objectives for that 
specific cohort/module; and

A detailed description of the method and performance characteristics of any test that will 
be used to identify the patient population to be enrolled in the cohort/module, if the 
population will be selected based on a diagnostic assay.
4.1.3.1
Europe and Rest of World
AstraZeneca will provide a substantial amendment for review and approval.
4.1.3.2
United States of America
AstraZeneca will provide an amendment to the Food and Drug Administration (FDA) 30 days 
in advance of planned enrolment in the cohort for any future combination.  AstraZeneca will 
begin enrolment of patients into that cohort in the United States (US) no sooner than 30 days 
from the date of submission and institutional review board (IRB) approval.
4.1.4
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis 
The guidance given below supersedes instructions provided elsewhere in this Clinical Study 
Protocol (CSP) and should be implemented only during cases of civil crisis, natural disaster, 
or public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study patients become infected with severe 
acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection) 
which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the patient’s ability to conduct the study. 

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To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis (eg, coronavirus disease 2019 [COVID-19]), changes may be implemented to ensure the 
safety of study patients, maintain compliance with Good Clinical Practice (GCP), and 
minimise risks to study integrity. 
The investigator or designee should contact the study Sponsor to discuss whether the 
mitigation plans below should be implemented.  
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

Obtaining consent (reconsent) for the mitigation procedures (note, in the case of verbal
consent (reconsent), the Informed Consent Form (ICF) should be signed at the patient’s
next contact with the study site.

Rescreening: Additional rescreening for screen failure due to study disruption and to 
confirm eligibility to participate in the clinical study can be performed in previously 
screened patients. The investigator should confirm this with the designated study 
physician. 

Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor.

Telemedicine visit: Remote contact with the patient using telecommunications technology 
including phone calls, virtual or video visits, and mobile health devices. 

All necessary supplies and instructions for administration and documentation of study 
treatment administration will be provided if site is able to complete all safety assessments 
as per CSP.
Any deviations to the protocol necessary to safeguard patient safety or data validity as a result 
of COVID-19 related disruption will be recorded and any permanent changes requiring an 
amendment to the protocol will be communicated to Regulatory Authorities and IRBs / 
independent ethics committees (IEC) in line with relevant local guidance and procedures (see
Appendix A 1).
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix J.
4.2
Scientific rationale for study design
The 
l.  In cancer 
cells,
 
n.  Such instability results in 
 
 
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AZD7648 is a novel potent and highly selective oral inhibitor of DNA-PK.  
 
 
  
 
 
This FTIH study with AZD7648 will be conducted within the context of a modular protocol to 
evaluate the safety, tolerability, PK and anti-tumour activity of AZD7648 at increasing doses 
as a monotherapy (Core Module) and in combination with PLD (Combination Module 1), in 
patients with advanced malignancies.  Whilst AZD7648 monotherapy may offer some clinical 
benefit to patients, preclinical evidence suggests that the greatest potential for benefit is likely 
to be achieved in combinations.  Therefore, rather than completing an AZD7648 monotherapy 
escalation to RP2D before initiating combination dosing, the combination dosing phase of the 
study with PLD will commence as soon as sufficient safety and PK data have been obtained 
from the monotherapy escalation.  
Key aspects of the study, such as the starting dose of AZD7648 in the Core Module, and the 
dose escalation, stopping criteria and cohort size of all study modules, are based upon 
accepted methodology for Phase I oncology studies.  Furthermore, blood samples will be 
collected to enable characterisation of AZD7648 PK and, if appropriate, investigation of 
additional metabolites to enable AstraZeneca to fulfil regulatory requirements related to the 
testing of the safety of AZD7648 and its metabolites.
As part of the clinical drug development programme for AZD7648, AstraZeneca will 
 
  There are many potential benefits of this exploratory 
research, including: 
 
 
  Ultimately, this research will provide the information and 
understanding required to deliver safe and effective new medicines to patients.
4.3
Justification for dose
A dose of  mg/day is proposed as the starting dose in this FTIH Phase 1 study in patients 
with advanced cancer, including patients with solid tumours.  This is based on international 
guidance for starting dose selection for agents in cancer patients (International Conference on 
Harmonisation [ICH] S9) which recommends that the starting dose should be set at a dose of 
1/10 of the Severely Toxic Dose in 10% of the animals (STD 10) in rodent toxicity studies.  If 
the non-rodent is considered the most appropriate species then 1/6th of the Highest 
Non-Severely Toxic Dose (HNSTD) observed in non-rodent studies is viewed as an 
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appropriate starting dose.  For AZD7648, the non-rodent was considered to be the most 
sensitive species.
A rat STD 10 was not identified in the 1-month toxicology study.  The highest dose tested 
(
mg/kg/day administered as 
mg/kg 
 was tolerated in all animals and is 
considered to be the MTD as higher doses administered in the dose range finding study 
(
mg/kg/day administered as 
mg/kg 
 led to body weight loss and clinical signs 
which were considered too severe for this dose to be suitable for longer term administration.  
At 
mg/kg (
mg/m2), body weight loss and decreased food intake was observed over 
the first few days of dose administration in both sexes.  However, by days 4 to 5, animals 
started to gain weight and food consumption increased.  Histopathological findings were 
restricted to decreased cellularity in lymphoid tissue, effects on the male reproductive tract 
and thyroid hypertrophy in females only.  Full recovery from the histopathological changes
was observed after 28 days off dose.
However, 1/10th of the MTD in rats gives a dog-equivalent dose of 
mg/kg/day and a 
dose of mg/kg/day was not tolerated in one male dog.  The animal was removed from the 
study on Day 11 due to marked body weight loss together with decreased or absence of food 
intake and adverse clinical signs, including liquid faeces with red traces, decreased activity 
and vomiting.  Histopathological examination showed mucosal degeneration, neutrophilic 
inflammation, ulceration, and haemorrhage in the gastrointestinal (GI) system and decreased 
cellularity in lymphoid tissue. 
The human equivalent dose derived from 1/6th of the dog HNSTD (  mg/kg/day) was 
calculated to be 
mg/kg, which equates to 
mg for a 
kg human.  In an in vitro GI 
organoid model, human and dog results were similar.  Therefore, the dog is considered an 
appropriate species and a starting dose of  mg/day is proposed for this study.
4.3.1
Justification for the dose escalation doses
The selection of the starting dose is based upon international guidance for an ICH S9 patient 
population, and is based on the HNSTD dose level.  However, when considering proposed 
human starting dose margins to measured exposure in the dog study, there is a 23-fold margin 
to AUC and a 16-fold margin to Cmax values recorded at the NOAEL of mg/kg/day in the 
dog.  At this dose level there were no significant toxicological findings.  Therefore, assuming 
human PK values are as predicted from real-time PK analysis, and that there are no 
drug-related Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 events, a 
maximum of dose doubling is proposed.
4.4
End of study definition
The end of study is defined as the last visit of the last patient undergoing the protocol-defined 
assessments. 
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The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or recruitment is low.  AstraZeneca may also terminate the 
entire study of individual cohorts prematurely if concerns for safety arise within this study or 
in any other study with any agent used in any of the study modules.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit or contact.
For each module or study part, there will be a data cut-off (DCO) defined as the earlier of 
6 months after the last patient recruited starts study treatment (in module/study part) or after 
the final patient discontinues study treatment (in module/study part).  Patients who are
receiving treatment following the data cut-off (DCO) for the final analysis can either choose 
to discontinue from the study or, where the Investigator believes the patients are gaining 
clinical benefit, patients may continue to receive study treatment.  All patients will receive 
follow-up care in accordance with standard local clinical practice.  For patients who do 
continue treatment beyond the time of the final DCO, Investigators will continue to report all 
SAEs until 90 days after the last dose of study treatment.  Additionally, any SAE or AE that is 
ongoing at the time of this DCO must be followed up to resolution unless the event is 
considered by the Investigator to be unlikely to resolve, or the patient is lost to follow-up.
Data analysis will be performed separately for each module or study part and a CSR will be 
written.  Informal data cuts may be performed at regular intervals across all modules/parts to 
inform internal decision making.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, are not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for the 
core and Combination Module 1 (if applicable).  Under no circumstances can there be 
exceptions to this rule.  If there are differences in cut-off values, the specific module takes 
precedence.  For example, if the haematological parameters are stricter in the combination 
module rather than the Core Module, the Investigator should adhere to the combination 
module criteria.  Patients who do not meet the entry requirements are screen failures, refer to 
Section 5.4.
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5.1
Inclusion criteria
The inclusion criteria that are applicable to all parts/cohorts of the study are described in this 
section.  Please refer to Section 13.1 for additional specific criteria applicable to Combination 
Module 1.
Informed Consent
1
Capable and willing to give signed informed consent which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol.
2
Provision of signed and dated written genetic informed consent prior to collection of 
sample for exploratory genetic analysis (optional).
The ICF process is described in Appendix A 3.
Age
3
Patient must be at least 18 years of age, at the time of signing the ICF.
Type of Patient and Disease Characteristics
4
Patients must have histological or cytological confirmation of advanced malignancy 
considered to be suitable for study treatment.
5
ECOG PS of 0 to 1.
6
Life expectancy greater than 12 weeks.
7
Progressive cancer at the time of study entry.
8
PD expansion cohorts (or PD expansion subgroup): Patients must have at least one
tumour suitable for biopsy and consent to having biopsies collected.
Reproduction
9
Negative pregnancy test (urine or serum) prior to start of dosing for women of 
child-bearing potential (WOCBP).  Women of child-bearing potential are defined as 
women between menarche and menopause who have not been permanently or surgically 
sterilised and are capable of procreation.
10 Female patients must be post-menopausal, surgically sterile, or using an acceptable 
method of contraception (acceptable methods of contraception are defined in 
Section 5.3.3) for the duration of the study (from the time they sign consent) and for 
12 weeks after the last dose of study treatment to prevent pregnancy.
11 For the duration of the study (from the time they sign consent) and for 12 weeks after the 
last dose of study treatment, sexually active male patients must be willing to use 
contraception as is defined in Section 5.3.3.
Post-menopausal is defined as:

No menses for 12 months without an alternative medical cause. A high follicle 
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post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.

Radiation-induced oophorectomy with last menses greater than 12 months ago.

Chemotherapy-induced menopause with greater than 12 month interval since last menses.

Surgical sterilisation (bilateral oophorectomy or hysterectomy).
5.2
Exclusion criteria
The exclusion criteria that are applicable to all parts/cohorts of the study are described in this 
section.  Please also refer to Section 13.2 for additional specific criteria applicable to 
Combination Module 1.
Medical Conditions
1
Any unresolved toxicities from prior therapy CTCAE Grade ≥2 (with the exception of 
alopecia).
2
Spinal cord compression or brain metastases unless definitively treated (minimum of 
3 weeks between completion of radiotherapy and first dose of study treatment and 
recovery from acute toxicity Grade ≥2), asymptomatic, stable (no clinical evidence of 
progression since completion of central nervous system-directed therapy) and not 
requiring steroids for at least 4 weeks.  Disease outside the central nervous system must 
be present.
3
As judged by the Investigator, any evidence of severe or uncontrolled medical conditions 
including but not limited to:

Uncontrolled diabetes mellitus, uncontrolled seizures, active infection requiring 
systemic antibiotics, antifungal or antiviral drugs, severe chronic obstructive 
pulmonary disease, severe Parkinson’s disease, active inflammatory bowel disease, 
psychiatric condition, active bleeding diatheses, renal transplant, or active infection 
including any patient with active hepatitis B, hepatitis C or human immunodeficiency 
virus.
4
Any other malignancy which has been active or treated within the past 3 years, with the 
exception of in situ cancer of the cervix, non-melanoma skin cancer, ductal carcinoma in 
situ, Stage 1 Grade 1 endometrial carcinoma, or other solid tumours including lymphomas 
(without bone marrow involvement) curatively treated with no evidence of disease for 
≥5 years.
5
Refractory nausea and vomiting or unable to swallow and retain oral medication, chronic 
GI diseases or previous bowel resection with clinically significant sequelae that would 
preclude adequate absorption of AZD7648, GI symptoms CTCAE Grade > 1, history of 

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GI ulceration and gastrointestinal haemorrhage within 6 months of first study drug 
administration. 
Prior/Concomitant Therapy
6
Receiving or having received anti-cancer treatment within the following periods prior to 
the first dose of investigational product:
(a) Cytotoxic treatment: 3 weeks
(b) Non-cytotoxic drugs, including small molecule investigational products: 3 weeks or 
5 half-lives (whichever is longest)
(c) Biological products including investigational immuno-oncology agents: 4 weeks
(d) Radiation with a limited field for palliation: 1 week (3 months for radiation to the 
abdomen or pelvis)
(e) Radiation to > 30% of the bone marrow or with a wide field: 4 weeks
(f) Lung radiation: 60 days
(g) Major surgery: 4 weeks; minor surgery or biopsy: 1 week
7
During the 4 weeks prior to the first dose, receiving corticosteroids at a dose of ≥10 mg 
prednisone/day or equivalent for any reason.  Ongoing low dose steroids for longer than 
3 months (excluding inhalational, nasal, creams, lotions, and gels) are not allowed.
8
Receiving or having received concomitant medications, herbal supplements and/or foods 
known to significantly modulate CYP3A4 activity (potent/strong inhibitors or inducers of 
CYP3A4).  The required washout period prior to starting study treatment is 3 weeks 
(5 weeks for enzalutamide or phenobarbital) until 28 days after the last dose of study 
treatment.  Patients can receive a stable dose of bisphosphonates or denosumab for bone 
metastases, before and during the study if these were started at least 2 weeks prior to 
study treatment.
Prior/Concurrent Clinical Study Experience
9
Prior exposure to a DNA-PK inhibitor or hypersensitivity to any excipient of the product.
Diagnostic Assessments
10 Cardiac dysfunction as defined by any of the following within 6 months of study entry:
(a) Acute myocardial infarction
(b) New York Heart Association Class II/III/IV heart failure
(c) Unstable angina
(d) Unstable cardiac arrhythmias eg, clinically important abnormalities in conduction or 
morphology of resting ECG such as complete left bundle branch block or 
third-degree- heart block
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(a) Known reduced left ventricular ejection fraction below the institutional lower limit of 
normal (LLN)
(b) Mean resting corrected QT interval (QTc) > 470 milliseconds obtained from 3 ECGs 
in 24 hours using the Fridericia formula
(c) Any factors that increase the risk of QTc prolongation or arrhythmic events such as 
hypokalaemia, congenital long QT syndrome, immediate family history of long QT 
syndrome or unexplained sudden death under 40 years of age
12 Inadequate haematological or organ function as defined by:
(a) Haemoglobin < 90 g/L with no blood transfusions or erythropoietin within 14 days of 
obtaining these values or before starting treatment
(b) Absolute neutrophil count (ANC) < 1500 cells/mm3 (< 1.5 x 109/L) with no 
haematopoietic growth factors within 14 days of obtaining these values or before 
starting treatment
(c) Platelet count <100,000/mm3 (< 100 x 109/L) with no platelet transfusions within 
14 days of obtaining these values or before starting treatment
(d) International normalised ratio (INR) ≥1.5 or other evidence of impaired hepatic 
synthesis function
(e) Bilirubin ≥1.5 x upper limit normal (ULN) or ≥2 x ULN for patients with 
documented/suspected Gilbert’s disease (or likely to be in 3 weeks)
(f) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN if 
no demonstrable liver metastases or ≥5 x ULN in the presence of liver metastases (or 
likely to be in 3 weeks)
(g) Creatinine clearance (CrCl) < 50 mL/minute, as assessed using Cockcroft-Gault, 
ethylenediaminetetraacetic acid (EDTA) clearance or 24 hours urine collection
Other Exclusions
13 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
14 Judgement by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements.
15 Previous enrolment in the present study.
16 For female patients only: currently pregnant (confirmed with positive pregnancy test) or 
breast-feeding.
17 For host genetics research study (optional):
(a) Previous allogenic bone marrow transplant
(b) Non-leukocyte depleted whole blood transfusion within 120 days for the date of the 
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18 For food effect cohort only: insulin-dependent diabetes. 
19 History and/or presence of COVID-19:
(a) Previous severe course of COVID-19 (ie, hospitalisation, extracorporeal membrane 
oxygenation, mechanically ventilated)
(b) Clinical signs and symptoms consistent with COVID-19, eg, fever, dry cough, 
dyspnoea, sore throat, fatigue or confirmed current infection by appropriate 
laboratory test within the last 4 weeks prior to screening 
5.3
Lifestyle restrictions
5.3.1
Fasting restrictions
AZD7648 tablets should be swallowed whole with water on an empty stomach (no food or 
drink other than water for 2 hours prior to dosing and 1 hour after dosing).
5.3.2
Dietary restrictions
During the studies, patients should avoid consuming grapefruits, Seville oranges, or other 
products that may contain these fruits as these may affect AZD7648 metabolism.
5.3.3
Contraception
Male patients

Should use barrier contraceptives (ie, by use of condoms) during sex with all partners 
from the time they sign consent and for 12 weeks after the last dose of study treatment.  If 
male patients wish to father children, they should be advised to arrange for freezing of 
sperm samples prior to the start of study treatment. 

A sexual partner of a male participant who is a WOCBP should also use a highly effective 
form of contraception.

Men should not donate sperm for 12 weeks after the last dose of study drug. 
Female patients

Women with evidence of non-child-bearing potential at screening have no restrictions 
around contraception.

From the time of signing consent, and for 12 weeks after the last dose of study treatment; 
WOCBP and their partners (who are sexually active) should agree to use 2 reliable 
methods of contraception in combination, or they must totally/truly abstain from any form 
of sexual intercourse.  All hormonal methods of contraception should be used in 
combination with the use of a condom by their male sexual partner for intercourse.  
Total/true abstinence is when a patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total 
duration of the trial until at least 1 month after the last dose of study drug.  Periodic 
abstinence (eg, calendar ovulation, symptothermal, post-ovulation methods, or declaration 

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of abstinence solely for the duration of the trial) and withdrawal are not acceptable 
methods of contraception.

Contraceptives that are prone to drug-drug interactions may not be effective due to a 
potential CYP3A4 interaction with AZD7648.  Contraception used must therefore include 
a condom and one of:

Medroxyprogesterone injections (eg, Depo-provera)

Intrauterine Device (IUD)

Levonorgestrol Intrauterine System (eg, Mirena)

Tubal occlusion

Vasectomised partner that is the sole sexual partner of the WOCBP trial participant 
provided the vasectomised partner has received medical assessment of the surgical 
success.
5.3.4
Concomitant medication
See Section 6.5, for details in restricted or prohibited medications.
5.3.5
Blood donation
Patients should not donate blood whilst participating in studies of AZD7648 and for at least 
12 weeks after receiving the last dose of study treatment.
5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently dosed with study treatment.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure patients to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from Regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.  Rescreened patients should be assigned the same patient number as for the initial 
screening.  However, rescreening should be documented so that its effect on study results, if 
any, can be assessed.
These patients should have the reason for screen failure recorded in the case report form 
(CRF).
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
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participant according to the study protocol.  Study treatment in the Core Module refers to 
AZD7648 (Table 3).
Further details on the combination treatment administered in Combination Module 1 can be 
found in Section 14.1.
6.1
Treatments administered
6.1.1
Investigational products
Table 3
Study treatments
Study treatment name:
AZD7648
Dosage formulation:
Provided as mg, 
mg, 
mg, and 
mg white film-coated oral tablets. 
The mg and
mg tablets are round. The 
mg and 
mg tablets are 
caplet shaped.
Note: In accordance with Quality IMPD, other intermediate strengths may be 
added at a later date.
Route of administration: 
Oral tablets
Starting dose instructions:
During Part A (dose escalation), a single dose of AZD7648 will be 
administered in the clinic (
) to enable collection of blood 
samples for PK analyses.  This is followed by a 
 
In cohort 1, at 
 the starting dose and schedule of AZD7648 is 
mg 
 on a 
.  AZD7648 will be 
administered orally on an empty stomach.
On clinic days, patients should not take the study treatment until instructed to 
do so by clinic staff.
Details of dose escalation and cohorts can be found in Section 6.1.2.
Packaging and labelling:
Study treatment will be provided in high-density polyethylene bottles.  The 
bottles are induction sealed and closed with child-resistant polypropylene 
screw caps.  Study treatment should be kept in a secure place under 
appropriate storage conditions.  The investigational product label on the bottle 
specifies the appropriate storage.
Each bottle will be labelled in accordance with Good Manufacturing Practice 
Annex 13 and per country regulatory requirement.  Label text will be 
translated into local language.
The site must complete the Patient Diary with the details of the dosing 
instructions at the time of dispensing.
Provider:
AstraZeneca 
6.1.2
Dose escalation scheme – Core Module
The dose escalation study flow chart for the Core Module is presented in Figure 6; further 
details on the dose escalation for Combination Module 1 can be found in Section 14.1.2
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AZD7648 will be administered as an oral dose, initially 
 (refer to Figure 7).  The 
individual patient observation period will be for the duration of the sampling as detailed in the 
SoA (Table 1).  When there is more than one patient enrolled to a dose cohort, sentinel dosing 
will be applied with a single patient exposed for a minimum of 48 hours after Cycle 1, Day 1
before further patients are enrolled at that dose level.  In the absence of any significant 
toxicities in the first patient, the patients for the remainder of the cohort may be enrolled, 
concurrently or sequentially, based upon the decision of the SRC. 
If significant toxicities are observed during the first 48 hours of observation in the first patient 
of the cohort, further enrolment into the cohort will be halted until the SRC has reviewed all 
the safety data (and the PK data for Cohorts 1 to 4) for that patient and cumulative data from
all trial patients to determine the appropriate action.
Figure 6
AZD7648 monotherapy study flow chart
RP2D=recommended Phase II dose.
Where dosing is 
 the tablets should be taken approximately 12 hours apart.  If a dose is 
missed, it is acceptable to take the scheduled dose up to 2 hours after the scheduled dose time.  
If greater than 2 hours, the missed dose should not be taken, and the patient should continue 
with the next dose at the allotted time.  If vomiting occurs shortly after AZD7648 is 
swallowed, the dose should not be replaced.  Resume dosing at the following scheduled dose.
Table 4 is an example dose escalation scheme.  However, all potential dose escalation levels 
after the starting dose may be adjusted in light of emerging safety, tolerability, and/or PK data 
(see Section 4.3.1).  Intermittent schedules may also be explored in the Core Module from 
Cohort 2 onwards.
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Table 4
Example of AZD7648 monotherapy dose escalation scheme
Cohort
AZD7648 dose (mg), 
 unless otherwise stated
1
 
2
 
3
4
5
6
7
8
Cohort n (escalate to MTD or MFD)
No more than 50% increment
Maximum dose level
 
=
; MFD=maximum feasible dose; MTD=maximum tolerated dose;
.
Actual doses and schedules may vary using Bayesian adaptive design modelling based on emerging safety and 
tolerability data, and/or pharmacokinetic (PK) data, and subject to Safety Review Committee (SRC)
agreement.  A maximum of dose doubling using single patient cohorts may be permitted up to and including 
the 
mg 
 cohort, if the following conditions are met:
No common terminology criteria for adverse event (CTCAE) Grade ≥2 drug related toxicity.
SRC provides the recommendation following the review of all available data (and informed by real-time PK 
analysis for Cohorts 1 to 4).
Figure 7
Starting dose and schedule for AZD7648 monotherapy
Using an accelerated titration design, single patient cohorts may be enrolled up to and 
including 
mg 
 provided that there is no CTCAE Grade ≥2 drug-related toxicity and 
with agreement by the SRC (informed by real-time PK analysis for Cohorts 1 to 4).  From 
mg 
 a minimum of 3 patients (and maximum of 6 patients) will be enrolled in each 
subsequent cohort.  At the RP2D up to 12 patients may be treated to explore chronic toxicity.
For SRC meetings prior to dose escalation where 3 patients have been enrolled, at least 
2 patients will need to be evaluable for DLT. However, if patients are receiving treatment 
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within the DLT assessment period, the dose escalation review meeting should be deferred so 
that the SRC accounts for all patient data.
Dose escalation and de-escalation will follow the Bayesian adaptive design below.

If no DLT at any dose has been observed, then dose escalation may occur without 
modelling.  Dose doubling may be permitted in single patient cohorts up to and including 
mg 
 if recommended by the SRC (informed by ‘real-time’ analysis of PK samples
for Cohorts 1 to 4).  However, if CTCAE Grade ≥2 drug-related toxicity is observed or at
the recommendation of the SRC, cohorts may be expanded to recruit a minimum of 3 
(and maximum of 6) patients in all subsequent cohorts. 
From 
mg 
 (or once cohorts are recruiting a minimum of 3 patients), after the first 
DLT has been observed (at any dose), a Bayesian logistic regression model will be used 
to inform subsequent dose selections.  After each cohort, cumulative data on the evaluable 
patients will be used to estimate the predicted probability of a DLT at each potential next 
dose.

The recommendation for the next dose will be based on the following principles:

The recommendation for the next dose will be chosen to target a DLT of 25% for 
monotherapy and 30% for combination but ignoring any dose for which the model 
suggests the probability of a DLT exceeds 35%.  This will allow efficient 
identification of the MTD whilst restricting the risk of overdosing.

Dose escalation and de-escalation will be completed when any of the following occur:

The target toxicity of 25% (for monotherapy) and 30% (for combination) is reached 
and the required precision of the estimated MTD is achieved (ie, the ratio of the 
upper/lower 95% credible interval limits for the estimated MTD < 5.0).

The maximum number of evaluable patients for the dose escalation cohort has been 
reached.

There is no anticipated improvement in efficacy with increasing dose.

The MFD is achieved.

Decision made by the SRC to stop dose escalation.

Prior established dose toxicity relationship at doses at which 10% and 50% (or similar) of 
patients experience DLTs will be used to inform the Bayesian model.

Emerging data from the Core Module or any combination module of this study may also 
be used to inform the Bayesian model in another module of this study or other clinical 
studies.

Dose increases will be permitted after review of data from a minimum of 2 out of the 
3 patients enrolled into each dose cohort (data from all evaluable patients will be used to 
make the dose escalation decision).
There is no minimum time period required between completion of dosing in the last evaluable 
patient from one cohort and the start of dosing in the subsequent cohort.
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To account for the dose range between the starting dose and target dose level, intra-patient 
dose escalations is permitted as part of the monotherapy dose escalation to maximise patient 
benefit and minimise exposure to non-efficacious doses.  However, the following criteria must 
be fulfilled before a patient is permitted to proceed with an intra-patient dose escalation:

The planned next higher dose must have been declared tolerated by the SRC (based on 
assessment of 2 to 6 evaluable patients).

Agreement by the SRC that the patient is permitted to have an intra-patient dose
escalation.

Intra-patient dose escalation occurs on Day 1 following a scheduled scan assessment.
Whilst a patient is being considered for an intra-patient dose escalation, they should continue 
treatment at their allotted dose level.  In the event of an intra-patient dose escalation, such 
patients will not be evaluable for DLT at the escalated dose.
After each patient has completed the DLT assessment period during the dose escalation phase 
of the study, the SRC will evaluate all available toxicity information (including AEs and 
laboratory abnormalities that are not DLTs), as well as available PK and PD information for 
the first cycle for all evaluable patients (data from Cycle 2 and beyond will also be evaluated 
if available).  Additional CRF data may be included in the SRC review including vital signs, 
clinical chemistry/haematology, ECG results, PK and PD data, ad hoc safety reports, AEs 
from previous cohorts and optional expansions and any other emerging data.  If appropriate, 
quantitative dose/exposure-response models will be used to describe the relationship for such 
data of interest to decide the next dose and/or schedule.
There is no limit to the number of intra-patient dose escalations that a patient can undergo. 
Intermediate dose levels, dosing intervals and/or frequency, and/or schedules may be 
evaluated prior to declaring the RP2D, which will be guided by the evolving safety, 
preliminary efficacy, PK and PD data.
For decisions on dose escalation (Part A), an evaluable patient is defined as a patient that has 
received AZD7648 and either:

Has completed minimum safety evaluation requirements and has received at least 75% of 
the total amount of planned dose of AZD7648 (and PLD for Combination Module 1) 
during Cycle 1 
or

Has experienced a DLT during Cycle 0 or Cycle 1.

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Triggers for Additional Modules
Combination modules, eg, Combination Module 1 (combination of AZD7648 + PLD) will 
start after PK data from monotherapy dose escalation has confirmed an understanding of the 
metabolic profile of AZD7648 and the dose selected as the starting dose for the combinations 
is safe and tolerated.  Triggers that will initiate the start of additional combination modules 
may include (but are not limited to):

PK dose proportional.  PK exposure vs. dose is well understood. 

Total drug exposure levels ≥50% of that predicted to be required for biological activity 
for a period defined for the specific combination.  It is anticipated that the combination 
modules will be triggered once exposure (based on clinical PK exposure and emerging 
safety and tolerability data) is determined to be in a suitable therapeutic range.

No toxicity red flags eg, DLT rate greater than that anticipated for a tolerated cohort.
Multiple combination modules may be triggered simultaneously.  
6.1.2.1
Optional Expansion Cohorts
In all modules of the study, Part A cohorts may be expanded at doses at or above the MBAD 
in parallel to continuing the dose escalation cohorts provided that the dose has been declared 
as tolerated.  Using this design, tolerability and PK will be characterised in the Part A 
population whilst providing evidence of PD and clinical activity in the populations most likely 
to benefit from drug and potentially across several doses.
The optional Part A expansion cohorts may be initiated for 3 reasons:

PD expansion cohort of up to 12 additional patients to obtain mandatory serial biopsies 
for signal searching of biological PD activity.

Efficacy expansion cohorts of up to 25 additional patients (of which a subset of up to 12 
in each cohort may have mandatory biopsies if PD data is also required) to explore 
clinical benefit.

Food effect expansion cohorts of up to 12 patients at doses between the MBAD and 
RP2D.
The expansion cohorts will also explore further the tolerability, safety and PK activity at these 
doses.
Food Effect 
At least one cohort may investigate the effect of food on AZD7648 PK.  If a food effect cohort 
is included in the monotherapy expansion cohort, then up to 12 evaluable patients may be 

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included in the food effect cohort if the dose and schedule has already been declared tolerated 
by the SRC.
If the dose and schedule has not yet been declared tolerated, then initially up to 6 evaluable 
patients will be enrolled to the food effect cohort, and an additional 6 evaluable patients may 
be added once the dose and schedule has been declared tolerated by the SRC. A cross over 
design will be used for the food effect cohort.  Each patient will be allocated to receive a 
single oral dose of AZD7648 on Cycle 0, Day 1 in either the fasted or fed state, followed by a 
single oral dose of AZD7648 in the other state for Cycle 1, Day 1 at least 72 hours later.  
Other criteria may be used for decision-making based on emerging AZD7648 PK data.  After 
Cycle 1, Day 1 patients may continue to receive AZD7648 monotherapy (at or below the 
RP2D and schedule), and all dosing from that point onwards must be administered in the 
fasted state.  For the fed dosing day, patients should ideally start the recommended meal 
30 minutes prior to the planned administration of the study drug.  The study drug should be 
administered 30 minutes after the start of the meal (or up to 45 minutes after the start of their 
meal if the patients couldn’t complete at least 75% of their meal within 30 minutes). Patients 
will be considered evaluable if they completed at least 75% of their meal before the 
administration of the study drug and the study drug is administered between 30 to 45 minutes
after the start of the meal. For the fasted state, patients must fast (water only) for ≥10 hours 
prior to taking a dose to ≥2 hour post-dose.  For the fed state patients must fast overnight 
(minimum of 8 hours) prior to consuming a standardised meal in the clinic.  The meal should 
consist of about 800 to 1000 total calories with around 54% of the calorific content made up 
from fat.  The dose should be administered with 240 mL of water.  Refer to Appendix I for 
full details.
6.1.3
Definition of dose-limiting toxicity
DLTs will be evaluated during Cycle 0 and Cycle 1 of treatment.  Toxicity will be graded 
according to the National Cancer Institute CTCAE v5.0.
A DLT is defined as an AE that occurs from the first dose of study treatment up to and 
including Cycle 1, Day 28 (the DLT assessment period) that is assessed as unrelated to the 
disease, intercurrent illness, or concomitant medications and that, despite optimal therapeutic 
interventions, meets any of the following criteria:
Haematological Toxicities:

Grade 4 neutropenia lasting > 4 days.

Grade 4 thrombocytopenia. 

Grade ≥3 neutropenia (ANC < 1000 cells/mm3 [< 1 x 109/L]) of any duration 
accompanied by fever ≥38.5ºC and/or systemic infection.

Grade ≥3 thrombocytopenia (< 50,000/mm3 [< 50 x 109/L]) with bleeding.

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Non-haematological Toxicity CTCAE Grade ≥3 Including:

Confirmed laboratory abnormalities greater than 72 hours of duration.

Nausea or vomiting for more than 3 consecutive days despite administration of maximal 
anti-emetic therapy.

Diarrhoea for more than 3 consecutive days despite administration of maximal 
anti-diarrhoeal therapy.

QTc prolongation > 500 milliseconds or QTcF prolongation from baseline by 
60 milliseconds confirmed on at least 2 separate ECGs.

Any other toxicity that is greater than that at baseline AND is clinically significant and/or 
unacceptable, and does not respond to optimal therapeutic intervention within 72 hours 
AND is judged to be a DLT by the SRC.

Any treatment-related event, including significant dose reductions, omissions or delays, 
judged to be a DLT by the SRC.  Examples may include CTCAE Grade 2 toxicities that 
are clinically significant and/or unacceptable according to the Investigator, toxicities that 
result in an inability to administer at least 75% of study treatment during Cycle 1 or delay 
the administration of study treatment in the subsequent cycle by ≥7 consecutive days.
DLT Will not Include the Following:

Transient isolated laboratory abnormalities which are not considered clinically significant 
and resolve to baseline within 72 hours without any intervention.

Alopecia.

Toxicity unrelated to treatment eg, related to the underlying disease or disease-related 
process under investigation.

Grade 4 vomiting and diarrhoea lasting < 72 hours in the absence of maximal medical 
therapy.

Grade 3 nausea, vomiting or diarrhoea that lasts < 48 hours and resolves to Grade ≤1 
either spontaneously or with maximal medical therapy.

Grade 3 fatigue < 5 days.

Grade 3 hypertension in the absence of maximal medical therapy.

Grade 3 electrolyte abnormalities that resolve to Grade ≤1 within 48 hours spontaneously 
or with conventional medical intervention and is not clinically complicated.

Grade 3 rash that resolves to Grade ≤1 within 3 weeks.

Grade 3 or Grade 4 elevation in serum amylase and/or lipase that are not associated with 
clinical or radiographic evidence of pancreatitis.
6.1.3.1
Definition of Maximum Tolerated Dose and Recommended Phase II Dose
The MTD is defined as the highest dose at which the predicted probability of a DLT is less 
than 25% (for monotherapy) or 30% (for combinations).  At least 6 evaluable patients are 
required to determine the MTD (refer to Section 6.1.2 for a detailed description of the 
Bayesian adaptive design).

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The RP2D will take into account the MTD (or alternative doses/schedules in the absence of 
MTD), MFD, PK, biological/clinical activity (PD data), as well as data beyond Cycle 1 during 
dose escalations.
6.1.3.2
Definition of Maximum Feasible Dose
A dose and schedule will be considered to be the MFD and dose escalation will stop if:  

There is evidence of saturation of absorption from emerging PK data that limits the 
exposure
and/or

An MFD has been reached, based on a maximum number of tablets per dose or day, or 
the maximum dose permitted based on CMC quality specifications (currently set against a 
maximum dose of 
mg 
 = 
mg/day), whichever is the lower dose. 
6.1.4
Safety review committee
The SRC Remit document for this study will define the exact membership and who will be 
present for decisions to be made. 
The SRC will guide all dose escalation and cohort expansion decisions in this study.  The dose 
or schedule for subsequent cohorts or a decision to stop recruitment will be agreed by the SRC 
after review of the data from each cohort.  When there are other patients that are ongoing at 
the time a review is planned, the SRC should defer their decision until these further patients 
become evaluable.  The data which will be reviewed at a dose decision meeting includes (but 
is not limited to):

All available safety information and laboratory abnormalities (including clinically 
significant AEs and laboratory safety variables).

Data on exposure eg, any dose interruptions or reductions.

All available PK (mandatory Cycle 0 and Cycle 1 PK data in single patient cohorts up to 
and including 
mg 
for Cohorts 1 to 4) and PD data.

The dose recommended from the Bayesian model.
The SRC can decide at each meeting to:

Determine DLTs

Change the schedule of drug administration

Stagger enrolment into a cohort based on toxicity in the sentinel patient

Stop enrolment into a cohort

Recommend a temporary halt on further dosing of patients to allow further evaluation of 
patients

Stop further dosing of all patients in the study
CCI
CCI
CCI
CCI
CCI

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
Escalate the dose

Expand the cohort to a maximum of 6 evaluable patients

De-escalate the dose

Initiate the combination modules of AZD7648

Stop the dose escalation

Adjust the dosing frequency, schedule or sequence of AZD7648, with or without a 
concurrent change in dose

Adjust the dosing frequency, schedule or sequence of the combination agent, with or 
without a concurrent change in dose

Initiate optional expansion cohorts (PD and/or efficacy expansion and/or food effect 
cohorts)

Declare the MTD, MFD, and/or RP2D for the Core Module or combination modules

Initiate Part B cohort expansions

Stop Part B of a study module

Permit a patient to dose escalation (intra-patient dose escalation). 
Investigators will be provided with written confirmation of the next dose level based upon the 
SRC decision.  Regulators/ethics bodies will be formally notified, as required by local 
regulation, of an SRC recommendation to temporarily halt or prematurely stop the study.
6.2
Preparation/handling/storage/accountability
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 authorised 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 
labelled storage conditions with access limited to the Investigator and authorised site staff.
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
Further guidance and information for the final disposition of unused study treatment are 
provided in the Pharmacy Manual.
6.3
Measures to minimise bias: randomisation and blinding
This is an open-label study; no blinding is required.

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In case of parallel recruitment to Part A and Part B (in the combination modules), a suitable 
patient allocation system will be implemented to manage any potential bias.  
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 to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
6.4
Treatment compliance
The first single dose of AZD7648 will be taken whilst the patient is in the clinic (Cycle 0, 
Day 1) and the administration of this dose will be recorded in the appropriate section of the 
CRF.
From Cycle 1 onwards, patients will self-administer AZD7648.  All patients will be required 
to complete a Patient Diary, which must be returned to the clinic for review at each visit.  The 
Patient Diary will contain detailed instructions on how to take the study treatment.  The 
patient should be instructed to record the date and time that all dose(s) of AZD7648 were 
taken in the Patient Diary.  If a dose is missed, the reason must be noted in the Patient Diary.  
The emergency address and telephone number should be written on a Patient Diary and the 
patient will be instructed to keep this in their possession at all times.  A copy of the Patient 
Diary is provided in the study reference materials.
Study site staff will make tablet counts at regular intervals during treatment.  Compliance will 
be assessed by the tablet count and the information will be recorded in the appropriate section 
of the CRF.  After the tablet count has been performed, the remaining tablets will not be 
returned to the patient but will be retained by the investigative site until reconciliation is 
completed by the study monitor.  All patients must return their bottle(s) of AZD7648 at the 
appropriate scheduled visit, when a new bottle will be dispensed.  Patients will be instructed to 
notify study site personnel of missed doses.  Dates of missed or held doses will be recorded by 
the patient on their Patient Diary and by the site staff on the CRF.
Patients must return all containers and any remaining tablets at the end of the study.
Any change from the dosing schedule, does interruptions, dose reductions, dose 
discontinuations should be recorded in the CRF.
The Investigational Product Storage Manager is responsible for managing the study treatment 
from receipt by the study site until the destruction or return of all unused study treatment.  The 
Investigator(s) is responsible for ensuring that the patient has returned all unused study 
treatment.

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6.5
Concomitant therapy
Unless clinically indicated, patients should avoid taking additional non-study medications that 
may interfere with the study treatments.  Any medication or vaccine, including 
over-the-counter or prescription medicines, that the patient is receiving at the time of 
enrolment or receives during the study must be recorded in the CRF along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Details of prohibited medications are detailed in Table 5 and Appendix F includes guidance 
regarding potential interactions with concomitant medications.
Table 5
Prohibited medications
Prohibited medication/class of drug:
Unless stated otherwise, these medications are prohibited from the time that patients enter the main screening 
period until the last dose of study treatment.  The pre-screen may be done whilst on prior therapy
Any investigational anti-cancer therapy other than 
those under investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment 
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, biologic or hormonal therapy, or 
any other novel agent for cancer treatment other 
than those under investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment
Note: concurrent use of hormones for non-cancer-related 
conditions, eg, insulin for diabetes and stable dose of 
hormone replacement therapy and luteinising hormone 
replacement therapy analogues (> 6 months) is 
acceptable.
Palliative radiotherapy may be used for the treatment of 
pain, provided the Investigator does not consider these 
are indicative of clinical progression.  Study treatment 
should be discontinued a minimum of 3 days before a 
patient undergoes palliative radiotherapy, and study 
treatment restarted within 4 weeks (provided any bone 
marrow toxicity has recovered)
Herbal medications and supplements 
Should not be given concomitantly unless agreed by the 
Sponsor.  This is due to their potential to modulate 
CYP3A4 activity (see below and further details in 
Appendix F)

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Table 5
Prohibited medications
Prohibited medication/class of drug:
Concomitant medications known to significantly 
modulate CYP3A4 activity
The principal enzyme for metabolising AZD7648 is 
CYP3A4.  Patients should avoid concomitant 
medications and foods known to significantly modulate 
CYP3A4 activity (potent/strong inhibitors or inducers of 
CYP3A4).  The required washout period prior to starting 
study treatment is 3 weeks (5 weeks for enzalutamide or 
phenobarbital) until 28 days after the last dose of study 
treatment
See also Appendix F
Live virus and bacterial vaccines
Prohibited whilst the patient is receiving study treatment 
and during the 28-day follow-up period
6.5.1
Other concomitant treatment
Other medication other 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 CRF.
If the Investigator, based on his medical judgement, feels that medications described above are 
essential to patient's wellbeing, such products may be administered with caution following 
discussion between the Investigator and the AZ Study Physician.
Patients who are taking warfarin may participate in this study; however, it is recommended 
that INR be monitored carefully at least once per week for the first month, then monthly if the 
INR is stable.  Subcutaneous heparin, low molecular weight heparin, and new oral 
anticoagulants (NOACs) are permitted.  The use of granulocyte-colony stimulating factor 
(G-CSF) is not permitted for primary prophylaxis or secondary prophylaxis during Cycle 0 or 
Cycle 1 (unless deemed by the investigator that this is essential to the patient’s well-being).  If 
required for secondary prophylaxis from Cycle 2 onwards, this should be administered 
following discussion between the Investigator and the AZ Study Physician.
6.5.2
Support medication
There is no antidote medication for AZD7648; restricted medications are described in 
Appendix F.  Rescue medication for PLD in Combination Module 1 will follow the local 
label.
The use of rescue medications is allowable at any time during the study.  The date and time of 
rescue medication administration as well as the name and dosage regimen of the rescue 
medication must be recorded in the CRF.

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Concomitant medications or treatments (eg, paracetamol or diphenhydramine) deemed 
necessary to provide adequate prophylactic or supportive care, except for those medications 
identified as “prohibited,” as described in Table 5), are to be administered as prescribed by the 
Investigator. 
Best supportive care, including antibiotics, nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain management (including palliative radiotherapy) 
should be used for all patients, when necessary. 
Inactivated viruses, such as those in the influenza vaccine are permitted during the study. 
AstraZeneca recommends avoiding administering COVID-19 vaccination for 72 hours prior to 
administration of the first dose of study drug, or during the dose-limiting toxicity period, to 
avoid biases in the interpretation of safety data due to the potential overlap of vaccine-related 
AEs with study drug-related AEs.
6.6
Dose modification
Details of dose escalation can be found in Section 6.1.2.
Study treatment will be repeated in 28-day cycles.  The dosing criteria for Day 1 of a new 
cycle of study treatment (blood tests should be reviewed prior to dosing) and continuation of 
treatment are:

ANC ≥1500 cells/mm3 (≥1.5 x 109/L)

platelets ≥75,000/mm3 (≥75 x 109/L)
If a patient experiences a clinically significant and/or unacceptable toxicity (including a DLT) 
study treatment will be interrupted (and appropriate treatment administered) for a maximum 
of 28 days until resolution of the toxicities to the patient’s baseline or until improvement 
(CTCAE Grade ≤2) (Table 6).  Clinically significant abnormal laboratory values must be 
repeated at regular intervals until resolved to the patient’s baseline or until improvement 
(CTCAE Grade ≤2).  If the patient is showing clinical benefit and the toxicity resolves to the 
patient’s baseline or until improvement (CTCAE Grade ≤2), treatment can be restarted; 
guidelines are provided below for dose modifications (Table 7).
If the toxicity does not resolve to the patient’s baseline or to CTCAE Grade ≤2 within 
28 days of onset, treatment with AZD7648 must be discontinued.

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Table 6
Management of AZD7648 treatment related toxicity 
Event (CTCAE V5.0)
Action 
Grade 1 to 2 toxicity (all 
events)
Investigator judgement to continue treatment or interrupt dose (maximum 
28 days), except for Day 1 of a new cycle of study treatment, as described 
above.  Initiate optimal supportive care and causality investigation.  
Consider resuming at the same dose level when toxicity has resolved or is 
resolving with prophylactic treatment (if appropriate).  If toxicity recurs on 
rechallenge and does not resolve in < 7 days despite optimal supportive care, 
consider a dose reduction.
Grade 3 to 4 toxicity (1st
event)
Interrupt study treatment, initiate optimal supportive care and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity 
has resolved or is resolving with prophylactic treatment (Grade ≤2 or returns 
to baseline), consider re-starting AZD7648 with 1 dose level reduction and 
prophylactic treatment (if appropriate).
Grade 3 toxicity (recurrence of 
same AE)
Interrupt study treatment, initiate optimal supportive care and causality 
investigation.  Maximum treatment interruption is 28 days.  When toxicity 
has resolved or is resolving (Grade ≤2 or returns to baseline), consider re-
starting AZD7648 with 1 dose reduction and prophylactic treatment (if 
appropriate).  After 2 dose reductions, consider permanent discontinuations 
of AZD7648 for Grade 3 events.
Grade 4 toxicity (recurrence of 
same AE)
Patients should permanently discontinue AZD7648.
Table 7
Dose modification of study treatment AZD7648
First dose reduction
Previously determined “acceptable safety” dose level.
Second dose reduction
Previously determined “acceptable safety” dose level.
Third dose reduction
Consider permanent discontinuation of AZD7648 unless the patient is 
deriving clinical benefit.
Patients enrolled into the first 3 dose cohorts are permitted to dose reduce to the previous dose cohort, but must 
discontinue if a dose reduction is required in the first dose level.
6.7
Treatment after the end of the study
Patients are permitted to either receive standard of care therapy, or to continue to receive 
study treatment following the end of the study if, in the opinion of the Investigator, they are 
continuing to receive benefit from treatment.  After discontinuation of study treatment, the 
Investigator will be at liberty to define further the most appropriate anti-cancer treatment.  
Subsequent anti-cancer treatment is expected to be initiated following the cancer recurrence or 
development of a new cancer.  Information on subsequent anti-cancer therapies should be 
recorded on the clinical database.

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7
PATIENT DISCONTINUATION OF TREATMENT AND
PATIENT WITHDRAWAL
7.1
Discontinuation of study treatment
Patients may be discontinued from study treatment in the following situations.  Note that 
discontinuation from study treatment is NOT the same as a complete withdrawal from the 
study:

Disease progression (confirmed progression or symptomatic deterioration or confirmed 
progression by RECIST criteria).

Adverse event, eg, study treatment-related toxicity that fail to recover to CTCAE 
Grade ≤2 or the patient’s baseline within 28 days.  Patients that withdraw due to 
treatment-related toxicity must be observed until resolution of toxicity to CTCAE 
Grade ≤1 or the patient’s baseline.

Patient or Investigator decision.  The patient is at any time free to discontinue treatment, 
without prejudice to further treatment.

Pregnancy.

Non-compliance with the CSP (Investigator or patient).

Patients incorrectly initiated on study treatment.

Unexpected, significant or unacceptable risk to the patients enrolled in the study.

Lack of evaluable and/or complete data.

Decision to modify the development plan of the drug.

Sponsor termination of study due to unfavourable risk-benefit.
See the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.1
Temporary discontinuation
See Section 6.6 for further details on study treatment interruptions.
7.1.2
Rechallenge
See Section 6.6 for further details on study treatment interruptions.
7.1.3
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.  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 should be documented in the CRF.  All study treatment should be returned by the 
patient at their next on-site study visit or unscheduled visit.  Patients permanently 

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discontinuing study treatment should be given locally available standard of care therapy, at the 
discretion of the Investigator.
Discontinuation of study treatment, for any reason, does not impact on the patient’s 
participation in the study.  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, or information from medical records.  
The approach taken should be recorded in the medical records.  A patient that agrees to 
modified follow-up is not considered to have withdrawn consent or to have withdrawn from 
the study.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site 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 by eg, 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 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 (eg, withdraw consent), at any time (study treatment 
and assessments) at his/her own request, without prejudice to further treatment.
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).

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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 from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The Investigator will follow up patients as medically indicated. 
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status at study 
end in all patients is crucial for the integrity of the study.
See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed.  All study treatment should be returned by 
the patient.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA.
The Investigator will ensure that data are recorded on the CRF.  The Web Based Data Capture 
system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement.  The 
Investigator will sign the completed CRF.  A copy of the completed CRF 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.

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Procedures conducted as part of the patient’s routine clinical management (eg, blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the 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 approximately 350 mL (over a 1 month period).  Any 
additional requirements are specified within the relevant section of Combination Module 1.  
Safety laboratory assessments will be performed locally at each centre’s laboratory by means 
of their established methods.  Therefore, the number of samples/blood volumes is patient to 
site-specific change.
8.1
Efficacy assessments
8.1.1
Tumour assessments by CT or MRI
RECIST 1.1 guidelines for measurable and non-measurable TLs and non-target lesions 
(NTLs) and the objective tumour response criteria are presented in Appendix H of this 
protocol.
At baseline, the imaging modalities used for assessment should be contrast enhanced 
computed tomography (CT) (magnetic resonance imaging [MRI] where CT is 
contraindicated) scans of the brain, chest, abdomen and pelvis (including liver and adrenal 
glands) and 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.  Follow-up CT or MRI assessments will cover 
chest, abdomen and pelvis with any other regions imaged at baseline where disease was 
present.  Any other sites at which new disease is suspected should also be appropriately 
imaged.  A CT/MRI scan of the brain should be performed in all patients at the main screen.
Radiological examinations performed in the conduct of this study should be retained at site as 
source data.  All treatment decisions will be based on site assessment of scans.  Baseline 
radiological 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.  
Scans obtained as part of standard clinical practice, prior to informed consent, but within the 
28-day period are acceptable.  The radiological confirmatory scans should be performed no 
less than 4 weeks after the prior assessment of tumour and preferably at the next scheduled 
visit (in the absence of clinically significant deterioration).
The methods of assessment used at baseline should be used at each subsequent follow-up 
assessment through to objective confirmed radiological disease progression, as defined by 

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RECIST 1.1 and as determined by the Investigator.  Tumour assessments should be performed 
every 8 weeks (2 cycles) (± 1 week) or earlier, if disease progression is suspected.  If a patient 
discontinues treatment (and/or receives a subsequent cancer therapy) prior to progression then 
the patient should continue to be followed (unless they withdraw consent) until confirmed 
objective disease progression, as defined by RECIST 1.1.  Scans confirming progression 
should not be conducted within 1 week after a progression biopsy to allow for reduction in 
inflammation.
If scans are performed outside of scheduled visit window interval and the patient has not 
progressed, every attempt should be made to perform the subsequent scans at their scheduled 
visits whilst the patient remains on study treatment.  If the patient interrupts treatment or 
incurs a treatment delay, scans should continue to occur at the protocol-defined frequency.
It is important to follow the assessment schedule as closely as possible.  Please refer to the 
SoA.
8.1.2
Tumour evaluation
Categorisation of objective tumour response assessment will be based on the RECIST 1.1 
criteria of response: CR, PR, and SD (see Appendix H).  The CR and PR will need to be 
confirmed.  In addition, the objective tumour response assessment will also be assessed for 
exploratory analysis on a modified RECIST 1.1 (mRECIST) criteria considering progression 
only when confirmed.  The mRECIST will not be used for the Core Module or Combination 
Module 1, but will be used if any immune oncology (IO) combination modules are added to 
the study in the future.  TL progression will be calculated in comparison to when the tumour 
burden was at a minimum (ie, smallest sum of diameters previously recorded on study).  In the 
absence of progression, tumour response will be calculated in comparison to the pre-dose 
tumour measurements obtained before starting treatment.
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 until 
the Investigator reassesses the patient’s status at the next scheduled assessment (confirmation) 
or sooner if clinically indicated.
To achieve ‘unequivocal progression’ based on 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 tumour burden has increased sufficiently to merit discontinuation of 
therapy.  A modest increase in the size of 1 or more NTLs is usually not sufficient to qualify 
for unequivocal disease progression status.
If repeated scans confirm progression, then the date of the initial scan should be declared as 
the date of progression.  All RECIST assessment images will be reviewed at site.  Duplicates 

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may be collected and stored by an AstraZeneca appointed representative, and sent for 
independent central RECIST review, if deemed appropriate.
8.1.3
Survival assessment
In Part B of Combination Module 1, survival status will be obtained for all patients who 
receive study treatment.  Vital status (dead or alive; date of death) will be collected every 
3 months (±1 week) post-permanent discontinuation of study treatment.  To aid the 
interpretation of the survival analysis, the use of subsequent anti-cancer therapies, after 
discontinuation of study treatment, will also be recorded on the CRF.
Survival status will continue to be collected until the earlier of 12 months after the last patient 
has discontinued treatment in a given module or 75% of patients have died in the module.  
The patient does not have to attend the clinic for the assessment to be carried out; it can either 
be done via a telephone call, or through a review of the patient’s notes, or using public 
records.  If the site becomes aware that a patient has died prior to the final analysis, the 
relevant CRF on the database should be completed at that time.
8.2
Safety assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical safety laboratory assessments
See Table 8 for the list of clinical safety laboratory tests to be performed and to the 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 SoA.
The Investigator should assess the available results with regard to clinically relevant 
abnormalities.  The laboratory results should be signed and dated and retained at centre 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.  Further details on CTCAE Grade 3 or 4 laboratory values defined as DLTs can 
be found in Section 6.1.3.  Clinically significant abnormal laboratory values must be repeated 
at regular intervals until resolved to the patient’s baseline or to CTCAE Grade ≤2.  
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 CRF.
The haematology, coagulation, clinical chemistry, and urinalysis will be performed at the local 
laboratory (a copy of laboratory reports will be available as source data).

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Table 8
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count) a
S/P-Alkaline phosphatase
B-Platelet count
S/P-Aspartate transaminase
B-Reticulocyte count
S/P-Alanine transaminase
Coagulation
S/P-Albumin
INR
S/P-Potassium
Activated Partial Thromboplastin Time (APTT)
S/P-Calcium, total
Urinalysis (dipstick)
S/P-Sodium
U-Hb/Erythrocytes/Blood 
S/P-Urea nitrogen
U-Protein/Albumin 
S/P-Phosphate
U-Glucose 
S/P-Magnesium
S/P-Gamma-glutamyl transferase
S/P-Total protein
Thyroid stimulating hormone (TSH) b
C-reactive protein (CRP) b
Tumour markers
a
If absolute differentials are not available, % differentials (differential includes neutrophils, lymphocytes, 
monocytes, basophils, eosinophils) will be provided.
b
TSH to be measured at baseline and every 3 cycles.  CRP to be collected at baseline, then on Day 1 from 
Cycle 1.  Urinalysis at Cycle 0, Cycle 0+1 and Day 1 of each cycle.  Tumour markers (if relevant) to be 
measured at baseline and on Day 1 of every cycle from Cycle 1 (only if elevated at baseline). 
NB. In case a patient shows an AST or ALT ≥3 x ULN together with total bilirubin (TBL) 
≥2 x ULN please refer to Appendix E ‘Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law (HL), for further instructions.
8.2.2
Physical examinations
Physical examinations will be conducted at visits described in the SoA; height will be 
measured at screening only.  
A complete physical examination will include an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen, pelvis, skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and 
extremities) and neurological systems.
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.

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Targeted physical examinations will be performed throughout the treatment period, at the 
discretion of the Investigator eg, for new or worsening symptoms and/or signs.
8.2.3
Body weight
Body weight will be recorded at each visit as indicated in the SoA.  
8.2.4
Vital signs

Oral temperature (in degrees Celsius), pulse rate, respiratory rate, and blood pressure will 
be assessed.

Blood pressure and pulse measurements will be assessed in supine or sitting position 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 5 minutes of rest 
for the patient in a quiet setting without distractions (eg, television, mobile phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist of one
pulse rate measurement, one blood pressure measurement, and one temperature 
measurement.

Vital signs will be measured prior to ECG and PK blood draws at all PK sample 
timepoints.  Timepoints may be modified based on initial data obtained.
8.2.5
Electrocardiograms

In Part A: triplicate 12-lead ECG will be obtained for all timepoints using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.  For triplicate ECG measurements, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart.  The full set of triplicates should be 
completed within 5 minutes.

In Part B, triplicate 12-lead ECG will be obtained for screening only, at all other 
timepoints a single 12-lead ECG will be obtained.

ECGs will be obtained after the patient has been resting.  All ECGs should be recorded 
with the patient in the same physical position.

ECGs will be measured after vital signs and prior to PK blood draws at all PK sample 
timepoints.  Timepoints may be modified based on initial data obtained.
8.2.6
Performance status
The patient’s performance status will be assessed at screening using the ECOG PS scale.  
Patients must have an ECOG PS of 0 to 1 to be eligible for enrolment.
These scales and criteria are used by doctors and researchers to assess how a patient's disease 
is progressing, assess how the disease affects the daily living abilities of the patient, and 
determine appropriate treatment and prognosis (Oken et al 1982, see Table 9).

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Table 9
Eastern Cooperative Oncology Group Performance Status 
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, eg, light house work, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead.
Vital status (dead or alive; date of death) will be collected during survival follow-up for patients entered in the 
study, and for patients that are screen failures
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorised representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE.  For information on how to follow-up AEs 
see Section 8.3.3.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information
AEs will be collected from time of signature of ICF throughout the treatment period and 
including the 28-day follow-up visit after treatment discontinuation. 
All SAEs will be recorded from the time of signing of ICF until the 28-day follow-up visit 
after treatment discontinuation.  Only SAEs related to the study treatment and/or procedure 
will be recorded thereafter (during the progression follow-up). 

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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 AE or SAE in former study patients.  However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts.  All events 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 in the study are followed up 
by the Investigator for as long as medically indicated, but without further recording in the 
CRF.  AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
8.3.4
AE data collection
The following variables will be collected for each AE:

Adverse event (verbatim)

The date and time when the AE started and stopped

The CTCAE grade (v5.0) and changes in CTCAE grade with the date they changed

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to study treatment

Adverse event caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

Adverse event is serious due to

Date of hospitalisation

Date of discharge

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
Probable cause of death (as applicable)

Date of death (as applicable)

Autopsy performed (as applicable)

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.5
Causality collection
The Investigator will assess causal relationship between study treatment and each AE, and
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the study treatment?’
For SAEs, causal relationship will also be assessed for other medications 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 CSP.
8.3.6
AEs based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the CRF.  When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
AEs based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
CSR.  Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs and clinical safety laboratory tests should therefore only be reported as AEs if they fulfil 
any of the criteria for a SAE, a DLT or are the reason for discontinuation of treatment with the 
investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).

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Deterioration of a laboratory value, 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 progression (see Section 8.3.9).
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 ≥3 x ULN together with TBL ≥2 x ULN may need to be 
reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of HL.
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 study treatment 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 an AE during the study.
8.3.10
New cancers
The development of a new cancer should be regarded as an SAE.  New primary cancers are 
those that are not the primary reason for the administration of the 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 treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study treatment, must be reported 
as follows:

Death clearly resulting from disease progression should be reported to the study 
Investigator at the next monitoring visit and should be documented in the CRF in the 
Statement of Death page.  It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported to the study Investigator as an SAE within 
24 hours.  It should also be documented in the Statement of Death page in the CRF.  The 
report should contain a comment regarding the co-involvement of disease progression, if 
appropriate, and should assign main and contributory causes of death.

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
Deaths with an unknown cause should always be reported as an SAE.  It should also be 
documented in the Statement of Death page in the CRF.  A post-mortem may be helpful 
in the assessment of the cause of death, and if performed, a copy of the post-mortem 
results should be forwarded to AstraZeneca Patient Safety or its representative within the 
usual timeframe.
Deaths occurring after the protocol-defined safety follow-up period or after the administration 
of the last dose of study treatment should be documented in the Statement of Death page.  If 
the death occurred as a result of an AE that started post the defined safety follow-up period 
and the AE is considered to be due to a late onset toxicity to study treatment, then it should 
also be reported as an SAE with an outcome of death.
8.4
Safety reporting and medical management
8.4.1
Reporting of SAEs
All SAEs have to be reported, whether or not considered causally related to the study 
treatment, or to the study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 calendar day ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the CRF, an 
automated email alert is sent from the electronic data capture system to the designated 
AstraZeneca representative.
If the electronic data capture system is not available, then the Investigator or other study site 
staff reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B of the CSP.

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8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any study treatment
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal Exposure
If a patient becomes pregnant during the course of the study, study treatment should be 
discontinued immediately but the patient will remain in the study.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) should be followed up and documented even if the patient was 
discontinued from the study.
If any pregnancy occurs during the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1day ie, immediately
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.2.2
Paternal Exposure
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.
Male patients must refrain from fathering a child or donating sperm during the study and for 
90 days following the last dose of study treatment.
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth,

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or congenital anomaly) should, if possible, be followed up and documented.  To capture 
information about a pregnancy from the partner of a male patient, consent must be obtained 
from the male patient’s partner in order to collect information related to the pregnancy and 
outcome; the male patient should not be asked to provide this information.  A consent form 
specific to this situation must be used.
The outcome of any conception occurring from the date of the first dose until 90 days after the 
last dose of study treatment should be followed up and documented.
8.4.3
Overdose
For this study, any dose of AZD7648 in excess of those specified in the protocol will be 
considered an overdose.  Further details on the combination treatments can be found in the 
relevant combination module protocol.
There is currently no specific treatment in the event of overdose of AZD7648 and possible 
symptoms of overdose are not established.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study treatment occurs in the course of the study, then the 
Investigator or other site personnel 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 a medication error occurs during the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day ie, immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.

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The definition of a medication error can be found in Appendix B.
8.4.5
Management of IP-related toxicities
Details of DLTs can be found in Section 6.6.
8.5
Pharmacokinetics
Venous blood samples (2 mL) for determination of concentrations of AZD7648 and the 
potential metabolites (if any) in plasma will be taken at times presented in Table 10.  Samples 
will be split to provide plasma for the primary analysis and secondary/backup analyses.  The 
backup sample may be used for the metabolite identification work.  Blood and urine samples 
for PK analysis will be collected as specified below (Table 10) and in the SoA (Table 1).
Full details of sample handling procedures, storage and shipping will be provided in the lab 
manual.  The date and time of collection of each sample will be recorded.
Urine samples (~10 mL) for the determination of AZD7648 concentration will be taken from 
the total urine sample provided during each of the collection intervals.  The date and time of 
collection and the volume of each total urine collection will be recorded.  Approximately 
50 mL of the urine sample may also be used to identify metabolites, if any. 
Results will only be reported for samples shipped within a timeframe for which the stability of 
AZD7648 in the samples has been validated and shown to be acceptable.
All patients start with a single dose of AZD7648 to fully profile the PK of AZD7648, 
followed by an approximately 3 to 7 day washout.  If the half-life of AZD7648 is shorter than 
expected the washout period can be shortened or may not be required at all.  
Pharmacokinetic samples will be taken at the times indicated in Table 10.
Table 10
AZD7648 PK sample collection schedule in monotherapy cohorts
Blood
Urine
Cycle 0, Day 1
Pre-dose, and 15 minutes (min), 
30 min, 60 min, 2 hours (h), 4 h, 
8 h, 10 h to12 h post-dose
Pre-dose, and 0 to 8 h, 8 to 24 h
post-dose
Cycle 0, Day 2
24 h post-dose
Cycle 0, Day 3
48 h post-dose
Cycle 0, Day 4
72 h post-dose
Cycle 1, Day 1
Pre-dose
Cycle 1, Day 8
(or Visit Y for intermittent 
schedules)
Pre-dose, and 15 min, 30 min, 
60 min, 2 h, 4 h, 8 h, 10 to12 h
post-dose
0 to 8 h, 8 to 24 h post-dose
note: urine not requited at Visit Y

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Blood
Urine
Cycle 2, Day 1
Pre-dose
Cycle 3, Day 1
Pre-dose
Cycle X, Day 1 (if a patient has a 
dose escalation to another dose, 
then, at the time of escalation); 
this provides the starting exposure 
at the time of escalation
Pre-dose and 1 h post-dose
Cycle X+1, Day 1 (if a patient has 
a dose escalation at Cycle X then, 
at the next cycle Day 1)
Pre-dose and 1 h post-dose
Discontinuation
Any 1 sample between 0 to 72 h 
post-last dose 
Please refer to Section 15.3 for PK collection details for Combination Module 1.
For patients who undergo intra-patient dose escalation (applicable to Core Module only), PK 
samples at pre-dose and 1 hour on the day of escalation (Cycle X, Day 1) and after one cycle 
(Cycle X+1, Day 1) of escalation will be obtained.  Other PK time points maybe added as 
appropriate based on the emerging PK data.
PK Window
The following time windows will be allowed: 

5 minutes (min) for samples taken up to 1 hour (h) post-dose

10 min for samples taken between 2 and 9 h

1 h for samples taken between 10 and 24 h post-dose

2 h for samples taken between 25 and 72 h
The timing of the PK samples may be adjusted during the study, dependent on emerging data, 
in order to ensure appropriate characterisation of the plasma concentration-time profiles.  
After 2 or more cohorts have been completed the timing of later PK samples will be 
re-assessed based on emerging PK data and the desire to characterise 80% of the AUC in all 
patients.  The total number of samples taken from each patient will not exceed that presented 
in Table 10.
If a patient misses any doses of AZD7648 within 3 days of PK sampling, the Investigator 
should contact the AstraZeneca PK representative as to any effect on the changes required on 
the timing of the PK assessments.  All other assessments, including laboratory safety 
assessments, vital signs and RECIST should continue to be performed as per study plan, 
relative to baseline assessments.

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Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual.
Any residual sample remaining after PK analysis has been performed may be used for 
exploratory biomarker research and characterisation of metabolites, if consent for this 
exploratory research has been obtained
Pharmacokinetic Sampling for Food Effect (if conducted)
Pharmacokinetic samples for food effect will be taken at the times indicated in Table 11.
Table 11
AZD7648 PK sample collection schedule in food effect cohort
Blood
Cycle 0, Day 1
Pre-dose, and 15 minutes (min), 30 min, 60 min, 2 hours (h), 4 h, 8 h, 
10 to 12 h post-dose
Cycle 0, Day 2
24 h post-dose
Cycle 0, Day 3
48 h post-dose
Cycle 0, Day 4
72 h post-dose
Cycle 1, Day 1
Pre-dose, and 15 min, 30 min, 60 min, 2 h, 4 h, 8 h, 10 to 12 h
post-dose
Cycle 1, Day 2
24 h post-dose
Cycle 1, Day 3
48 h post-dose
Cycle 1, Day 4
72 h post-dose; continuous dosing starts here
Cycle 2, Day 1
Pre-dose
Cycle 3, Day 1
Pre-dose
Discontinuation
Any 1 sample between 0 to 72 h post-last dose
8.5.1
Determination of drug concentration
Samples for determination of AZD7648 and PLD (as total doxorubicin) concentrations in 
plasma, and AZD7648 concentrations in urine will be analysed by Covance on behalf of 
AstraZeneca, using appropriate bioanalytical methods.  Full details of the analytical methods 
used will be described in a separate Bioanalytical Report.
All samples still within the known stability of the analytes of interest (ie, AZD7648 and PLD,) 
at the time of receipt by the bioanalytical laboratory will be analysed.
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.

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8.5.2
Determination of 4β-hydroxy cholesterol concentrations for assessment 
of CYP3A4 induction potential
Blood samples will be collected from all patients at pre-dose of Cycle 0, Day 1; Cycle 1, 
Day 8, and Cycle 2, Day 1 in the AZD7648 monotherapy for the determination of 4β-hydroxy 
cholesterol concentrations in plasma.  Analysis of 4β-hydroxy cholesterol will be performed 
by Covance on behalf of AstraZeneca, using an appropriate bioanalytical method.  Full details 
of the analytical methods used will be described in a separate Bioanalytical Report.
8.5.3
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalisation 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 anonymised by pooling.  Additional analyses 
may be conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method.  Any results from such analyses may be reported separately from 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.
8.6
Pharmacodynamics
The assessment of
 
  
 
 
Investigation of PK/PD Relationship
Where possible, population modelling and simulation methods will be used as part of the 
evaluation to assess relationships between emerging safety, tolerability, PK and PD and 
covariates data.  AstraZeneca will be responsible for these analyses and, if conducted, will be 
reported separately from the CSR.
8.6.1
Collection of blood for pharmacodynamics biomarker analysis
8.6.1.1
Collection of peripheral blood for pharmacodynamics biomarker analysis
The collection of blood-based 
 is mandatory in all parts of the study to 
obtain a preliminary assessment of 
.  Peripheral blood 
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samples will be collected pre-dose and 2 to 4 hours post-dose for AZD7648 as detailed in 
Table 12 and the SoA.  In addition, there will be PK samples collected at the same time as PD 
samples to allow exploration of the exposure/PD relationships (see Table 10). The exact time 
of PD samples collection will be noted.
 
.
Peripheral whole blood subpopulations may also be enumerated to determine any PD effects 
of potential immunological relevance, such as changes in the number of B lymphocytes or 
regulatory T lymphocytes. 
The number of samples taken, as well as the volume required for each analysis, may be 
changed during the study as new data on AZD7648 becomes available.  The estimated total 
volume of blood that will be drawn from each patient in this study for mandatory samples by 
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Details of sample collection, processing, shipping and storage will be described in the 
Laboratory Manual.
8.6.3
Collection of tumour samples for pharmacodynamics assessments
Fresh tumour biopsies are optional for all patients, unless they are enrolled into a Part A PD 
expansion cohort in which case, they are mandatory.

Serial biopsies will be collected during screening, on treatment (any time in Cycle 1 
between Day 3 and Day 8 [or Y] 2 to 8 hours post AZD7648 dosing), and on progression.

A PK sample should also be taken at the time of any biopsy sample.
These samples will be analysed for the effects on
 
On-treatment biopsy timing may be refined with emerging PK and/or PD data during the 
course of the study. 
Accessible lesions are defined as tumour lesions which are amenable to repeat biopsy, unless 
clinically contraindicated or the patient has withdrawn consent.  Failure to obtain sufficient 
tumour sample after making best efforts to biopsy the tumour will not be considered a 
protocol deviation.
8.7
Genetics
8.7.1
Approximately 10 mL blood sample for DNA isolation will be collected from patients who 
have consented to participate in the genetic analysis component of the study.  Participation is 
optional.  Patients who do not wish to participate in the genetic research may still participate 
in the study.
A pharmacogenetic sample will be collected at baseline and analysed for 
 
.  This sample may 
also be analysed for other patient-selection markers and as a reference sample 
 
  Only
 
See Appendix D for information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples may be stored for a maximum of 
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Other Optional Samples for Biomarker Research
Optional pre-dose plasma and serum sample and/or surplus blood, urine or tissue including 
patient specific archival or fresh tumour tissue, if available.
Samples will be used for potential future exploratory research and assay development for 
factors that may influence the development of AZD7648 to treat human disease and/or 
response to AZD7648 (where response is defined broadly to include efficacy, tolerability or 
safety). 
 
. 
 
 
8.8.1
Storage, re-use and destruction of biomarker samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed.  The results of this biomarker research will be 
reported either in the CSR itself or as an addendum, or separately in a scientific report or 
publication.  The results of this biomarker research may be pooled with biomarker data from 
other studies with the study treatment to generate hypotheses to be tested in future research.
8.9
Health Economics 
Health Economics parameters are not evaluated in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical hypotheses
No statistical hypotheses are planned in this study. 
9.2
Sample size determination
Approximately 192 evaluable patients may be enrolled in the Core Module (95 evaluable 
patients: 46 patients in the dose escalation (Part A) and up to 49 additional patients in optional 
expansion cohorts) and Combination Module 1 (97 evaluable patients: 30 patients in the dose 
escalation with the potential for an additional 30 patients once maximum tolerate dose [MTD] 
has been determined, and 37 patients in the expansion cohort).
Core Module: Monotherapy AZD7648
Part A: will require approximately 46 evaluable patients across approximately 10 cohorts 
(n = 1 to 6 per cohort) to provide a model-based estimate of MTD with a target toxicity of 
25% in patients with advanced solid tumours.  The RP2D will be declared on data available 
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from a minimum of 6 evaluable patients, but up to 12 patients may be treated at the RP2D to 
explore chronic toxicity.
Expansion cohorts: as described in Section 6.1.2.1, 3 cohorts may be initiated; the anticipated 
sample sizes are: 

PD expansion cohort: up to 12 additional patients

Efficacy expansion cohort: up to 25 additional patients (a subset of up to 12 patients 
which may have mandatory biopsies if PD data is also required)

Food effect expansion cohort: up to 12 additional patients
Sample size details for Combination Module 1 can be found in Section 16.2.
9.3
Populations for analyses
For purposes of analysis, the following analysis sets are defined: 
Analysis set
Definition
Enrolled 
All patients who sign the ICF
Safety set 
All patients who received at least 1 dose of any study treatment 
DLT evaluable set
All patients who received at least 1 dose of any study treatment and either 
experienced DLT during the cycle 0 or 1, or who completed minimum 
safety evaluation requirements and has received at least 75% of the total 
amount of planned dose of AZD 7648 (and PLD for 
Combination Module 1). In the event of an intra-patient dose escalation, 
such patients will not be evaluable for DLT at the escalated dose
PK set
All patients who received at least 1 dose of any study treatment and have at 
least 1 reportable PK concentration without any protocol deviations that 
might affect PK
PD set
All patients who received at least 1 dose of any study treatment with at least 
1 reportable PD measurement
Evaluable for efficacy set
All patients who received at least 1 dose of any study treatment and have a 
baseline tumour assessment 
Evaluable for objective 
response
All patients who had a measurable baseline disease a by RECIST 1.1 
assessment and received at least 1 dose of any study treatment
a Measurable disease is defined as having at least one measurable target lesion, not previously irradiated, which 
is ≥10 mm in the longest diameter (LD) (except lymph nodes which must have short axis ≥15 mm)
9.4
Statistical analyses
The statistical analyses will be performed by Parexel or other designated third-party providers, 
under the direction of the Biostatistics Group, AstraZeneca.  Further detail will be provided in 
the Statistical Analysis Plan (SAP). 

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Data from each part/module will be presented separately.  All patients who undergo 
intra-patient dose escalation will be analysed & reported as per their starting dose. 
Methods common to all modules are detailed below.
Demographic Data
Characteristics of the patients, including medical history and disease characteristics at baseline 
will be listed for each patient and summarised by cohort.
Reasons for discontinuation of study treatment will be listed including the study day of 
treatment discontinuation and will be summarised by cohort.
Exposure
Exposure to each study treatment, ie, total amount of study treatment received will be listed 
for all patients.
Total treatment duration (=date of last dose minus date of first dose + 1) and actual treatment 
duration (=total treatment duration excluding dose interruptions not in accordance with the 
protocol) will be summarised for each study treatment and cohort by the following: mean, 
standard deviation, minimum, maximum, median, and number of observations.  In addition, 
the number and percentage of patients with at least 1 non-protocolled dose interruption and at 
least 1 dose reduction will be presented separately for the initial period of evaluability defined 
as 28 days and for any time following this initial period of the study.
9.4.1
Efficacy analyses
These are secondary variables.
The efficacy assessment of Part A (dose escalation) will be done using ORR.  All efficacy 
endpoints will be used in Part B (expansions) efficacy assessment.
Tumour Response Data
Data will be summarised for dosed patients with measurable disease at baseline and separately 
for dosed patients with a baseline tumour assessment, unless otherwise specified.
Data will be listed and summarised by cohort using the following response categories: CR, 
PR, SD, disease progression and not evaluable (NE).
Waterfall plots (bar charts) indicating the percentage best change from baseline in sum of the 
diameters of TLs may be produced by cohort.
Tumour response includes the following variables:

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
Percentage best change in TL

Duration of response 

PFS 

ORR
Derivation of tumour response variables
Every 8 weeks (2 cycles), or earlier if disease progression is suspected, patients will be 
programmatically assigned a RECIST visit response of CR, PR, SD, and disease progression 
depending on the status of their disease compared to baseline and previous assessments.
Progression of TLs will be calculated in comparison to when the tumour burden was at a 
minimum (ie, smallest sum of diameters previously recorded during the study).  In the absence 
of progression, tumour response (CR, PR, SD) will be calculated in comparison to the baseline 
tumour measurements obtained before starting treatment.
If a patient has had a tumour assessment, which cannot be evaluated, then the patient will be 
assigned a response of NE unless there is evidence of progression in which case the response 
will be assigned as disease progression.
For TL measurements, if ⅓ of the TL sizes are missing then a scaling up rule will be applied 
as follows:

If ≤ ⅓ of lesions recorded at baseline are missing then the results will be scaled up (based 
on the baseline 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 baseline sum of diameters excluding the lesions that are missing and 
determining at what rate the lesions are changing).

If > ⅓ 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 disease progression 
(ie, 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), disease progression 
takes precedence over NE.

A response of CR will not be allowed if any of the TL data are missing.
Percentage Best Change in TL
Percentage change in tumour 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.

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Duration of Response
Duration of response is 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 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.
PFS
PFS is defined as the time from first dose of any study treatment at Cycle 1 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 (ie, date of PFS event or censoring – date of first dose + 1).  Patients who 
have not progressed or died at the time of analysis will be censored at the time of the latest 
date of assessment from their last evaluable RECIST assessment.  However, if the patient 
progresses or dies after 2 or more missed visits, the patient will be censored at the time of the 
latest evaluable RECIST 1.1 assessment prior to the 2 missed visits.
ORR
ORR will be assessed per RECIST criteria.  ORR is defined as the percentage of patients who 
have a confirmed visit response of CR or PR prior to any evidence of progression (as defined 
by RECIST 1.1).  Note that responses that occur after the start of subsequent anti-cancer 
therapy must be excluded from the derivation of ORR.
A visit response of CR is defined when all TLs and NTLs 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, measurements should have met the SD criteria at least once after the study 
start.
When the Investigator reassesses the progression of 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.

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Overall Survival
Overall survival is defined as the time from first dose of any study treatment at Cycle 1 until 
death due to any cause regardless of whether the patient withdraws from study treatment or 
receives another anti-cancer therapy (ie, 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 based on the last 
recorded date on which the patient was known to be alive. 
Survival calls will be made in the week following the date of DCO for the analysis, and if 
patients are confirmed to be alive or if the death date is after the DCO date these patients will 
be censored at the date of DCO.
9.4.2
Safety analyses
These are primary variables.
All safety analyses will be performed on the safety analysis set.  All patients who receive at 
least 1 dose of study treatment will be included in the assessment of the safety profile.  At the 
end of the study, appropriate summaries of all safety data will be produced, as defined below.
Data from all cycles of initial treatment will be combined in the presentation of safety data.  
AEs will be listed individually by patient and cohort.  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 summarised 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 
(eg, causally related, CTCAE Grade ≥3 etc) will be summarised by dose regimen, and events 
in each category will be further summarised by MedDRA system organ class and preferred 
term, by dose group.  SAEs will be summarised separately.
Any AE occurring before the first dose of study treatment (ie, before study Day 1) will be 
included in the data listings but will not be included in the summary tables of AEs.  
Treatment-emergent AEs occurring prior to first dose of investigational product (ie, before 
study Day 1) which subsequently worsen in severity following dosing will be included in the 
summary tables.
Any AE occurring within the defined 28-day follow-up period after discontinuation of study 
treatment 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 study treatment) 
will be flagged in the data listings.  AEs occurring after the 28-day follow-up period after 
discontinuation of study treatment will be listed separately, but not included in the summaries.

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Haematology, clinical chemistry, vital signs, ECG data, ECOG PS, physical examination, 
demographic data, medical histories and concomitant medications will be listed individually 
by patient and suitably summarised.  For all laboratory variables, which are included in the 
current version of CTCAE, the CTCAE grade will be calculated.  Summary statistics of mean, 
median, standard deviation, minimum, maximum and number of observations will be used for 
continuous variables.  Categorical variables will be summarised by frequency counts and 
percentages for each category [n (%)].
Details of any deaths will be listed for all patients.
Graphical presentations of safety data may 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 may also be considered to investigate trends in parameters 
compared to baseline. 
ECG Changes
QTc will be calculated using Fridericia’s formula. 
QTcF = QT/(RR1/3)
Clinical decisions at the site will be made based on QTcF.
9.4.3
Other analyses
PK, PD, and biomarker research and pharmacogenetics exploratory analyses will be described 
in a separate document.  The population PK analysis and PD analyses will be presented 
separately from the main CSR.
9.4.3.1
PK Analyses
PK of AZD7648 is a secondary variable.
The PK Analysis Set includes patients who have reportable plasma concentrations and PK 
parameters and who have no important protocol deviations or AEs that may impact on PK. 
Following single dose the following parameters maybe determined: Cmax, time to reach 
maximum plasma concentration (tmax), terminal rate constant (λz), terminal half-life (t1/2 λz), 
area under the plasma concentration-time curve from zero to 24 hours (AUC0-24), from zero to 
the time of the last measurable concentration (AUC0-t) and from zero to infinity (AUC), 
apparent plasma clearance (CL/F), apparent volume of distribution (Vss/f ; Vz/f), mean 
residence time (MRT), renal clearance (CLR) and amount of drug excreted unchanged (Ae; 
% dose).

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Following multiple dose (assuming SS conditions): Maximum plasma concentration at steady 
state (Cmax,ss), time to Css max (tmax,ss), Cmin,ss, area under the plasma concentration-time curve 
from zero to the end of the dosing interval (AUCss ), apparent plasma clearance at steady state 
(CLss/f), extent of accumulation on multiple dosing (RAC), time dependency of the PK.  
Where possible other appropriate PK parameters may also be determined.
PK analysis of plasma concentration data for AZD7648 will be performed by AstraZeneca, or 
a CRO on behalf of AstraZeneca, using actual elapsed sampling times and standard Non 
Compartmental methods.
Statistical Analysis Methods for Assessment of Pharmacokinetic Food Effect
To evaluate the effect of food on the PK obtained after dosing with AZD7648 tablet, the 
primary PK parameters will be analysed using a linear mixed Effects model with treatment 
(fed/fasted) as a fixed effect and patient as a random effect to compare AUC0-t and Cmax in 
the fed state with AUC0-t and Cmax in the fasted state respectively. Log-transformation of 
exposure measurements (AUC0-t and Cmax) will be performed prior to analysis. The point 
estimate and 90% confidence interval (CI) for the ratio of geometric means for fed and fasted 
states will be provided. The food effect on a log scale (fed – fasted) and its upper and lower 
confidence limits will be exponentially back transformed to (and presented in) the linear scale. 
Further details will be provided in the SAP. 
COMBINATION MODULE 1 – AZD7648 AND PEGYLATED 
LIPOSOMAL DOXORUBICIN
This section contains additional information specific to Combination Module 1; please refer to 
Sections 1 to 9 for information which applies to the overall study. 
10
PROTOCOL SUMMARY
10.1
Schedule of Assessments – Combination Module 1
The SoA for the lead-in and on-treatment period for Combination Module 1 is shown in 
Table 13 below. 

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Table 13
Schedule of assessments – Combination Module 1
Part A:
Screening
Single Dose
Multiple Dose
IP 
Disc
28-day 
FU 
After 
IP Disc
Details
in 
Section
Cycle 0
Cycle 1a
Weekly Visitb
Cycle
2a
Cycle
3a
Cycle
4-6a
Cycle
7+a
Day
-28 to -1
1
2
3
4
1
Yb,c
8b,c
15
22
1
15
1
1
1
Visit Windowd
-
-
-
-
-
-
-
-
-
-
±1
±1
±2
±2
±2
-
±7
Informed consent
X
5.1
Demographics and 
medical history, 
including tumour gene 
mutationse
X
5.1
Physical examination
X
X
Xf
X
Xf
X
Xf
Xf
Xf
Xf
Xf
8.2
Height
X
8.2
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
ECGg
X
X
X
X
X
X
X
X
X
8.2
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
14.3
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
8.3
Pregnancy testi
X
Xi
Xi
X
X
X
X
X
5.1
Haematology, 
coagulation, 
chemistry, urinalysis, 
tumour marker, TSHj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
ECOG PS
X
X
X
X
X
X
X
X
X
8.2
ECHOk
X
X
X
15.2

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Screening
Single Dose
Multiple Dose
IP 
Disc
28-day 
FU 
After 
IP Disc
Details
in 
Section
Cycle 0
Cycle 1a
Weekly Visitb
Cycle
2a
Cycle
3a
Cycle
4-6a
Cycle
7+a
Day
-28 to -1
1
2
3
4
1
Yb,c
8b,c
15
22
1
15
1
1
1
Visit Windowd
-
-
-
-
-
-
-
-
-
-
±1
±1
±2
±2
±2
-
±7
Archival tumourl
X
8.8
Fresh tumour biopsy 
with biomarker 
analysesm
X
X
X
8.8
15.5
PK AZD7648 blood n
X
X
X
X
X
X
X
X
X
X
8.5
PK PLD bloodn
X
X
8.5 15.3
X
Xp
Xq
Xq
Xp
Xr,s
8.6.1.1
8.6.1.4
X
Xp
Xq
Xq
Xq
Xp
Xq
Xq,r
Xp,r
Xq,r
Xr
8.6.1.2
X
Xp
Xq
Xq
Xq
Xp
Xq
Xq,r
Xq,r
Xq,r
Xr
8.6.1.3
Tumour assessment
X
Xt
Xt
Xt
8.1
PGx (optional)
(X)
8.7
Appendix D
X
X
X
(X)
(X) (X)
X
(X)
X
X
X
14.1
PLD dosing
X
X
X
X
14.1
; Disc=discontinuation; DNA=deoxyribonucleic acid; ECG=Electrocardiogram; 
ECHO=Echocardiography; ECOG PS=Eastern Cooperative Oncology Group performance status; FU=Follow-up; IP=Investigational Product; 
PD=Pharmacodynamics; PGx=pharmacogenetic sample; PK=Pharmacokinetics; PLD=Pegylated liposomal doxorubicin; TSH=Thyroid-stimulating hormone.
a
1 cycle = 28 days.  Cycles repeat on a continuous basis with no interval between cycles.
b
Weekly visit may be omitted if Visit Y is within 2 days of weekly visit.
c
Visit Y is only utilised if the dosing schedule is intermittent.  Visit Y represents the last AZD7648 dosing day in the first block of AZD7648 treatment in a 
cycle eg, 
d
There are no visit windows in Cycle 0 and Cycle 1.
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Part B:
Screening
Multiple Dose
IP 
Disc
28-day 
FU 
After 
IP Disc
Survival Details in 
Section
Cycle 1a
Weekly Visitb
Cycle
2a
Cycle
3a
Cycle
4-6a
Cycle
7+a
Day
-28 to -1
1
Yb,c
8b,c
15
22
1
15
1
1
1
Visit Windowd
-
-
-
-
-
-
±1
±1
±1
±2
±2
-
±7
Informed consent
X
5.1
Demographics and 
medical history, 
including tumour 
gene mutationse
X
5.1
Physical examination
X
X
Xf
Xf
Xf
Xf
Xf
Xf
Xf
8.2
Height
X
8.2
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
ECGg
X
X
X
X
X
X
X
X
8.2
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
14.3
Adverse events
X
X
X
X
X
X
X
X
X
X
X
Xh
X
8.3
Pregnancy testi
X
Xi
X
X
X
X
X
5.1
Haematology, 
coagulation, 
chemistry, urinalysis, 
tumour marker, TSHj
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2
ECOG PS
X
X
X
X
X
X
X
X
8.2
ECHOk
X
X
X
15.2
Archival tumourl
X
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Screening
Multiple Dose
IP 
Disc
28-day 
FU 
After 
IP Disc
Survival Details in 
Section
Cycle 1a
Weekly Visitb
Cycle
2a
Cycle
3a
Cycle
4-6a
Cycle
7+a
Day
-28 to -1
1
Yb,c
8b,c
15
22
1
15
1
1
1
Visit Windowd
-
-
-
-
-
-
±1
±1
±1
±2
±2
-
±7
Fresh tumour biopsy 
with biomarker 
analysesm
X
X
X
8.8 15.5
PK AZD7648 bloodn
X
X
X
X
X
8.5
PK PLD bloodn
X
X
8.5 15.3
X
Xo
Xp
Xp
Xo
Xq,r
8.6.1.1
8.6.1.4
X
Xo
Xp
Xp
Xp
Xo
Xp
Xp,q 
Xp,q
Xp,q
Xq
8.6.1.2
X
Xo
Xp
Xp
Xp
Xo
Xp
Xp,q
Xp,q 
Xp,q
Xq
8.6.1.3
Tumour assessment
X
Xs
Xs
Xs
8.1
Survival assessment
Xt
8.1
PGx (optional)
(X)
8.7
Appendix D
AZD7648 dosingu
X
X
(X)
(X)
(X)
X
(X)
X
X
X
14.1
PLD dosing
X
X
X
X
14.1
; 
; Disc=discontinuation; DNA=deoxyribonucleic acid; ECG=Electrocardiogram; 
ECHO=Echocardiography; ECOG PS=Eastern Cooperative Oncology Group performance status; FU=Follow-up; IP=Investigational Product; 
PD=Pharmacodynamics; PGx=pharmacogenetic sample; PK=Pharmacokinetics; PLD=Pegylated liposomal doxorubicin; TSH=Thyroid-stimulating hormone.
a
1 cycle = 28 days.  Cycles repeat on a continuous basis with no interval between cycles.
b
Weekly visit may be omitted if Visit Y is within 2 days of weekly visit.
c
Visit Y is only utilised if the dosing schedule is intermittent.  Visit Y represents the last AZD7648 dosing day in the first block of AZD7648 treatment in a 
cycle eg, 
d
There are no visit windows in Cycle 1.
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11
INTRODUCTION
Combination Module 1 will investigate the safety, tolerability, and preliminary efficacy of 
AZD7648 administered in combination with PLD.
11.1
Study rationale
Doxorubicin is an inhibitor of topoisomerase-II that generates topoisomerase-DNA adducts 
and DSBs and used as a cancer therapy.  PLD is FDA approved for treatment of ovarian 
cancer and multiple myeloma offering the same efficacy with less cardiotoxicity and 
haematotoxicity than the uncapsulated form.  
 
. 
 
 
11.2
Background
As described in Section 2.2 the DNA-PK inhibitor AZD7648 is being developed as an 
anti-cancer therapy for patients with advanced malignancies.  Combination Module 1 will 
investigate the safety, tolerability, PK, PD, and preliminary efficacy (anti-tumour activity) of 
AZD7648 in combination with PLD in patients with advanced malignancies.  Combination 
Module 1 consists of the following parts: AZD7648 combined with PLD in dose escalation 
(Part A) and PoC expansion in patients with platinum-resistant ovarian cancer (Part B).
Epithelial ovarian cancer, which accounts for 90% of all ovarian cancers, is further subdivided 
into various cell types, grades, and anatomic locations.  The most common form is high-grade 
serous ovarian cancer, which accounts for approximately 70% of all epithelial ovarian cancer.  
Historically, the treatment of ovarian cancer has been surgical cytoreduction followed by 
adjuvant chemotherapy.  Ovarian cancer remains a deadly malignancy because most patients 
develop recurrent disease that is resistant to chemotherapy, including platinum.  For 
platinum-resistant patients (patients who relapse ≤6 months after any line of platinum-based 
chemotherapy or having disease progression whilst receiving platinum-based chemotherapy in 
the ≥second-line setting), other chemotherapies including PLD are used.  For partially 
platinum-sensitive patients (patients who relapse > 6 to 12 months from the last 
platinum-based chemotherapy) and platinum-sensitive patients (patients who relapse 
> 12 months from the last chemotherapy), patients may derive benefit from further 
platinum-based chemotherapies.  Time from last platinum treatment to relapse remains an 
integral measure for defining patient populations and predicting outcomes for treatments, 
although response rates fall on a continuum (Wilson et al 2017).
A brief background on PLD, including its mechanisms of action, is provided below.  For 
detailed descriptions of the chemistry, pharmacology, efficacy, and safety of AZD7648 and 
PLD, refer to the IB (AZD7648) or Summary of Product Characteristics (PLD).
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11.2.1
Pegylated liposomal doxorubicin
11.2.1.1
Overview of pegylated liposomal doxorubicin
Doxorubicin is an inhibitor of topoisomerase 2 that generates topoisomerase-DNA adducts 
and DSBs and used as a cancer therapy.  PLD has been approved by FDA and the European 
Medicines Agency for treatment of ovarian cancer and multiple myeloma offering the same 
efficacy with less cardiotoxicity and haematotoxicity than the uncapsulated form.  
Doxorubicin directly generates DSBs and therefore could potentiate the activity of DNA-PK 
inhibitor, which is the critical component of NHEJ DNA DSB repair.
11.2.1.2
Pegylated liposomal doxorubicin data
DOXIL® (FDA-approved):
DOXIL is indicated for the treatment of patients with ovarian cancer whose disease has 
progressed or recurred after platinum-based chemotherapy.
DOXIL was studied in 3 open-label, single-arm, clinical studies of 176 patients with 
metastatic ovarian cancer (Trials 1, 2 and 3).  One hundred forty-five of these patients were 
refractory to both paclitaxel- and platinum-based chemotherapy regimens, defined as disease 
progression while on treatment or relapse within 6 months of completing treatment.  Patients 
received DOXIL at 50 mg/m2 every 3 or 4 weeks for 3-6+ cycles in the absence of DLT or 
disease progression.  In a pooled analysis of Trials 1-3, the response rate for all patients 
refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1, 19.3).  The median time 
to progression (TTP) was 15.9 weeks, the median time to response was 17.6 weeks and the 
duration of response was 39.4 weeks.
In an open-label Trial 4, a total of 474 patients with epithelial ovarian cancer after 
platinum-based chemotherapy were randomised to receive either DOXIL 50 mg/m2 every 
4 weeks or topotecan 1.5 mg/m2 daily for 5 consecutive days every 3 weeks.  Patients were 
stratified according to platinum sensitivity (response to initial platinum-based therapy and a 
progression-free interval of > 6 months off treatment) and the presence of bulky disease 
(tumour mass > 5 cm in size).  The median TTP showed no statistically significant difference 
between the 2 arms (4.1 months in the DOXIL arm and 4.2 months in the topotecan arm).  The 
median OS was 14.4 months in the DOXIL arm and 13.7 months in the topotecan arm.  The 
median duration of response was 6.9 months in the DOXIL arm and 5.9 months in the 
topotecan arm.
Caelyx (EMA-approved):
A Phase III comparative study of Caelyx versus topotecan in patients with epithelial ovarian 
cancer following the failure of first-line, platinum-based chemotherapy was completed in 
474 patients.  There was a benefit in OS for Caelyx-treated patients over topotecan-treated 
patients as indicated by a hazard ratio of 1.216 (95% CI: 1.000, 1.478), p = 0.050. The 

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survival rates at 1, 2 and 3 years were 56.3%, 34.7% and 20.2% respectively on Caelyx, 
compared to 54.0%, 23.6% and 13.2% on topotecan.
Preclinical data:
Preclinical studies support the hypotheses that a combination of AZD7648 with a 
DNA-damaging agent such as PLD would demonstrate synergistic anti-tumour activity 
(Figure 8).
Figure 8
Ovarian cancer xenograft – mean tumour volume
PDX = patient-derived xenograft; PLD = pegylated liposomal doxorubicin.
11.3
Benefit/risk assessment
As described in Section 2.3 patients enrolled to this study have advanced cancer with a limited 
number of treatment options available, including chemotherapy such as PLD.  The survival 
outcome and toxicity profile of chemotherapy in this setting mean that other active therapies 
are highly desirable and present a potential advantage for patients.
The study design aims to evaluate and determine a dose and schedule of AZD7648 in 
combination with PLD and identify patient populations who may respond favourably to the 
combination. Based upon the available non-clinical and clinical safety data, the limited 
survival benefit provided by the current treatment options, the limited life expectancy due to 
advanced malignant disease, and the hypothesis of a synergistic effect of the 2 agents, the 
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in patients with advanced or platinum-resistant ovarian cancer is acceptable, and the overall 
benefit/risk assessment supports the proposed study design.
12
STUDY DESIGN
12.1
Overall design
Combination Module 1 will evaluate the safety, tolerability, PK, PD, and preliminary efficacy 
(anti-tumour activity) of AZD7648 (given orally) in combination with PLD (given IV) as 
below:
Part A: Dose escalation of AZD7648 in combination with PLD in approximately 
30 evaluable patients with advanced solid tumours in whom PLD is an appropriate therapy.  
Prior information for PLD toxicity will be based on the locally approved label, whilst prior 
information for AZD7648 toxicity will be based on emerging data from the monotherapy arm
(Core Module).
The starting dose of PLD will be 40 mg/m2 administered IV once every 4 weeks for up to 
6 cycles.  Patients who respond or have stable disease following 6 cycles of PLD, are 
permitted to continue AZD7648 at the monotherapy RP2D (or lower dose) from the Core 
Module during the ‘continuation phase’.  Although AZD7648 is administered continuously as 
monotherapy, it is anticipated that an intermittent schedule will be required in combination.  
Two intermittent schedules that may be explored, including but not limited to, are: i) an 
intermittent within cycle schedule starting from 
 dosing eg, days 
on/
days off, and/or ii) an 
 starting from 
 
dosing eg,
days on/ days 
.  The duration and/or frequency of dosing for
both schedules may be altered based on emerging data and multiple schedules may be run 
concurrently if agreed by the SRC.
The PLD dose is consistent with local clinical practice (common usage of 40 mg/m2).
Part B: A safety and PoC Phase 2a expansion is planned to assess the combination in 
approximately 37 evaluable patients with advanced ovarian cancer who have relapsed within 
12 months of completing a platinum-containing therapy.  This includes patients who have 
platinum-resistant disease who have not received more than one cytotoxic regimen for 
platinum-resistant disease and patients with partial platinum sensitivity.  
Sites must send formalin-fixed paraffin embedded (FFPE) tissue for retrospective central 
laboratory confirmation of advanced ovarian cancer.
12.2
Scientific rationale for study design
 
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12.3
Justification for dose
12.3.1
Justification for AZD7648 dose
The actual starting dose of AZD7648 for this module will be dependent on clinical PK 
exposure and emerging safety and tolerability data seen during the monotherapy escalation 
(refer to the Core Module). However, the actual AZD7648 starting dose will be triggered
when the equivalent AZD7648 monotherapy dose cohort is declared tolerated in the Core 
Module. The starting schedule of AZD7648 from 
 dosing, 
 
t (an intermittent within cycle schedule). Therefore, the total per cycle 
dose in the combination is ≤25% of the per cycle dose administered as continuous 
monotherapy.
12.3.2
Justification for pegylated liposomal doxorubicin dose
Although PLD is approved at a dose of 50 mg/m2 every 4 weeks, it is common for patients to 
require a dose reduction to 40 mg/m2 due to AEs such as palmar-plantar erythrodysesthesia, 
stomatitis or haematological toxicity.  Several large studies including combinations (eg, 
AURELIA trial) have deployed a starting dose of PLD of 40 mg/m2.  For these reasons, 
40 mg/m2 has been selected as the starting dose in Combination Module 1.
13
STUDY POPULATION
13.1
Inclusion criteria
Patients are eligible to be included in the study only if all the inclusion criteria apply.  Please 
also refer to Section 5.1 for the inclusion criteria applicable to all modules in the study.  
If the criteria in the modules is different from that in the Core Module criteria, the 
module-specific criteria should be followed.  Inclusion criteria applicable to Combination 
Module 1 only are described in this section.
Part A and B
1
Patients must meet the eligibility criteria described in the Core Module.
2
Suitable for treatment with PLD as per local prescribing information.
3
Left ventricular ejection fraction above the institutional lower limit of normal, assessed by 
echocardiography or MUltiGated Angiography (MUGA).
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Part B only
1
Provision of FFPE specimen from the primary tumour is mandatory.  An archival tissue 
specimen is preferred but a new tissue sample may be used (if, for example, it is routine at 
a site to undertake biopsy of metastatic lesions).  If an archival FFPE specimen is not 
available, a fresh tumour biopsy (FFPE) is mandatory.
2
Histologically confirmed advanced epithelial* ovarian, fallopian tube or primary 
peritoneal cancer which has relapsed within 12 months of completing a minimum of 
4 cycles of platinum-containing chemotherapy regimen and for whom PLD is an 
appropriate therapy.  Time to relapse after last platinum is based on Investigator 
assessment.  Prior maintenance treatment is allowed and does not count as a line of 
therapy, including bevacizumab or PARPi, but treatment must be discontinued prior to 
study entry.
*
Patients with carcinosarcoma histology may be included; patients with stromal, sex 
cord or germ cell tumours are excluded.
3
For platinum-resistant patients, ≤1 prior line of cytotoxic chemotherapy for the treatment 
of platinum-resistant disease.  Patients must have had a radiological or CA-125 response 
to initial chemotherapy in the platinum-resistant setting, with no evidence of disease 
progression within 28 days of completing chemotherapy.
OR
For partially-platinum sensitive patients, there is no restriction on the number of prior 
lines of cytotoxic chemotherapy.
(platinum-resistant is defined as a platinum-free interval of ≤6 months after any line of 
platinum-based chemotherapy or disease progression whilst receiving platinum-based 
chemotherapy in the ≥second-line setting.  Partially-platinum sensitivity is defined as a 
platinum-free interval of > 6 to 12 months after the last line of platinum-based 
chemotherapy.)
4
ECOG performance status performance status 0-1.
5
At least one lesion, not previously irradiated (or with evidence of disease progression 
following radiation), 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 CT or 
MRI and which is suitable for accurate repeated assessment AND/OR patients with an 
assessable Ca 125 by GCIG CA-125 response criteria (pre-treatment sample must be at 
least twice the upper limit of normal within 2 weeks prior to starting treatment).
13.2
Exclusion criteria
Patients must not enter Combination Module 1 of the study if any of the exclusion criteria 
apply.  Please also refer to Section 5.2 for the exclusion criteria applicable to all modules 
in the study.  If the criteria in the modules is different from that in the Core Module criteria, 

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the module-specific criteria should be followed.  Exclusion criteria applicable to Combination 
Module 1 only are described in this section.
Part A and B
1
Any contraindication to the PLD or any excipients as per local prescribing information 
eg, hypersensitivity.  
2
Patients who have had drainage of their ascites during the preceding 4 weeks prior to 
enrolment of the study (patients with indwelling peritoneal catheters are permitted).
3
Patients who have had a previous CTCAE Grade ≥4 haematological toxicity with PLD.
Part B only
1
Patients with platinum refractory disease (defined as disease progression whilst receiving 
first-line platinum-containing therapy or within 1 month of completion).
2
Prior anthracycline therapy, including prior treatment with PLD in any setting.
3
History of clinical symptoms requiring hospital admission for acute bowel obstruction 
within 3 months of study enrolment.
4
History of abdominal fistula, GI perforation, intra-abdominal abscess, rectosigmoid or 
bowel involvement eg, bowel invasion on CT.
5
Prior (or anticipated need for) radiotherapy to pelvis or abdomen, major surgery 
anticipated during study treatment or within 4 weeks before starting study treatment.
13.3
Lifestyle restrictions
Restrictions for PLD should follow the institutional guidelines.
Please refer to Appendix G for contraception restrictions.
14
STUDY TREATMENTS
Study treatment in Combination Module 1 refers to AZD7648 and PLD (Table 14). 

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14.1
Treatments administered
14.1.1
Investigational products
Table 14
Study treatments
Study treatment 
name:
AZD7648
Pegylated liposomal 
doxorubicin
Dosage formulation:
Provided as mg, 
mg, 
mg, and 
mg white 
film-coated oral tablets. The mg and 
mg tablets 
are round. The 
mg and 
mg tablets are caplet 
shaped.
Note: In accordance with Quality IMPD, other 
intermediate strengths may be added at a later date.
2 mg/mL 
suspension/dispersion for 
IV use (eg, Caelyx, Doxil 
or equivalent).
Route of 
administration:
Oral tablets
IV infusion
Starting dose 
instructions:
The starting dose of AZD7648 is dependent on 
emerging data from the Core Module.  AZD7648 will 
be administered 
 
 of PLD.
The starting dose of PLD 
is 40 mg/m2, administered 
by IV infusion once every 
4 weeks, for a maximum 
of 6 cycles.
Packaging and 
labelling:
Study treatment will be provided in high-density 
polyethylene bottles with child-resistant 
polypropylene screw caps.
Each bottle will be labelled in accordance with Good 
Manufacturing Practice Annex 13 and per country 
regulatory requirement.  Label text will be translated 
into local language.
The site must complete the Patient Diary with the 
details of the dosing instructions at the time of 
dispensing.
The site must complete the 
Patient Diary with the 
details of the dosing 
instructions at the time of 
dispensing.
Provider:
AstraZeneca
Sourced by site
14.1.2
Dose escalation scheme
For Combination Module 1, the dose escalation schedule is presented in Figure 9.  When there 
is more than one patient enrolled to a dose cohort, sentinel dosing will be applied with a single 
patient exposed for a minimum of 48 hours after Cycle 1, Day 1 before further patients are 
enrolled at that dose level.  In the absence of any significant toxicities in the first patient, the 
patients for the remainder of the cohort may be enrolled, concurrently or sequentially, based 
upon the decision of the SRC. 
For each cohort in dose escalation a SRC will review the safety of the first and each 
subsequent cohort.
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Figure 9
AZD7648 combinations study flow chart
RP2D=recommended Phase II dose
The starting dose of PLD is 40 mg/m2, administered by IV infusion once every 4 weeks, for a 
maximum of 6 cycles (Table 15).  Patients who are deriving clinical benefit may continue 
AZD7648 beyond 6 cycles as monotherapy in the continuation phase; using a dose and 
schedule declared tolerated in the Core Module.
During Part A (dose escalation), a single dose of AZD7648 will be administered to enable 
collection of blood samples for PK analyses, followed by a drug washout of 
 
 (Figure 10).  The dose of PLD may also be escalated to 50 mg/m2
(or de-escalated to 30 mg/m2) every 4 weeks with agreement of the SRC.  Intermittent 
schedules for AZD7648 will also be explored.
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ad hoc safety reports, AEs from previous cohorts and optional expansions and any other 
emerging data. 
Dose escalation and de-escalation will follow the Bayesian adaptive design described in 
Section 6.1.2. 
14.2
Treatment compliance
PLD will be administered on site and will be recorded in the appropriate section of the CRF.  

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14.3
Concomitant therapy
14.3.1
Effect of pegylated liposomal doxorubicin on other drugs
No formal medicinal product interaction studies have been performed with PLD, although 
Phase II combination trials with conventional chemotherapy agents have been conducted in 
patients with gynaecological malignancies.  Exercise caution in the concomitant use of 
medicinal products known to interact with standard doxorubicin hydrochloride.  PLD, like 
other doxorubicin hydrochloride preparations, may potentiate the toxicity of other anti-cancer 
therapies.  During clinical trials in patients with solid tumours (including breast and ovarian 
cancer) who have received concomitant cyclophosphamide or taxanes, no new additive 
toxicities were noted.  Caution must be exercised when giving any other cytotoxic agents, 
especially myelotoxic agents, at the same time.
14.4
Dose modification
Refer to Section 6.6 for management of treatment related toxicity applicable to all study 
modules. 
If the toxicity does not resolve to the patient’s baseline or to CTCAE Grade ≤2 within 
28 days of onset, treatment with AZD7648 and PLD must be discontinued.  However, if 
toxicity is clearly attributed to PLD alone, the patient is permitted to continue receiving 
AZD7648 as monotherapy following discussion between the Investigator and the AZ Study 
Physician.  If PLD is discontinued due to reasons other than toxicity, AZD7648 monotherapy 
may continue following discussion between the Investigator and the AZ Study Physician.
15
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Table 13). 
15.1
Management of study treatment-related toxicities
At this time, there are limited safety data regarding the combination of AZD7648 and PLD.  
Given the differing mechanisms of action of AZD7648 and PLD, the potential for potentiation 
of toxicities is thought to be limited.  Some toxicities, for example pneumonitis and 
asthenia/fatigue may, on theoretical grounds, be potentiated in the combination arm and 
particular attention should be paid to these.
In the event of toxicity in this combination module of the study which cannot be managed by 
supportive measures alone, stopping one or both study treatments should be an Investigator 
decision based on the available information and, if necessary, following discussion with the 
Sponsor.
The following general guidance should be followed for management of toxicities:

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
Treat each of the toxicities with maximum supportive care (including withholding the 
agent suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned study treatment along with appropriate 
continuing supportive care.  If medically appropriate, dose modifications are permitted for 
AZD7648.  In addition, guidelines on AZD7648 dose modifications are provided in 
Section 6.6 and 14.4.  In the event of toxicity that cannot be managed by following the 
toxicity management guidelines for AZD7648 and PLD, consider stopping treatment.
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken.
Management of PLD related toxicities will be performed in accordance with local practice.
15.2
Echocardiogram
An echocardiogram or MUGA scan will be conducted on all patients at screening for Parts A 
and B, and at the timepoints in the SoA (Table 13). The screening echocardiogram or MUGA 
scan will not be required if a previous echocardiogram or MUGA scan was performed 
6 months prior to screening, unless there has been a change in the patient’s cardiac status.
15.3
Pharmacokinetics
Venous blood samples (2 mL) for determination of concentrations of PLD (as total 
doxorubicin), will be taken at the times presented in the SoA (Table 13) in addition to the 
venous blood samples (2 mL) for determination of concentrations of AZD7648 in plasma. The 
date and time of collection of each sample will be recorded.  Further details can be found in 
Section 8.5. 
Pharmacokinetic samples will be taken at the times indicated in Table 16. 
Table 16
AZD7648 and PLD PK sample collection schedule
Part A
Part B 
Blood for 
AZD7648
Blood for PLD
Blood for 
AZD7648
Blood for PLD
Cycle 0, Day 1
Pre-dose and 
15 minutes (min), 
30 min, 60 min, 
2 hours (h), 4 h, 
6 h, and 8 h 
post-dose
Cycle 0 not 
applicable (NA)
Cycle 0, Day 2
24 h post-dose
NA
Cycle 0, Day 3
48 h post-dose
NA
Cycle 0, Day 4
72 h post-dose
NA

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15.4
Pharmacodynamics
Refer to Section 8.6.1 for further details which also apply to this Module. 
Peripheral blood samples will be collected 4 hours after the start of the PLD infusion and 
2 to 4 hours post-dose for AZD7648 as detailed in Table 17 and the SoAs.  In addition, there 
will be PK samples collected at the same time as PD samples to allow exploration of the 
exposure/ PD relationships (see Table 16).  The exact time of PD samples collection will be 
noted. 
CCI

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Biological samples will be collected as detailed in the Laboratory Manual for the reasons 
listed below:

To carry out retrospective central confirmation and prospective screening, when required 
(Part B only).

Alternative biomarkers may be evaluated as determined by additional data associated with 
disease progression or response to study drugs evaluated as part of this protocol.
16
STATISTICAL CONSIDERATIONS
16.1
Interim analysis
One interim analysis is planned during Part B of the study, as described in . 
Table 18
Interim analysis
Drug combination (module)
Population
TV%
LRV%
Sample 
size (N)
Interim 
(n)
AZD7648 + PLD 
(Combination Module 1)
Acquired platinum-resistant 
ovarian cancer 
30
15
37
21
LRV=lower reference value; PLD=pegylated liposomal doxorubicin; TV=target value.
The sample size for the interim analysis has been determined by Lalonde criteria set for ORR 
(LRV% and TV% defined in Table 18).  The sample size ensures success (Go) if there is a 
≥80% chance of exceeding the LRV and stop if there is < 10% chance of exceeding the TV.  
Recruitment will not be stopped for the interim analysis.
The SAP will describe the planned interim analysis in greater detail.
16.2
Sample size determination
Part A will require approximately 30 evaluable patients across approximately 5 cohorts 
(n = 3 to 6 per cohort) to provide a model-based estimate of MTD within target toxicity 
(30%).  Once MTD has been determined, an additional 30 evaluable patients may be recruited 
to investigate intermittent dosing schedules. If two schedules recruit patients at the same time, 
a patient systematic allocation algorithm will be followed.
Part B will require approximately 37 evaluable patients with advanced platinum-resistant 
ovarian cancer.

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17
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Shintani S, Mihara M, Li C, Nakahara Y, Hino S, Nakashiro K, et al. Up-regulation of DNA-
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Van Bussel et al 2017
Van Bussel M, Mau-Soerensen M, Damstrup L, Nielsen D, Verheul HMW, Aftimos PG. A 
multicentre phase I trial of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814 in 
patients with solid tumors. J Clin Oncol 35, 2017 (suppl: abstr 2556).
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Van Triest B, Damstrup L, Falkenius J, Budach V, Troost E, Samuels M, et al. A phase 1a/1b 
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18
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 International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines.

Applicable laws and regulations.
The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure, and 
other relevant documents (eg, advertisements) must be submitted to an institutional review 
board (IRB)/independent ethics committee (IEC) by the Investigator, Sponsor or designee 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 serious adverse events (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.
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 

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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 authorised representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary.  Patients or their legally 
authorised 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 
centre.
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 authorised 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 authorised 
representative.
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
If a patient’s partner becomes pregnant during or within 6 months after the study, the partner 
will be asked to sign the "Adult Study Informed Consent Form for Pregnant Partners of Study 
Patients" and provide information about the pregnancy accordingly.
A patient who is rescreened is not required to sign another ICF if the rescreening occurs 
within 28 days from the previous ICF signature date.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The Investigator or authorised 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 

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documented.  If samples already have been analysed 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 authorised personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from Regulatory authorities.
A 5
Committees structure
No Data Monitoring Committee will be used in this study; however a safety review committee 
(SRC) will closely monitor patient safety on an ongoing basis.  The SRC Members will 
include the following:

Principal Investigator, or delegate, who will chair the committee

Study Chair (if not Principal Investigator)

Principal Investigator or delegate from investigational site

AstraZeneca Medical Science Director or delegate

AstraZeneca Global Safety Physician, or delegate
The Sponsor or Clinical Research Organisation Medical Monitor, or delegate, should always 
be present at the SRC.
The AstraZeneca Clinical Pharmacology Scientist, study Statistician, Patient Safety Scientist, 
study Leader and other AstraZeneca and non-AstraZeneca technical experts may also be 
invited as appropriate.  The SRC Remit document for this study will define the exact 
membership and who will be present for decisions to be made. 
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on 
https://astrazenecagrouptrials.pharmacm.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.

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A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic case report form 
(CRF) unless transmitted to the Sponsor or designee electronically (eg, laboratory data).  The 
Investigator is responsible for verifying that data entries are accurate and correct by physically 
or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
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 CRF by authorised 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 CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The Investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Source data may include but is not limited to: medical history and physical examination notes, 
hospital discharge summary, autopsy report when available, results of relevant diagnostic tests 
completed.

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A 9
Study and site closure 
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and 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 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.
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 multi-centre studies only in their entirety and not as individual site data.  In this 
case, a co-ordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix B
Adverse 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 unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardise the 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 (eg, hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the 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 judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the patient or may require 
medical treatment to prevent 1 or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment.

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine.

Intensive treatment in an emergency room or at home for allergic bronchospasm.

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation.

Development of drug dependency or drug abuse.
B 6
Intensity rating scale:
The grading scales found in the revised National Cancer Institute common terminology 
criteria for adverse event (CTCAE) version 5.0 will be utilised for all events with an assigned 
CTCAE grading.  For those events without assigned CTCAE grades, the recommendation in 
the CTCAE criteria that converts mild, moderate and severe events into CTCAE grades 
should be used.  A copy of the CTCAE can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov).
It is important to distinguish between SAEs 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 aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped?  AstraZeneca would not normally recommend or support a 
rechallenge.

Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgement.  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 treatment 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 whilst 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 patient received the drug.

did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the patient.

Drug not administered as indicated, for example, wrong route or wrong site of 
administration.

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature.

Wrong patient received the medication.

Wrong drug administered to patient.
Examples of events that do not require reporting as medication errors in clinical studies:

Patient accidentally missed drug dose(s) eg, forgot to take medication.

Accidental overdose (will be captured as an overdose).

Patient 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 life cycle.
The Investigator at each centre keeps full traceability of collected biological samples from the 
patients whilst in storage at the centre until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples whilst 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 analysed,
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 organisation(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 organisations 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
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm).  For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005).  Infectious 
substances are now classified either as Category A, Category B or Exempt.  There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are eg, Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2.  They are assigned the following UN number 
and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical 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
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient’s DNA, ie, the 
entire genome.
The results of genetic analyses may be reported in the CSR or in a separate study summary.
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained whilst research on the study treatment in this protocol continues 
but no longer than 15 years or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of Genetic Research Population
Study Selection Record
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.

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Inclusion Criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP and provide informed consent for the genetic sampling and 
analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant.

Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
Withdrawal of Consent for Genetic Research:
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7 of the main 
CSP.
Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the patients at the Cycle 1, Day 1
Visit.  Although DNA is stable, early sample collection is preferred to avoid introducing bias 
through excluding patients who may withdraw due to an AE, such patients would be important 
to include in any genetic analysis.  If for any reason the sample is not drawn at the Cycle 1, 
Day 1 Visit, it may be taken at any visit until the last study visit.  Only 1 sample should be 
collected per-patient for genetics during the study.  Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 

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organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).
The link between the patient enrolment code and the second number will be maintained and 
stored in a secure environment, with restricted access at AstraZeneca or designated 
organisations.  The link will be used to identify the relevant DNA samples for analysis, 
facilitate correlation of genotypic results with clinical data, allow regulatory audit, and permit 
tracing of samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed Consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient Data Protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the patient’s medical information and the 
genetic files would remain physically separate.

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Data Management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health-related research purposes.  Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A statistical 
analysis plan may be prepared where appropriate.

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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 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 
Medicinal Product (IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAEs) and AEs according to the outcome of the review 
and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× ULN together 
with total bilirubin (TBL) ≥ 2×ULN at any point during the study following the start of study 
treatment, irrespective of an increase in alkaline phosphatase (ALP).

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Hy’s Law (HL)
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other reason, other than the 
study treatment, can be found to explain the combination of increases, eg, elevated ALP 
indicating cholestasis, viral hepatitis, another drug.
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified 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 ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Determine whether the subject meets PHL criteria (see Section E2 Definitions within this 
Appendix for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF.
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 CSP.
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 Appendix E, Section 6. Actions Required When Potential Hy’s Law 
Criteria are Met Before and After Starting Study Treatment).

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 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

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
For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change# in the subject’s condition

The Study Physician contacts the Investigator to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data

Subsequent to this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated.  Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician.

Complete the three Liver CRF Modules as information becomes available.
E 5
Review and assessment of potential Hy’s Law cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date the 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 patient 
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 CRF.

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE CRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes:

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
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan.  Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met.  Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review 
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 Appendix E, 
Section 4.2.
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator, this 
may be in consultation with the study Physician if there is any uncertainty.
E 7
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.

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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, eg, chronic or progressing malignant disease, severe infection 
or liver disease, or did the patient meet PHL criteria prior to starting study treatment and 
at first on study treatment visit, as described in Section 6 of this Appendix
If No: Follow the process described in Appendix E, Section 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 Appendix E, Section 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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms.  The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the study Physician if there is any uncertainty.

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Appendix F
Guidance Regarding Potential Interactions with Concomitant 
Medications
F 1
Restrictions regarding drugs affecting CYP3A4
There are currently no data confirming that there is a pharmacokinetic interaction between 
these agents and AZD7648; any potential interaction is considered on the basis of preclinical 
and in vitro human data only.  The principal enzymes for metabolising AZD7648 are CYP3A, 
therefore potent cytochrome P450 3A4 (CYP3A4) inhibitors or inducers may increase or 
decrease exposure to AZD7648, respectively.  Potent inhibitors or inducers of CYP3A4 
should not be combined with AZD7648.  Moderate CYP3A inhibitors and inducers should be 
used with caution.
These lists are not intended to be exhaustive, and similar restrictions will apply to other agents 
that are known to modulate CYP3A4 activity.  Appropriate medical judgement is required.  
Please contact AstraZeneca with any queries you have on this issue.  Please refer to full 
prescribing information for all drugs prior to co-administration with AZD7648.
Table 1
Drugs Known to be Inhibitors of CYP3A
Potent CYP3A4 inhibitors may increase exposure to 
AZD7648
boceprevir
clarithromycin
conivaptan
elvitegravir/ritonivir
fluconazole
grapefruit juiceab
indinavir
itraconazole
ketoconazole
lopinavir/ RIT
mibefradil
nefazodone
nelfinavir
posaconazole
ritonavir
saquinavir
telaprevir
telithromycin
tipranavir/ ritonivir
troleandomycin
voriconazole
List created using the University of Washington Drug-Drug Interaction Database January 2013.
a
Double-strength grapefruit juice.

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b
Patients should abstain from eating large amounts of grapefruit and Seville oranges (and other products 
containing these fruits eg, grapefruit juice or marmalade) during the study (eg, no more than a small glass of 
grapefruit juice (120 mL) or half a grapefruit or 1-2 teaspoons (15 g) of Seville orange marmalade daily)
Table 2
Drugs Known to be Potent Inducers of CYP3A4
Potent Inducers (AZD7648 AUC may decrease or CL 
increase)
avasimibe
carbamazepine
enzalutamide
mitotane
phenobarbital
phenytoin
rifabutin
rifampin
St John's Wort
AUC=area under curve; CL= apparent total body clearance.
[Not available on the US market].  
a
Ritonavir has dual effects of simultaneous CYP3A inhibition and induction, and the net pharmacokinetic 
outcome during chronic ritonavir therapy is inhibition of CYP3A activity.

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Appendix G
Acceptable Birth Control Methods
Pegylated liposomal doxorubicin is regarded as a compound with medium/high foetal 
risk.
Women of childbearing potential and their partners, who are sexually active, must agree to the 
use of one highly effective form of contraception [as listed below] and their partners must use 
a male condom.  This should be started from the signing of the informed consent and continue
throughout the period of taking study treatment and for 12 weeks after last dose of study 
drug(s), or they must totally/truly abstain from any form of sexual intercourse (see below).
Male patients must use a condom from the signing of the informed consent, during treatment 
and for 12 weeks after the last dose of study drug(s) when having sexual intercourse with a 
pregnant woman or with a woman of childbearing potential.  Female partners of male patients 
should also use a highly effective form of contraception if they are of childbearing potential 
(as listed below).  Male patients should not donate sperm throughout the period of taking 
study drug(s) and for 12 weeks following the last dose of study drug(s).
Acceptable non-hormonal birth control methods include:

Total/True abstinence: When the patient refrains from any form of sexual intercourse and 
this is in line with their usual and/or preferred lifestyle; this must continue for the total 
duration of the trial and for 12 weeks after the last dose of study drug. Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods, or declaration of 
abstinence solely for the duration of a trial) and withdrawal are not acceptable methods of 
contraception.

Vasectomised sexual partner PLUS male condom.  Vasectomised partner is a highly 
effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical 
assessment of the surgical success.

Tubal occlusion PLUS male condom.

IUD PLUS male condom.  Provided coils are copper-banded.
Acceptable hormonal methods:

Normal and low dose combined oral pills PLUS male condom.

Cerazette (desogestrel) PLUS male condom.  Cerazette is currently the only highly 
efficacious progesterone based pill.

Hormonal shot or injection (eg, Depo-Provera) PLUS male condom.

Etonogestrel implants (eg, Implanon, Norplant) PLUS male condom.

Norelgestromin / EE transdermal system PLUS male condom.

Intrauterine system [IUS] device (eg, levonorgestrel releasing IUS -Mirena®) PLUS male 
condom.

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
Intravaginal device (eg, EE and etonogestrel) PLUS male condom.

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Appendix H
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
Introduction
This Appendix details the implementation of response evaluation criteria in solid tumours 
(RECIST) 1.1 guidelines (Eisenhauer et al, 2009) for the study with regards to Investigator 
assessment of tumour burden including protocol-specific requirements for this study.
Definition of Measurable, Non-measurable, Target and Non-target Lesions
Patients with at least 1 lesion (measurable and/or non-measurable) that can be accurately 
assessed at baseline by computed tomography (CT), MRI or plain X-ray should be included in 
this study.  Patients with previously irradiated TLs can be included in this study provided that 
there has been progression in the irradiated site following the treatment.
Measurable Lesions
A lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10 mm in 
the longest diameter (except lymph nodes) which must have a short axis ≥ 15 mm with CT or 
MRI and which is suitable for accurate repeated measurements.
Non-measurable Lesions

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 mm to < 15 mm short axis at baseline).  Nodes with < 10 mm 
short axis are considered non-pathological and should not be recorded as non-target 
lesions (NTLs).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that are not measurable by CT or MRI.

Previously irradiated lesions as localised post-radiation changes, which affect lesion sizes, 
may occur.  Therefore, lesions that have been previously irradiated will not be considered 
measurable and should be selected as NTLs at baseline and followed up as part of the 
NTL assessment.

Skin lesions assessed by clinical examination.

Brain metastasis.
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.

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
Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in the 
same patient, these non-cystic lesions should be selected as the TLs.
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 TLs 
at baseline.
Non-target Lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline.
Methods of Measurement
The Same Method of Assessment and the Same Technique Should Be Used to 
Characterise Each Identified and Reported Lesion at Baseline and During Follow-up.
The methods to be used for RECIST assessment are summarised in Table 1 and those 
excluded for tumour assessments in this study are discussed below, with the rationale 
provided.
Table 1
Summary of Methods of Assessment
Target Lesions
Non-target lesions
New Lesions
CT (preferred)
MRI
CT (preferred)
MRI
Plain X-ray (includes chest X-
ray)
Clinical examination 
CT (preferred)
MRI
Plain X-ray (includes chest X-
ray)
Clinical examination
Ultrasound
Bone scan
FDG-PET
CT and MRI 
CT and MRI are generally considered to be the best currently available and reproducible 
methods to measure TLs selected for response assessment and to assess NTLs and 
identification of new lesions.
In this study it is recommended that CT examinations will be used to assess tumour burden at 
baseline and follow-up visits.  CT examination with intravenous contrast media administration 
is the preferred method.  MRI should be used where CT is not feasible or it is medically 
contraindicated.  For assessment of brain lesions MRI is the preferred method.

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Clinical Examination 
Clinical examination will not be used for assessment of TLs.  Clinically detected lesions can 
be selected as TLs if they are then assessed by CT or MRI scans.  Clinical examination can be 
used to assess NTLs in patients that also have other lesions assessable by CT, MRI or plain X-
ray and to identify the presence of new lesions.
X-rays
Plain X-ray
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
Chest X-rays will not be used for assessment of TLs as they will be assessed by CT or MRI 
examination.  Chest X-rays can, however, be used to assess NTLs and to identify the presence 
of new lesions.
Ultrasound 
Ultrasound examination will not be used for assessment of TLs and NTLs as it is not a 
reproducible method, does not provide an accurate assessment of tumour size and it is 
subjective and operator dependent.  Ultrasound examination can, however, be used to identify 
the presence of new lesions.  If new clinical symptoms occur and an ultrasound is performed 
then new lesions should be confirmed by CT or MRI examination.
Endoscopy and Laparoscopy
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour measurements.
Tumour Markers 
Tumour markers will not be used for tumour response assessments per RECIST 1.1.
In this study the following marker, 
, is being collected for separate analysis.  However 
the results will not contribute to tumour response based on RECIST 1.1 assessment.
Cytology and Histology 
Histology will not be used as part of the tumour response assessment per RECIST 1.1. 
CCI

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Cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment is required when the measurable tumour has met criteria for response or 
stable disease (SD).  In such circumstances, the cytology is necessary to differentiate between 
response/SD (an effusion may be a side effect of the treatment) and progressive disease (if the 
neoplastic origin of the fluid is confirmed).  Where cytology findings are not available, any 
effusion that significantly worsens (from trace to large) or the appearance of a clinically 
significant effusion (requiring change in drug therapy) during the study treatment will be 
considered to be progression of NTLs or disease progression due to new lesions.
Isotopic Bone Scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI or X-
ray at baseline should be recorded as NTLs and followed by the same method as per baseline 
assessment.
Isotopic bone scans may 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 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.  Confirmation by CT, MRI and X-ray is recommended where bone scan 
findings are equivocal.
FDG-PET Scan 
FDG-PET (fluorodeoxyglucose positron emission tomography) 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 (defined as when an uptake greater than twice 
that of the surrounding tissue is observed) 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.
Tumour Response Evaluation 
Schedule of Evaluation
Baseline tumour assessments should encompass all areas of known predilection for metastases 
in the disease under evaluation and should additionally investigate areas that may be involved 
based on signs and symptoms of individual patients and should be performed no more than 
28 days before the start of study treatment.  In Combination module 1, follow-up assessments 

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should be performed every 8 weeks (± 1 week) after the start of treatment until 
discontinuation of study treatment or withdrawal of consent.  
If AZD7648 is combined with any immuno-oncology drugs (in future combination modules)
modified RECIST will be used in an exploratory analysis. If progression is not confirmed, 
then the overall visit response as per modified RECIST should be assessed as SD/partial 
response (PR) or CR and the patient should continue scheduled RECIST 1.1. CT/MRI scans.  
If progression is confirmed the overall visit response should be assessed as progressive disease 
as per modified RECIST.
Target Lesions
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 TLs at baseline.  
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions) but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest 
lesion, which can be measured reproducibly, should be selected.
The site and location of each TL should be documented as well as the longest diameter for 
non-nodal lesions (or short axis for lymph nodes).  All measurements should be recorded in 
millimetres.  At baseline, the sum of the diameters for all TLs will be calculated and reported 
as the baseline sum of diameters.  At follow-up visits the sum of diameters for all TLs will be 
calculated and reported as the follow-up sum of diameters.  
Special Cases:

For TLs measurable in 2 or 3 dimensions, always report the longest diameter.  For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis. 

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the 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 TLs merge then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s).

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned.  If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.

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
When a TL has had any intervention eg, radiotherapy, embolisation, surgery etc, during 
the study, the size of the TL should still be provided where possible.
Evaluation of target lesions
Table 2 provides the definitions of the criteria used to determine objective tumour visit 
response for TLs.
Table 2
Overall Visit Response for Target Lesions
Complete Response (CR)
Disappearance of all TLs since baseline.  Any pathological 
lymph nodes selected as TLs must have a reduction in short axis 
to < 10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Progressive Disease
At least a 20 % increase in the sum of diameters of TLs, 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 TLs 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 NE as a TL response.
Non-Target lesions
Evaluation of Non-target Lesions
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs 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.  Table 3 provides the definitions of the criteria used to determine 
and record overall response for NTLs at the investigational site at each visit.
Table 3
Overall Visit Response for Non-Target Lesions
Complete Response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (< 10 mm short axis).
Non-CR/Non-progressive 
disease
Persistence of 1 or more NTLs.

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Table 3
Overall Visit Response for Non-Target Lesions
Progressive Disease
Unequivocal progression of existing NTLs.  Unequivocal 
progression may be due to an important progression in 1 lesion 
only or in several lesions.  In all cases the progression MUST 
clinically significant for the physician to consider changing or 
stopping therapy.
Not Evaluable (NE)
Only relevant when 1 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.
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit discontinuation of therapy.  A 
modest ‘increase’ in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status.
New Lesions
Details of any new lesions will also be recorded with the date of assessment.  The presence of 
1 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: ie, not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
If a new lesion is equivocal, for example because of its small size, the treatment and tumour 
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.
Patients with ‘symptomatic deterioration’ requiring discontinuation of study treatment without 
objective evidence of disease progression at that time will undergo no further tumour 

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assessments in this study.  Tumour response data for such patients will be censored at the date 
of their last RECIST assessment.
Evaluation of Overall Visit Response and Best Overall Response
The overall visit response will be derived using the algorithm shown in Table 4.
Table 4
Overall Visit Response
Target lesions
Non-Target lesions
New Lesions
Overall response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-progressive 
disease
No
PR
CR
NE
No
PR
PR
Non- progressive disease 
or NE
No
PR
SD 
Non- progressive disease 
or NE
No
SD
NA
Non-CR/Non- progressive 
disease
No
SD (Non-CR/non-
progressive disease)
NE
Non- progressive disease 
or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
progressive disease
Any
progressive disease
Yes or No
progressive disease
Any
Any
Yes
progressive disease
CR = complete response, PR = partial response, SD = stable disease, IR = incomplete response, NE = not 
evaluable, NA = not applicable (relevant when no TLs/NTLs at baseline)
Specifications for Radiological Imaging
These notes are recommendations for use in clinical studies.  The use of standardised 
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.  

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The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST 1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
Anatomic Coverage
Optimal anatomic coverage for most solid tumours is the chest, abdomen and pelvis.  
Coverage should encompass all areas of known predilection for metastases in the disease 
under evaluation and should additionally investigate areas that may be involved based on 
signs and symptoms of individual patients.  Because a lesion later identified in a body part not 
scanned at baseline would be considered as a new lesion representing disease progression, 
careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points.  This will enable better consistency not only of tumour 
measurements but also identification of new disease.
Intravenous Contrast Administration
Optimal visualisation and measurement of metastases in solid tumours 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 tumour type, anatomic 
location of the disease and should be optimised 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 
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 CT 
without intravenous contrast is an option for the thorax, abdomen and pelvic examinations.  
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 

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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 optimised for the specific body part being imaged as 
well as the scanner utilised.  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.
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 min 
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 can assess 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 min 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 trial.

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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 tumour
measurements by RECIST 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.
REFERENCES
Eisenhauer et al, 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  European 
Journal of Cancer 2009;45:228-247.
Wolchok et al, 2009
Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, et al.  Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria.  Clin 
Cancer Res 2009;15:7412-20.

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Appendix I
Food Effect Cohort Plan
Summary

The food effect cohort of the study comprises a cross over design.

Each patient in the food effect cohort will initially receive a single oral dose of AZD7648 
(dose to be decided by the SRC) on Cycle 0, Day 1 in either the fasted or fed state.  The 
Parexel project manager (in appropriate consultation with AZ study team) will advise 
each site on whether a particular patient participating in the food effect cohort has been 
allocated to the fed or fasted group for their Cycle 0, Day 1 dose. 

The patient will then cross over to receive their single Cycle 1, Day 1 dose in the opposite 
state to their Cycle 0, Day 0 dose.  So, if the patient had the Cycle 0, Day 1 dose in the 
fasted state, the Cycle 1, Day 1 dose will be taken in the fed state, after a high fat 
breakfast meal.  If the patient had the Cycle 0, Day 1 dose in the fed state, the Cycle 1, 
Day 1 dose will be taken in the fasted state (water only for ≥2 hours prior to taking a dose 
to ≥1 hour post-dose).  The Cycle 1, Day 1 dose should be given in the morning at least 
72 hours after the Cycle 0, Day 1 dose.
Meal and Timing Requirements 

Please note that for the fasted state, patients must fast (water only) for ≥10 hours prior to 
taking a dose to ≥2 hour post-dose.  For the fed state patients must fast overnight 
(minimum of 10 hours) prior to consuming a standardised meal in the clinic.

For the fed dosing day, the meal should consist of about 800 to 1000 total calories, with 
around 54% of the calorific content made up from fat.  The dose should be administered 
with 240 mL of water.

Patients should ideally start the recommended meal 30 min prior to planned 
administration of the study drug and aim to consume at least 75% of the meal within 
30 min. 

If the patient takes less than 30 min to complete the meal, it is still expected that the drug 
is dosed not earlier than 30 min after the start of the meal.

If the patient is unable to consume at least 75% of the meal within 30 min an additional 
15 min will be allowed.

The study drug should be administered after a minimum of 75% of the meal is completed 
between 30 min and up to 45 min after starting the meal. 

Please note that patients will only be considered evaluable for the food effect cohort if 
they eat at least 75% of their meal within a maximum of 45 min.  Patients will remain in 
the Part A continuous scheduling cohort and should continue to receive their dose and 
undergo planned sampling/procedures even if they have been unable to consume the 
required amount of food within the 45 min window, but will not be considered evaluable 
for the food effect cohort.

After Cycle 1, Day 1 patients may continue to receive AZD7648 monotherapy 
(continuous dosing) and all dosing from that point onwards must be administered in the 
fasted state. 

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
Pharmacokinetic samples will be taken at the times indicated in the study protocol.

Please note that patients with insulin-dependent diabetes must be excluded from the food 
effect cohort(s).  Eligibility of patients with Diabetes Type I or uncontrolled Type II 
(HbA1c > 7 mmol/L assessed locally) will be judged by the Investigator. 
Summary of 5 High-fat Breakfast Meals
In accordance with FDA guidance (FDA Guidance for Industry 2002), the high fat meal 
should have a total of approximately 800 to 1000 kcal, with approximately 50-60% of the 
calorific content made up from fat.  The meal should therefore derive approximately 150, 250 
and 500 to 600 kcal from protein, carbohydrate and fat respectively, as shown in Table 1.
Some high fat breakfast meal examples are given in Table 2 to Table 6.  The exact 
composition of the meal may vary as long as the totals are similar to those detailed in Table 1. 
Table 1
Calorie Composition
Protein (kcal)
Carbohydrate 
(kcal)
Fat (kcal)
Total (kcal)
Fat (%)
Target
150
250
500-600
800-1000
50
Regular
215
266
543
1000
54.3
Gluten Free
197.2
232
497
890
53.5
Lactose Free
198
252
504
956
53
Vegetarian
161.4
208
449
800
56
Table 2
Regular High Fat
Kcals
Fat
CHO
Protein
1 cup whole milk
150
8
12
8
1/2 cup cheerios 
(1 container) 
70
1
14
1
1/2 slice French toast
110
3.5
15.5
4.5
2 turkey sausage patties
160
12
-
14
3.5 oz scrambled eggs
160
11.89
4
13.36
2 slices provolone cheese
160
12
2
10
1 slice toast
80
1
15
3
3 packets butter
100
11
-
-
1 sugar free syrup
10
-
4
-

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Kcals
Fat
CHO
Protein
Totals
60.39g
66.5g
53.86g
1000 kcal
543 kcal
266 kcal
215 kcal
54.3% kcals
26.6% kcals
21.5% kcals
Table 3
Gluten Free High Fat
Kcals
Fat
CHO
Protein
1 cup whole milk
150
8
12
8
3/4 cup cereal (rice chex 
1 container)
70
-
16
1
1 slice gluten-free bread
120
2.5
23
2
1 pouch cream cheese
70
7
1
1
2 turkey sausage patties
160
12
-
14
3.5 oz scrambled eggs
160
11.89
4
13.36
2 slices provolone cheese
160
12
2
10
Totals
53 g
58g
49.3g
890 kcals
477 kcal
232 kcals
197.2 kcals
53.5%
26%
22%
Table 4
Lactose Free High Fat
1 cup Lactaid whole milk
160
8
13
8
2 hard-boiled eggs
156
10
2
12
3 turkey sausage
240
18
-
21
1 slice whole grain toast
120
3
19
5
3 packets butter
100
11
-
-
½ Belgium waffle 
170
6
25
3.5
1 sugar free syrup
10
4
Totals
956 kcals
56g
63g
49.5g
504 kcal
252 kcal
198 kcal
53%
26.3%
20.7%

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Table 5
Vegetarian High Fat
1 cup whole milk
150
8
12
8
1 slice French toast
220
7
31
9
1 sugar free syrup
10
-
3
-
3 packets butter
100
11
-
-
3.5 oz scrambled eggs
160
11.89
4
13.36
2 slices provolone cheese
160
12
2
10
Totals
49.89 g
52g
40.36g
800 kcals
449 kcal
208 kcal
161.4 kcal
56%
26%
20%
Table 6
Continental Breakfast
Kcals
Fat
CHO
Protein
Tea/ coffee 
0 
0 
0 
0 
Yogurt 
176 
13 
7 
6 
Cheese 
152 
11 
0 
11 
Bread 
110 
0 
24 
3 
1 croissant 
189 
9 
23 
4 
butter 
147 
16 
0 
0 
sugar 
40 
0 
10 
0 
Ham (2 slices) 
143 
7 
0 
20 
Totals
57
64
45
959 kcals
519 kcals
258 kcals
181 kcals
54%
27%
19%
FDA Guidance for Industry 2002
Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. Department of Health and 
Human Services Food and Drug Administration Center for Drug Evaluation and Research 
(CDER). December 2002. Available at: 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm070241.pdf. Accessed 16 October 2018.

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Appendix J
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis 
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.  
J 1
Reconsent of Study Patients During Study Interruptions
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections J 2 to J 5. Local and regional regulations and/or guidelines regarding 
reconsent of study patients should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the informed 
consent form [ICF] should be signed at the patient’s next contact with the study site). Visiting 
the study sites for the sole purpose of obtaining reconsent should be avoided. 
J 2
Rescreening of Patients To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrolment into the study or commencing of dosing with investigational 
product. If this delay is outside the screening window specified in in the appropriate 
Schedule of Assessment Table, the patient will need to be rescreened to reconfirm eligibility 
before commencing study procedures. This will provide another opportunity to re-screen a 
patient in addition to that detailed in Section 5.4. 
J 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified Health Care Professional (HCP) from the study site or third-party vendor service 
will visit the patients home / or other remote location as per local standard operating 

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procedures (SOPs), as applicable. Supplies will be provided for a safe and efficient visit. The 
qualified HCP will be expected to collect information per the clinical study protocol (CSP).
J 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow adverse events, concomitant medication, Eastern Cooperative 
Oncology Group performance status (ECOG PS) to be reported and documented.
J 5
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of investigational 
product may be performed by a qualified HCP, provided this is acceptable within local 
regulation/guidance, or by the patient or his/her caregiver. The option of at-home or remote 
location investigational product administration ensures patients safety in cases of a pandemic 
where patients may be at increased risk by traveling to the site/clinic. This will also minimize 
interruption of investigational product administration during other study disruptions, eg, site 
closures due to natural disaster. All necessary supplies and instructions for administration and 
documentation of investigational product administration will be provided if site is able to 
complete all safety assessments as per CSP.
J 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or third-party vendor service, or by the patient themselves eg, details 
of self-administration of study medication in diary card.

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Appendix K
Abbreviations
Abbreviation or special 
term
Explanation
AE
adverse event
ALP
alkaline phosphatise
ALT
alanine aminotransferase
AML
acute myeloid leukaemia 
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATM
ataxia telangiectasia mutated
ATR
ataxia telangiectasia and Rad3-related protein
AUC
area under the curve 
 
BRCAm
breast cancer gene 1 and 2 mutations
CAP
College of American Pathologists 
CI
confidence interval 
CLIA
Clinical Laboratory Improvement Amendments 
Cmax 
maximum plasma concentration
Cmin,ss 
minimum plasma concentration at steady state
COVID-19
coronavirus disease 2019
CR
complete response 
CrCl
creatinine clearance 
CRF
case report form (electronic/paper)
CSP
clinical study protocol 
CSR
clinical study report
CT
computed tomography
CTCAE
common terminology criteria for adverse event
CYP3A4
cytochrome P450 3A4
DCO
data cut-off 
DDR
DNA damage response agent
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DNA-PK 
DNA-dependent protein kinase
DNA-PKcs
DNA-dependent protein kinase catalytic subunit
CCI
CCI
CCI
CCI
CCI
CCI

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Abbreviation or special 
term
Explanation
DSB
double-strand break
ECG
electrocardiogram
ECHO
echocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
EDTA
ethylenediaminetetraacetic acid
FDA
food and drug administration 
FFPE
formalin-fixed paraffin embedded
FTIH
first time in human
gBRCAm
germline breast cancer gene 1 and 2 mutations
GCP
good clinical practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal 
HCP
Health Care Professional
HNSTD
highest non-severely toxic dose
h
hour
HR
homologous recombination
HL
Hy’s Law
IB
Investigator’s brochure
ICF
informed consent form
ICH
international conference on harmonisation
IEC
independent ethics committee 
INR
international normalised ratio
IRB
institutional review board
IV
intravenously 
MBAD
minimum biologically active dose
MDS
myelodysplastic syndrome 
MedDRA
medical dictionary for regulatory activities
MFD
maximum feasible dose
Min
minute
mPFS
median progression-free survival
mRECIST
modified response evaluation criteria in solid tumours (RECIST) 1.1
MRI 
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
MUltiGated Angiography
CCI
CCI

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Abbreviation or special 
term
Explanation
NA
not applicable 
NE 
not evaluable 
NHEJ
non-homologous end joining
NOACs
new oral anticoagulants
NTL
non-target lesions
ORR
objective response rate
OS
overall survival
PARPi
poly ADP ribose polymerase inhibitor
PD
pharmacodynamics
PD-L1
programmed death-ligand 1
PDX
patient-derived xenograft
PFS
progression-free survival
PGx
pharmacogenetic sample
PHL
potential Hy’s Law
PIKK
phosphatidylinositol 3-kinase-related kinase
PK
pharmacokinetics
PLD
pegylated liposomal doxorubicin
PoC
proof of concept
PR
partial response 
 
QTc
corrected QT interval
RECIST
response evaluation criteria in solid tumours
RNA
ribonucleic acid
RP2D
recommended Phase II dose
SAE
serious adverse event 
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease 
STD 10
severely toxic dose in 10% of the animals
SoA
schedule of assessments 
SRC
safety review committee
SSB
single-strand break
t1/2 
half-life 
TL
target lesion 
CCI
CCI
CCI
CCI

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Abbreviation or special 
term
Explanation
tmax 
time to reach maximum plasma concentration 
TBL
total bilirubin
TSH
thyroid-stimulating hormone
ULN
upper limit normal 
US
United States
WOCBP
women of child-bearing potential

SIGNATURE PAGE
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Document Name: d9170c00001-csp-v5
Document Title:
D9170C00001 Clinical Study Protocol Version 5
Document ID:
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