Clinical trial NCT04590248
Conditions: Uterine Serous Carcinoma
Keywords: Adavosertib Phase 2b open-label single-arm
Sponsor: AstraZeneca
Start date: 2020-11-30; Completion date: 2023-02-07
Enrollment: 109 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 2b study aims to evaluate the efficacy and safety of adavosertib, an inhibitor of the tyrosine kinase WEE1, in subjects with recurrent or persistent uterine serous carcinoma (USC) who have previously received at least 1 prior platinum-based chemotherapy regimen for the management of USC.

Detailed description:
This Phase 2b, open-label, single-arm, multi-center study will assess the efficacy and safety of adavosertib in eligible subjects with histologically confirmed recurrent or persistent USC, evidence of measurable disease as per Response Evaluation Criteria in Solid Tumors.(RECIST) v1.1, and who have received at least 1 prior platinum-based chemotherapy regimen for the management of USC. Subjects with carcinosarcomas are not eligible.

Arms: arm 1: Subjects will receive adavosertib 300 mg administered orally, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle.
Interventions: intervention 1: Adavosertib
Intervention descriptions: intervention 1: The subjects will receive oral adavosertib 300 mg, once daily on Days 1 to 5 and Days 8 to 12 of a 21-day treatment cycle.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol – 6.0
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Clinical Study Protocol 
Study Intervention
Adavosertib (AZD1775)
Study Code
D601HC00002
Version
6.0 
Date
20 May 2022
   
A Phase 2b, Open-label, Single-arm, Multi-centre Study Assessing 
the Efficacy and Safety of Adavosertib as Treatment for Recurrent 
or Persistent Uterine Serous Carcinoma (ADAGIO)
Sponsor Name: 
Legal Registered Address: 
AstraZeneca AB, S-151 85 Södertälje, Sweden.  
Regulatory Agency Identifier Number(s):
EudraCT number: 2020-000138-16
IND number: 147430


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VERSION HISTORY
Version 1.0, 25 June 2020
Initial creation
Version 2.0, 30 July 2020
The protocol was revised to address the FDA recommendations received on 17 and 28 July 2020:
Section 8.3.13.1 was updated to reflect changes in the haematologic toxicity dose modifications 
management. 

Table 11 was revised to reflect the following: 

A second instance of Grade 3 neutropenia with documented infection and/or fever should 
result in adavosertib discontinuation. 
However, it is proposed that in exceptional circumstances, the investigator/treating 
physician may consider continuing dosing at dose level -2 only when the benefits are 
considered to outweigh the risks and after approval by the Medical Monitor. 

Table 12 was revised to reflect the following: 

Further dose reduction to dose level -2 on a third instance of Grade 2 thrombocytopenia. 

Action for all events of Grade 2 thrombocytopenia should be taken when the sample was 
obtained at pre-dose assessment, rather than during the cycle. 

Discontinuation of adavosertib on a third instance of Grade 3 thrombocytopenia.
However, it is proposed that in exceptional circumstances, for example, when a patient is 
objectively benefiting from several cycles of treatment and the investigator/treating 
physician considers that the benefit to the patient of continuing on treatment outweighs the 
risks, that the dose be resumed at dose level -2 after approval by the Medical Monitor.

Table 13 was revised to provide further guidance on dose interruption and dose reduction steps 
if the patient has a recurrent Hb <9 but ≥8 g/dL.
Sections 8.3.13.2 and 8.3.13.3 were updated to provide additional clarity on the management of 
non-haematologic toxicities, with detailed information on dose modifications for the management of 
gastrointestinal (GI) toxicities.

New tables were added to provide clarity on the management of non-haematologic toxicities 
(Table 14), with detailed information on dose modifications for the management of diarrhoea 
(Table 16) and nausea and vomiting (Table 17). 


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
Information included in Tables 14, 16, and 17 duplicated in the text in Sections 8.3.13.2 and 
8.3.13.3 (CSPv1) was deleted.
The option of the third dose reduction has been removed and text revised in Sections 1.1, 6.6 
(including Table 9) and 8.3.13.
Sections 1.1, 4.1, and 9.4.1.1 were updated to clarify that maturity of data will also be taken into 
account when selecting the date for primary analysis.
Section 9.4.1.2 was updated to clarify that a separate analysis will be performed using those 
confirmed responders that have been followed for a minimum of 6 months after response and using 
all confirmed responders regardless of follow-up time.
Sections 4.1 and 8.6.1.1 were updated to clarify that all diagnostic tumor tissue samples should be 
submitted, not only if the diagnostic sample is different from the 
Section 4.1 Figure 2 was updated to reflect a change in tumor assessment frequency from “every 
6 weeks for the first 24 weeks” to every “6 weeks for the first 48 weeks.”
Section 4.1.1 and Appendix J were added to include guidance on how the study could continue in 
the event of a serious disruption due to cases of civil crisis, natural disaster, or public health crisis 
with details on mitigation that could be employed to ensure study continuity.
Section 9.5.1 was updated to add additional detail regarding the Safety Review Committee.
Appendix A was updated to remove reference to CT/MRI of the liver and adrenal glands, as this is 
not applicable for this study.
Version 3.0, 20 April 2021
The protocol was revised to address the recommendations of the Safety Review Committee received 
on 9th April 2021.
Recommendation 1: Additional safety haematology and clinical chemistry assessment along on-site 
visit on Day 15 (+/- 1 day window) in Cycle 1 and Cycle 2. Safety haematology and clinical 
chemistry assessment along on-site visit on Day 5 (+/- 1 day window) in Cycle 1 and Cycle 2, in 
addition to the PK samples already collected. Section 1.3 Table 1, Section 8.2.4 and Section 8.3.13.1 
were updated to reflect this recommendation. 
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Recommendation 2: Review of the Toxicity Management Guidelines for participants with CTCAE 
Grade 4 infection with Grade 4 neutropenia, to allow participants who recover and have clear 
clinical benefit that outweighs the risks to continue dosing (at a reduced dose), only after sponsor 
approval. Section 8.3.13.1 Table 11 was updated to reflect this recommendation.
Recommendation 3: Additional guidance in Toxicity Management Guidelines for the G-CSF use in 
severe neutropenia. Section 8.3.13.1 was updated to reflect this recommendation. 
Section 8 was updated in view of the additional laboratory assessments required, to increase the
amount of blood collected from each participant accordingly. 
Section 8.3.13.1 Tables 11, 12,13,14,15,16 and 17 dose level reductions have been updated for 
clarity to ‘next reduced dose level’, to account for the fact that participants may have previously had 
a dose level reduction due to another toxicity. 
Version 4.0, 08 Nov 2021
The protocol was revised in line with the urgent safety measures implemented on 29th October 2021. 
Based on a preliminary analysis, AstraZeneca identified an association between reduced renal 
function and the risk of Grade 4 neutropenia. Risk minimization measures implemented regarding 
renal function.
Section 1.3 Table 1 and Section 8.2.4 updated to include creatinine clearance calculation at each 
study visit where clinical chemistry is assessed.
  
Section 2.3.1: Update to risk assessment section to include sepsis as an identified risk. IB (section 
5.4) will be updated with DCO Nov-2021.  
Section 5.1: Update to threshold for Creatinine Clearance within inclusion criterion 9.   
Section 5.2: Supplemental exclusion criterion specifically relating to infection. 
Section 8.3.13.1 Toxicity management guidelines for Blood neutrophil count decrease updated for 
first and third occurrence of Grade 3 neutropenia. Recommendation of prophylactic antibiotics and 
G-CSF in case of severe neutropenia/febrile neutropenia added. Recommendation of secondary 
prophylaxis by G-CSF in participants who had severe neutropenia in a previous cycle.
Section 8.3.13.3 Toxicity management guidelines for moderate/severe renal impairment (low 
creatinine clearance) added. 
Section 8.3.13.4 Gastrointestinal toxicity management (title updated) and renal function monitoring 
reference added. 


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Version 5.0, 03 Mar 2022
Following the recent safety events of sepsis cases, a comprehensive analysis of the safety and 
tolerability profile of adavosertib in the overall monotherapy adavosertib program, including the 
ADAGIO study, was performed leading to implementation of the following additional risk 
mitigation strategies.
Sections 1.1, 1.2, 1.3, 4.1, Fig 2, 6.1 and 6.6: The starting dose has been changed from 300mg to 
 QD adavosertib for the remaining participants to be recruited to the study; the dosing 
schedule and regimen has not been changed. Therefore, two cohorts have been defined Cohorts A 
and B: Cohort A with participants dosed at starting dose of 300mg QD, and Cohort B with 
participants dosed at a starting dose of 
 QD. No further participants will be enrolled to 
Cohort A. The enrolment will continue with Cohort B only with participants dosed at a starting dose 
of 
 QD once this amendment has been approved and implemented. 
Sections 1.1, 4.1, 9.4.1.1, 9.5.2: Updated to state that primary analysis will be based on data from 
Cohort A and final analysis will be based on data from both Cohort A and Cohort B. 
Section 1.2, Fig 1: Updated to include updated eligibility criteria and Cohort A and B.
Section 1.3 (Table 1, SoA) and Sections 8.2.4, 8.3.13.1: Additional safety on -site  
visit, including haematology and clinical chemistry assessments, vital signs , AE and concomitant 
medication review on  Day 12 (+/- 1 day window) in Cycle 1 and Cycle 2. 
Table 1 also updated for formatting.  
Section 2.3: Risk assessment updated to align with IB version 20 (DCO 11-November-2021)
Section 4.3: Section updated to provide rationale for starting dose of
 QD adavosertib for 
Cohort B.  
Section 4.4: End of study definition updated in view of introduction of Cohort B.  
Section 5.1: Inclusion criteria 11 updated to clarify the definition of postmenopausal women ≥ 50 
years. 
Section 5.2: Exclusion criteria 4 updated for participants with refractory nausea and vomiting. 
Section 5.3.3: Updated to include permanent sterilization as a highly effective method of 
contraception. 
Section 6.6, Table 9: Table updated for dose reduction levels for new starting dose of 
 QD.  
Section 7.1.2: Updated to clarify onset of 21-day drug interruption period.
Section 8.3.13: Toxicity Management Guidelines updated as below: 
Section 8.3.13.1 (Table 11): Toxicity management guidelines for Blood neutrophil count decrease 
updated for febrile neutropenia.
Section 8.3.13.2 (Table 14) and 8.3.13.4 (Table 17 and Table 18): Administrative error updates.
Section 8.3.13.3 (Table 16): Updated to include investigation of cause of renal impairment and to 
clarify renal thresholds. 
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Section 8.3.13.4 (Table 18): Updated guidelines for the management of nausea and vomiting; the 
updated guideline does not mandate use of dexamethasone as anti-emetic prophylaxis during cycles 
1 and 2.
Section 8.3.13.5 (Table 19): Introduction of Infection Toxicity Dose modification guideline.
Sections 9.4.1 and 9.4.2: Updated to reflect that efficacy and safety endpoints will be summarised 
by starting dose.
Version 6.0, 20 May 2022
Throughout the protocol all reference to Cohorts (A and B), and 
 dose have been removed.    
The 
 dose will not be included in this protocol.  Recruitment will close and primary analysis 
performed based on the 109 patients currently enrolled (91% of planned recruitment).
Additional risk mitigation strategies being implemented in the ADAGIO study following the recent 
safety events of sepsis cases: 
Section 8.3.13: Toxicity Management Guidelines updated as below: 
Section 8.3.13.1 (Table 11): Toxicity management guidelines for Grade 3 and 4 neutropenia have 
been updated. 
Section 8.3.13.2 (Table 14): Updated to reflect that an initial occurrence of an Grade 4 non-
haematologic toxicity should result in adavosertib discontinuation. 
Section 8.3.13.3 (Table 16): Updated management guidelines for renal impairment during treatment
Section 8.3.13.4 (Table 17): Updated to reflect that an initial occurrence of an Grade 4 diarrhoea 
should result in adavosertib discontinuation.
Section 8.3.13.4 (Table 18): Updated to reflect that an initial occurrence of an Grade 4 nausea and 
vomiting should result in adavosertib discontinuation.
Section 8.3.13.5 (Table 19): Update to Infection Toxicity Dose modification guidelines.
Sections 4.1, 4.4, 8.1.1 and 9.4.1.1: The final analysis DCO has been removed.
Sections 9.4.1 and 9.4.2: Updated to reflect the removal of Cohort B.
Section 4.4 (End of Study Definition): Updated to reflect that in the event that a roll-over study is 
available at the time of the primary DCO and database closure, participant(s) currently receiving 
treatment with adavosertib may then be transitioned to such a study.
This Clinical Study Protocol has been subjected 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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Protocol Number: D601HC00002
Amendment Number: 6.0
Study Intervention: Adavosertib (AZD1775)
Study Phase: Phase 2b
Short Title: Phase 2b Study of Adavosertib as Treatment for Uterine Serous Carcinoma
Medical Monitor Name and Contact Information will be provided separately
International Co-ordinating Investigator
Joyce Liu, MD, MPH
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
USA


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY ........................................................................................................... 2
TABLE OF CONTENTS ...................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................ 13
1.1
Synopsis ........................................................................................................... 13
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities ....................................................................................... 20
2
INTRODUCTION............................................................................................ 31
2.1
Study Rationale ................................................................................................ 31
2.2
Background ...................................................................................................... 31
2.2.1
Endometrial Cancer and Uterine Serous Carcinoma.......................................... 31
2.2.2
Current Standard of Care .................................................................................. 32
2.2.3
Adavosertib ...................................................................................................... 33
2.3
Benefit/Risk Assessment................................................................................... 34
2.3.1
Risk Assessment ............................................................................................... 34
2.3.2
Benefit Assessment........................................................................................... 35
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 35
3
OBJECTIVES AND ENDPOINTS................................................................... 35
3.1
Primary Objectives ........................................................................................... 35
3.2
Secondary Objectives........................................................................................ 35
3.3
..................................................................................... 37
4
STUDY DESIGN ............................................................................................. 38
4.1
Overall Design.................................................................................................. 38
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 40
4.2
Scientific Rationale for Study Design ............................................................... 41
4.3
Justification for Dose........................................................................................ 41
4.4
End of Study Definition.................................................................................... 44
5
STUDY POPULATION.................................................................................... 45
5.1
Inclusion Criteria .............................................................................................. 45
5.2
Exclusion Criteria ............................................................................................. 48
5.3
Lifestyle Considerations ................................................................................... 50
5.3.1
Meals and Dietary Restrictions ......................................................................... 50
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 50
5.3.3
Contraception ................................................................................................... 50
5.4
Screen Failures ................................................................................................. 51
6
STUDY INTERVENTION ............................................................................... 51
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6.1
Study Intervention Administered....................................................................... 52
6.1.1
Investigational Product ..................................................................................... 52
6.2
Preparation/Handling/Storage/Accountability of Intervention ........................... 53
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 53
6.4
Study Intervention Compliance......................................................................... 53
6.5
Concomitant Therapy........................................................................................ 53
6.5.1
Permitted Concomitant Medications ................................................................. 54
6.5.2
Prohibited and Restricted Concomitant Medications ......................................... 54
6.5.3
Palliative Radiotherapy..................................................................................... 56
6.5.4
Other Concomitant Treatment........................................................................... 56
6.6
Dose Modification ............................................................................................ 56
6.7
Intervention after the End of the Study.............................................................. 57
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 57
7.1
Discontinuation of Study Intervention............................................................... 57
7.1.1
Procedure for Discontinuation of Study Intervention......................................... 58
7.1.2
Study Intervention Interruption......................................................................... 59
7.2
Participant Withdrawal from the Study.............................................................. 59
7.3
Lost to Follow-up ............................................................................................. 59
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 60
8.1
Efficacy Assessments........................................................................................ 61
8.1.1
RECIST v1.1 Assessments................................................................................ 61
8.1.2
Survival Follow-up ........................................................................................... 62
8.1.2.1
Subsequent Cancer Therapy Following Discontinuation of Study Intervention.. 62
8.1.3
............................. 62
8.1.3.1
............................. 63
8.1.3.2
............................. 64
8.1.3.3
............................. 65
8.1.3.4
............................. 66
8.1.3.5
............................. 66
8.1.3.6
............................. 66
8.1.3.7
............................. 66
8.2
Safety Assessments........................................................................................... 66
8.2.1
Physical Examinations...................................................................................... 66
8.2.2
Vital Signs ........................................................................................................ 66
8.2.3
Electrocardiograms........................................................................................... 67
8.2.4
Clinical Safety Laboratory Assessments............................................................ 67
8.3
Adverse Events and Serious Adverse Events..................................................... 69
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 70
8.3.2
Follow-up of AEs and SAEs ............................................................................. 70
8.3.3
Causality Collection.......................................................................................... 71
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 71
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 71
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8.3.6
Hy’s Law.......................................................................................................... 72
8.3.7
Disease Progression.......................................................................................... 72
8.3.8
New Cancers..................................................................................................... 72
8.3.9
Handling of Deaths........................................................................................... 72
8.3.10
Reporting of Serious Adverse Events ................................................................ 73
8.3.11
Pregnancy......................................................................................................... 74
8.3.12
Medication Error............................................................................................... 74
8.3.13
Management of Adavosertib-related Toxicities.................................................. 75
8.3.13.1
Haematologic Toxicity Dose Modifications....................................................... 76
8.3.13.2
Non-haematologic Toxicity Dose Modifications ............................................... 80
8.3.13.3
Management of Renal Function Impairment ..................................................... 81
8.3.13.4
Gastrointestinal Toxicity Management Guidelines ............................................ 82
8.3.13.5
Management of Infection.................................................................................. 85
8.4
Overdose .......................................................................................................... 86
8.5
Human Biological Samples............................................................................... 87
8.5.1
Pharmacokinetics.............................................................................................. 87
8.5.1.1
Determination of Drug Concentration ............................................................... 88
8.5.1.2
Storage, Re-use and Destruction of Pharmacokinetic Samples .......................... 88
8.6
............................... 88
8.6.1
............................... 88
8.6.1.1
............................... 88
8.6.1.2
............................... 89
8.6.2
............................... 89
8.6.3
............................... 90
8.7
............................... 90
9
STATISTICAL CONSIDERATIONS................................................................ 91
9.1
Statistical Hypotheses....................................................................................... 91
9.2
Sample Size Determination............................................................................... 91
9.3
Populations for Analyses................................................................................... 91
9.4
Statistical Analyses ........................................................................................... 92
9.4.1
Efficacy ............................................................................................................ 92
9.4.1.1
Primary Endpoint: ORR.................................................................................... 92
9.4.1.2
Secondary Endpoint: DoR................................................................................. 93
9.4.1.3
Secondary Endpoint: Depth of Response........................................................... 93
9.4.1.4
Secondary Endpoint: PFS ................................................................................. 94
9.4.1.5
Secondary Endpoint: PFS6 ............................................................................... 94
9.4.1.6
Secondary Endpoint: OS................................................................................... 94
9.4.1.7
Secondary Endpoint: DCR................................................................................ 95
9.4.1.8
Secondary Endpoint: PK................................................................................... 95
9.4.2
Safety ............................................................................................................... 95
9.4.2.1
Adverse Events................................................................................................. 96
9.4.2.2
Vital Signs ........................................................................................................ 97
9.4.2.3
Laboratory Analyses ......................................................................................... 97
9.5
Data Monitoring Committee ............................................................................. 97
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9.5.1
Safety Review Committee................................................................................. 97
9.5.2
Independent Data Monitoring Committee ......................................................... 97
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 98
11
REFERENCES............................................................................................... 152
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 19
Figure 2
Study Flow Chart..................................................................................... 39
Figure 3
Treatment Schedule per 21-day Cycle...................................................... 52
LIST OF TABLES
Table 1
Schedule of Activities (Cohort A and B).................................................. 21
Table 2
Primary Objective.................................................................................... 35
Table 3
Secondary Objectives .............................................................................. 36
Table 4
............................................................................ 37
Table 5
Investigational Product ............................................................................ 52
Table 6
Permitted Concomitant Medications ........................................................ 54
Table 7
Prohibited Concomitant Medications ....................................................... 55
Table 8
Restricted Concomitant Medications........................................................ 55
Table 9
Dose Levels for Adavosertib.................................................................... 57
Table 10
Laboratory Safety Variables..................................................................... 69
Table 11
Management of Blood Neutrophil Count Decrease .................................. 77
Table 12
Management of Blood Platelet Count Decrease........................................ 79
Table 13
Management of Anaemia......................................................................... 79
Table 14
Management of Non-haematological Toxicities ....................................... 80
Table 15
QTc Interval Prolongation (Adavosertib Dose Modifications).................. 81
Table 16
Management of Renal Impairment........................................................... 82
Table 17
Management of Diarrhoea........................................................................ 83
Table 18
Management of Nausea and Vomiting ..................................................... 84
Table 19
Management of Infection......................................................................... 86
Table 20
Populations for Analyses ......................................................................... 91
Table 21
Summary of Imaging Modalities for Tumour Assessment...................... 100
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Table 22
RECIST v1.1 Evaluation of Target Lesions ........................................... 104
Table 23
RECIST v1.1 Evaluation of Non-Target Lesions.................................... 105
Table 24
RECIST v1.1 Overall Visit Response..................................................... 106
Table 25
ECOG Performance Status Scale ........................................................... 110
LIST OF APPENDICES
Appendix A
Guidelines for Evaluation of Objective Tumour Response using 
RECIST v1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 99
Appendix B
ECOG Performance Status..................................................................... 110
Appendix C
Regulatory, Ethical, and Study Oversight Considerations....................... 111
Appendix D
Guidance Regarding Potential Interactions of Adavosertib with 
Concomitant Medications ...................................................................... 116
Appendix E
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 121
Appendix F
Handling of Human Biological Samples ................................................ 126
Appendix G
.................................................... 128
Appendix H
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 131
Appendix I
.......................................... 137
Appendix J
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 146
Appendix K
Abbreviations ........................................................................................ 148
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b, Open-label, Single-arm, Multi-centre Study assessing the Efficacy 
and Safety of Adavosertib as Treatment for Recurrent or Persistent Uterine Serous Carcinoma 
(ADAGIO)
Short Title: Phase 2b Study of Adavosertib as Treatment for Uterine Serous Carcinoma
Rationale: 
There is an important unmet medical need for treatments in uterine serous carcinoma (USC), 
an aggressive variant of endometrial carcinoma, with an increased likelihood of recurrence 
and limited treatment options; the overall 5-year survival for USC is estimated to be only 35 
to 50% for women with Stage I-II disease and 0 to 15% for women with Stage III-IV disease. 
Data from The Cancer Genome Atlas (TCGA) have shown that USC exhibits several genetic 
alterations that could make this variant more likely to respond to WEE1 kinase inhibition. 
Specifically, USC exhibits high rates of mutation in TP53 (up to 90 to 92% of cases) as well 
as high rates of mutation or amplification in other cell cycle regulators, including CCNE1, 
FBXW7, MYC, RB1, CCND1, TAF1, and KRAS/NRAS.
This Phase 2b study aims to evaluate the efficacy and safety of adavosertib, an inhibitor of the 
tyrosine kinase WEE1, in participants with recurrent or persistent USC who have previously 
received at least 1 prior platinum based chemotherapy regimen for the management of USC.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the efficacy of adavosertib 
by the assessment of objective response 
rate (ORR).

ORR is defined as the proportion of participants with 
measurable disease at baseline who have a confirmed 
complete response (CR) or partial response (PR), as 
determined by Blinded Independent Central Review 
(BICR) per RECIST v1.1.
Secondary

To evaluate efficacy of adavosertib by 
assessment of duration of response 
(DoR).

DoR is defined as the time from the date of first 
documented response until date of documented 
progression per RECIST v1.1 as assessed by BICR, or 
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
To evaluate efficacy of adavosertib by 
assessment of depth of response.

Depth of response is defined as the best percentage 
change from baseline in Target Lesions.

To evaluate the efficacy of adavosertib 
by assessment of progression-free 
survival (PFS).

PFS is defined as time from date of first dose until 
progression per RECIST v1.1 as assessed by BICR, or 
death due to any cause. 

To evaluate the efficacy of adavosertib 
by assessment of PFS6.

PFS6 is defined as the proportion of participants alive 
and progression free at 6 months, and will be reported 
as the Kaplan-Meier estimate of PFS per RECIST v1.1 
as assessed by BICR at 6 months.

To evaluate the efficacy of adavosertib 
by assessment of overall survival (OS).

OS is defined as time from date of first dose until the 
date of death due to any cause.

To evaluate the efficacy of adavosertib 
by assessment of disease control rate 
(DCR).

DCR is defined as the percentage of participants who 
have a best overall response of CR or PR or who have 
stable disease for at least 5 weeks after start of 
treatment (to allow for an early assessment within the 
assessment window).

To evaluate the pharmacokinetics of 
adavosertib.

Plasma concentration of adavosertib: Ctrough (pre-dose)
and Cmax.

To assess the safety and tolerability of 
adavosertib in participants with USC.

Safety and tolerability will be evaluated in terms of 
AEs, vital signs, clinical laboratory assessments, ECGs, 
and AEs leading to dose interruptions, dose reductions, 
and dose discontinuations.

Vital signs parameters include systolic and diastolic 
blood pressure, and pulse as well as heart rate, body 
temperature, body weight, height, and BMI.

Laboratory parameters include clinical chemistry and 
haematology parameters as well as urinalysis. 
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AE, adverse event; BICR, Blinded Independent Central Review; BMI, body mass index; 
 
 Cmax, maximum concentration; Ctrough, lowest concentration; CR, complete response; 
CTCAE v5.0, Common Terminology Criteria for Adverse Events Version 5.0; 
 
DCR, disease control rate; 
 DoR, duration of response; ECG, electrocardiogram; 
 
 
 ORR, objective response rate; OS, overall survival; PFS, progression-free 
survival; PFS6, proportion of participants alive and progression free at 6 months;
 
 PK, pharmacokinetic; PR, partial response; 
 
RECIST v1.1, Response Evaluation Criteria in Solid Tumors; 
 SAE, serious adverse 
event; USC, uterine serous carcinoma.
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Overall Design
This Phase 2b, single-arm, multi-centre study will assess the efficacy and safety of adavosertib 
in eligible participants with histologically confirmed recurrent or persistent USC (for the 
purposes of this study, this includes participants with endometrial carcinoma of mixed 
histology where the serous component comprises at least 10% of the tumour [McMeekin et al 
2007]), evidence of measurable disease as per RECIST v1.1, and who have received at least 1 
prior platinum based chemotherapy regimen for the management of USC. Participants with 
carcinosarcomas are not eligible. There is no restriction on the number of prior lines of 
systemic therapy a participant may have previously received, and the platinum based
chemotherapy may have been given in the adjuvant setting. 
Participants are required to provide a formalin-fixed paraffin-embedded (FFPE) tumour 
sample, collected as part of routine clinical practice, for central confirmation of USC 
diagnosis and 
 
It is estimated that up to approximately 40 sites from approximately 6 countries will 
participate in the study. 
Disclosure Statement: This is a single group treatment study with an open-label single arm 
design.
Number of Participants:
Approximately 120 participants will be enrolled and dosed, with an intent to include 
approximately 40 participants or more who have previously been exposed to programmed cell 
death-1 receptor (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors. The primary 
objective is to estimate objective response rate (ORR), and no formal statistical comparisons 
will be performed. With 120 participants, if the observed ORR is 
 the width of the 2-
sided 90% CI will be 
Intervention Groups and Duration:
At the time of protocol amendment version 6.0, 109 participants have been dosed with the 
starting dose of 300 mg QD.  No further participants will be enrolled to the study. 
Participants will receive oral adavosertib once daily (QD) for 5 days followed by 2 days off in 
Weeks 1 and 2 out of a 21-day cycle (Days 1 to 5 and Days 8 to 12). Dose reductions or holds 
are allowed as clinically indicated by the treating physician. For each participant, a maximum 
of 2 successive dose reductions will be allowed during the study. Dose re-escalations are not 
allowed.  
After start of treatment (Day 1), treatment will be given in 21-day cycles until objective 
radiological disease progression by investigator assessment using RECIST v1.1, unacceptable 
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toxicity, withdrawal of consent, or another discontinuation criterion is met.
Participants are permitted to continue to receive adavosertib treatment beyond the end of study 
if, in the opinion of the investigator, they are continuing to receive clinical benefit. Treatment 
of participants with adavosertib beyond progression is not allowed.
Independent Data Monitoring Committee: Yes (external)
Statistical methods
The All Patients Set will include all participants who have signed the informed consent form 
(ICF) (ie, screening failures plus participants dosed) and will be used to describe the patient 
disposition. The Full Analysis Set (FAS) and the Centrally Confirmed Analysis Set (CCAS) 
will both be used for all analyses of the efficacy endpoints, and the FAS will be used for the 
safety endpoints. The FAS will include all participants who received at least one (non-zero) 
dose of study treatment. The CCAS includes all centrally confirmed USC participants who 
received at least one (non-zero) dose of study treatment. The Pharmacokinetics Analysis Set 
will include all dosed participants who had at least one measurable plasma concentration 
collected post-dose which was obtained without any deviation or event thought to 
significantly affect the PK analysis.
The primary endpoint of ORR (defined as the percentage of participants with a confirmed 
complete response [CR] or partial response [PR], based on a subset of all treated participants 
with measurable disease at baseline per Blinded Independent Central Review [BICR]), and its 
90% and 95% confidence interval (CI) (Clopper-Pearson) will be summarized.. Summaries of 
ORR will be based on imaging BICR; ORR per investigator review will be a sensitivity 
analysis. The primary analysis will be performed, in both the FAS and centrally confirmed 
USC populations, 6 months after the last patient first dose or when all participants have 
progressed or died due to any cause, whichever is earlier. Maturity of duration of response 
(DoR) data will also be taken into account when selecting the data cut-off (DCO) date for 
primary analysis No further analyses will be performed beyond the primary analysis.
An interim analysis is planned after approximately 30 participants in the CCAS have had the 
opportunity to be treated for at least 4 months. Recruitment will not be paused whilst the 
participants required for the interim are evaluated. 
A comprehensive statistical analysis plan (SAP) will be developed and will include a more 
technical and detailed description of the statistical analyses. A Continuous Monitoring Plan 
(CMP) will also be produced to describe the approach, decision criteria, statistical analyses 
and communication plan for continuous monitoring in this study.
Descriptive statistics will be used for all variables. Continuous variables will be summarised 
by the number of observations, mean, standard deviation, median, minimum and maximum. 


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Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated out of the population total.
Additional subgroup analyses of efficacy and safety may be performed and will be specified 
in the SAP. 


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1.2
Schema
Figure 1
Study Design
BICR, Blinded Independent Central Review; CT, computed tomography; DCO, data cut-off; ECOG, Eastern Cooperative Oncology Group; 
FFPE, formalin-fixed paraffin-embedded; HER2, Human epidermal growth factor receptor 2; LPFD, last participant first dose; mo, months; MRI, magnetic 
resonance imaging; ORR, objective response rate; USC, uterine serous carcinoma; VEGF, vascular endothelial growth factor.


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1.3
Schedule of Activities
The schedule of study assessments is provided in Table 1.


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Table 1
Schedule of Activities
Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
Informed consent
X
Section 5.
1 & 
Appendix
C
Inclusion/exclusio
n criteria
X
Recheck 
inclusion 
and 
exclusion 
criteria 
prior to 
first dose
Sections 
5.1 & 5.2
Routine clinical procedures
Demography
X
Sections 
5.1 & 5.2
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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
Medical/surgical 
history
X
Sections 
5.1 & 5.2
Previous cancer 
therapy
X
Section 
5.2
Concomitant 
medication
X
At every study visit
Section 
6.5
ECOG 
performance 
status
X
X
X
X
X
Appendix
B
Physical 
examination
X
X
X
X
X
Section 
8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
X
Section 
8.2.2
Height
X
Section 
8.2.1
Weight
X
X
X
X
X
Section 
8.2.1


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
12-lead ECG
X
As clinically indicated
Section 
8.2.3
General 
assessment 
through phone 
call
X
Day 3 
phone call 
for AE 
assessment
Section 
8.3.13.4
Routine safety measurements
Adverse events
X
At every study visit
Section 
8.3 & 
Appendix
E
Pregnancy test 
(if applicable)
X
X
X
X
Section 
8.2.4
Haematology
X
X
X
X
X
X
X
X
X
X
C1/2 D5 
safety labs 
visit 
window ±1 
days
Section 
8.2.4


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
C1/2 D5 
safety labs 
visit 
window ±1 
days.
CrCl to be 
calculated at 
each time-
point
Section 
8.2.4
Coagulation
X
As clinically indicated
Section 
8.2.4
Urinalysis
X
As clinically indicated
Section 
8.2.4
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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
FFPE tumour 
sample
X
Section 
8.6.1
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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
CCI


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
Pharmacokinetic measurements
PK plasma 
samples
Pre-
dose 
and
2h 
post
-
dose
Section 
8.5.1
Imaging and other assessments
RECIST v1.1 
tumour 
assessments (CT 
and/or MRI)
X
Every 6 weeks (±7 days) for the first 48 weeks and then every 9 weeks (±7 days) thereafter, 
from Day 1 to radiological progression by investigator assessment using RECIST v1.1.  
Participants who discontinue treatment prior to progression should continue to be scanned until progression.
Section 
8.1.1 & 
Appendix
A
Subsequent 
cancer therapy 
following 
discontinuation of 
study intervention
X
X
Section 
8.1.2.1
Survival status
X
Section 
8.1.2


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
CCI


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuati
on 
Progressio
n 
Post-
treatme
nt 
follow-
up
Survival 
follow-
up
Notes
Details in 
CSP 
section or 
appendix
Timing
-28 to -
1
Da
y 1
Day 3
Day 
5
Day 8
Day 
12
      
Day 
15
Day 1
Day 
8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after 
last 
dose
Every 
12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window ±1 
days
Adavosertib dispensing and administration
Adavosertib 
dispensing
X
X
Section 
6.1.1
Adavosertib 
administration
Dosing on Days 1 to 5 and Days 8 to 12 of 21-day cycle
A 
minimum 
of 9 days 
between 
the last 
dosing of a 
cycle and 
Day 1 of 
the next 
cycle is 
required.
Section 
6.1.1


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AE, adverse event; 
 CT, computed tomography; 
 
 ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; 
 
 
FFPE, formalin-fixed paraffin-embedded; 
 MRI, magnetic 
resonance imaging; 
 ORR, objective response rate; OS, overall survival;
 
PK, pharmacokinetics; 
 RECIST v1.1, Response 
Evaluation Criteria in Solid Tumors; 
 
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2
INTRODUCTION
Adavosertib (AZD1775) is an inhibitor of the tyrosine kinase WEE1. AstraZeneca is 
developing adavosertib for use as monotherapy and in combination with other anticancer 
agents for a range of therapeutic indications, including recurrent or persistent 
advanced/metastatic uterine serous carcinoma (USC) and other advanced solid tumours.
2.1
Study Rationale
This Phase 2b study aims to evaluate the efficacy and safety of adavosertib in participants
with recurrent or persistent USC who have previously received at least 1 prior platinum based
chemotherapy regimen for the management of USC. The rationale for conducting the study is 
supported by the following:

Unmet medical need: USC is an aggressive variant of endometrial carcinoma, with an 
increased likelihood of recurrence and limited treatment options, with the overall 5-year 
survival for USC estimated to be only 35-50% for women with Stage I-II disease, and 
0-15% for women with Stage III-IV disease (Acharya et al 2005) 

Mechanism of action of adavosertib (see Section 2.2.3): data from The Cancer Genome 
Atlas (TCGA) have shown that USC exhibits several genetic alterations that could make 
this variant more likely to respond to WEE1 kinase inhibition. Specifically, USC exhibits 
high rates of mutation in TP53 (up to 90-92% of cases) in combination with high rates of 
mutation or amplification in other cell cycle regulators, including CCNE1, FBXW7, MYC, 
RB1, CCND1, TAF1, and KRAS/NRAS (Cancer Genome Atlas Research Network 2013, 
Zhao et al 2013) 

Clinical data from an ongoing Phase 2 clinical study of adavosertib in participants with 
recurrent or persistent USC: preliminary objective response rate (ORR) of 29.4% 
(95% CI: 15.1%, 47.5%; n=34) (Liu et al 2020) 
The background to the rationale is summarised below in Sections 2.2 and 2.3.
2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of adavosertib is 
provided in the Investigator’s Brochure.
2.2.1
Endometrial Cancer and Uterine Serous Carcinoma
Endometrial cancer is one of the most common malignancies in the female genital tract with 
over 380000 new cases worldwide in 2018 (Bray et al 2018), and an estimated 61880 new 
cases diagnosed in the United States (US) in 2019 (Siegel et al 2019). There is an increasing 


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prevalence in developed countries and the highest incidences have been observed in the US, 
Canada, and Northern and Western Europe (Bray et al 2018). From 2006 to 2015, the 
incidence rate increased by about 1% per year and from 2007 to 2016, the death rate increased 
by about 2% per year (American Cancer Society 2019).
USC is one of the less common variants of endometrial cancer. However, despite representing 
only approximately 10% of all endometrial cancer diagnoses, it accounts for up to 39% of 
endometrial cancer-related deaths (Hamilton et al 2006). Unlike the more common 
endometrioid variants of uterine cancer, the majority of women with USC have a high risk of 
relapse, even in the absence of traditional “high-risk” features, such as myometrial invasion or 
lymphovascular involvement, and USC histology is considered to be high-risk and high-grade 
by default in the National Comprehensive Cancer Network (NCCN) guidelines (NCCN 2019). 
The overall 5-year survival for USC is estimated to be only 35-50% for women with Stage I-II 
disease, and 0-15% for women with Stage III-IV disease (Acharya et al 2005). 
2.2.2
Current Standard of Care
Treatment options for these cancers are limited. Currently, the preferred standard of care for 
participants with recurrent, metastatic, or high risk endometrial cancer is combination 
chemotherapy with carboplatin and paclitaxel (NCCN 2019). More recently, targeted 
therapies specifically for USC have been explored, but results thus far have been 
disappointing. One area of great interest has been targeting of HER2/neu, which has been 
reported to be highly expressed in between 17 and 50% of women with USC (Talwar and 
Cohen 2012), and case reports of trastuzumab activity have been reported (Santin et al 2008; 
Talwar and Cohen 2012). A case report describes the clinical response of a heavily pre-treated 
patient with a recurrent USC, overexpressing HER2/neu at 3+ level by immunohistochemistry 
(IHC), to anti-HER2/neu antibody-drug-conjugate trastuzumab-emtansine (TDM-1) with 
complete resolution of a large metastatic, radiation/chemotherapy resistant tumour (Santin et 
al 2017). However, a Gynecologic Oncology Group study of single-agent trastuzumab in 
33 women with HER2-positive endometrial cancer (of whom 11 had USC) did not 
demonstrate significant activity, with no women achieving a tumour response 
(Fleming et al 2010). A recent study (Fader et al 2018) compared carboplatin-paclitaxel with 
and without trastuzumab in participants with primary advanced or recurrent HER2/neu-
positive USC (defined by an IHC score of 3+ or 2+ with gene amplification confirmed by 
fluorescence in situ hybridization, and with a serous component of ≥10%) reported increased 
progression-free survival (PFS) for participants treated with the combination compared to 
those on the carboplatin-paclitaxel control arm; median PFS was 8.0 months (carboplatin-
paclitaxel) versus 12.6 months (carboplatin-paclitaxel-trastuzumab; p=0.005; hazard ratio:
0.44; 90% confidence interval [CI]: 0.26, 0.76). Further investigation of these results is 
needed to determine the impact on overall survival (OS) in this patient population.


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Inhibition of programmed cell death-1 receptor (PD-1) signalling by an immune checkpoint 
inhibitor (pembrolizumab) or co-inhibition of angiogenesis (via vascular endothelial growth 
factor-mediated suppression; lenvatinib) and PD-1 signalling is emerging as an efficacious 
anti-tumour strategy for the treatment of endometrial cancer (Makker et al 2019). 
KEYNOTE-146/Study 111 assessed lenvatinib/pembrolizumab combination in participants
with advanced endometrial carcinoma. In the 94 participants with tumours that were not 
microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR), the combination 
demonstrated an ORR of 38.3% (95% CI: 29%, 49%), with a complete response (CR) rate of 
10.6% (n=10) and a partial response (PR) rate of 27.7% (n=26) (FDA 2019, Makker et al 
2019). In the US, the FDA has recently approved pembrolizumab for the subset of women 
with MSI-H, metastatic disease, and the combination of pembrolizumab/lenvatinib for the 
treatment of participants with advanced endometrial carcinoma that is not MSI-H or dMMR, 
who have disease progression following prior systemic therapy and are not candidates for 
curative surgery or radiation (FDA 2019).
Deficient mismatch repair has been reported in 33.5% (n=65/194) of endometrioid tumours 
and 1.6% (n=1/61) of serous tumours (Aghajanian et al 2018), and MSI-H in 40% of 
endometrioid tumours and 2% of serous tumours (Cancer Genome Atlas Research 
Network 2013). While USC participants are thus predominantly microsatellite stable (not 
MSI-H), several ongoing studies are exploring the addition of a PD-1/programmed death-
ligand 1 (PD-L1) inhibitor to standard of care combination chemotherapy in the first-line 
advanced disease setting (clintrials.gov), and new treatments potentially beyond the use of 
PD-1/PD-L1 are urgently needed. Durvalumab with or without olaparib, as maintenance 
therapy after first-line treatment of advanced and recurrent endometrial cancer (DUO-E; 
NCT04269200), is currently being investigated. Therefore, USC still represents an area of 
unmet medical need. 
2.2.3
Adavosertib
Adavosertib is an inhibitor of WEE1, a protein tyrosine kinase. WEE1 phosphorylates and 
inhibits cyclin-dependent kinase 1 and 2 (CDK1 and CDK2) and is involved in regulation of 
the intra-S and G2 cell cycle checkpoints. Proper functioning of these checkpoints is essential 
for DNA metabolism and the DNA damage response (Coleman and Dunphy 1994, Parker and 
Piwnica-Worms 1992).
Activity of CDK1 (also called cell division cycle 2 protein, or CDC2) drives a cell from the 
G2 phase of the cell cycle into mitosis. In response to DNA damage, WEE1 inhibits CDK1 to 
prevent the cell from dividing until the damaged DNA is repaired (G2 checkpoint arrest).  
CDK2 activity drives a cell into, and through, S-phase of the cell cycle in which the genome is 
duplicated in preparation for cell division.  Inhibition of WEE1 is expected to cause aberrantly 
high CDK2 activity in S-phase cells that, in turn leads to unstable DNA replication structures 
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Inhibition of WEE1 is expected to release a tumour cell from DNA damage induced arrest at 
the G2/M boundary, so that unrepaired DNA damage may be taken into mitosis (M-phase).  
Since cancer cells exhibit higher levels of endogenous damage than normal cells, as well as 
exhibiting loss of 1 or more DNA damage response capabilities, this is expected to 
preferentially enhance cancer cell death through mitotic catastrophe compared to normal cells.  
In the nonclinical setting, adavosertib has demonstrated significant single-agent anti-tumour 
activity in cancer cell models associated with high levels of endogenous replication stress 
resulting from a combination of G1/S checkpoint deficiencies due to p53 mutations or 
CDKN2A deletions and the over-expression of oncogenic drivers such as MYC, mutant 
KRAS or the amplification of Cyclin E. 
As USC exhibits high rates of mutation in TP53 (up to 90-92% of cases) in combination with 
high rates of mutation or amplification in other cell cycle regulators, including CCNE1, 
FBXW7, MYC, RB1, CCND1, TAF1 and KRAS/NRAS (Cancer Genome Atlas Research 
Network 2013, Zhao et al 2013), this tumour type is expected to have high levels of 
replication stress and endogenous DNA damage, and is therefore expected to be sensitive to 
WEE1 kinase inhibition. 
2.3
Benefit/Risk Assessment
2.3.1
Risk Assessment
As of 11 November 2021, approximately 2083 participants have received adavosertib in its 
clinical development program, with approximately 349 participants receiving adavosertib 
monotherapy in AstraZeneca sponsored and Merck sponsored studies. 
Based on the safety data from completed adavosertib clinical studies and preliminary data 
from ongoing studies, identified risks (reported by ≥10% of participants) to adavosertib 
monotherapy include diarrhoea, nausea and/or vomiting, difficulty with digestion, decreased 
appetite, a decreased number of red blood cells/haemoglobin level, neutrophils and platelets in 
the blood. Other identified risks include sepsis and febrile neutropenia. 
Sepsis has recently been categorised as an identified risk with adavosertib therapy. 
Adavosertib has a well characterised safety profile, and the toxicity is considered manageable 
with effective toxicity management, including dose delays, dose reductions, intermittent 
dosing and/or the use of supportive care approach in the participants with poor tolerance. 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of adavosertib may be found in Sections 5 and 6 of the current 
adavosertib IB.


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2.3.2
Benefit Assessment
Liu et al (Liu et al 2020) recently assessed the activity of adavosertib as monotherapy in 
recurrent USC (n=34, evaluable) in an ongoing Phase 2 study (NCT03668340). A preliminary 
ORR of 29.4% (95% CI: 15.1%, 47.5%), including 9 partial responses (8 confirmed and 
1 unconfirmed) and 1 complete response, was observed. The median PFS time was reported to 
be 6.14 months (95% CI: 4.21 months, 9.92 months), and the proportion of participants
progression-free at 6 months (PFS6) was 59.6% (95% CI: 40.6%, 74.3%). The median 
duration of response (DoR) was 9.03 months (95% CI: 5.29 months, NA).
2.3.3 Overall Benefit: Risk Conclusion
Treatment options for USC are limited (see Section 2.2.2), with poor 5-year estimated OS 
(35-50%, Stage I-II disease; 0-15% Stage III-IV disease; Acharya et al 2005). Overall, based 
on the available clinical efficacy and safety data and the limited long-term efficacy provided 
by the currently available treatment options for USC, the benefit/risk assessment supports the 
proposed investigation of the therapeutic efficacy of adavosertib in participants with USC in 
second line plus setting. 
3
OBJECTIVES AND ENDPOINTS
3.1
Primary Objectives
The primary objective for the study and associated outcome measures are summarised in 
Table 2.
Table 2
Primary Objective
Primary Objective
Endpoint
•
To evaluate the efficacy of adavosertib by the 
assessment of objective response rate (ORR).
•
ORR is defined as the proportion of participants
with measurable disease at baseline who have a 
confirmed complete response (CR) or partial 
response (PR), as determined by Blinded 
Independent Central Review (BICR) per 
RECIST v1.1.
RECIST v1.1, Response Evaluation Criteria in Solid Tumors
3.2
Secondary Objectives
The secondary objectives for the study and associated outcome measures are summarised in 
Table 3.


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Table 3
Secondary Objectives
Secondary Objectives
Endpoints
•
To evaluate efficacy of adavosertib by 
assessment of DoR.
•
DoR is defined as the time from the date of first 
documented response until date of documented 
progression per RECIST v1.1 as assessed by 
Blinded Independent Central Review (BICR), or 
death in the absence of disease progression.
•
To evaluate efficacy of adavosertib by 
assessment of depth of response.
•
Depth of response is defined as the best 
percentage change from baseline in Target 
Lesions.
•
To evaluate the efficacy of adavosertib by 
assessment of progression-free survival (PFS).
•
PFS is defined as time from date of first dose 
until progression per RECIST v1.1 as assessed 
by BICR, or death due to any cause. 
•
To evaluate the efficacy of adavosertib by 
assessment of PFS6.
•
PFS6 is defined as the proportion of participants
alive and progression free at 6 months, and will 
be reported as the Kaplan-Meier estimate of PFS 
per RECIST v1.1 as assessed by BICR at 6 
months.
•
To evaluate the efficacy of adavosertib by 
assessment of OS.
•
OS is defined as time from date of first dose 
until the date of death due to any cause.
•
To evaluate the efficacy of adavosertib by 
assessment of disease control rate (DCR).
•
DCR is defined as the percentage of participants
who have a best overall response of CR or PR or 
who have stable disease for at least 5 weeks after 
start of treatment (to allow for an early 
assessment within the assessment window).
•
To evaluate the pharmacokinetics of 
adavosertib.
•
Plasma concentration of adavosertib: Ctrough 
(pre-dose) and Cmax.
•
To assess the safety and tolerability of 
adavosertib in participants with USC.
•
Safety and tolerability will be evaluated in terms 
of AEs, vital signs, clinical laboratory 
assessments, ECGs, and AEs leading to dose 
interruptions, dose reductions, and dose 
discontinuations.
•
Vital signs parameters include systolic and 
diastolic blood pressure, and pulse as well as 
heart rate, body temperature, body weight, 
height, and BMI.
•
Laboratory parameters include clinical 
chemistry and haematology parameters as well 
as urinalysis.
AE, adverse event; BICR, Blinded Independent Central Review; BMI, body mass index; Cmax, maximum 
concentration; Ctrough, lowest concentration; CR, confirmed response; CTCAE v5.0, Common Terminology 
Criteria for Adverse Events Version 5.0; ctDNA, circulating tumour DNA; DCR, disease control rate; 
DNA, deoxyribonucleic acid; DoR, duration of response; ECG, electrocardiogram; ORR, objective response rate; 
OS, overall survival; PFS, progression-free survival; PFS6, proportion of participants alive and progression free 
at 6 months; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors; 
RNA, ribonucleic acid; SAE, serious adverse event; USC, uterine serous carcinoma. 


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3.3
Table 4
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4
STUDY DESIGN
4.1
Overall Design
This Phase 2b, single-arm, multi-centre study will assess the efficacy and safety of adavosertib 
in eligible participants with histologically confirmed recurrent or persistent USC (for the 
purposes of this study, this includes participants with endometrial carcinoma of mixed 
histology where the serous component comprises at least 10% of the tumour [McMeekin et al 
2007]), evidence of measurable disease as per RECIST v1.1, and who have received at least 1 
prior platinum based chemotherapy regimen for the management of USC. Participants with 
carcinosarcomas are not eligible.
Participants are required to provide a formalin-fixed paraffin-embedded (FFPE) tumour 
sample, collected as part of routine clinical practice, for central testing and central 
confirmation of USC diagnosis. This should preferably be an FFPE tissue block, or if not 
possible, freshly-cut, unstained, serial tumour slides from the most recently collected tumour 
tissue that should be a sufficient quantity to allow for the central confirmation of USC and 
 (Section 8.6.1.1). For the USC central confirmation, haematoxylin and 
eosin (HE)-stained slide(s) of the sample used by the site for eligibility should also be 
submitted. Further details on tissue specifications are outlined in the Pathology Manual, 
Laboratory Manual and the Diagnostic Testing Manual. 
 
 
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It is estimated that up to approximately 40 sites from approximately 6 countries will 
participate in the study. Approximately 120 eligible participants will receive oral adavosertib. 
At the time of protocol amendment version 60, 109 participants have been dosed with the 
starting dose of 300 mg QD for 5 days followed by 2 days off in Weeks 1 and 2 out of a 21-
day cycle until objective radiological disease progression by investigator assessment using 
RECIST v1.1, unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met. Safety and tolerability will be reviewed periodically by a Safety Review 
Committee. No further participants will be enrolled to the study.
The primary analysis will be performed in both locally and centrally confirmed USC 
populations, 6 months after the last patient first dose, or when all participants in have 
progressed or died due to any cause, whichever is earlier. Maturity of DoR data will also be 
taken into account when selecting the data cut-off (DCO) date for primary analysis. No further 
analyses will be performed beyond the primary analysis.. An interim analysis is planned after 
approximately 30 participants in the Centrally Confirmed Analysis Set (CCAS) have had the 
opportunity to be treated for at least 4 months. Recruitment will not be paused whilst the 
participants required for the interim analysis are evaluated.
Section 6.7 describes possible treatment continuation after the end of the study.
The study design is illustrated in a study flow chart (Figure 2) and study schema (Figure 1).
Figure 2
Study Flow Chart


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QD, once daily; 
 RECIST v1.1, Response Evaluation Criteria in Solid Tumors.
4.1.1
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 participants become infected with 
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 
participant’s ability to conduct or participate in the study. The investigator or designee should 
contact the study sponsor to discuss whether the mitigation plans below should be 
implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice (GCP), and minimize risks to study integrity.
Where allowable by local health authorities, Ethics Committees, healthcare provider 
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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 participant’s 
next contact with the study site)

Rescreening: Additional rescreening for screen failures and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician.

Home or remote visit: Performed by a site-qualified healthcare professional (HCP) or 
HCP provided by a third-party vendor

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices

At-home Investigational Product administration: Performed by the participants or the 
participant’s caregiver, if possible. Additional information related to the visit can be 
obtained via telemedicine.
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
Adavosertib is under investigation by AstraZeneca for a range of therapeutic indications 
including recurrent or persistent advanced USC and other advanced solid tumours. Given its 
mechanism of action (see Section 2.2.3) and benefit/risk assessment (see Section 2.3), there is 
strong rationale for the evaluation of adavosertib in participants with USC in the second-line 
and beyond treatment setting where standard of care treatment options are limited.
The single-arm, open-label study design is a standard design for a Phase 2 study where the 
primary objective of the study is to assess efficacy (ORR, as determined by imaging Blinded 
Independent Central Review [BICR]) of adavosertib.
The eligibility criteria have been designed to recruit a patient population that is representative 
of those with recurrent or persistent USC, and who have received at least 1 prior platinum 
based chemotherapy regimen for the management of USC (the platinum based chemotherapy 
may have been received in the adjuvant setting). 
4.3
Justification for Dose
The study was initiated with a recommended Phase 2 dose (RP2D) of adavosertib  300 mg QD 
for 5 days followed by 2 days off in Weeks 1 and 2 out of a 21-day schedule .This dose and 
schedule were established based on the safety, PK and clinical activity observed in PN011 
(NCT01748825), REFMAL 398 (NCT02610075) and a Phase 2 study (NCT03668340). 


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PN011 and REFMAL 398 were Phase 1 studies designed to determine the maximum tolerated
dose (MTD)/RP2D for adavosertib monotherapy using different dose levels and schedules as 
well as QD and twice daily (BID) dosing (Takebe et al 2018, Falchook et al 2019). Steady-
state plasma concentration at the 300 mg dose was above that required to provide the 
necessary IC50 for phosphorylated CDK1 activity that had been determined preclinically as 
well as being within the preclinically-defined targeted cell kill range (500 to 1000 nM) for 
approximately 16 hours post-dose, supporting adequate target coverage.
The preclinical dose-PK-PD-efficacy modelling, based on two independent animal cancer 
models and the mathematical modelling looking at the biologically effective dose for 
adavosertib monotherapy activity, has confirmed the key factors for dose decision in the order 
of importance are as follows: dose, followed by the number of days of consecutive treatment, 
followed by the length of the treatment gap. The latter two are important because both in 
preclinical animal models, and in the early clinical experience, the dose of adavosertib 
required to provide efficacy could not be sustained as a continuous treatment schedule and 
therefore an intermittent schedule was needed for RP2D.  Multiple intermittent schedules were 
assessed in preclinical animal models including 5days on/2days off, 7days on/7days off, 5days 
on/9days off or 3days on/4days off.
These preclinical data identified that:
1
The pharmacokinetics of adavosertib on single or repeat dose in the mouse could be 
accurately modelled.
2
Preclinical doses of between 60 mg/kg QD and 90 mg/kg QD were effective in inducing 
tumour regression across multiple models.
3
Time and dose dependence of pCDK1 and RRM2 expression (a surrogate of CDK2 
activation) could be modelled with a single IC50 value of 0.273 μM total plasma 
concentration.
4
The changes in pCDK1 and RRM2 could be related to the dose and schedule dependence 
of efficacy where it was estimated that plasma concentrations above 0.5 μM were 
required for anti-tumor activity, with maximal tumor cell kill rate achieved at 
approximately 1 μM.
5
Different doses and schedules provide a consistent relationship between efficacy, dose 
level and number of days dosed but is greater than linear at the highest dose (90 mg/kg) 
while a schedule of 5 days on 2 days off represented the optimal intermittent schedule in 
terms of efficacy and preclinical safety studies.
6
The preclinical efficacious doses of adavosertib of between 60 mg/kg and 90 mg/kg are 
equivalent to the free drug exposures obtained by the clinical QD doses of 250 mg and 
300 mg QD respectively.


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Clinical activity of adavosertib as monotherapy was evaluated at RP2D in recurrent USC 
(n=34, evaluable) in an ongoing Phase 2 study (NCT03668340) (Liu et al 2020). A 
preliminary ORR of 29.4% (95% CI: 15.1%, 47.5%), including 9 partial responses 
(8 confirmed and 1 unconfirmed) and 1 complete response, was observed. The median PFS 
time was reported to be 6.14 months (95% CI: 4.21 months, 9.92 months), and the PFS6 was 
59.6% (95% CI: 40.6%, 74.3%). The median DoR was 9.03 months (95% CI: 5.29 months, 
NA). The most frequently observed AEs included diarrhoea (85%), anaemia (65%), fatigue 
(65%), and nausea (62%).
As of 11 November 2021, 101 participants have been dosed at 300mg QD adavosertib in the 
ADAGIO study. The study is ongoing, and hence the data presented below is not fully cleaned 
and subject to change. Overall, 96 (95.0%) participants have experienced TEAEs. The most 
common (≥ 30%) TEAEs were diarrhoea (63 [62.4%] participants), nausea (60 [59.4%] 
participants), anaemia (49 [48.5%] participants), fatigue (39 [38.6%] participants), 
thrombocytopenia (37 [36.6%], constipation (37 [36.6%] participants), neutropenia (36 
[35.6%] participants) and asthenia (36 [35.6%] participants). Overall, 40 (39.6%) participants
have experienced SAEs; those experienced by > 1 (1.0%) patient were neutrophil count 
decreased (4 [4.0%] participants); neutropenia, dyspnoea, pulmonary embolism, and sepsis (3 
[3.0%] participants each); and vomiting, fatigue, anaemia, thrombocytopenia, syncope, pleural 
effusion, embolism, hypotension, and acute kidney injury (2 [2.0%] participants each). Forty
participants (39.6%) had an adverse event leading to dose reduction. 
At the time of this DCO, five cases of sepsis in the ADAGIO study were reported; three 
events recovered, and two events were fatal. Four of these five sepsis cases (including the two 
fatal cases) were associated with Grade 4 neutropenia, which occurred within the first two 
cycles of treatment and these four cases had either a baseline or on-study decrease in 
creatinine clearance to <50 ml/min. Both fatalities (Grade 5 biliary sepsis [not related to 
adavosertib per investigator]; Grade 5 urosepsis [related to adavosertib per investigator]) 
occurred in patients who had a pre-existing infection (biliary) or a specific predilection for 
infectious complications (vesico-vaginal fistula).
To understand the relationship of adavosertib exposure and severe haematological events in 
monotherapy treatment, a pooled exposure-safety analysis was performed and showed that 
there is a strong correlation between adavosertib plasma exposure, and the predicted 
probability of Grade ≥3 neutropenia and thrombocytopenia. The predicted probability of 
neutropenia and thrombocytopenia increases as adavosertib plasma exposure increases. The 
model predicted probability of developing neutropenia (Grade ≥ 3) at median and 95th 
percentile of AUCss after 300 mg QD dosing is 12.9% and 45.0 %, respectively, while at 250 
mg QD dosing it is 10.6 % and 20.4 %, respectively. This indicates approximately 18% and 
55% reduction of predicted probability of neutropenia at 50th and 95th percentile of exposure, 
respectively, when the dose is reduced to 250 mg QD from 300 mg QD, irrespective of 


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baseline renal function. This analysis suggests that by reducing the starting dose to 250 mg 
QD, the risk of severe neutropenia and haematological toxicities will be reduced.  Clinical 
benefit is expected to be maintained at the reduced dose of 250 mg. 
A starting dose of adavosertib at 250 mg QD (5 days on, 2 days off in Weeks 1 and 2 out of a 
21-day schedule) is recommended for adavosertib monotherapy clinical development.  This 
assessment is based on the preclinical efficacy findings, overall tolerability profile, frequency 
of dose reductions due to AEs reported at 300 mg QD, exposure-safety analyses, and the 
reduced predicted occurrence of severe neutropenia and sepsis with lower exposure. For this 
reason, in future studies with adavosertib monotherapy a starting dose of 250 mg QD will be 
used (for further details refer to Investigator’s Brochure ) . In the ADAGIO study no further 
patients will be enrolled and there are no patients being treated at the 300mg QD dose level. 
4.4
End of Study Definition
A participant is considered to have completed the study if she has completed all phases of the 
study including the last scheduled procedure shown in the Schedule of Activities (SoA) 
(Section 1.3).
The end of the study is defined as the date of the last visit of the last participant in the study. 
The last visit occurs when the last participant of Cohort B has their last scheduled visit, or  6 
months after last participant first dose in Cohort B, whichever comes first.
After the primary analysis DCO, the clinical study database will be closed to new data. The 
final  primary analysis DCO will be followed by clinical database lock when all data for all 
participants have been collected. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to Good Clinical Practice (GCP), or if recruitment is slow. AstraZeneca 
may also terminate the entire study prematurely if concerns for safety arise within this study 
or in any other study with adavosertib.
Participants are permitted to continue to receive adavosertib beyond primary DCO in the 
continued access phase of this study if, in the opinion of the investigator, they are continuing 
to receive clinical benefit. Participants who continue to receive clinical benefit without 
meeting any discontinuation criteria at primary DCO may continue to receive adavosertib (to 
be provided by the Sponsor) if they are deriving clinical benefit in the opinion of the 
investigator and not fulfilling any discontinuation criteria.
Such participants are to be followed in accordance with the Medical Standard of Care and as 
deemed appropriate by the investigators. Serious adverse event (SAE) reporting (standard 
pharmacovigilance process) will continue to ensure safety data collection and monitoring of 
the participants while receiving the investigational product. It is recommended that 


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investigators continue to observe ongoing participants at the frequency employed prior to the 
primary DCO. Protocol dose modification and stopping criteria are to be followed while a 
participant is receiving adavosertib. Restrictions regarding concomitant medications 
(Section 6.5) must be followed while the participant is receiving adavosertib. A change in the 
dose/schedule of adavosertib should only occur for safety reasons, based on the investigator’s 
judgement, and should generally follow the approach for dose reduction and discontinuation 
as described in this protocol. Combining adavosertib with other anticancer therapy is not 
allowed.
If in the opinion of the investigator, a participant is no longer receiving clinical benefit from 
the IP, then the IP will be stopped. The investigator will inform AstraZeneca when a 
participant discontinues the IP. Participants must return unused medication during routine 
clinic visits; drug accountability information must continue to be collected in patient source 
documents until the participant discontinues treatment. Participants will continue to be 
monitored by their treating physician/investigator for all SAEs and pregnancies while 
receiving IPs and for 30 days after the last dose of IP.
In the event that a roll-over study is available at the time of the primary DCO and database 
closure, participants(s) currently receiving treatment will adavosertib may then be transitioned 
to such a study, and the current study would reach its end. The roll-over or extension study 
would ensure treatment continuation with visit assessments per its protocol, as applicable. Any 
participants who would be eligible to move to such a study would be given a new informed 
consent, as applicable.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to receive Cycle 1 of adavosertib. 
Under no circumstances can there be exceptions to this rule. Participants who do not meet the 
entry requirements are screen failures (see Section 5.4).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria are met:
Informed Consent


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1
Capable of giving signed informed consent and has given signed informed consent as 
described in Appendix C which includes compliance with the requirements and 
restrictions listed in the ICF and in this protocol.
2
Age
3
Participant must be aged ≥18 years of age inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
4
Histologically confirmed recurrent or persistent USC.  For the purposes of this study, 
participants with endometrial carcinoma of mixed histology where the serous component 
comprises at least 10% of the tumour will be considered eligible. Participants with 
carcinosarcomas are not eligible.
5
Evidence of measurable disease as per RECIST v1.1 defined as at least one lesion, not 
previously irradiated, that can be accurately measured in at least one dimension (longest 
diameter to be recorded) as ≥10 mm with computed tomography (CT) scan or magnetic 
resonance imaging (MRI) (except lymph nodes which must have short axis ≥15 mm) and 
which is suitable for accurate repeated measurements.
6
At least 1 prior platinum based chemotherapy regimen for the management of USC (there 
is no restriction on the number of prior lines of systemic therapy that a participant may 
have previously received, and the platinum based chemotherapy may have been given in 
the adjuvant setting). Chemotherapy administered only in conjunction with primary 
radiotherapy as a radiosensitiser should not count as a systemic regimen.

Prior anticancer therapies (eg, immune checkpoint inhibitors, vascular endothelial 
growth factor (VEGF) inhibitors and HER2 targeted therapy) are allowed

Participants who have known MSI-H or dMMR tumours will not be eligible unless 
they have already received prior therapy with pembrolizumab or another 
PD-1/PD-L1 immune checkpoint inhibitor, in territories where this treatment is 
available for this indication, or are deemed not to be a candidate for immune 
checkpoint therapy
7
Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (see Appendix B) 
with no deterioration over the previous 2 weeks prior to day of first dosing.
8
Life expectancy ≥12 weeks.
9
Participants must have normal organ and marrow function at baseline, as defined below 
by laboratory values within 7 days prior to study drug(s) administration:

Absolute neutrophil count (ANC) ≥1.5 × 109/L
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
Haemoglobin (Hb) ≥9 g/dL

Platelet count ≥100 × 109/L

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 x upper 
limit of normal (ULN) or ≤5 x ULN if known hepatic metastases 

Serum bilirubin within normal limits (WNL) or ≤1.5 x ULN in participants with 
liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in 
participants with documented Gilbert’s Syndrome

Calculated creatinine clearance (CrCl) >50 mL/min as determined by  the Cockcroft-
Gault method (using actual body weight), 
Cockcroft-Gault equation for estimated CrCL:
CrCl (glomerular filtration rate) = (140-age) x (weight/kg) x F
         (72 x serum creatinine mg/dL)
NOTE: F= 0.85 for females
10 Consent to submit and provide a mandatory FFPE tumour sample for central testing. The 
site must confirm that the FFPE sample is available prior to dosing.  
Reproduction
11 Female participants who are not of childbearing potential* and women of childbearing 
potential who agree to use adequate contraceptive measures (see Section 5.3.3) from the 
time of signing the ICF and until 1 month after study treatment discontinuation, who are 
not breastfeeding, and who have a negative serum or urine pregnancy test during 
screening and confirmed on Cycle 1, Day 1 (prior to the start of study treatment).
* Postmenopausal or premenopausal with evidence of non-childbearing potential.  
Women will be considered post-menopausal if they have been amenorrhoeic for 12 
months without an alternative medical cause. The following age-specific requirement 
apply: 

Women ≥ 50 years of age would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago or

Women < 50 years of age with any one or more of the conditions below:
o
Amenorrheic for ≥1 year in the absence of chemotherapy and/or hormonal 
treatments,
o
Luteinizing hormone and/or follicle stimulating hormone and/or oestradiol levels 
in the postmenopausal range,
o
Radiation-induced oophorectomy with last menses > 1 year ago,


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o
Chemotherapy-induced menopause with > 1-year interval since last menses,
o
Surgical sterilization (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria applies on Day 1 of 
the study or as indicated:
Medical Conditions
1
Any underlying medical condition that would impair the ability of the participant to 
receive study treatment, as judged by the investigator.
2
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection*, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.
-
*Recurrent, active or suspected infection and/or participants who are predisposed to 
an increased risk of severe infection. Patients with infections that require antibiotics or 
antifungal agents may be eligible, provided that infection is resolved and treatment is 
completed at least 7 days prior to study treatment start.  
3
CTCAE v5.0 Grade > 1 toxicity from prior therapy (except alopecia, anorexia or CTCAE 
grade 2 peripheral neuropathy).
4
Refractory nausea and vomiting, unable to swallow oral medications (NOTE: Patient 
may not have a percutaneous endoscopic gastrostomy tube or be receiving total parenteral 
nutrition).
5
History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease ≥5 years 
before the first dose of Day 1 of Cycle 1 and of low potential risk for recurrence, as 
determined by the investigator (participants who have received prior adjuvant 
chemotherapy for early stage breast cancer may be eligible, provided that it was 
completed ≥3 years prior to registration, and that the patient remains free of 
recurrent or metastatic disease)

Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of 
the skin that has undergone potentially curative therapy

Adequately treated carcinoma in situ without evidence of disease
6
Spinal cord compression or metastases unless asymptomatic, stable, and not requiring 
steroids for at least 4 weeks prior to start of study intervention.
7
Patients with current (or within 28 days prior to Cycle 1, Day 1) signs or symptoms of 
bowel obstruction, including sub-occlusive disease, related to underlying disease.


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8
Any of the following cardiac diseases currently or within the last 6 months:

Unstable angina pectoris

Acute myocardial infarction

Congestive heart failure ≥ Class 2 (as defined by New York Heart Association) 

Conduction abnormality not controlled with pacemaker or medication

Significant ventricular or supraventricular arrhythmias (participants with chronic 
rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible)
9
History of Torsades de pointes unless all risk factors that contributed to Torsades have 
been corrected.
10 a) Resting corrected QTc interval using the Fridericia formula (QTcF) > 480 msec (as 
calculated per institutional standards) obtained from an electrocardiogram (ECG) 
(NOTE: if one ECG demonstrates a QTcF > 480 msec, then a mean QTcF of ≤480 msec 
obtained from 3 ECGs 2-5 minutes apart, is required at study entry), or b) congenital long 
QT syndrome
11 Immunocompromised participants, eg, participants who are known to be serologically 
positive for human immunodeficiency virus (HIV).
12 Patients with known active hepatitis (ie, hepatitis B or C):

Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen 
(HBsAg) result. Patients with a past or resolved HBV infection (defined as the 
presence of hepatitis B core antibody and absence of HBsAg) are eligible

Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA
Prior/Concomitant Therapy
13 Use of anticancer treatment drug ≤21 days (≤ 6 weeks for nitrosoureas or mitomycin C) 
or use of an investigational product within 5 half-lives prior to the first dose of 
adavosertib. For PD-1/PD-L1 inhibitors, a minimum of 28 days since last dose is 
required.
Patients on luteinising-hormone releasing hormone analogue treatment for more than 
6 months are allowed entry into the study and may continue at the discretion of the 
investigator. 
14 Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field 
of radiation or to more than 30% of bone marrow within 4 weeks prior to the first dose of 
study intervention.
15 Major surgical procedures ≤28 days, or minor surgical procedures ≤7 days, prior to 
beginning study treatment. No waiting period required following port-a-cath or other 
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16 Prior receipt of a cell cycle checkpoint inhibitor (eg, CHK1, WEE1, or ATR inhibition)
17 Has had prescription or non-prescription drugs or other products known to be moderate to 
strong inhibitors/inducers of CYP3A4 (see Appendix D). If the drug could be 
discontinued, then a wash out of ≥2 weeks prior to Day 1 of dosing is required and the 
drug will be withheld throughout the study until 2 weeks after the last dose of study drug.
18 Use of herbal medications 7 days prior to first dose of study treatment. Please see 
Appendix D for further details.
Prior/Concurrent Clinical Study Experience
19 Participants with a known hypersensitivity or contraindication to adavosertib or any of the 
excipients of the product.
Other Exclusions
20 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
21 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements
22 Previous enrolment in the present study.
23 Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Grapefruit and Seville oranges are moderate inhibitors of CYP3A4; these fruits or their 
products (eg, juice, marmalade, etc) should be avoided while taking adavosertib. Please refer 
to Appendix D for further guidance.
5.3.2
Caffeine, Alcohol, and Tobacco
No interactions with caffeine, alcohol or tobacco have been identified.
5.3.3
Contraception
Women of childbearing potential, defined as women between menarche and menopause who 
have not been permanently or surgically sterilised, must agree to use a highly effective method 
of contraception, defined as one that can achieve a failure rate of less than 1% per year when 
used consistently and correctly, from the time of signing of ICF, while taking adavosertib, and 
for 1 month after stopping adavosertib. Cessation of contraception 1 month after stopping 
adavosertib should be discussed with a responsible physician. 
All highly effective methods of contraception (with the exception of total abstinence) must be 
used in combination with the use of a condom by a male sexual partner for intercourse.
Highly effective methods of contraception include:


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
Total abstinence

Permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy)

Tubal ligation (tubes tied)

Combined oral, transdermal or intra-vaginal hormonal contraceptives (pills, skin patches, 
or inside the vagina)

Medroxyprogesterone injections (eg, Depo-provera™)

Cerzette (desogestrel) pill

Copper-banded intra-uterine devices

Hormone impregnated intra-uterine systems (eg, NuvaRing®, Implanon®)

Vasectomised partner
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable 
methods of contraception. Female condom and male condom should not be used together.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may not 
be rescreened. However, retesting of eligibility blood samples will be allowed within the 
28-day screening window, if the patient has a blood sample abnormality that subsequently 
improves such that the eligibility criteria are met.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. Details of adavosertib are shown in Table 5. 
A schematic presentation of the treatment schedule is presented in Figure 3. 


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6.1
Study Intervention Administered
6.1.1
Investigational Product
Table 5
Investigational Product
Intervention Name
AZD1775
Type 
Drug
Dose Formulation
Dry-filled capsules
Unit Dose Strength(s)
 and/or 
Dispensing
Day 1 of a 21-day treatment cycle.
Dosage Level(s)
300 mg QD. Participants will be dosed on Days 1 to 5 
and Days 8 to 12 of a 21-day treatment cycle.
A minimum of 9 days between the last dosing of a 
cycle and Day 1 of the next cycle is required.
Route of Administration
Oral
Use
Experimental
IMP and NIMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and Labelling
Study Intervention will be provided in a high-density 
polyethylene bottle. Each bottle will be labelled as 
required per country requirement
Current Alias
Adavosertib
IMP, Investigational Medicinal Product; NIMP, Non-Investigational Medicinal Product; QD, once daily
Adavosertib at the appropriate dose should be taken with 8 ounces (approximately 250 mL) of 
water and may be taken with or without food. If a participant misses the daily dose according 
to the schedule, the dose should be taken as soon as possible, but not more than 12 hours after 
the missed dose was scheduled. If greater than 12 hours, the missed dose should be skipped, 
and the participant should take the next dose when scheduled.
If vomiting occurs after a participant takes the adavosertib dose, the participant should be 
instructed not to retake the dose, but to wait until the next scheduled dose of adavosertib. If no 
dose is scheduled for the following day, the dose will not be ‘made up’. If vomiting persists, 
the participant should contact the investigator. For guidance on management of nausea and 
vomiting, refer to Section 8.3.13.4.
Adavosertib dose reductions are permitted (see Section 6.6).
Figure 3
Treatment Schedule per 21-day Cycle
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6.2
Preparation/Handling/Storage/Accountability of Intervention
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention and only authorised site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labelled storage conditions with access limited to the investigator and authorised site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
Any study drug remaining at the end of the study must be destroyed or returned according to 
the sites local standard operating procedures following authorisation by the sponsor.
6.3
Measures to Minimise Bias: Randomization and Blinding
Not applicable – this is a single arm, open-label study.
6.4
Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed by a patient dosing diary on adavosertib dispensing visits as 
specified in the SoA (Section 1.3) and documented in the source documents and electronic 
case report form (eCRF). Deviation(s) from the prescribed dosage regimen should be recorded 
in the eCRF.
A record of the number of adavosertib capsules dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine, including over-the-counter or prescription medicines, and/or 
supplements that the participant is receiving at the time of enrolment or receives during the 
study (including any prohibited concomitant medications) must be recorded along with:

Reason for use

Dates of administration including start and end dates


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
Dosage information including dose and frequency
Guidance regarding prohibited concomitant medication and potential interactions of 
adavosertib with concomitant medications is provided below and in Appendix D.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1 Permitted Concomitant Medications
All concomitant medications received within 14 days before the first dose of study medication 
and 30 days after the last dose of study medication should be recorded. Concomitant 
medications must be recorded in the appropriate sections of the eCRF. Permitted concomitant 
medications are described in Table 6.
Table 6
Permitted Concomitant Medications
Supportive Medication/Class of drug
Usage
Anti-emetics (excluding aprepitant [Emend] and 
fosaprepitant)
Premedication with anti-emetics is mandatory (excluding 
aprepitant [Emend] and fosaprepitant) as presented in 
Section 8.3.13.4
Loperamide (Imodium) 
Loperamide (Imodium) is required at the first onset of 
diarrhoea according to ASCO guidelines (see 
Section 8.3.13.4). 
Medications including but not limited to the 
following:
Bisphosphonates and receptor activator of nuclear 
factor kappa-B ligand (RANKL) inhibitors 
(eg, denosumab).
Participants requiring therapeutic warfarin or 
coumadin-derivative anticoagulants will be 
monitored with INR and Prothrombin Time (PT) as
clinically indicated.
Low molecular weight heparin, rivaroxaban, or 
equivalent anticoagulant therapy is permitted where 
clinically indicated.
Medications may be administered for maintenance of 
existing conditions prior to study enrolment or for a new 
condition that develops while on study.
ASCO, American Society of Clinical Oncology; INR, International Normalised Ratio
6.5.2 Prohibited and Restricted Concomitant Medications
The following treatments and the medications listed in Appendix D are prohibited or should 
be used with caution while on this study. Any further questions regarding concomitant 
treatments should be referred to the Medical Monitor. Prohibited and restricted concomitant 
medications are described in Table 7 and Table 8, respectively.


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Table 7
Prohibited Concomitant Medications
Prohibited Medication/Class of Drug
Additional Information
Anticancer agents other than the study medications: 
chemotherapy, immunotherapy, hormonal 
anticancer therapy, radiotherapy (except for 
palliative local radiotherapy), biological therapy or 
other novel agent.
If such agents are required for a participant, then the 
participant must first be withdrawn from the study.  
Concomitant treatment with aprepitant and 
fosaprepitant is not allowable per protocol until 
further evaluation.
An exploratory assessment of the effect of aprepitant on 
adavosertib exposure in oncology participants suggests that 
there is a drug interaction between adavosertib and 
aprepitant, as exposure to adavosertib increased by ~60% 
when aprepitant was co-administered with adavosertib. The 
observed increase in adavosertib exposure is likely the 
result of CYP3A4 inhibition by aprepitant. This increase in 
exposure is statistically significant. At the selected MTDs, 
this increase may also be of clinical importance.  
Herbal preparations/medications are not allowed 
throughout the study.  These herbal medications 
include, but are not limited to: St. John’s wort, 
kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw 
palmetto, and ginseng.  
Participants should stop using these herbal medications 7 
days prior to first dose of adavosertib.
Avoid concomitant use of strong CYP3A inhibitors 
and moderate CYP3A inhibitors.
See Appendix D
Grapefruit, Seville oranges and their products 
(eg, juice, marmalade, etc.)
As grapefruit and Seville oranges are moderate inhibitors 
of CYP3A4, these fruits or their products should be 
avoided while taking adavosertib.  
Receipt of live virus and live bacterial vaccines is 
not permitted while the participant is receiving 
study medication and during the 30-day follow-up 
period. Inactivated flu vaccines are permitted.
See Appendix D
CYP, cytochrome P450; MTD, maximum tolerated dose
Table 8
Restricted Concomitant Medications
Restricted Medication/Class of Drug
Usage
Inhibitors or substrates of P-glycoprotein (P-gp)
In vitro studies have shown that adavosertib may be a 
substrate and inhibitor for human P-gp. Caution should be 
exercised when agents that are inhibitors or substrates of 
P-gp are administered concomitantly with adavosertib (see 
Appendix D).


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Restricted Medication/Class of Drug
Usage
Substrates of Multidrug and Toxin Extruder 1 
(MATE1) and MATE2K transporters 
(eg, cimetidine, acyclovir, fexofenadine) 
Caution should be used when administering substrates of 
MATE1 and MATE2K transporters (eg, cimetidine, 
acyclovir, fexofenadine) as the clinical relevance of 
adavosertib inhibition of the MATE pathway is not known 
in these compounds.
Metformin
Metformin should be used with caution. Adavosertib has 
been shown to be an inhibitor of MATE1 and MATE2K 
transporters. A drug interaction with substrates of either 
transporter cannot be ruled out, the most important 
substrate known to date being metformin.
BCRP substrates with narrow therapeutic index
Recent in vitro transporter studies have shown adavosertib 
to be an inhibitor of BCRP (IC50 5.1 µM). This finding is 
particularly relevant for drugs administered orally where 
exposure is normally limited by BCRP-mediated efflux, in 
particular some statins, such as rosuvastatin. Other drugs 
where the disposition is mediated via BCRP should be 
administered with caution, dose modification considered or 
substituted by an alternative drug.
BCRP, breast cancer resistance protein
6.5.3
Palliative Radiotherapy
Participants may receive palliative radiotherapy during the study only for local pain control, 
and only if in the opinion of the treating investigator the participant does not have disease 
progression. If palliative radiotherapy is needed for disease progression, the patient should be 
taken off study treatment.
6.5.4
Other Concomitant Treatment
Medication other than those described above, which is considered necessary for the 
participant’s safety and wellbeing, may be given at the discretion of the investigator and 
recorded in the appropriate sections of the eCRF.
6.6
Dose Modification
Dose reductions or holds are allowed as clinically indicated by the treating physician in line 
with Table 9. Dose adjustments will be based on the organ system exhibiting the greatest 
degree of toxicity. For each participant, a maximum of 2 successive dose reductions will be 
allowed during the study. Dose re-escalations are not allowed. 
For guidance on treatment interruptions, refer to Section 7.1.2.
For guidance on dose reductions for the management of adavosertib-related AEs, refer to 
Section 8.3.13.


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Table 9
Dose Levels for Adavosertib
Dose Level
Adavosertib Dose
Units
Dosing Schedule
Starting 
dose
300 mg QD 
Days 1 to 5 and Days 8 to 12 of a 
21-day treatment cycle
-1
250 mg QD 
No change
-2
200 mg QD 
No change
QD, once daily
6.7
Intervention after the End of the Study
Participants are permitted to continue to receive treatment beyond the end of study if, in the
opinion of the investigator, they are continuing to receive clinical benefit. Adavosertib will 
continue to be provided by AstraZeneca until the availability of either a local commercial
supplier and reimbursement program or an early access program; at which point a change in
supply will be requested. Treatment of participants with adavosertib beyond progression is not
allowed. For further information on end of study, refer to Section 4.4.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Participants MUST be discontinued from study treatment in the following situations.

RECIST v1.1-defined radiological progression (refer to Section 8.1.1 and Appendix A) 

Investigator determination that the participant is no longer benefiting from study 
treatment

An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing

Any AE that meets criteria for discontinuation defined in the guidelines for management 
of treatment-related toxicities (see Section 8.3.13)

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2).
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
Severe non-compliance with the CSP as judged by the investigator or AstraZeneca

Pregnancy or intent to become pregnant

Initiation of subsequent anticancer therapy, including another investigational agent
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study. See the SoA (Section 1.3) for data to be collected at the time of 
treatment discontinuation (ie, Discontinuation visit) and follow-up and for any further 
evaluations that need to be completed. If the reason for discontinuation is disease progression, 
then only the discontinuation visit is required. The 7-day window (+7 days) applies from the 
point a decision to discontinue adavosertib is taken either due to progression or another 
discontinuation criterion. 
Participants who have discontinued study treatment prior to objective RECIST v1.1-defined 
radiological progression will be followed up with tumour assessments as indicated in the SoA 
(Section 1.3) until RECIST v1.1-defined progressive disease or death, regardless of whether 
or not the participant started a subsequent anticancer therapy, unless they have withdrawn all 
consent to study-related assessments.
After discontinuation of study medication at any point in the study, all ongoing AEs or SAEs 
must be followed until resolution unless, in the investigator’s opinion the condition is unlikely 
to resolve due to the participants underlying disease, or the participant is lost to follow-up (see 
Section 7.3). All new AEs and SAEs occurring during the follow-up period after the last dose 
of study medication must be reported (if SAEs, they must be reported to AstraZeneca within 
24 hours as described in Section 8.3.10) and followed to resolution as above. For guidance on 
reporting AEs after the follow-up period see Section 8.3.2.
If the participant does not agree to continue in-person study visits, a modified follow-up 
should be arranged, whenever possible, to ensure the collection of endpoints and safety 
information. This could be a telephone contact with the participant, a contact with a relative or 
treating physician, or information from medical records. The approach taken should be 
recorded in the medical records. A participant that agrees to modified follow-up is not 
considered to have withdrawn consent or to have withdrawn from the study.
7.1.1
Procedure for Discontinuation of Study Intervention
The investigator should instruct the participant to contact the site before or at the time if study 
treatment is stopped. A participant who 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 eCRF. All unused adavosertib treatment should be 
returned by the participant at their next on-site study visit or unscheduled visit. Participants 
permanently discontinuing adavosertib treatment should be given locally available standard of 
care therapy at the discretion of the investigator.


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7.1.2
Study Intervention Interruption
Treatment interruptions up to a maximum of 21 days are permitted in the event of toxicity (see 
adavosertib dose modification guidelines [Section 6.6]). The treatment interruption period 
should be considered from the onset of the toxicity. In the event of a treatment interruption 
greater than 21 days, then the investigator will require approval from the sponsor to restart the 
participant on adavosertib treatment. 
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons.

A participant 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).

At the time of withdrawal from the study, if possible, a discontinuation visit should be 
conducted, as shown in the SoA (Section 1.3).

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if she still agrees for 
existing samples to be used in line with the original consent. If she requests withdrawal of 
consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
AstraZeneca or its delegate will request investigators to collect information on participants’ 
vital status (dead or alive; date of death when applicable), including participants that withdrew 
consent or are classified as "lost to follow-up", from publicly available sources, in accordance
with local regulations. Knowledge of the vital status at study end in all participants is crucial 
for the integrity of the study.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
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
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, she will be considered to have 
withdrawn from the study. 

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants. Public sources may be 
searched for vital status information. If vital status is determined as deceased, this will be 
documented, and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix C 9.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (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 amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will be approximately 450 mL. 


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Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Efficacy Assessments
8.1.1
RECIST v1.1 Assessments
RECIST v1.1 tumour assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis (with additional anatomy as clinically indicated by extent of disease) at 
baseline (no more than 28 days before the start of study treatment). A dedicated pelvic MRI 
protocol is recommended for optimal assessment. After start of treatment (Cycle 1, Day 1), 
scans will be repeated every 6 weeks (±7 days) for the first 48 weeks and every 9 weeks 
(±7 days) thereafter, until objective radiological disease progression by investigator 
assessment using RECIST v1.1. If an unscheduled assessment is performed (eg, to investigate 
clinical signs/symptoms of progression) and the participant has not progressed, every attempt 
should be made to perform the subsequent image acquisition at the next scheduled imaging 
visit. For ORR, a visit response of CR or PR must be confirmed by a subsequent scan 
conducted at least 4 weeks after the initial response is observed. The next RECIST scheduled 
assessment can be used for the confirmatory scan.  
Participants who discontinue treatment prior to RECIST v1.1 progression (eg, discontinuation 
due to toxicity or clinical progression) should continue to be scanned until RECIST v1.1 
progression. If the investigator is in doubt as to whether radiological progression has occurred, 
particularly with response on non-target lesions or the appearance of new lesions, it is 
advisable to continue treatment until the next scheduled assessment (or sooner assessment, if 
clinically indicated) and reassess the participant’s status. If repeat scans confirm progression, 
then the date of the initial scan should be declared as the date of progression.
The same imaging modality and the same assessment (eg, the same contrast protocol for CT 
scans of the chest and MRI scans of the pelvis) should be performed at baseline and at all 
follow-up time-points if possible. Guidelines on the valid methods of assessment and the 
evaluation of objective tumour response using RECIST v1.1 are provided in Appendix A.
Efficacy assessments of confirmed ORR, DoR, percentage change from baseline in tumour 
size, PFS, and DCR will also be derived (by AstraZeneca) using RECIST v1.1 assessments 
based on BICR. All images, including unscheduled visit scans, will be collected on an ongoing 
basis and sent to an AstraZeneca-appointed Contract Research Organisation (CRO) to enable 
BICR up to the primary analysis DCO (when the last participant has their last scheduled visit, 
or 6 months after last participant first dose, whichever is earlier). After the primary analysis 
DCO, images will no longer need to be collected centrally. Ongoing collection of 
site-reviewed tumour assessment is required and must be recorded in the eCRF. Radiological 
examinations performed in the conduct of this study should be retained at site as source data. 


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Guidelines for image acquisition, de-identification, and transfer to the imaging CRO will be 
provided in separate documents. Further details of the BICR will be documented in the 
Independent Review Charter (also referred to as “Imaging Charter”). Results of the 
independent reviews will not be communicated to investigators, and results of investigator 
RECIST v1.1 assessments will not be shared with the central reviewers. The management of 
participants will be based wholly upon the results of the RECIST v1.1 assessment conducted 
by the investigator. 
For information on ORR, DoR, percentage change from baseline in tumour size, PFS and 
DCR endpoints, refer to Section 9.4.1.1, Section 9.4.1.2, Section 9.4.1.3, Section 9.4.1.4 and 
Section 9.4.1.7, respectively.
8.1.2
Survival Follow-up
Assessments for survival will be conducted every 12 weeks from the time of objective disease 
progression or treatment discontinuation. Survival information may be obtained via telephone 
contact with the participant, participant’s family, by contact with the participant’s current 
physician, or local death registries as described in Section 7.3.
For information on OS, refer to Section 9.4.1.6.
8.1.2.1
Subsequent Cancer Therapy Following Discontinuation of Study 
Intervention 
Details of subsequent cancer therapy following discontinuation of adavosertib will be 
collected as part of the post-treatment follow-up visit, and at the survival follow-up visit. The 
choice of subsequent systemic anticancer treatment will be entirely at the discretion of the 
investigator.
8.1.3
CCI
CCI


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8.1.3.1
CCI
CCI


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8.1.3.2
CCI
CCI
CCI


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8.1.3.3
CCI
CCI
CCI


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8.1.3.4
8.1.3.5
8.1.3.6
8.1.3.7
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
The physical examination will be performed at timelines as specified in the SoA (Section 1.3). 
A complete physical examination will be performed and will include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems. 
Weight and height will be assessed at timelines as specified in the SoA (Section 1.3).
If new or aggravated physical findings imply deterioration compared with baseline, the 
finding should be reported as an AE (Section 8.3). Performance status will be assessed using 
the ECOG performance status criteria (see SoA [Section 1.3] and Appendix B).
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the SoA (Section 1.3) and prior to 
dosing with adavosertib. Vital signs to be assessed include: pulse rate, blood pressure, and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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temperature. 
8.2.3
Electrocardiograms
ECG will be performed at timelines as specified in the SoA (Section 1.3). A 12-lead safety 
ECG (paper ECG printout of 10 seconds for investigator review) will be taken at screening, 
and if a prolongation of the QTc interval is detected this must be closely monitored as 
clinically indicated, and to the best of clinical practice. 
The participants will rest for at least 10 minutes before the start of the ECG recording and they 
must be in the same supine body position (maximum 30 degrees flexion in the hip and feet not 
in contact with the footboard) at the recording time point.
If one ECG demonstrates a QTcF > 480 msec, then a mean QTcF of ≤480 msec obtained from 
3 ECGs 2-5 minutes apart, is required for the patient to be eligible for study entry.
The investigator will judge the overall interpretation as normal or abnormal. If abnormal, it 
will be decided as to whether or not the abnormality is clinically significant or not clinically 
significant. The paper copy of each ECG reading will be retained with the participant’s 
completed source documents. Any clinically significant abnormalities detected require 
triplicate ECG results. At each time point at which triplicate ECG are required, 3 individual 
ECG tracings should be obtained in succession, within 5 minutes. If there is a clinically 
significant abnormal unscheduled ECG finding during the treatment period, this should be 
recorded on the AE eCRF, according to standard AE collection and reporting processes (see 
Section 8.3). 
Attention should be paid to any detected increases in QTc interval. Participants who develop a 
single resting value of QTc interval of > 480 msec or a shift from baseline of ≥60 ms, should 
pause taking adavosertib. Dosing may be resumed at the same or reduced dose after return of 
the resting QTc interval to Grade 1 or baseline has been confirmed and correction of possible 
electrolyte imbalance has been made, if needed, following cardiologists’s advice. For more 
details, see Section 8.3.13.2 and Table 15.
Monitoring of QTc, checking and correction of abnormal electrolyte levels and renal function 
are advised, especially in case of severe/prolonged diarrhoea. If QTc increases markedly from 
baseline but stays below the above limit of Grade 1 (per CTCAE v5.0), a cardiologist’s advice 
is recommended.
The concomitant use of ondansetron (known to prolong the QTc interval in rare cases, per 
labelling) should be taken into account when interpreting QTc changes.
8.2.4
Clinical Safety Laboratory Assessments
Blood and samples for determination of clinical chemistry, haematology, coagulation, and PK 


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will be taken at the times indicated in the SoA (Section 1.3). 
Additional safety samples may be collected if clinically indicated at any time during the cycle 
at the discretion of the investigator. The date, time of collection and results (values, units and 
reference ranges) will be recorded on the appropriate eCRF.
The clinical chemistry, haematology, urinalysis and pregnancy test will be performed at a local 
laboratory at or near to the investigator site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site. 
Complete haematology blood counts and clinical chemistry will be obtained for all 
participants at visits on Day 1, Day 5, Day 8, Day 12 and Day 15 in Cycle 1 and Cycle 2, and 
at the beginning of each treatment week (on Day 1 and Day 8) in Cycle 3 onwards. Creatinine 
clearance (CrCl) must be estimated using the Cockcroft-Gault equation at all visits. On dosing 
days, the results must be reviewed prior to dose administration to ensure that they meet the 
dosing thresholds. For management of adavosertib-related toxicity management, refer to 
Section 8.3.13.
Women of childbearing potential must have a negative urine or serum pregnancy test during 
screening and a confirmatory negative test prior to dosing on Day 1 of each treatment cycle. In 
the event of suspected pregnancy during the study, the test should be repeated prior to dosing 
and, if positive, the participant discontinued from study treatment immediately.
The laboratory variables presented in Table 10 will be measured as a minimum (some of these 
variables may be measured at baseline only). 
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. Any clinically significant abnormal laboratory values should be 
repeated as clinically indicated and recorded on the eCRF. 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.


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Table 10
Laboratory Safety Variables
Haematology (2.7 mL whole blood sample)
Clinical Chemistry (2.7 mL serum or plasma 
sample)
B-Haemoglobin
S/P-Albumin
B-Leukocyte
S/P-Alanine aminotransferase (ALT)
B-Haematocrit
S/P-Aspartate aminotransferase (AST)
B-Red blood cell count
S/P-Alkaline phosphatase (ALP)
B-Absolute leukocyte differential count
S/P-Bilirubin, total
B-Neutrophils
S/P-Calcium, total
B-Lymphocytes
S/P-Creatinine
B-Monocytes
S/P-Chloride
B-Basophils
S/P-Potassium
B-Eosinophils
S/P-Sodium
B-Platelet counts
S/P-Urea nitrogen or blood urea nitrogen
B-Absolute neutrophil count 
Coagulation (1.8 mL sample)
Pregnancy test (blood or urine)
B-PT or INR with PTT
Urinalysis (dipstick)
U-Hb/erythrocytes/blood
U-Protein/albumin
U-Glucose
NB. In case a participant shows an AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN please refer 
to Appendix H: Actions required in cases of increases in liver biochemistry and evaluation of Hy’s Law’, for 
further instructions. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, blood; 
Hb, haemoglobin; INR, International Normalised Ratio; P, plasma; PT, prothrombin time; PTT, partial 
thromboplastin time; S, serum; U, urine.
8.3
Adverse Events and Serious Adverse Events
The Principal investigator (PI) is responsible for ensuring that all staff involved in the study 
are familiar with the content of this section.
The definitions of an AE and SAE can be found in Appendix E.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 


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events that meet the definition of an AE. For more information on how to follow up AEs see 
Section 8.3.2.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs will be collected from the time of signature of the ICF throughout the treatment period 
and including the 30-day follow-up period after the last dose of study drug.
SAEs will be recorded from the time of signing of the ICF.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

AE (verbatim)

The date when the AE started and stopped

CTCAE v5.0 grade, max CTCAE grade, and changes in CTCAE grade

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

AE caused participant’s withdrawal from study (yes or no)

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

Seriousness criteria

Date of hospitalisation


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
Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication

Description of AE
8.3.3
Causality Collection
The investigator should assess causal relationship between Investigational Product and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix E.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff (eg, ‘Have you had any health problems since the previous visit/you 
were last asked?) or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
They do not include metastases of the original cancer.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR). 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs and 
ECG abnormalities should therefore only be reported as AEs if they fulfil any of the SAE 
criteria, are the reason for discontinuation of treatment with the investigational product or are 
considered to be clinically relevant as judged by the investigator (which may include but is not 


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limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study treatment, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign 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).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study (see Section 8.3.7).
8.3.6
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN 
will need to be reported as SAEs if criteria are met for a Potential Hy’s Law case. Please refer 
to Appendix H for further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s Law.
8.3.7
Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new or progression of existing metastasis to the primary cancer under study 
should be considered as disease progression and not an AE. Events, which are unequivocally 
due to disease progression, should not be reported as an AE during the study.
8.3.8
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New cancers are those that are not the primary reason for the 
administration of the study treatment and have been identified after the participant’s inclusion 
in this study. They do not include metastases of the original cancer.
8.3.9
Handling of Deaths
All deaths that occur during the study, or within the 30-day follow-up period after the 
administration of the last dose of study treatment must be reported as follows:


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
Death, which is unequivocally due to disease progression, should be communicated to the 
study monitor at the next monitoring visit and should be documented in the eCRF 
module, but should not be reported as a SAE during the study.

Where death is not clearly due to disease progression of the disease under study the AE 
causing the death should be reported by entering into the web-based data capture 
(WBDC) system as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of progression of disease, if appropriate, and should assign 
a single primary cause of death together with any contributory causes.

Death with an unknown cause should always be reported as a SAE but every effort should 
be made to establish a cause of death. A post-mortem may be helpful in the assessment of 
the cause of death, and if performed a copy of the post-mortem results (with translation of 
important parts into English) should be reported in an expedited fashion to an 
AstraZeneca representative within the usual timeframes. 
8.3.10
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day 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 one 
calendar day ie, immediately but no later than 24 hours of when he or she becomes aware of
it.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
using paper form to the appropriate AstraZeneca representative by email or fax.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.


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The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug adavosertib.
8.3.11
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.
If a participant becomes pregnant during the course of the study, treatment should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
under investigation may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other study centre 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.10) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report.
8.3.12
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for the study drug that either causes harm to the participant or has the 
potential to cause harm to the participant.
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error has:

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were identified that could have led to an error


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Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature

Wrong participant received the medication

Wrong drug administered to participant
Examples of events that do not require reporting as medication errors in clinical studies:

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose see Section 8.4)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in
open label studies, even if an AstraZeneca product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day 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 8.3.1) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix E.
8.3.13
Management of Adavosertib-related Toxicities
Please refer to Section 6.6 for guidance on the dose levels to be used for dose modifications. 
Treatment with adavosertib should be temporarily interrupted for any intolerable AE regardless of 
grade or for any AEs grade ≥3 that occurs despite optimal supportive care, are not attributable to 


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the disease under investigation, where the investigator considers the AE of concern to be 
specifically associated with adavosertib. Appropriate and optimal supportive treatment of the 
toxicity is assumed prior to considering dose modifications. The Medical Monitor may be 
consulted prior to dose reduction or discontinuation of study drug due to toxicities.
8.3.13.1
Haematologic Toxicity Dose Modifications
Complete blood counts (CBC) will be obtained for all participants at Day 1, Day 5, Day 8, 
Day 12 and Day 15 in the first 2 cycles, and at the beginning of each treatment week (on Day 
1 and Day 8) in Cycle 3 onwards. The CBC results must be reviewed prior to dose 
administration. If haematologic toxicity occurs, treatment should be held, and ANC and 
platelets should be monitored at least weekly. Participants should be managed as medically 
indicated in Table 11, Table 12 and Table 13 below.
No more than two dose reductions will be allowed for any participant. Participants requiring 
further dose reduction due to haematologic toxicity must discontinue study treatment. Dose re-
escalation is not allowed. If the participant has concurrent neutropenia and thrombocytopenia, 
the most conservative guidance in the table below should be followed and discussed with 
Medical Monitor as needed.
Treatment should not be resumed until the haematological toxicity is resolved (or severity 
reduced to Grade ≤1 for platelet count and to Grade ≤2 for neutrophil count).
If haematological parameters do not recover within 21 days, the participant should be 
removed from study treatment [see Section 7.1.2].


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Table 11
Management of Blood Neutrophil Count Decrease
Grade/
neutrophil count
Number of occurrences of haematological toxicity
1st Event
Action 
2nd Event
Action
3rd Event
Action
Grade 2 
< 1.5-1.0 x 109/L
Investigator judgement to continue adavosertib or interrupt until Grade 1
(< LLN to 1.5 × 109/L) 
Grade 3a
< 1.0-0.5 x 109/L
Hold
Resume at next reduced 
dose level
Hold
Resume at next reduced 
dose level 
Discontinue and follow 
for disease progressionb
Grade 3a
< 1.0-0.5 x 109/L with 
<Grade 3 documented 
infectionc
Hold
Resume at next reduced 
dose level 
Discontinue and follow 
for disease progression
Grade 3a
< 1.0-0.5 x 109/L with 
≥ Grade 3 
documented infectionc
Discontinue and follow for 
disease progression
Grade 4a
< 0.5 x 109/L
Hold
Resume at next reduced 
dose level 
Discontinue and follow 
for disease progression
Grade 4a
(< 0.5 x 109/L) 
with documented 
infectionc
Discontinue and follow for 
disease progression
Febrile neutropeniaa 
Discontinue and follow for 
disease progressionb
a
Consider empirical prophylactic antibiotics and G-CSF.
b
In exceptional situations, where it is considered that benefits outweigh the risks, patient can continue dosing 
at reduced dose level, only after approval by the medical monitor.
c
Refer to Management of Infection for additional guidance (Table 19).
Neutropenia and/or Febrile neutropenia
Participants experiencing febrile neutropenia with significant symptoms and participants with 
severe neutropenia at high risk of sepsis should be managed in a hospital setting according to 
standard procedures, with interruption of study treatment, the urgent initiation of intravenous 
(IV) antibiotic therapy, and use of granulocyte colony-stimulating factor (G-CSF) according to 
institutional standards.
Antibiotics and G-CSF are recommended in cases of severe neutropenia, to be administered 
for 3 days or until the neutrophil count improves to ≤ Grade 2. G-CSF administration should 
commence 24 – 48 hours after last dose of adavosertib. 


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Participants with febrile neutropenia without symptoms should be managed according to 
standard institutional guidelines.
For participants experiencing severe neutropenia in a preceding cycle, secondary prophylaxis 
with (non-pegylated) G-CSF daily for 3 days commencing 24 – 48 hours after last dose of 
adavosertib in a treatment cycle is recommended. Secondary prophylaxis is to be administered 
in addition to any required dose reduction.
Please note that G-CSF is not recommended within 24 hours of the last dose of study 
treatment. Non-pegylated G-CSF should be stopped at least 48 hours before restarting study 
drug, and pegylated G-CSF should be stopped 14 days before restarting study drug.
Renal function (measured by creatinine clearance) should be monitored and dose 
modifications to manage renal impairment followed (Section 8.3.13.3.) as adavosertib 
exposure and the risk of severe neutropenia might be increased in participants with low 
creatinine clearance.


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Table 12
Management of Blood Platelet Count Decrease
Grade/
platelet count
Number of occurrences of haematological toxicity
1st Event Action 
2nd Event Action 
3rd Event Action 
Grade 2 
< 75.0 × 109/L-50.0 × 109/L
Holda
Resume at same dose
Holda
Resume at next reduced 
dose level
Holda
Resume at next reduced 
dose level 
Grade 3
< 50.0 × 109/L-25.0 × 109/L 
Hold
Resume at next reduced 
dose level 
Hold
Resume at next reduced 
dose level
Discontinue and follow 
for disease progressionb
Grade 4
< 25.0 × 109/L without any 
evidence of bleeding
Hold
Resume at next reduced 
dose level
Hold
Resume at next reduced 
dose level 
Discontinue and follow 
for disease progression
Thrombocytopenic 
haemorrhage (gross occult 
bleeding) associated with 
platelet count < 50.0 × 109/L
Discontinue and follow 
for disease progression
a
Pre-dose assessment.
b
In exceptional situations where it is considered that benefits outweigh the risks, the patient may continue 
dosing only after approval by the Medical Monitor.
Table 13
Management of Anaemia
Haemoglobin (Hb)
Action to be Taken
Hb <9 but ≥8 g/dL 
(CTCAE v5.0 Grade 2)
Give appropriate supportive treatment and investigate causality. 
Investigator judgement to continue adavosertib with supportive treatment or 
interrupt dose for a maximum of 21 days.
If recurrent Hb <9 but ≥8 g/dL, interrupt dose (for a maximum of 21 days) 
until Hb ≥9 g/dL, and upon recovery, dose reduction may be considered (to 
next reduced dose level as a first step and to next reduced dose level at 
reoccurrence of the same toxicity).
Hb <8 g/dL 
Give appropriate supportive treatment and investigate causality. Interrupt 
adavosertib for a maximum of 21 days, until improved to Hb ≥9 g/dL. Upon 
recovery, dose reduce adavosertib. 
In case of a repeat episode of Hb <8g/dL, interrupt dose for a maximum of 
21 days until Hb ≥9 g/dL, and upon recovery, further dose reduce adavosertib. 
In case of a third episode of Hb <8g/dL, discontinue treatment.
CTCAE v5.0, Common Terminology Criteria for Adverse Events Version 5.0; Hb, haemoglobin


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8.3.13.2
Non-haematologic Toxicity Dose Modifications
Participants should be managed as medically indicated in Table 14.
Table 14
Management of Non-haematological Toxicities
Grade 
Action
Grade 1/Grade 2
Investigator judgement to initiate supportive treatment and continue 
adavosertib, or interrupt dose for a maximum of 21 days. 
For persistent Grade 2 adverse events despite maximum supportive 
treatment, dosing may be resumed at next reduced dose level, as 
clinically indicated.
Grade 3a
Grade 3 toxicity for ≤21 days
Initiate supportive treatment, interrupt adavosertib for a maximum 
of 21 days, until improved to ≤ Grade 1, and follow algorithm as 
below:

Resume at next reduced dose level, maintaining supportive 
treatment. 

At recurrence, dosing may be resumed only with a further 
dose level reduction, maintaining supportive treatment. Up 
to a maximum of two dose reductions are permitted. 
       Grade 3 toxicity for >21 days

Discontinue treatment, unless approved by the Medical 
Monitor.b
Grade 4a
Discontinue treatment permanently.
a Despite appropriate supportive care.
b In exceptional situations where it is considered that benefits outweigh the risks, the patient may continue dosing 
only after approval by the Medical Monitor.
ECG should be assessed if electrolyte abnormalities are detected or suspected (eg, in relation 
to gastrointestinal toxicity). If a prolongation of the QTc interval is detected, this must be 
closely monitored as clinically indicated. Dose modification guidance for QTc interval 
prolongation is presented in Table 15.


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Table 15
QTc Interval Prolongation (Adavosertib Dose Modifications)
QTc Value (triplicate)a,b
Action to be Taken
QTc 481-500 ms (Grade 2) c
Hold treatment for up to 21 days. 
Consider seeking cardiologist’s advice. 
Once QTc interval has returned to Grade 1 and correction 
of possible electrolyte imbalance has been made, 
treatment may resume at the same dose level. 
QTc ≥501 ms or
Shift from baseline of ≥60 ms (Grade 3)c
Hold treatment for up to 21 days. 
Seek cardiologist’s advice and correct any electrolyte 
imbalance.
If QTc interval recovers to ≤480 ms (Grade 1) or 
baseline if there was a shift from baseline of ≥60 ms, 
then treatment may resume at next reduced dose level, if 
cardiologist agrees.
If QTc interval doesn’t recover to ≤480 ms or baseline if 
there was a shift from baseline of ≥60 ms, then 
discontinue treatment permanently.
Torsades de pointes or
polymorphic ventricular tachycardia or
signs/symptoms of serious arrhythmia (Grade 4).
Discontinue treatment permanently. 
Seek cardiologist’s advice. 
a
Mean triplicate value
b
Based on a dedicated QT study conducted to evaluate the effect of single & multiple doses of adavosertib 
225 mg on QT prolongation in advanced solid tumour participants, there was no significant relationship 
found between ΔQTcF and adavosertib concentration. Model prediction of change in QTcF at the geometric 
mean of Cmax on Day 1 (712.8 nM) was 2.405 msec (90% CI: 5.939, 1.129). Similarly, model prediction of 
QTcF at the geometric mean Cmax on Day 3 (1462 nM) was -0.7568 msec (90% CI: 5.148, 3.634). The 
upper limit of the predicted 90% CIs for ∆QTcF were well below 10 msec, supporting the conclusion that 
adavosertib does not have a clinically relevant impact on cardiac repolarization. 
c
Per Common Terminology Criteria for Adverse Events Version 5.0
8.3.13.3
Management of Renal Function Impairment
Creatinine clearance should be monitored intracycle (estimated by the Cockcroft-Gault 
equation) at the timepoints per the schedule of assessments. 
Treatment interruptions up to a maximum of 21 days are permitted in the event of toxicity.
Patients should be managed as per table below: 


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Table 16
Management of Renal Impairment
Renal Impairment
Adavosertib Dose Adjustment
Moderate
(CrCl >30 to <50 ml/min)
Hold dosing, investigate for cause, introduce supportive measures (including 
hydration)
Upon recovery to > 50 ml/min resume at same dose. 
If CrCl does not recover to > 50 ml/min, resume at next reduced dose levela.
Severe
(CrCl ≤30 ml/min)
Hold dosing, investigate for cause, introduce supportive measures (including 
hydration)
Upon recovery to > 50 ml/min, resume at next reduced dose levela.  
If CrCl does not recover to > 50 ml/min within 21 days, permanently discontinue 
dosing
a
In the absence of a further clinically relevant decrease in CrCl, the investigator may use their judgment to 
determine whether a further dose modification or discontinuation of adavosertib is necessary.
8.3.13.4
Gastrointestinal Toxicity Management Guidelines
As per the SoA (Section 1.3), each participant will be contacted for a general assessment on 
Day 3 (±1 day) of Cycle 1 and 2 to assess for AEs potentially related to adavosertib. In the 
event of significant diarrhoea, nausea and/or vomiting, or reduced oral intake, it is strongly 
recommended that the participant is considered for IV fluid rehydration therapy and 
supportive care measures.
For participants  experiencing gastrointestinal toxicities or  who are otherwise at risk of 
dehydration, creatinine clearance should be closely monitored and dose modifications to 
manage renal impairment followed (see previous section).   
Diarrhoea
Due to frequent reports of diarrhoea with adavosertib administration, anti-diarrhoeal treatment 
with loperamide (Imodium) is required at the first onset of diarrhoea according to American 
Society of Clinical Oncology (ASCO) guidelines. Oral loperamide 4 mg should be 
administered at the first onset of diarrhoea and then 2 mg every 2 hours until participant is 
diarrhoea-free for at least 12 hours. The first dose of loperamide could be lowered to 2 mg if 
the diarrhoea is recurrent and if, in the opinion of the treating physician, the diarrhoea is not 
severe.
Participants should be managed as medically indicated in Table 17. 


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Table 17
Management of Diarrhoea
Grade/GI toxicity
Action
Investigator to provide patient with prescription for loperamide to enable 
immediate initiation of anti-diarrhoeal treatment. 
Grade 1/Grade 2 
Diarrhoea
Initiate anti-diarrhoeal treatment immediately with oral loperamide 4 mg and 
then 2 mg every 2 hours until diarrhoea-free for at least 12 hours (maximum 
of 16 mg/24 hours).
Maintain liberal oral fluid intake. Participants should also be counselled to 
start a BRAT (bananas, rice, applesauce, toast) diet.
Investigator judgement to continue adavosertib with supportive treatment or 
interrupt dose for a maximum of 21 days
For persistent Grade 2 diarrhoea despite maximum supportive treatment, 
dosing may be resumed at next reduced dose level, as clinically indicated.
Grade 3/ Grade 4 
Diarrhoea
Initiate anti-diarrhoeal treatment with oral loperamide 4 mg and then 2 mg 
every 2 hours until diarrhoea-free for at least 12 hours (maximum of 16 mg/24 
hours).
Consider admission for IV rehydration and correction of electrolyte 
imbalances.
Interrupt adavosertib for a maximum of 21 days, until improved to ≤ Grade 1.
Grade 3 toxicity for ≤21 days 
Grade 3 toxicity for > 21 days

Upon recovery, resume at  next reduced dose level , maintaining 
supportive treatment. 

For recurrent Grade 3, dosing may be resumed only with a further 
dose level reduction, maintaining supportive treatment. Up to a 
maximum of two dose reductions are permitted.

Discontinue treatment, unless approved by the Medical Monitor.a
Grade 4 toxicity 
Discontinue treatment permanently
GI, gastrointestinal; IV, intravenous
a
In exceptional situations where it is considered that benefits outweigh the risks, the patient may continue 
dosing only after approval by the Medical Monitor.
Participants should be instructed to notify the investigator or research staff of the occurrence 


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of bloody or black stools, symptoms of dehydration, fever, inability to take liquids by mouth, 
and inability to control diarrhoea within 24 hours of using loperamide or other prescribed 
anti-diarrhoeal medications.
If diarrhoea is severe (ie, requiring IV rehydration) and/or associated with fever or severe 
neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. Participants with 
severe diarrhoea or any diarrhoea associated with severe nausea or vomiting should be 
hospitalised for IV hydration and correction of electrolyte imbalances.
Nausea and vomiting
Participants should be managed as medically indicated in Table 18.
Table 18
Management of Nausea and Vomiting
Grade/GI toxicity
Action
Prophylaxis
Nausea and vomiting
Mandatory anti-emetic prophylaxis in Cycle 1 and Cycle 2 with the 
following: 

Ondansetron (Zofran) 8 mg QD orally or granisetron (Kytril) 
1 mg QD orally prior to each dose of adavosertib

Additional antiemetics can be used as needed, as per 
local/institutional guidance and/or investigator discretion.

Additional antiemetics can be used as needed, as per 
local/institutional guidance and/or investigator discretion.
Adavosertib can be taken in the evening and/or with a light snack to reduce 
nausea.Investigator discretion may be applied regarding the mandatory 
anti-emetic prophylaxis requirements of the participant from Cycle 3 
onwards. 
Promethazine (Phenergan), prochlorperazine (Compazine), and 
benzodiazepine may still be used as additional adjunctive treatments during 
adavosertib therapy.
Aprepitant (Emend) and fosaprepitant are not permitted due to 
known drug-drug interactions (DDIs).
Dexamethasone can be used as needed per local/institutional guidance 
and/or investigator’s judgment. Dexamethasone can mask the signs 
and symptoms of infection, including sepsis.
Grade 1/Grade 2 
Nausea and vomiting
Consider additional anti-emetics along with ondansetron/granisetron, as per 
local/institutional guidance and/or investigator judgment.
Maintain liberal oral fluid intake.
Investigator judgement to continue adavosertib with supportive treatment 
or interrupt dose for a maximum of 21 days.
For persistent Grade 2 vomiting despite maximum supportive treatment, 
dosing may be resumed at next reduced dose level, as clinically indicated.


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Dexamethasone can be used as needed per local/institutional guidance 
and/or investigator’s judgment. Dexamethasone can mask the signs and 
symptoms of infection, including sepsis.
Grade 3 
Nausea and vomiting
Consider additional anti-emetics along with ondansetron/granisetron, as per 
local/institutional guidance and/or investigator judgement.
Consider admission for IV rehydration and correction of electrolyte 
imbalances. 
Interrupt adavosertib for a maximum of 21 days, until improved ≤ Grade 1.
Dexamethasone can be used as needed per local/institutional guidance 
and/or investigator’s judgment. Dexamethasone can mask the signs and 
symptoms of infection, including sepsis.
Grade 3 toxicity for ≤21 
days 
Grade 3 toxicity for > 21 
days

Upon recovery, resume at next reduced dose level, maintaining 
supportive treatment.  

For recurrent Grade 3, dosing may be resumed only with a further 
dose level reduction, maintaining supportive treatment. Up to a 
maximum of two dose reductions are permitted.

Discontinue treatment.
Grade 4 
Discontinue treatment permanently
GI, gastrointestinal; IV, intravenous; PO, oral; QD, once daily
a
Suitable alternative medications may be used, with adequate justification, if the use of any of 
the above medications might interfere with other study procedures or are deemed insufficient.
8.3.13.5
Management of Infection
Participants should be managed as medically indicated in Table 19.


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Table 19
Management of Infection
Grade of infection 
(suspected or confirmed)
Action
Any grade

Hold adavosertib immediately until infection is resolved and 
intervention is no longer required. The resolution of infection must be 
documented.

Start interventiona promptly and empirically according to institutional 
guidelines while awaiting the results of work up.

Monitor participants for signs and symptoms of infection; either new 
onset or worsening of the existing.

Infection should be evaluated for diagnostic work up including but 
not limited to, source of infection with susceptibility and appropriate 
imaging, including diagnostic procedures.

Discontinue adavosertib permanently if infection does not resolve 
within 21 days.
Grade 1 or 2

Resume at same dose level after resolution of infection and 
intervention is no longer required.

At recurrence of the same event, investigator judgment to resume 
adavosertib at the same dose level or resume at next reduced dose 
levelb after resolution of infection and intervention is no longer 
required.

If associated with an event of Grade 3 neutropenia, please refer to 
table 11
Grade 3c

Resume at next reduced dose levelb

Consider discontinuing adavosertib permanently, as per investigator 
judgement based on severity and type of infection.

If associated with Grade 3 neutropenia, discontinue advosertib 
permanently.
Grade 4c

Discontinue adavosertib permanently and follow up for disease 
progression.
a
Consider drug/drug interactions and CYP3A4 effects with adavosertib
b
Where it is considered that benefits outweigh the risks, the patient may continue dosing only after approval 
by the Medical Monitor
c
IV therapy is strongly recommended.   
8.4
Overdose
A dose of adavosertib in excess of that specified according to the protocol will constitute an 
overdose. There is currently no known antidote to adavosertib, and the treatment of overdose 
should be supportive for the underlying symptoms. In addition, adavosertib may be withheld 
and close monitoring should be implemented as needed.


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Such overdoses should be recorded as follows:

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose of adavosertib occurs in the course of the study, then the investigator or other 
site personnel will inform AstraZeneca 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.
For overdoses associated with AEs, the same reporting timelines apply as for reporting of 
SAEs (see Section 8.3.10). For other overdoses, reporting should be done within 30 days.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample see Appendix F.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 
8.5.1
Pharmacokinetics
Blood samples of approximately 2 mL will be collected for measurement of plasma
concentrations of adavosertib as specified in the SoA (Section 1.3) in at least 50% of 
participants:

Cycle 1, Day 5 (-1 day): pre-dose and 2 hours post-dose

Cycle 2, Day 5 (-1 day): pre-dose and 2 hours post-dose 
All PK samples need to be collected within 10% of the nominal time (± 6 minutes for a 
60-minute sample) to be protocol compliant. Pre-dose samples should be collected within 
60 minutes prior to dosing. Samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor (eg, for safety 
reasons). 
Plasma samples will be used to analyse the PK of adavosertib. Samples collected for analysis 
of adavosertib plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study.


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Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of adavosertib concentrations in plasma will be analysed by 
Covance on behalf of AstraZeneca R&D, using an appropriate bioanalytical method. Full 
details of the analytical method used will be described in a separate bioanalytical report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.1.2
Storage, Re-use and Destruction of Pharmacokinetic Samples
Pharmacokinetic 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 destroyed and 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.
8.6
8.6.1
8.6.1.1
CCI
CCI
CCI
CCI
CCI
CCI


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8.6.1.2
8.6.2
CCI
CCI
CCI
CCI
CCI


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8.6.3
8.7
CCI
CCI
CCI
CCI
CCI


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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
No formal statistical hypothesis will be tested. For the primary endpoint of ORR, response 
rate (with 90% and 95% CIs) will be estimated for all dosed participants and for dosed 
participants with centrally-confirmed USC.
9.2
Sample Size Determination
Approximately 120 participants will be enrolled and dosed, with an intent to include 
approximately 40 participants or more who have previously been exposed to PD-1/PD-L1 
inhibitors. The primary objective is to estimate ORR and no formal statistical comparisons 
will be performed. With 120 participants, if the observed ORR is 
 the width of the 2-
sided 90% CI will be 
9.3
Populations for Analyses
The primary analysis population is the FAS. In addition, the CCAS population is the key 
subgroup for decision making.
The populations for analyses are defined in Table 20.
Table 20
Populations for Analyses
Population/Analysis set
Description
All Patients
The All Patients Set will include all participants who have signed the 
informed consent form (ie, screening failures plus participants dosed). The 
All Patients Set will be used to describe the patient disposition.
Full Analysis Set 
The FAS will include all participants who received at least one (non-zero) 
dose of study treatment. This population will be used for the primary 
analyses of the efficacy and safety endpoints.
Centrally Confirmed Analysis 
Set 
The CCAS will include all centrally-confirmed uterine serous carcinoma 
participants who received at least one (non-zero) dose of study treatment. 
This population will be used for the analyses of efficacy.
Pharmacokinetic Analysis Set
Pharmacokinetics will be summarised as per the PK Analysis Set.
The PK analysis set will include all dosed participants who had at least one 
measurable plasma concentration collected post-dose which was obtained 
without any deviation or event thought to significantly affect the PK 
analysis.
All plasma concentration data will be summarised and presented according 
to AstraZeneca standards. This will be described in the statistical analysis 
plan.
CCAS, Centrally Confirmed Analysis Set; FAS, Full Analysis Set; PK, Pharmacokinetics
CCI
CCI
CCI


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9.4
Statistical Analyses
A comprehensive statistical analysis plan (SAP) will be developed and it will include a more 
technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. A Continuous Monitoring Plan (CMP) will 
also be produced to describe the approach, decision criteria, statistical analyses and 
communication plan for continuous monitoring in this study.
Descriptive statistics will be used for all variables. Continuous variables will be summarised 
by the number of observations, mean, standard deviation, median, minimum and maximum. 
Categorical variables will be summarised by frequency counts and percentages for each 
category. Unless otherwise stated, percentages will be calculated out of the population total.
Additional subgroup analyses of efficacy and safety may be performed and will be specified 
in the SAP.
9.4.1
Efficacy 
All efficacy analyses will be performed separately on the FAS and the CCAS.
9.4.1.1
Primary Endpoint: ORR
ORR is derived using the BICR data to define a confirmed response of CR or PR, with the 
denominator defined as a subset of all treated participants with measurable disease at baseline 
per BICR. ORR will also be defined as the percentage of participants with a confirmed 
investigator-assessed response of CR or PR and will based on a subset of all treated 
participants with measurable disease at baseline per the site investigator.
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. 
Summaries of ORR for the primary analysis will be based on BICR. 
ORR and its 90% and 95% CI (Clopper-Pearson) will be summarised. ORR per investigator 
review will be a sensitivity analysis.
The primary analysis will be performed, in both the FAS and centrally confirmed USC 
populations, 6 months after the last patient first dose, or when all have progressed or died due 
to any cause, whichever is earlier. Maturity of DoR data will also be taken into account when 
selecting the DCO date for primary analysis.No further analyses will be performed beyond the 
primary analysis.
An interim analysis is planned after approximately 30 participants in the CCAS in Cohort A


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have had the opportunity to be treated for at least 4 months. Recruitment will not be paused 
whilst the participants required for the interim are evaluated. It may be considered futile to 
continue recruitment into the study if there is 
 probability for the ORR to be greater 
than 
 This translates into observing
or fewer responders out of 30 participants; an 
ORR of 
 which has a 2-sided exact binomial 80% CI of 
 to 
 wherein the 
upper confidence limit is below 
 The analysis will be performed on participants who had 
the opportunity to be treated for at least 4 months. A sensitivity analysis will be performed on 
all participants who had the opportunity to be treated for at least 4 months, and those with a 
best overall response of CR, PR, and progressive disease. 
9.4.1.2
Secondary Endpoint: DoR
DoR will be defined as the time from the date of first documented response (which is 
subsequently confirmed) until date of documented progression or death in the absence of 
disease progression (ie, date of PFS event or censoring – date of first response + 1). The end 
of response should coincide with the date of progression or death from any cause 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 CR or PR that was subsequently confirmed.
If a participant does not progress following a response, then their DoR will use the PFS 
censoring time.
If there are sufficient numbers of responders, and sufficient numbers of responses that have 
progressed by the point of the analysis, Kaplan-Meier plots of DoR in the responding 
participants will be produced, and appropriate descriptive summary statistics will be presented
by starting dose (n, number of responses that have progressed, median, quartile, minimum and 
maximum DoR).
Summaries of DoR will be based on BICR; DoR per investigator review will be a sensitivity 
analysis.
A separate analysis will be performed using those confirmed responders that have been 
followed for a minimum of 6 months after response and using all confirmed responders 
regardless of follow-up time.
9.4.1.3
Secondary Endpoint: Depth of Response
Absolute change and percentage change from baseline will be based on RECIST v1.1 Target 
Lesions (TLs) measurements. Tumour size is the sum of the longest diameters of the TLs. 
Baseline for RECIST v1.1 is defined as the last evaluable assessment prior to the start of 
treatment. Percent changes in tumour size from baseline will be determined for participants 
with measurable disease at baseline and is derived at each visit as the % change in the sum of 
the diameters of TLs. % change = [(post baseline TL sum – baseline TL sum) / baseline TL 
sum] *100. Handling of missing data will be described in the SAP. Depth of response will be 
C
CI
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summarised using descriptive statistics. Waterfall plots showing the best percentage change 
from baseline in sum of the diameters of TLs will be produced. Spider plots showing the 
percentage change from baseline in tumour size for each participant over time may be 
produced.
Summaries of percentage change from baseline will be based on BICR.
9.4.1.4
Secondary Endpoint: PFS
PFS is defined as the time from first dose until the date of objective disease progression or 
death (by any cause in the absence of progression) regardless of whether the participant 
withdraws from study drug or receives another anticancer therapy prior to progression 
(ie, date of PFS event or censoring – date of first dose + 1). Participants who have not 
progressed or died at the time of analysis will be censored at the time of the latest date of 
assessment from their last evaluable RECIST v1.1 assessment. However, if the participant 
progresses or dies after two or more missed visits, the participant will be censored at the time 
of the latest evaluable RECIST v1.1 assessment prior to the two missed visits.
Summaries of PFS (n, events, medians, quartiles, proportion progression free at 3, 6, 9 and 
12 months and corresponding 95% CIs) and Kaplan-Meier plots will be provided by starting 
dose.
Summaries of PFS will be based on BICR; PFS per investigator review will be a sensitivity 
analysis.
9.4.1.5
Secondary Endpoint: PFS6
The PFS6 will be defined as the Kaplan-Meier estimate of PFS (per RECIST v1.1) at 6 
months.
Summaries of PFS6 will be based on BICR; PFS6 per investigator review will be a sensitivity 
analysis.
9.4.1.6
Secondary Endpoint: OS
Overall survival is defined as the time from the date of first dose until death due to any cause 
regardless of whether the participant withdraws from randomised therapy or receives another 
anticancer therapy (ie, date of death or censoring – date of first dose + 1). Any participant not 
known to have died at the time of analysis will be censored based on the last recorded date on 
which the participant was known to be alive (SUR_DAT, recorded within the SURVIVE 
module of the eCRF). 
Note: Survival calls will be made in the week following the date of DCO for the analysis, and 
if participants are confirmed to be alive or if the death date is post the DCO date these 
participants will be censored at the date of DCO. The status of ongoing, withdrawn (from the 


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study) and “lost to follow-up” participants at the time of the final OS analysis should be 
obtained by the site personnel by checking the participant’s notes, hospital records, contacting 
the participant’s general practitioner and checking publicly-available death registries. In the 
event that the participant has actively withdrawn consent to the processing of their personal 
data, the vital status of the participant can be obtained by site personnel from publicly 
available resources where it is possible to do so under applicable local laws.
Summaries of OS (n, events, medians, quartiles, proportion alive at 3, 6, 9 and 12 months and 
corresponding 95% CIs) and a Kaplan-Meier plot will be provided by starting dose.
9.4.1.7
Secondary Endpoint: DCR
Disease control rate is defined as the proportion of participants with best response of 
confirmed CR, confirmed PR, or who have stable disease at least 5 weeks after first dose (to 
allow for an early assessment within the assessment window).
DCR and its 95% CI (Clopper-Pearson) will be summarised. Summaries of DCR will be based 
on BICR; DCR per investigator review will be a sensitivity analysis.
9.4.1.8
Secondary Endpoint: PK
Pharmacokinetic concentration data and summary statistics will be tabulated. Pharmacokinetic 
parameters will be determined from the raw data. The following PK parameters will be 
determined after the first and steady-state doses: Cmax and Ctrough (as data allows).
9.4.2
Safety
Safety analyses will be performed using the FAS. Safety data will be presented using 
descriptive statistics unless otherwise specified. 
Baseline
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of adavosertib. Details are described in the SAP.
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9.4.2.1
Adverse Events
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at AZ/designee. 
AEs will be presented by System Organ Class and/or Preferred Term covering number and 
percentage of participants reporting at least one event and number of events where 
appropriate. 
AEs occurring prior to start of adavosertib and treatment emergent AEs will be presented 
separately.
An overview of AEs will present the number and percentage of participants with any AE, AEs 
with outcome of death, serious AEs, and AEs leading to discontinuation of adavosertib, as 
well as AEs leading to adavosertib dose interruptions, AEs leading to adavosertib dose 
reduction and AEs leading to withdrawal from study as well as the number of individual 
occurrences in those categories.
Separate AE tables will be provided taking into consideration relationship as assessed by the 
investigator, CTC grading, seriousness, death and events leading to discontinuation of 
adavosertib as well as other action taken related to adavosertib, and timing of events.
An additional table will present number and percentage of participants with most common 
AEs. Most common (eg, frequency of >x%, ≥x%) will be defined in the SAP.
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of participants. 
Key subject information will be presented for participants with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of IP.
An AE listing for the safety analysis set will cover details for each individual AE.
Full details of AE analyses will be provided in the SAP.
Treatment emergent
The following events are considered treatment emergent:

Adverse events with an onset date on or after first dose of adavosertib and within 30 days 
after last dose of adavosertib 

Worsening of pre-existing events on or after first dose of adavosertib and within 30 days 
after last dose of adavosertib


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9.4.2.2
Vital Signs
Vital sign parameters will be presented. Summary statistics for continuous variables cover n, 
mean, SD, Min, Q1, median, Q3, and Max. Frequency tables and shift tables cover number 
and percentage of participants in the respective category. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline. 
Supportive vital sign listings cover observed values and changes from baseline as well as 
abnormalities. 
Details of vital sign analyses will be provided in the SAP. 
9.4.2.3
Laboratory Analyses
Laboratory parameters will be presented. Summary statistics for continuous variables cover n, 
mean, SD, Min, Q1, median, Q3, and Max. Frequency tables and shift tables cover number 
and percentage of participants in the respective category. 
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline. 
Details of laboratory analyses will be provided in the SAP. 
9.5
Data Monitoring Committee
9.5.1
Safety Review Committee
A Safety Review Committee will be formed to review safety data during the study conduct.  
SRC will include approximately 3 key study investigators, and AstraZeneca study personnel. 
All clinical data, including safety, tolerability, dose modifications, and available PK data will 
be reviewed periodically at an appropriate time interval (eg 8 weeks). When at least 6 
participants have either received ≥2 cycles of study treatment or have discontinued study 
treatment due to unacceptable toxicity, the Safety Review Committee will convene.  SRC will 
be empowered to make recommendations including the option to modify dosing regimen or 
stop the study. Full details of SRC procedures and processes are provided in the SRC Charter.
9.5.2
Independent Data Monitoring Committee
The Independent Data Monitoring Committee (IDMC) will meet for the planned interim 
analysis when approximately 30 participants in the CCAS have had the opportunity to be 
treated for at least 4 months, to provide a recommendation based on efficacy observed. 
The IDMC will review safety data and will make recommendations to continue, amend, or 
stop the study based on findings. Serious AEs, AEs, and other safety data will be reviewed, 
and individual and aggregated safety data will be evaluated by the IDMC. 


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Full details of the IDMC procedure and processes can be found in the IDMC Charter.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Guidelines for Evaluation of Objective Tumour Response 
using RECIST v1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
Introduction
This appendix details the implementation of Response Evaluation Criteria in Solid Tumours 
version 1.1 (RECIST v1.1) guidelines (Eisenhauer et al 2009) for this study with regard to 
investigator assessment of tumour burden including protocol-specific requirements for this 
study. The differences from the published RECIST v1.1 guidelines are the exclusion of 
clinical examination and ultrasound as valid modalities to evaluate Target Lesions (TL), 
Non-Target Lesions (NTL) or new lesions; and a clarification of the use of 18FDG-PET to 
identify new lesions. 
Definitions of measurable, non-measurable, target and non-target lesions
Measurable:

A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter for non-nodal lesions or ≥15 mm in short axis diameter1 for lymph node lesions 
with computed tomography (CT) or magnetic resonance imaging (MRI) and that is 
suitable for accurate repeated measurements.
Non-measurable:

All other lesions, including small lesions (longest diameter <10 mm or pathological 
lymph nodes with ≥10 mm to <15 mm short axis diameter at baseline2).

Truly non-measurable lesions include the following: bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion and abdominal masses/abdominal 
organomegaly identified by physical examination (manual palpation) that is not 
measurable by CT or MRI.

Previously irradiated lesions3
                                               
1 The short axis is defined as the longest axis perpendicular to long axis.
2 Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
3 Localised post-radiation changes which affect lesion sizes may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment.


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
Skin lesions
Special cases:

Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
can be considered measurable if the soft tissue component meets the definition of 
measurability. Blastic lesions are considered non-measurable.

Cystic metastases can be considered measurable lesions if they meet the criteria for 
measurability from a radiological point of view, but if non-cystic lesions are present in 
the same patient, these should be selected over cystic lesions as TLs.
Target Lesions (TLs):
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. Lymph nodes, in any location (local/regional and distant), are collectively 
considered as a single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, 
adrenal glands), a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each 
considered as a single organ.
Tumour lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least ~2 weeks after biopsy, allowing time for healing.
Non-Target Lesions (NTLs):
Additional measurable lesions not recorded as TLs and non-measurable lesions (or sites of 
disease) should be identified as NTLs at baseline.
Imaging Modalities
A summary of the imaging modalities to be used for RECIST v1.1 assessment of Target 
Lesions, Non-Target Lesions, and New Lesions is provided in Table 21.
Table 21
Summary of Imaging Modalities for Tumour Assessment
Target lesions 
Non-target lesions
New lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT, Computed tomography; MRI, Magnetic resonance imaging; FDG-PET/CT, 18F-Fluoro-deoxyglucose 
positron emission tomography/CT 


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CT and MRI 
CT and MRI, each preferably with IV contrast, are generally considered to generate the best 
currently available and reproducible anatomical images for measurement of TL, assessment of 
NTL, and identification of any New Lesions. 
It is recommended that IV contrast-enhanced CT or MRI examinations of the chest, abdomen 
and pelvis will be used to assess tumour burden at baseline and follow-up visits. Any other 
areas of disease involvement (eg, brain) should be additionally imaged based on the signs and 
symptoms of individual participants. In participants who are sensitive to intravenous CT 
contrast, a non-contrast CT examination of the chest and an MRI with intravenous MRI 
contrast of the abdomen is appropriate. In participants with severely compromised renal 
function a non-contrast CT examination of the chest and abdomen is appropriate. For brain 
lesion assessment, MRI with IV contrast is the preferred method over IV contrast-enhanced 
CT. It is strongly recommended to maintain use of the same imaging modality (CT or MRI), 
acquisition protocol, facility and scanner across all imaging time points per patient.
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST assessments. Tumours identified by clinical examination will need to 
be assessed by correlative CT or MRI anatomical scans.
Chest X-ray
Chest X-ray assessment will not be used for assessment of TL. Chest X-ray can, however, be 
used to assess NTL and to identify the presence of new lesions.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTL and to identify the presence 
of new bone lesions. 
Ultrasound 
Ultrasound examination will not be used for RECIST assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation and may 
not provide an accurate assessment of true tumour size. Tumours identified by ultrasound will 
need to be assessed by correlative CT or MRI anatomical scan.


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Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
Histology and cytology
Histology on tumour biopsy samples will not be used as part of the tumour response 
assessment as per RECIST v1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites,
pericardial effusion, pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment in this study. An effusion that appears or 
significantly worsens (from trace to large) radiologically by CT/MRI anatomical scans will be 
considered to be disease progression due to New Lesions or progression of NTLs, 
respectively.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTL and followed by the same method 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 may be recorded in case positive hot-spots 
appear on a bone scan that were not present on a previous bone scan; however, a newly 
observed equivocal hot-spot on a bone scan which cannot be verified with correlative imaging 
(CT, MRI, X-ray) of the same anatomical region shall not be the only trigger for a PD 
assessment at that timepoint. 
FDG-PET
18F-Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans may be used as a 
method for identifying new lesions, according to the following algorithm: New lesions will be 
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recorded where there is positive 18F-fluoro-deoxyglucose uptake4 not present on an FDG-PET 
scan from a previous visit or in a location corresponding to a new lesion on CT/MRI at the 
same follow-up visit. If there is no FDG-PET scan available from a previous visit, and no 
evidence of new lesions on CT/MRI scans then follow-up CT/MRI assessments should be 
continued, scheduled as per protocol or as clinically indicated, in order to confirm new 
lesions.
Tumour response evaluation
Schedule of evaluation
Baseline assessments should encompass all areas of known predilection for metastases in the 
disease under evaluation and should additionally investigate areas that may be involved based 
on signs and symptoms of individual participants and should be performed within the 28 days 
prior to Day 1 of Cycle 1 of study treatment and ideally as close as possible to the start of 
study treatment. Follow-up assessments will be performed at the times specified in the SoA 
(see Section 1.3).
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 imaging visits.
Target lesions
Documentation of target lesions
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TL at baseline. Target lesions should be selected on the basis of their 
size (longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion, 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 TL will be calculated and reported as 
the baseline sum of diameters. At follow-up visits the sum of diameters for all TL will be 
                                               
4 A positive FDG-PET scan lesion should be reported only when an uptake (eg, standardised uptake value) 
greater than twice that of the surrounding tissue or liver is observed.


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calculated and reported as the follow-up sum of diameters.
Special cases

For TL measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 

If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a New 
Lesion.

If a TL splits into two 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 one of the lesions and 0 mm recorded for the other lesion(s). 

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 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. 

When a TL has had any intervention eg, definitive radiotherapy, embolisation, surgery, 
etc. during the study, the size of the TL should still be provided where possible and the 
intervention recorded in the RECIST case report form. If a TL has been completely 
removed (surgery), the longest diameter should be recorded as 0 mm.
Evaluation of target lesions
This section provides the definitions of the criteria used to determine objective tumour visit 
response for TL (Table 22).
Table 22
RECIST v1.1 Evaluation of Target Lesions
Complete response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters
Stable disease (SD)
Neither sufficient decrease in sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD


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Progression of disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – this includes 
the baseline sum if that is the smallest on study.  In addition to the 
relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm from nadir
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (eg, missing anatomy) or had a lesion intervention at this 
visit.  NOTE: if the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL response
Not applicable (NA) 
Only relevant if no TLs present at baseline
TL, target lesion.
Non-target lesions
Evaluation of non-target lesions
All other lesions (or sites of disease) not recorded as TL should be identified as NTL at 
baseline. Measurements are not required for these lesions, but their status should be followed
at subsequent visits. At each visit an overall assessment of the NTL response should be 
recorded by the investigator. This section provides the definitions of the criteria used to 
determine and record overall response for NTL at the investigational site at each visit
(Table 23).
Table 23
RECIST v1.1 Evaluation of Non-Target Lesions
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must be 
non-pathological in size (<10 mm short axis).
Non-CR/Non-PD
Persistence of one or more NTL
Progression (PD)
Unequivocal progression of existing NTLs. Unequivocal progression 
may be due to an important progression in one lesion only or in several 
lesions.  In all cases the progression MUST be clinically significant for 
the physician to consider changing (or stopping) therapy
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed and, in 
the investigator’s opinion, they are not able to provide an evaluable 
overall NTL assessment at this visit
NOTE: for participants without TLs at baseline, this is relevant if any of 
the NTLs were not assessed at this visit and the progression criteria have 
not been met
Not applicable (NA) 
Only relevant if no NTLs present at baseline
NTL, non-target lesion; TL, target lesion.
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 stable disease or 


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partial response in TLs, the overall tumour burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more NTLs is usually not 
sufficient to qualify for unequivocal progression status.
New lesions
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression. 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 previously new lesion has been assessed as unequivocal and then the 
progression date should be declared using the date of the initial scan when the new lesion first 
appeared.
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.
Symptomatic deterioration
Symptomatic (clinical) deterioration is not a descriptor of an objective response: it is a reason 
for stopping study therapy.
Patients with ‘symptomatic deterioration’ requiring discontinuation of treatment without 
objective radiologic evidence of disease progression at that time should continue to undergo 
tumour assessments where clinically feasible.
Evaluation of overall visit response
The overall visit response will be derived using the algorithm shown in Table 24.
Table 24
RECIST v1.1 Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/Non-PD)


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Target lesions
Non-target lesions
New lesions
Overall visit response
NE
Non-PD or NE or NA
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NA, not applicable (only relevant if there were no target lesions at baseline or no 
non-target lesions at baseline); NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable 
disease; TL, target lesion.
Study treatment will be discontinued when disease progression per RECIST v1.1 is 
determined. In the rare instances when the RECIST v1.1-defined radiological findings are 
considered equivocal by the investigator or there is doubt whether or not there is evidence of 
objective progression (eg, technical issues including image artefacts), a follow-up scan will be 
performed preferably at the next (and no later than the next) scheduled imaging visit, and no 
less than 4 weeks after the prior assessment of PD. If the repeat scan confirms progression, 
then study treatment must be discontinued, and the date of the initial scan should be declared 
as the date of PD. If the subsequent scan does not confirm the immediate prior radiological 
PD, scanning should continue until the next RECIST v1.1-defined PD. 
Study treatment may be administered until radiological PD is confirmed by the subsequent 
scan, unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met. Patients with rapid tumour progression or with symptomatic progression that 
requires urgent medical intervention (eg, central nervous system metastasis, respiratory failure 
due to tumour compression, or spinal cord compression) will not be eligible to continue study 
treatment. 
Specifications for anatomical imaging
CT scan
CT scans of the chest, abdomen, and pelvis should be contiguous throughout all the anatomic 
region of interest.
The most critical CT image acquisition parameters for optimal tumour evaluation using 
RECIST v1.1 are anatomic coverage, contrast administration, slice thickness, and 
reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the chest, 
abdomen and pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 


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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.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours requires consistent administration (dose and rate) of IV 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 participants 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 scans 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, the recommended methods are: CT thoracic (chest) examination without 
contrast and abdominal (and pelvis) MRI with contrast. If MRI cannot be performed, CT 
without IV contrast is an option for the thorax and abdomen (and pelvis) examination. For 
brain imaging, MRI with IV contrast is the preferred method.
c. Slice thickness and reconstruction interval: It is recommended that CT scans be 
performed at 5 mm contiguous slice thickness and this guideline presumes a maximum 5 mm 
thickness in recommendations for measurable lesion definition. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses greater than 5 mm. If 
this occurs, the minimum size of measurable lesions at baseline should be twice the slice 
thickness of the baseline scans.
All window settings should be included in the assessment, particularly in the thorax where 
lung and soft tissue windows should be considered. When measuring lesions, the TL 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.


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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 (and other anatomies [eg, neck]) with T1 and T2 weighted imaging along with 
gadolinium-enhanced imaging can be performed. The field of view, matrix, number of 
excitations, phase encoding steps, use of fat suppression and fast sequences should be 
optimised for the specific body part being imaged as well as the scanner utilised. CT of the 
chest is typically recommended over MRI due to significant motion artifacts (heart, major 
blood vessels, breathing) associated with MRI. 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.
More details on the recommended imaging parameters can be found in the image acquisition 
guidelines.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.


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Appendix B
ECOG Performance Status
The Eastern Cooperative Oncology Group (ECOG) performance status scale is presented in 
Table 25. 
Table 25
ECOG Performance Status Scale


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Appendix C
Regulatory, Ethical, and Study Oversight Considerations
C 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 Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure (IB), and other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation (CRO) but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events (SAEs)

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.


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C 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
C 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or her legally authorised representative and answer all questions regarding the 
study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 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 participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
C 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.


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
The participant must be informed that her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure and use of 
their data must also be explained to the participant in the informed consent.

The participant must be informed that 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.
C 5
Committees Structure
A Safety Review Committee will be formed to review safety data during the study conduct. 
All data, including safety, tolerability, and available PK data will be reviewed periodically. 
The Safety Review Committee will include experts with relevant experience in clinical trial 
conduct, methodology, and procedures in participants with endometrial carcinoma, and 
AstraZeneca personnel. Full details of the Safety Review Committee procedures and 
processes can be found in the Safety Review Committee Charter. 
The Independent Data Monitoring Committee (IDMC) will meet for the planned interim 
analysis when approximately 30 participants in the CCAS have had the opportunity to be 
treated for at least 4 months, to provide a recommendation based on efficacy observed. 
The IDMC will review safety data and will make recommendations to continue, amend, or 
stop the study based on findings. Serious AEs, AEs, and other safety data will be reviewed, 
and individual and aggregated safety data will be evaluated by the IDMC. The IDMC will be 
comprised of fully independent members; full details of the IDMC procedure and processes 
can be found in the IDMC Charter.
C 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the Study D601HC00002 results when 
they are available. The clinical study and/or summary of Study D601HC00002 results may 
also be available on other websites according to the regulations of the countries in which 
Study D601HC00002 is conducted.
C 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.


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
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved 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.
C 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as sourced documents. Source data 
are contained in sourced documents (original records or certified copies).
C 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.


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The first act of recruitment is the date of the first participant enrolment and will be the study 
start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participants and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
C 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix D
Guidance Regarding Potential Interactions of Adavosertib 
with Concomitant Medications
The potential for drug-drug interaction described in this protocol are based on findings from in 
vitro studies and clinical experience.

A formal clinical drug interaction study (D6014C00006) evaluating the effect of 
adavosertib on pharmacokinetics of substrates for CYP3A, CYP2C19, CYP1A2 has been 
conducted in advanced solid tumour participants. The results of this study suggest that 
adavosertib is a weak inhibitor of these enzymes and is unlikely to result in clinically 
significant drug interaction. 
The following treatments and the medications listed in this Appendix are prohibited or should 
be used with caution. Any further questions regarding concomitant treatments should be 
referred to the Medical Monitor.
Prohibited Medications

Adavosertib is predominantly metabolized by CYP3A4. Strong or moderate inhibitors or 
inducers of CYP3A4 are prohibited until additional data on drug-drug interactions (DDIs) 
becomes available. As grapefruit and Seville oranges are known to contain moderate 
inhibitors of CYP3A4, these fruits or their products (including marmalade, juice, etc.) 
should be avoided while taking adavosertib.
An exploratory assessment of the effect of aprepitant on adavosertib exposure in 
oncology participants suggests that there is a drug interaction between adavosertib and 
aprepitant, as exposure to adavosertib increased by ~40% when aprepitant was 
co-administered with adavosertib. The observed increase in adavosertib exposure is likely 
the result of CYP3A4 inhibition by aprepitant. This increase in exposure is statistically 
significant. At the selected maximum tolerated doses (MTDs), this increase may also be 
of clinical importance. Therefore, concomitant treatment with aprepitant and fosaprepitant 
is not allowable per protocol until further evaluation. 

Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include but are not limited to those containing: St. John’s wort, kava, ephedra 
(ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto,
and ginseng. Participants should stop using these herbal medications 7 days prior to first 
dose of adavosertib.

No other anticancer-therapy (chemotherapy, immunotherapy, hormonal anticancer 
therapy, radiotherapy [except for palliative local radiotherapy]), biological therapy or 
other novel agent is to be permitted while the participant is receiving study medication. 


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
Receipt of live virus and live bacterial vaccines is not permitted while the participant is 
receiving study medication and during the 30-day follow-up period. Inactivated flu 
vaccines are permitted.
Medications to be used with Caution

In vitro studies have shown that adavosertib may be a substrate and inhibitor for human 
P-glycoprotein (P-gp). Caution should be exercised when agents that are inhibitors or 
substrates of P-gp are administered concomitantly with adavosertib (see relevant section 
below).

in vitro transporter studies have shown adavosertib to be an inhibitor of BCRP (IC50 
5.1 μM). This finding is particularly relevant for drugs administered orally where 
exposure is normally limited by BCRP-mediated efflux, in particular some statins, such as 
rosuvastatin. Other drugs where the disposition is mediated via BCRP should be 
administered with caution, dose modification considered or substituted by an alternative 
drug.

Metformin should be used with caution. Adavosertib has been shown to be an inhibitor of 
MATE1 and MATE2K transporters. A drug interaction with substrates of either 
transporter cannot be ruled out, the most important substrate known to date being 
metformin.
In addition, any other drugs should be avoided at the investigator’s discretion if, in their 
opinion, the co-administration with adavosertib may increase the risk of a clinically significant 
drug interaction.
A list of the main CYP3A4 inhibitors and inducers, P-gp substrates and inhibitors, and BCRP 
substrates are shown below. This is not an exhaustive list and further details can be found at 
Expert Opin. Drug Metab. Toxicol 2013;9(6):737-51. 
CYP3A4 inhibitors
Strong

Boceprevir

Clarithromycin

Cobicistat (GS-9350)

Conivaptan

Danoprevir

Elvitegravir

Fosamprenavir

Grapefruit juice

Idelalisib

Indinavir

Itraconazole

Ketoconazole

LCL161

Lopinavir

Mibefradil

Nefazodone

Nelfinavir

Posaconazole

Ritonavir

Saquinavir

Telaprevir

Telithromycin

Tipranavir

Troleandomycin

Voriconazole


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Moderate

ACT-178882

Amprenavir

Aprepitant

Atazanavir

Casopitant

Ciprofloxacin

Crizotinib 

Darunavir

Dronedarone

Diltiazem

Erythromycin

FK1706

Fluconazole 

Fosamprenavir

Imatinib

Ledipasvir

Lomitapide

Netupitant

Schisandra sphenanthera

Tofisopam

Verapamil

Grapefruit

Seville oranges
Weak

Almorexant 

Alprazolam 

AMD070

Amiodarone

Amlodipine

Atorvastatin 

Azithromycin 

Berberine

Bicalutamide

Blueberry juice 

Chlorzoxazone 

Cilostazol

Cimetidine

Clotrimazole

Cranberry juice

Cyclosporine

Daclatasvir

Delavirdine

Everolimus

Faldaprevir

Fluvoxamine

Fosaprepitant (IV)

Ginkgo

Goldenseal

GSK1292263

GSK2248761

Isoniazid

Ivacaftor

Lacidipine

Linagliptin

Lomitapide

M100240

Nilotinib

Oral contraceptives

Pazopanib

Peppermint oil

Propiverine 

Ranitidine 

Ranolazine

Resveratrol

Roxithromycin

Seville orange juice 

Simeprevir

Sitaxentan

Suvorexant

Tabimorelin

Tacrolimus

Teriflunomide

Ticagrelor

Tipranavir/ritonavir

Tolvaptan

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CYP3A4 inducers
Strong and Moderate

Avasimibe

Bosentan

Carbamazepine 

Efavirenz

Enzalutamide 

Etravirine

Genistein 

Lersivirine 

Lopinavir 

Mitotane 

Modafinil

Nafcillin 

Phenobarbital 

Phenytoin 

Rifabutin

Rifampin

Ritonavir 

Semagacestat 

St John's wort

Thioridazine 

Tipranavir
Weak

Amprenavir 

Aprepitant 

Armodafinil 

AZD 7325

Bexarotene 

Boceprevir 

Brivaracetam 

Clobazam 

Danshen 

Dexamethasone 

Echinacea 

Eslicarbazepine

Garlic 

Gingko

Ginseng 

Glycyrrhizin 

LCL161

Methylprednisolone 

Nevirapine 

Oritavancin 

Oxcarbazepine 

PA-824

Pleconaril 

Prednisone

Quercetin 

Raltegravir 

Ritonavir

Rufinamide

Sorafenib 

Stribild 

Telaprevir 

Terbinafine 

Ticagrelor 

Ticlopidine

Topiramate

Troglitazone  

Vemurafenib 

Vicriviroc and ritonavir

Vinblastine
P-gp substrates

Colchicine

Digoxin

Fexofenadine

Indinavir

Paclitaxel

Topotecan

Vincristine


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If a participant requires initiation of digoxin during the study, or is already receiving treatment 
with digoxin, monitoring of digoxin levels is recommended according to local practice (as the 
levels of digoxin may increase). Monitoring of digoxin levels is also recommended when the 
participant has completed dosing with study treatment (as the levels of digoxin may then 
decrease).
P-gp inhibitors (strong)

Cyclosporine

Elacridar

Erythromycin

Itraconazole

Ketoconazole

LY335979

Quinidine

Ritonavir

Valspodar

Verapamil
BCRP substrates

Daunorubicin

Doxorubicin

Rosuvastatin

Sulfasalazine

Topotecan


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


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


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Intensity rating scale:
The grading scales found in the revised National Cancer Institute 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). The applicable 
version of CTCAE should be described clearly.  
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix E 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 E 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 E 2.
E 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.


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


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
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication

Wrong drug administered to participant
Examples of events that do not require reporting as medication errors in clinical studies:

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix F
Handling of Human Biological Samples
F 1
Chain of custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team for the 
remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
F 2
Withdrawal of Informed Consent for donated biological samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 


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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
F 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A pathogens are eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix H
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
H 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. 
Specific guidance on managing liver abnormalities can be found in Section 8.3.6 of the 
Clinical Study Protocol.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review 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.
H 2
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) ≥ 3x upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).


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Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
H 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
Central laboratories being used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory without delay

Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:

Determine whether the participant meets PHL criteria (see Section H 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)


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H 4
Follow-up
H 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
H 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (See Section H 6).

Notify the AstraZeneca representative who will then inform the central Study Team.

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition.

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Complete follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the HL lab kit should be used.

Complete the three Liver eCRF Modules as information becomes available 
#A ‘significant’ change in the participant’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in 
isolation or in combination, or a clinically relevant change in associated symptoms. The 
determination of whether there has been a significant change will be at the discretion of the 
investigator, this may be in consultation with the Study Physician if there is any uncertainty.


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H 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, and to ensure timely analysis and reporting to health authorities within 15 calendar days 
from the date PHL criteria were met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:


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
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
H 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Treatment 
This section is applicable to participants with liver metastases who meet PHL criteria on study 
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 participant’s condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change no action is required

If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Section H 4.2  
H 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection or liver disease or did the participant meet PHL criteria prior to starting study 
treatment and at their first on-study treatment visit as described in Section H 6 of this 
Appendix?


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If No: follow the process described in Section H 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met

If there is no significant change no action is required

If there is a significant change follow the process described in Section H 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
H 8
References
Aithal et al, 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Clinical 
Pharmacology and Therapeutics 2001;89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix I
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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 
participant become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
J 1
Consent/reconsent of study participants during study 
interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site, and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Consent/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 Section 8. Local and regional regulations and/or guidelines regarding 
consent/reconsent of study participants should be checked and followed. Consent/reconsent 
may be verbal if allowed by local and regional guidelines (note, in the case of verbal 
consent/reconsent, the informed consent form should be signed at the participant’s next 
contact with the study site). Visiting the study sites for the sole purpose of obtaining 
consent/reconsent should be avoided.
J 2
Rescreening of participants to reconfirm study eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with investigational 
product (IP). If this delay is outside the screening window specified in Section 5.4, the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to re-screen a participant in addition to that 
detailed in Section 5.4.  The procedures detailed in Sections 5.4 must be undertaken to 
confirm eligibility using the same randomization number as for the participant.
J 3
Home or remote visit to replace on-site visit (where applicable)
A qualified healthcare professional (HCP) from the study site or third-party vendor service 


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may visit the participant’s home or other remote location as per local standard operating 
procedures, as applicable. Supplies will be provided for a safe and efficient visit. The qualified 
HCP will be expected to collect information per the Clinical Study Protocol. 
J 4
Telemedicine visit to replace on-site visit (where applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medications, participant report 
outcome questionnaires, and health economic data to be reported and documented. 
J 5
At-home or remote location investigational product 
administration instructions
If a site visit is not possible, at-home or remote location administration of investigational 
product may be performed by the participant or his/her caregiver. The option of at-home or 
remote location investigational product administration ensures participant’s safety in cases of 
a pandemic where participants 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.
J 6
At-home or remote location investigational product 
administration by the participant or his/her caregiver
Prior to at-home or remote location investigational product administration, the investigator 
must assess the participant or his/her caregiver to determine whether they are appropriate for 
at-home or remote location administration of investigational product. Once the participant or 
his/her caregiver is deemed appropriate for at-home or remote location administration, he/she 
must receive appropriate training. All necessary supplies and instructions for administration 
and documentation of investigational product administration will be provided. More 
information related to the visit can be obtained via a telemedicine or home/remote visit.
J 7
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 in the source documents, or by the 
participant themselves.


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Appendix K
Abbreviations
Abbreviation or special 
term
Explanation
18FDG-PET  
18F-fluoro-2-deoxy-D-glucose positron emission tomography
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC
Plasma concentration time curve (area under the curve)
BCRP
Breast cancer resistance protein
BICR
Blinded Independent Central Review
BID
Twice-daily
BMI
Body mass index
CCAS
Centrally-confirmed analysis set
CDK1
Cyclin-dependent kinase 1
CDK2
Cyclin-dependent kinase 2
CI
Confidence interval
Cmax
Maximum concentration
CMP
Continuous Monitoring Plan
Ctrough
Lowest concentration
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organisation
CSP
Clinical study protocol
CSR
Clinical study report
CT
Clinical trial
CTCAE 
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DCO
Data cut-off
DCR
Disease control rate
DILI
Drug induced liver injury
dMMR
Mismatch repair deficient
CCI
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Abbreviation or special 
term
Explanation
DoR
Duration of response
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECD
Electronic data capture
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
FAS
Full analysis set
FDA
U.S. Food and Drug Administration
FFPE
Formalin-fixed paraffin-embedded
G-CSF
Granulocyte colony-stimulating factor
GCP
Good Clinical Practice
Hb
Haemoglobin
HBV
Hepatitis B virus
HBC
Hepatitis C virus
HCP
Healthcare professional
HE
Haematoxylin and eosin
HER2
Human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HL
Hy’s Law
IC50
Half maximal inhibitory concentration
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IV
Intravenous
LPFD
Last participant first dose
CCI
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Abbreviation or special 
term
Explanation
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
MSI-H
Microsatellite instability-high
MSS
Microsatellite stable
MTD
Maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
Non-Investigational Medical Product
NTL
Non-Target Lesion
ORR
Objective response rate
OS
Overall survival
PD-1
Programmed cell death-1 receptor
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PFS6
Proportion of participants alive and progression free at 6 months
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PR
Partial response
PSSR
Project Specific Safety Requirements
QD
Once daily
QoL
Quality of life
QT
ECG interval measured from the onset of the QRS complex to the end of the
T wave
QTc
Corrected QT interval
QTcF
QT corrected by Fridericia’s formula
RECIST
Response Evaluation Criteria in Solid Tumours. This study will use RECIST
version 1.1.
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Abbreviation or special 
term
Explanation
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event 
SAP
Statistical analysis plan
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
TBL
Total bilirubin
TCGA
The Cancer Genome Atlas
TL
Target Lesion
ULN
Upper limit of normal
US
United States
USC
Uterine serous carcinoma
VEGF
Vascular endothelial growth factor
WNL
Within normal limits


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11
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ixabepilone/carboplatin/bevacizumab in advanced/recurrent endometrial cancer. Gynecol 
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American Cancer Society 2019
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Bray et al 2018
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin 2018;68:394-424.
Cancer Genome Atlas Research Network 2013
Cancer Genome Atlas Research Network, Kandoth C, Schultz N, Cherniack AD, Akbani R, 
Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature 
2013;497:67-73.
Coleman and Dunphy 1994
Coleman TR, Dunphy WG. CDK1 regulatory factors. Curr Opin Cell Biol 1994;6(6):877-82.
Fader et al 2018
Fader AN, Roque DM, Siegel E, Buza N, Hui P, Abdelghany O, et al. Randomized Phase II 
Trial of Carboplatin-Paclitaxel Versus Carboplatin-Paclitaxel-Trastuzumab in Uterine Serous 
Carcinomas That Overexpress Human Epidermal Growth Factor Receptor 2/neu. J Clin Oncol 
2018;36:2044-51.
Falchook et al 2019
Falchook GS, Sachdev J, Imedio ER, Kumar S, Mugundu G, Chmielecki J, et al. A Phase Ib 
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Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 
Mar 29–Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 
Suppl):Abstract nr CT022.
FDA 2019
FDA. Simultaneous review decisions for pembrolizumab plus lenvatinib in Australia, Canada 
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Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, Berek JS, et al. 
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Greimel E, Nordin A, Lanceley A, Creutzberg CL, van de Poll-Franse LV, Radisic VB, et al. 
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Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA, et al. Uterine papillary 
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Liu et al 2020
Liu JF, Tayob N, Campos SM, Wright AA, Krasner C, Schumer S, et al. A Phase 2 trial of the 
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Santin et al 2017
Santin AD, Bellone S, Buza N, Schwartz PE. Regression of metastatic, 
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Santin et al 2008
Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in 
participants with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int 
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Siegel RL, Miller KD, and Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:7-34. 
Takebe et al 2018
Takebe N, Coyne GHO, Kummar S, Do KT, Bruns A, Juwara L, et al. Safety, tolerability, and 
antitumor activity of once-daily Wee-1 inhibitor AZD1775. J Clin Oncol 2018;36: 15 suppl, 
2587-87.
Talwar and Cohen 2012
Talwar S and Cohen S.  Her-2 targeting in uterine papillary serous carcinoma. Gynecol Oncol 
Case Rep 2012;2:94-6.
Zhao et al 2013
Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, et al. Landscape of somatic 
single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci 
2013;110:2916-21.


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d601hc00002-csp-v6
Document Title:
D601HC00002 Clinical Study Protocol version 6
Document ID:
Doc ID-004203422
Version Label:
7.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
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Management Approval
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Content Approval
26-May-2022 12:11 UTC
Content Approval
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Clinical Study Protocol Errata to Global CSP 6.0 
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Clinical Study Protocol
Study Intervention
Adavosertib (AZD1775)
Study Code
D601HC00002
Version
Errata to Global – v6.0
Date
09 June 2022
A Phase 2b, Open-label, Single-arm, Multi-centre Study Assessing 
the Efficacy and Safety of Adavosertib as Treatment for Recurrent 
or Persistent Uterine Serous Carcinoma (ADAGIO)
Sponsor Name: 
Legal Registered Address: 
AstraZeneca AB, S-151 85 Södertälje, Sweden.  
Regulatory Agency Identifier Number(s):
EudraCT number: 2020-000138-16
IND number: 147430


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ERRATA
This addendum accompanies the Global CSP 6.0 and corrects the following passages: 
Table 1
Schedule of Activities (Cohort A and B)
Clarification: As part of Global CSP 6.0 update, all reference to Cohorts (A and B), and 
 
 dose have been removed – this reference to a cohort has incorrectly remained in the 
protocol.
4.4 End of Study Definition
“…The end of the study is defined as the date of the last visit of the last participant in the 
study. The last visit occurs when the last participant of Cohort B has their last scheduled visit, 
or 6 months after last participant first dose in Cohort B, whichever comes first…”
Clarification: As part of Global CSP 6.0 update, all reference to Cohorts (A and B), and 
 
 dose have been removed – this reference to a cohort has incorrectly remained in the 
protocol.
9.4.1.1 Primary Endpoint: ORR
“…An interim analysis is planned after approximately 30 participants in the CCAS in Cohort 
A have had the opportunity to be treated for at least 4 months. Recruitment will not be paused
whilst the participants required for the interim are evaluated…”
Clarification: As part of Global CSP 6.0 update, all reference to Cohorts (A and B), and 
 
 dose have been removed – this reference to a cohort has incorrectly remained in the 
protocol.
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SIGNATURE PAGE
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Document Name: d601hc00002-csp-errata-to-global-v6
Document Title:
D601HC00002 Clinical Study Protocol Errata to Global V6
Document ID:
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Server Date
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Management Approval
15-Jun-2022 13:48 UTC
Management Approval
14-Jun-2022 11:38 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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SAP_001.pdf: 
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Statistical Analysis Plan
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Parexel International
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D601HC00002
A Phase 2b, Open-label, Single-arm, Multi-centre Study assessing the Efficacy and Safety of 
Adavosertib as Treatment for Recurrent or Persistent Uterine Serous Carcinoma (ADAGIO)
Statistical Analysis Plan
Version: 2.0
Parexel Project Number: 247600


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TABLE OF CONTENTS
1
STUDY DETAILS ...................................................................................................... 9
1.1
Study Objectives.......................................................................................................... 9
1.2
Study Design ............................................................................................................. 12
1.3
Timing of Analysis .................................................................................................... 12
1.4
Number of Participants .............................................................................................. 12
2
ANALYSIS SET ....................................................................................................... 13
2.1
Definition of Analysis Sets ........................................................................................ 13
2.2
Protocol Deviations.................................................................................................... 14
3
PRIMARY AND SECONDARY VARIABLES ........................................................ 17
3.1
General Principles...................................................................................................... 17
3.1.1
Definitions of Visit Windows..................................................................................... 18
3.2
Derivation of RECIST Visit Responses...................................................................... 20
3.2.1
Target lesions (TLs) – site investigator data............................................................... 20
3.2.2
Non-target lesions (NTLs) and new lesions – site investigator data ............................ 25
3.2.3
Overall visit response – site investigator data............................................................. 26
3.2.4
Independent review.................................................................................................... 26
3.3
Efficacy Variables...................................................................................................... 27
3.3.1
Objective Response Rate............................................................................................ 27
3.3.2
Best Objective Response............................................................................................ 28
3.3.3
Duration of Response................................................................................................. 28
3.3.4
Depth of Response..................................................................................................... 29
3.3.5
Progression-Free Survival (PFS)................................................................................ 29
3.3.6
Progression-Free Survival at 6 months (PFS6) ........................................................... 30
3.3.7
Overall Survival......................................................................................................... 30
3.3.8
Disease control rate.................................................................................................... 31
3.4
................................... 31
3.4.1
................................... 31
3.4.2
................................... 33
3.4.3
................................... 34
3.4.4
................................... 35
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3.5
Other Variables.......................................................................................................... 35
3.5.1
Prior and Concomitant Medications and Therapies..................................................... 35
3.6
Safety Variables......................................................................................................... 36
3.6.1
Exposure and dose interruptions................................................................................. 36
3.6.2
Adverse events........................................................................................................... 37
3.6.3
Hy’s law .................................................................................................................... 38
3.6.4
ECG changes ............................................................................................................. 38
3.6.5
Vital sign changes...................................................................................................... 39
3.6.6
Laboratory data.......................................................................................................... 39
3.6.7
ECOG Performance Status......................................................................................... 40
3.7
Pharmacokinetic Variables......................................................................................... 41
3.7.1
Pharmacokinetics....................................................................................................... 41
4
ANALYSIS METHODS............................................................................................ 41
4.1
General Principles...................................................................................................... 41
4.1.1
Handling of Dropouts or Missing Data....................................................................... 42
4.2
Analysis Methods ...................................................................................................... 43
4.2.1
Disposition, Demography and Baseline Characteristics.............................................. 43
4.2.2
Tumour response and efficacy.................................................................................... 45
4.2.3
....................................................................................... 47
4.2.4
Safety Analyses ......................................................................................................... 48
4.2.5
Pharmacokinetic data................................................................................................. 51
4.2.6
Subgroup Analyses .................................................................................................... 52
5
SAFETY REVIEW COMMITTEE............................................................................ 52
6
INDEPENDENT DATA MONITORING COMMITTEE .......................................... 53
7
INTERIM ANALYSIS .............................................................................................. 53
8
CHANGES OF ANALYSIS FROM PROTOCOL..................................................... 53
9
REFERENCES.......................................................................................................... 53
10
APPENDIX ............................................................................................................... 55
10.1
Appendix A: Schedule of Assessments ...................................................................... 55
10.2
Appendix B: Study design and flow chart .................................................................. 68
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REVISION HISTORY
Version No.
Effective Date
Summary of Change(s)
1.0
[9 Oct 2020]
New document
1.1
[22 Jan 2021]
1. Section 4.1 Added a paragraph related to participants who 
failed screening and later rescreened.
2. CCAS was removed from Table 1 under 
 section as per 
AZ study team request.
1.2
[15 Mar 2021]
Added a footnote to Table 3 in section 3.1.1.
1.3
[22 Apr 2021]
Additional 
safety 
haematology and clinical chemistry 
assessment been added in section 173.1.1 Table 3 and Schedule 
of Assessments in Appendix A following Protocol update.
1.4
[13 Jul 2021]
The imputation rule of AE date updated in section 4.1.1 as per 
AZ comments from IDMC1 delivery.
1.5
[10 Sep 2021]
“Please note radiotherapy is not considered as subsequent 
cancer therapy while calculating ORR.” was added to section 
3.3.1 as per AZ study team suggestion.
Sensitivity analyses will be performed based on BICR 
assessments instead of investigator data as per AZ team request.
2.0
[17 June 2022]
In Section 1.1 All exploratory objectives will not be included in 
CSR.
In Section 1.3 Final analysis DCO is removed and in Sections 
3.1, 3.2.4 and 4.2.6 reference to final analysis was replaced by 
primary analysis.
In Section 2.2, CrCl >50 mL/min is added under inclusion 
criteria 9. Inclusion criteria 1, exclusion criteria 9 and 14 are 
added.
In Section 3.1 End of study definition has changed.
In section 3.2, the sentence on sensitivity analysis is deleted as 
it will not be presented in CSR.
In Section 3.3.3 Duration of response will be presented in 
months is added.
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In Section 4.2.1.1 ‘and participants who did not receive’ 
treatment is deleted from the first bullet as the team agreed to 
consider this category as screen failure.
In Section 4.2.2.2 reference to the duration of response outputs 
for patients with 6 months follow-up is removed.


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LIST OF ABBREVIATIONS
Abbreviation / Acronym
Definition / Expansion
AE
Adverse event
ALP
Alkaline phosphatase 
ALT
Alanine aminotransferase 
AST
Aspartate aminotransferase 
ATC
anatomical therapeutic chemical 
BICR
Blinded Independent Central Review
BLQ
below the lower limit of quantitation
BMI
body mass index
BoR
Best Objective Response
CCAS
centrally confirmed analysis set
CI
confidence interval
Cmax
maximum concentration
CR
complete response
CRF
case report form
CSP
clinical study protocol
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
concentration trough
CV
coefficient of variation
d.p
decimal place
DBL
Database lock
DBP
diastolic blood pressure
DCO
data cut-off
DCR
disease control rate
DMC
data monitoring committee
DoR
duration of response
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Abbreviation / Acronym
Definition / Expansion
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
full analysis set
FIGO
International Federation of Gynecology and Obstetrics
FFPE
formalin-fixed paraffin-embedded
Hb
Haemoglobin
HER2
human epidermal growth factor receptor 2
ICF
informed consent form
INR
International Normalised Ratio
IPD
important protocol deviation
LD
longest diameter
LPFD
last participant first dose
LPLV
last participant last visit
MRI
magnetic resonance imaging
NA
not applicable
NE
not evaluable
NQ
not quantifiable
NTL
non-target lesion
ORR
objective response rate
OS
Overall survival
PD
progressive disease
PFS
Progression-free survival
PFS6
Progression-free survival at 6 months
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Abbreviation / Acronym
Definition / Expansion
PK
Pharmacokinetic
PR
partial response
PT
preferred term
QD
once daily
RDI
relative dose intensity
RECIST v1.1
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
stable disease
SoA
schedule of assessments
SOC
system organ class
StD
Standard Deviation
TEAE
treatment-emergent adverse event
TL
target lesion
USC
uterine serous carcinoma
VEGF
vascular endothelial growth factor
WHO
World Health Organization
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1
STUDY DETAILS
The analyses described in this statistical analysis plan (SAP) are based upon the following study 
documents:

Clinical Study Protocol, Version 6.0 (20th May 2022)
1.1
Study Objectives
The exploratory objectives (in grey) are not part of the CSR and will not be analysed by Parexel.
Objectives
Endpoints/Variables
Primary 
To evaluate the efficacy of adavosertib by the 
assessment of objective response rate (ORR).
ORR is defined as the proportion of participants 
with measurable disease at baseline who have a 
confirmed complete response (CR) or partial 
response (PR), as determined by Blinded 
Independent Central Review (BICR) per 
RECIST v1.1.
Secondary
To evaluate the efficacy of adavosertib by 
assessment of duration of response (DoR).
DoR is defined as the time from the date of first 
documented response until date of documented 
progression per RECIST v1.1 as assessed by 
Blinded Independent Central Review (BICR), 
or death in the absence of disease progression.
To evaluate the efficacy of adavosertib by 
assessment of the depth of response.
Depth of response is defined as the best 
percentage change from baseline in Target 
Lesions.
To evaluate the efficacy of adavosertib by 
assessment of progression-free survival (PFS).
PFS is defined as time from date of first dose 
until progression per RECIST v1.1 as assessed 
by BICR, or death due to any cause.
To evaluate the efficacy of adavosertib by 
assessment of PFS6.
PFS6 is defined as the proportion of 
participants alive and progression free at 6 
months and will be reported as the Kaplan-
Meier estimate of PFS per RECIST v1.1 as 
assessed by BICR at 6 months.
To evaluate the efficacy of adavosertib by 
assessment of overall survival (OS).
OS is defined as time from date of first dose 
until the date of death due to any cause.


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To evaluate the efficacy of adavosertib by 
assessment of disease control rate (DCR).
DCR is defined as the percentage of 
participants who have a best overall response 
of CR or PR or who have stable disease for at 
least 5 weeks after start of treatment (to allow 
for an early assessment within the assessment 
window).
To evaluate the pharmacokinetics of 
adavosertib.
Plasma concentration of adavosertib: Ctrough
(pre-dose) and Cmax.
To assess the safety and tolerability of 
adavosertib in participants with USC.
Safety and tolerability will be evaluated in 
terms of adverse events (AEs), vital signs, 
clinical laboratory assessments, ECGs, and 
AEs leading to dose interruptions, dose 
reductions, and dose discontinuations.
Vital signs parameters include systolic and 
diastolic blood pressure, and pulse as well as 
heart rate, body temperature, body weight, 
height and body mass index (BMI).
Laboratory parameters include clinical 
chemistry and haematology parameters as well 
as urinalysis.
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.
RECIST v1.1, Response Evaluation Criteria in Solid Tumors. AE, adverse event; BICR, Blinded Independent Central 
Review; BMI, body mass index; Cmax, maximum concentration; Ctrough, lowest concentration; CR, complete response; 
CTCAE v5.0, Common Terminology Criteria for Adverse Events Version 5.0; 
 DCR, 
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disease control rate; 
 DoR, duration of response; ECG, electrocardiogram; ORR, objective 
response rate; OS, overall survival; PFS, progression-free survival; PFS6, proportion of participants alive and progression 
free at 6 months; PR, partial response; RECIST v1.1, Response Evaluation Criteria in Solid Tumors; 
 
 SAE, serious adverse event; USC, uterine serous carcinoma.
 
 
 
 
 ORR, objective response rate; PFS6, proportion of 
participants alive and progression free at 6 months; 
 
 
PK, 
Pharmacokinetics.
1.2
Study Design
This is a Phase 2b, single-arm, open-label, multi-centre study to assess the efficacy and safety of 
adavosertib in eligible participants with histologically confirmed recurrent or persistent USC for the
purposes of this study, this includes participants with endometrial carcinoma of mixed histology 
where the serous component comprises at least 10% of the tumour [1]), evidence of measurable 
disease as per RECIST v1.1, and who have received at least 1 prior platinum-based chemotherapy 
regimen for the management of USC. Participants with carcinosarcomas are not eligible.
Approximately 120 eligible participants will receive oral adavosertib 300 mg once daily (QD) for 5 
days followed by 2 days off in Weeks 1 and 2 out of a 21-day cycle until objective radiological disease 
progression by investigator assessment using RECIST v1.1, unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met.
For the Schedule of Assessments (SoA), see Appendix A. The study design schema (Figure 1) and 
study flow chart (Figure 2) can be found in Appendix B.
1.3
Timing of Analysis
The primary analysis will be performed in both locally and centrally confirmed USC populations, 6 
months after the last participant first dose, or when all participants have progressed or died due to any 
cause, whichever is earlier. Maturity of DoR data will also be taken into account when selecting the 
DCO date for primary analysis. An interim analysis is planned after approximately 30 participants in 
the Centrally Confirmed Analysis Set (CCAS) have had the opportunity to be treated for at least 4 
months. Recruitment will not be paused whilst the participants required for the interim analysis are 
evaluated.
1.4
Number of Participants
Approximately 120 participants will be enrolled and dosed, with an intent to include approximately 
40 participants or more who have previously been exposed to PD-1/PD-L1 inhibitors. The primary 
objective is to estimate ORR and no formal statistical comparisons will be performed. With 120 
participants, if the observed ORR is 
 the width of the 2-sided 90% CI will be 
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2
ANALYSIS SET
2.1
Definition of Analysis Sets
The primary analysis population is the FAS. In addition, the CCAS population is the key
subgroup for decision making. Details of the analysis sets are presented in Table 1 and Table 2.
Table 1
Analysis Sets
Population/Analysis Set
Description
All Participants
The All Participants Set will include all participants who 
have signed the informed consent form (ie, screening 
failures plus participants dosed). The All Participants Set 
will be used to describe participant disposition.
Full Analysis Set (FAS)
The Full Analysis Set (FAS) will include all participants 
who received at least one (non-zero) dose of study 
treatment. This population will be used for the primary 
analyses of the efficacy and safety endpoints.
Centrally Confirmed Analysis Set (CCAS)
The Centrally Confirmed Analysis Set (CCAS) will 
include all centrally-confirmed USC participants who 
received at least one (non-zero) dose of study treatment. 
This population will be used for the analyses of efficacy.
Pharmacokinetic Analysis Set
The pharmacokinetic (PK) analysis set will include all 
dosed participants who had at least one measurable 
plasma concentration collected post-dose which was 
obtained without any deviation or event thought to 
significantly affect the PK analysis. All plasma 
concentration data will be summarized and presented 
according to AstraZeneca standards. This population will 
be used for the analysis of the PK data.


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Table 2
Summary of outcome variables and analysis sets
Outcome variable
Analysis Sets
Participant disposition
All Participants
Demography and baseline characteristics                                                
Full analysis set
Safety data
Exposure
Full analysis set
Adverse Events
Full analysis set
Laboratory measurements
Full analysis set
Vital Signs/ECG/Physical examination 
Full analysis set
Concomitant medications
Full analysis set
Efficacy Data
Objective Response Rate
Full analysis set, CCAS
Duration of Response
Full analysis set, CCAS
Depth of Response
Full analysis set, CCAS
PFS
Full analysis set, CCAS
PFS6
Full analysis set, CCAS
OS
Full analysis set, CCAS
DCR
Full analysis set, CCAS
Full analysis set
Pharmacokinetics
Plasma Pharmacokinetic variables
PK analysis set
2.2
Protocol Deviations
Important protocol deviations (IPDs) are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments. The impact of important 
protocol deviations on the efficacy and/or safety results will be investigated by assessing the
robustness of the study results and conclusions to the choice of analysis set, both including and 
excluding data potentially affected by important protocol deviations.
Important protocol deviations and any action to be taken regarding the exclusion of participants or 
affected data from specific analyses are defined in the project-specific Protocol Deviation 
Specification.
For this study, the following general categories will be considered IPDs and will be summarized in 
the Clinical Study Report (CSR):

Deviation 1: Participants who received treatment and who deviated from the following key 
entry criteria in the Clinical Study Protocol (CSP):
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
Inclusion criteria 1: Capable of giving signed informed consent and has given signed 
informed consent as described in Appendix C of CSP which includes compliance with 
the requirements and restrictions listed in the ICF and in this protocol.

Inclusion Criteria 4: Histologically confirmed recurrent or persistent USC. For the 
purposes of this study, participants with endometrial carcinoma of mixed histology 
where the serous component comprises at least 10% of the tumour will be considered 
eligible. Participants with carcinosarcomas are not eligible.

Inclusion Criteria 5: Evidence of measurable disease as per RECIST v1.1 defined as at 
least one lesion, not previously irradiated, that can be accurately measured in at least 
one dimension (longest diameter to be recorded) as ≥10mm with computed tomography 
(CT) scan or magnetic resonance imaging (MRI) (except lymph nodes which must have 
short axis ≥15mm) and which is suitable for accurate repeated measurements.

Inclusion Criteria 6: At least 1 prior platinum-based chemotherapy regimen for the 
management of USC (there is no restriction on the number of prior lines of systemic 
therapy that a participant may have previously received, and the platinum-based 
chemotherapy may have been given in the adjuvant setting). Chemotherapy 
administered only in conjunction with primary radiotherapy as a radiosensitiser should 
not count as a systemic regimen.
o
Prior anticancer therapies (eg, immune checkpoint inhibitors, vascular endothelial 
growth factor (VEGF) inhibitors and HER2 targeted therapy) are allowed.

Inclusion Criteria 7: Eastern Cooperative Oncology Group (ECOG) performance status 
0-1

Inclusion Criteria 9: Participants must have normal organ and marrow function at 
baseline, as defined below by laboratory values within 7 days prior to study drug(s) 
administration:
o
Absolute neutrophil count (ANC) ≥1.5 × 109/L
o
Haemoglobin (Hb) ≥9 g/dL
o
Platelet count ≥100 × 109/L
Calculated creatinine clearance (CrCl) >50 mL/min as determined by  the 
Cockcroft-Gault method (using actual body weight).

Exclusion criteria 9: History of Torsades de pointes unless all risk factors that 
contributed to Torsades have been corrected.

Inclusion Criteria 10: Consent to submit and provide a mandatory FFPE tumour sample 
for central testing. The site must confirm that the FFPE sample is available prior to 
dosing.

Exclusion Criteria 13: Use of anticancer treatment drug ≤ 21 days (≤ 6 weeks for 
nitrosoureas or mitomycin C) or use of an investigational product within 5 half-lives 
prior to the first dose of adavosertib. For PD-1/PD-L1 inhibitors, a minimum of 28 days 
since last dose is required.
Patients on luteinising-hormone releasing hormone analogue treatment for more than 6 
months are allowed entry into the study and may continue at the discretion of the 
investigator.


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
Exclusion criteria 14: Palliative radiotherapy with a limited field of radiation within 2 
weeks or with wide field of radiation or to more than 30% of bone marrow within 4 
weeks prior to the first dose of study intervention.

Exclusion Criteria 16: Prior receipt of a cell cycle checkpoint inhibitor (eg, CHK1, 
WEE1, or ATR inhibition)

Deviation 2: Patients assigned to treatment who received their assigned study treatment at 
an incorrect dose at more than 1 occasion.

Deviation 3:
Persistently missing important protocol required safety assessments 
(haematology, liver function test, chemistry panel and/or as per medical monitor discretion) 
and potentially having major impact to patient safety (clinical review on a case by case base).

Deviation 4: Baseline RECIST >42 days before start of assigned treatment (unless agreed 
with medical team), or no baseline RECIST 1.1 assessment on or before start of treatment.

Deviation 5: Patient received study treatment, but post-baseline tumour assessment scans not 
performed at all or major issues with scans not being performed in accordance with the 
protocol.

Deviation 6: Prohibited or restricted concomitant medications or therapies have been used.

Deviation 7: Met study treatment discontinuation criteria but continued study treatment and 
potentially had major impact to patients’ safety according to clinical judgement.

Deviation 8: Patient met criteria for RECIST v1.1-defined radiological progression, but was 
not withdrawn from study treatment.

Deviation 9: Missed visits, assessments, or treatments that, in the opinion of the principal 
investigator, were due to the COVID-19 global pandemic and there was a significant effect 
on EITHER completeness, accuracy, and/or reliability of the participant’s data, OR the 
participant’s rights, safety or well-being.

Deviation 10: Dose was re-escalated for subject.

Deviation 11: Participant received another systemic anti-cancer therapy during study 
conduct, but did not discontinue the study treatment.
Deviations not pre-specified in the above list that are considered to be important by the study team 
will also be classified as IPD's.
The number and percentage of participants with any IPD will be summarized for each IPD category
based on the FAS. Participants with more than one deviation in the same IPD category will be counted 
once for that IPD category. Any participants who have deviations in more than one IPD category will 
be counted once in the overall summary.
A list of all protocol deviations, including those reported by monitors, will be reviewed and decisions 
regarding how to handle these deviations will be documented by the study team physician, clinical 
pharmacology scientist and statistician prior to database lock. The final classification will be made 
prior to database lock.
A by-participant listing of important protocol deviations will be provided.


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3
PRIMARY AND SECONDARY VARIABLES
3.1
General Principles
Baseline measurements and change from baseline variables
Baseline will be the last non-missing value obtained prior to the first dose/administration of study 
medication and any information taken after first dose/administration of study medication will be 
regarded as post baseline information. If two visits are equally eligible to assess participant status at 
baseline (e.g., screening and baseline assessments both on the same date prior to first 
dose/administration), the average should be taken as the baseline value.  For non-numeric laboratory 
tests (i.e., some of the urinalysis parameters) where taking an average is not possible, then the clinical 
favourite value would be taken as baseline (i.e., normal and abnormal were observed on the same 
date prior to first dose/administration, then normal is considered as baseline value). In the scenario 
where there are two assessments on Day 1 prior to the first dose, one with time recorded and the other 
without time recorded, the one with time recorded would be selected as baseline. For assessments on 
the day of first dose where time is not captured, a nominal pre-dose indicator, if available, will serve 
as sufficient evidence that the assessment occurred prior to first dose.  Where safety data are 
summarised over time, study day will be calculated in relation to date of first treatment.  If no value 
exists before the first dose/administration, then the baseline value will be treated as missing.
In all summaries, change from baseline variables will be calculated as the post treatment value minus 
the value at baseline. For % change from baseline, calculate:
100× (Post baseline value – Baseline value)/Baseline value 
Study Day 1 is defined as the date of first dose of study treatment.  For visits (or events) that occur 
on or after first dose, study day is defined as 
Date of assessment/visit – Date of first dose/administration of study medication +1 
For visits (or events) that occur prior to first dose, study day is defined as 
Date of assessment/visit – Date of first dose/administration of study medication 
There is no Study Day 0.
End of Study Definition
A participant is considered to have completed the study if she has completed all phases of the study 
including the last scheduled procedure shown in the Schedule of Activities (SoA) Appendix A. The 
end of the study is defined as the date of the last visit of the last participant in the study. The last visit 
occurs when the last participant has their last scheduled visit, or 6 months after last participant first 
dose, whichever comes first.
After the primary analysis data cut-off (DCO), the clinical study database will be closed to new data. 
The primary analysis DCO will be followed by clinical database lock when all data for all participants 
have been collected.
The study may be terminated at individual centres if the study procedures are not being performed 
according to Good Clinical Practice (GCP), or if recruitment is slow. AstraZeneca may also terminate 


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the entire study prematurely if concerns for safety arise within this study or in any other study with 
adavosertib.
Participants will continue to be monitored by their treating physician/investigator for all SAEs and 
pregnancies while receiving IPs and for 30 days after the last dose of IP.
3.1.1
Definitions of Visit Windows
Analysis visit windows are displayed in SoA (Appendix A) for all assessments. Vital signs, ECG,
laboratory and PK data are all cycle-based will be mapped as shown in Table 3.
 
 
Table 3
Visit Windowing for laboratory assessments, vital signs, ECG and PK
Visit window label
Visit window
Screening
[28 days prior to first dose; 1 day prior to first dose]
C1 D1
Day of first dose in Cycle 1 (exact)
C1 D5
[Day 4 in Cycle 1, Day 5 in Cycle 1]*
[Day 4 in Cycle 1, Day 6 in Cycle 1]
C1 D8
[Day 8 in Cycle 1, Day 10 in Cycle 1] 
C1 D15
[Day 14 in Cycle 1, Day 16 in Cycle 1]
C2 D1
Day of first dose in Cycle 2 (exact)
C2 D5
[Day 4 in Cycle 2, Day 5 in Cycle 2]*
[Day 4 in Cycle 2, Day 6 in Cycle 2]
C2 D8
[Day 8 in Cycle 2, Day 10 in Cycle 2]
C2 D15
[Day 14 in Cycle 2, Day 16 in Cycle 2]
C3 D1
[Day 1 in Cycle 3, Day 4 in Cycle 3]
C3 D8
[Day 8 in Cycle 3, Day 10 in Cycle 3]
etc…**
etc…
      *Visit windowing is only for PK assessment.
      **Cycle 4 and all subsequent visits will be similar to cycle 3.
       
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The following conventions should apply: 

The analysis visit window should be exhaustive so that data recorded at any time point has 
the potential to be summarized. Inclusion within the analysis visit window should be based 
on the actual date and not the intended date of the visit.

All unscheduled visit data will have the potential to be included in the summaries.

Visits post treatment discontinuation will not be assigned to visit windows but presented as 
scheduled.

For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a participant.

For visit based summaries, if there is more than one value per participant within a time 
window then the closest value to the scheduled visit date should be used, or the earlier in the 
event the values are equidistant from the nominal visit date. If there are two values recorded 
on the same day and the parameter is CTCAE gradable then the record with the highest 
toxicity grade should be used. 

Note: in summaries of extreme values all post baseline values collected are used including 
those collected at unscheduled visits regardless of whether or not the value is closest to the 
scheduled visit date.  

For summaries at a participant level, all values should be included, regardless of whether 
they appear in a corresponding visit-based summary, when deriving a participant level 
statistic such as a maximum. 
3.1.1.1
Visit Windows for Tumour Assessments
The following conventions will apply for tumour assessment data:

All tumour assessments available during the study should be used for the efficacy analysis. 
A windowing rule will be applied and will follow the CSP allowed visit window; therefore, 
any RECIST assessment performed within ± 7 days of the CSP scheduled visit will be used 
for that visit.

If there are any assessments outside these visit windows, they will also be included in the 
closest visit window following the intent-to-treat principle.  The tumour assessments which 
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are outside the visit windows will be flagged in the data listings. 
The above could result in more than one tumour assessments within a window and in that case, the 
one closest to the scheduled assessment will be used.
3.2
Derivation of RECIST Visit Responses
For all participants, the RECIST tumour response data will be used to determine each participant’s 
visit response according to RECIST version 1.1.  It will also be used to determine if and when a 
participant has progressed in accordance with RECIST and their objective response to study 
treatment.  
Baseline radiological tumour assessments are to be performed no more than 28 days before the start 
of randomised treatment and ideally as close as possible to the start of study treatment.  Tumour 
assessments are then performed every 6 weeks (±7 days) following the start of study treatment for 
the first 48 weeks then every 9 weeks (±7 days) thereafter, until objective radiological disease 
progression by investigator assessment using RECIST v1.1.
If an unscheduled assessment is performed, and the participant has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule is to 
be followed in order to minimise any unintentional bias caused by some participants being assessed 
at a different frequency than other participants.
For ORR, a visit response of CR or PR must be confirmed by a subsequent scan conducted at least 4 
weeks after the initial response is observed. The next RECIST scheduled assessment can be used for 
the confirmatory scan.  
The RECIST tumour response data will be used to determine each participant’s visit response 
according to RECIST version 1.1. At each visit, participants will be programmatically assigned a 
RECIST 1.1 visit response of CR, PR, SD, PD or NE, using the information from target lesions (TLs), 
non-target lesions (NTLs) and new lesions and depending on the status of their disease compared 
with baseline and previous assessments. If a participant has had a tumour assessment that cannot be 
evaluated then the participant will be assigned a visit response of not evaluable (NE), (unless there is 
evidence of progression in which case the response will be assigned as PD).
Please refer to Section 3.2.1 for the definitions of CR, PR, SD, PD and NE. 
RECIST outcomes (i.e. confirmed ORR, DoR, percentage change from baseline in tumour size, PFS,
and DCR.) will be calculated programmatically from the RECIST tumour response data.
RECIST outcomes will be derived using RECIST v1.1 assessments based on BICR (see Section
3.2.4).  The efficacy analysis will be based on BICR assessments.  
3.2.1
Target lesions (TLs) – site investigator data
Measurable disease is defined as having at least one measurable lesion, not previously irradiated, 
which is ≥ 10 mm in the longest diameter (LD), (except lymph nodes which must have short axis ≥ 
15 mm) with CT or MRI and which is suitable for accurate repeated measurements. A participant can 
have a maximum of five measurable lesions recorded at baseline with a maximum of two lesions per 
organ (representative of all lesions involved and suitable for accurate repeated measurement) and 


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these are referred to as target lesions (TLs).  If more than one baseline scan is recorded then 
measurements from the one that is closest and prior to first dose/administration of study medication 
will be used to define the baseline sum of TLs. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance the next largest lesion, which 
can be measured reproducibly, should be selected.
All other lesions (or sites of disease) not recorded as TL should be identified as non-target lesions 
(NTLs) at baseline.  Measurements are not required for these lesions, but their status should be 
followed at subsequent visits.
Note: For participants who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL assessment 
and the absence/presence of new lesions (see Section 3.2.2 for further details). If a participant does 
not have measurable disease at baseline then the TL visit response will be not applicable (NA). This 
will be a protocol deviation for this study.
Table 5
TL Visit Responses (RECIST 1.1)
Visit Responses
Description
Complete response (CR)
Disappearance of all TLs since baseline.  Any pathological lymph 
nodes selected as TLs must have a reduction in short axis diameter 
to <10 mm.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters
Progressive disease (PD)
At least a 20% increase in the sum of diameters of TLs, taking as 
reference the smallest previous sum of diameters (nadir) – this 
includes the baseline sum if that is the smallest on study.  In addition 
to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm from nadir
Stable disease (SD)
Neither sufficient decrease in sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or 
not evaluable (eg, missing anatomy) or had a lesion intervention at 
this visit.  NOTE: if the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a TL 
response
Not applicable (NA)
Only relevant if no TLs present at baseline
Rounding of TL data
For calculation of PD and PR for TLs percentage changes from baseline and previous minimum 
should be rounded to one d.p. before assigning a TL response.  For example, 19.95% should be 
rounded to 20.0% but 19.94% should be rounded to 19.9%  


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Missing TL data
For a visit to be evaluable then all TL measurements should be recorded.  However, a visit response 
of PD should still be assigned if any of the following occurred

A new lesion is recorded

A NTL visit response of PD is recorded

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute increase 
of ≥5mm, from nadir even assuming the non-recorded TLs have disappeared
Note: the nadir can only be taken from assessments where all the TLs had a LD recorded. 
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, the 
visit response is NE.
If all TL measurements are missing, then the TL visit response is NE.  Overall visit response will also 
be NE, unless there is a progression of non-TLs or new lesions, in which case the response will be 
PD.
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. However, 
a size will still be given, and this size should still be used to determine the TL visit response as normal.  
In the special case where all lymph nodes are < 10mm and all other TLs are 0mm then although the 
sum may be > 0mm the calculation of TL response should be over-written as a CR. 
TL visit responses subsequent to CR
Only CR, PD or NE can follow a CR.  If a CR has occurred, then the following rules at the subsequent 
visits must be applied:

Step 1:  If all lesions meet the CR criteria (i.e. 0mm or < 10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met i.e. if 
a lymph node short axis increases by 20% but remains < 10mm. 

Step 2:  If some lesion measurements are missing but all other lesions meet the CR criteria 
(i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE irrespective of 
whether, when referencing the sum of TL diameters, the criteria for PD are also met. 

Step 3:  If not all lesions meet the CR criteria (i.e. a pathological lymph node selected as TL 
has short axis > 10mm or the reappearance of previously disappeared lesion) or a new lesion 
appears, then response will be set to PD

Step 4:  If after steps 1 – 3 a response can still not be determined the response will be set to 
remain as CR
TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) above 
which it cannot be accurately measured should be recorded.  If using a value of x in the calculation 
of TL response would not give an overall visit response of PD, then this will be flagged and reviewed 
by the study team.  It is expected that a visit response of PD will remain in the vast majority of cases.  


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TL too small to measure
If a TL becomes too small to measure, then this will be indicated as such on the case report form and 
a value of 5mm will be entered into the database and used in TL calculations. However, a smaller 
value may be used if the radiologist has not indicated ‘too small to measure’ on the case report form 
and has entered a smaller value that can be reliably measured.  If a TL response of PD results then 
this will be reviewed by the study team.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be recorded as 
NTLs and should not form part of the TL assessment.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the following way. Once a lesion 
has had intervention then it should be treated as having intervention for the remainder of the study 
noting that an intervention will most likely shrink the size of tumours:

Step 1: the diameters of the TLs (including the lesions that have had intervention) will be summed 
and the calculation will be performed in the usual manner. If the visit response is PD, this will 
remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter (for those 
lesions with intervention) as missing and if 1/3 of the TLs have missing measurements then 
scale up as described in the ‘Scaling’ section below.  If the scaling results in a visit response of 
PD then the participant would be assigned a TL response of PD.  

Step 3: If, after both steps, PD has not been assigned, then, if appropriate (i.e. if 1/3 of the TLs 
have missing measurements), the scaled sum of diameters calculated in step 2 should be used, 
and PR or SD then assigned as the visit response.  Participants with intervention are evaluable 
for CR as long as all non-intervened lesions are 0 (or <10mm for lymph nodes) and the lesions 
that have been subject to intervention also have a value of 0 (or <10mm for lymph nodes) 
recorded.  If scaling up is not appropriate due to too few non-missing measurements, then the 
visit response will be set as NE.
At subsequent visits, the above steps will be repeated to determine the TL and overall visit response.  
When calculating the previous minimum, lesions with intervention should be treated as missing and 
scaled up (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are missing (because of intervention) then the TL response will be NE, 
unless the sum of diameters of non-missing TL would result in PD (i.e. if using a value of 0 for 
missing lesions, the sum of diameters has still increased by 20% or more compared to nadir and the 
sum of TLs has increased by ≥5mm from nadir).  
If ≤ 1/3 of the TL measurements are missing (because of intervention) then the results will be scaled 
up (based on the sizes at the nadir visit to give an estimated sum of diameters) and this will be used 
in calculations; this is equivalent to comparing the visit sum of diameters of the non-missing lesions 
to the nadir sum of diameters excluding the lesions with missing measurements.


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Example of scaling
Lesion
Longest diameter (mm) 
at nadir visit
Longest diameter (mm) at 
follow-up visit
1
16
18
2
14
16
3
14
16
4
18
18
5
12
Intervention
Sum
74
68
Lesion 5 is missing at the follow-up visit; the nadir TL sum including lesions 1-5 was 74 mm. 
The sum of lesions 1-4 at the follow-up is 68 mm.  The sum of the corresponding lesions at the nadir 
visit is 62 mm.
Scale up as follows to give an estimated TL sum of 81 mm:
68 x 74 / 62 = 81 mm
CR will not be allowed as a TL response for visits where there is missing data.  Only PR, SD or PD 
(or NE) could be assigned as the TL visit response in these cases.  However, for visits with 1/3 
lesion assessments not recorded, the scaled-up sum of TLs diameters will be included when defining 
the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the LD for 
the lesion that split.
Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL sizes and 
the other TL size should be recorded as 0 mm.
Change in method of assessment of TLs
CT, MRI and clinical examination are the only methods of assessment that can be used within a trial, 
with CT and MRI being the preferred methods and clinical examination only used in special cases. 
If a change in method of assessment occurs, between CT and MRI this will be considered acceptable 
and no adjustment within the programming is needed.  
If a change in method involves clinical examination (e.g. CT changes to clinical examination or vice 
versa), any affected lesions should be treated as missing.   The TL visit response may still be evaluable 
if the number of missing TL measurements at a visit is ≤1/3 of the total number of TLs.  


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3.2.2
Non-target lesions (NTLs) and new lesions – site investigator data
At each visit, the investigator should record an overall assessment of the NTL response. This section 
provides the definitions of the criteria used to determine and record overall response for NTL at the 
investigational site at each visit.
NTL response will be derived based on the investigator’s overall assessment of NTLs as follows:  
Table 6
NTL Visit Responses
Visit Responses
Description
Complete response (CR)
Disappearance of all NTLs since baseline.  All lymph nodes must 
be non-pathological in size (<10 mm short axis).
Progressive disease (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions.  In all cases the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy
Non-CR/Non-PD
Persistence of one or more NTL
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the investigator’s opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit
NOTE: for participants without TLs at baseline, this is relevant 
if any of the NTLs were not assessed at this visit and the 
progression criteria have not been met
Not applicable (NA)
Only relevant if no NTLs present at baseline
To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in TLs, the 
overall tumour burden has increased sufficiently to merit a determination of disease progression.  A 
modest ‘increase’ in the size of one or more NTLs is usually not sufficient to qualify for unequivocal 
progression status.
Details of any new lesions will also be recorded with the date of assessment.  The presence of one or 
more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning 
technique, change in imaging modality or findings thought to represent something other than tumour.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions at 
each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the TL and 
NTL response.


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If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and the new 
lesion details are blank this is not evidence that no new lesions are present, but should not overtly 
affect the derivation.   
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for stopping study 
therapy and will not be included in any assessment of NTLs.
Participants with ‘symptomatic progression’ requiring discontinuation of treatment without objective 
evidence of disease progression at that time should continue to undergo tumour assessments where 
possible until objective disease progression is observed.
3.2.3
Overall visit response – site investigator data
Table 7 defines how the previously defined TL and NTL visit responses will be combined with new 
lesion information to give an overall visit response.
Table 7 
Overall visit responses
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NA
Non-CR/Non-PD
No
SD (Non-CR/Non-PD)
NE
Non-PD or NE or NA
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR, complete response; NA, not applicable (only relevant if there were no target lesions at baseline or no non target 
lesions at baseline); NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease; TL, target lesion.
3.2.4
Independent review
A planned BICR of all radiological imaging data will be carried out using RECIST version 1.1. All 
radiological scans for all participants (including those at unscheduled visits, or outside visit windows) 
will be collected on an ongoing basis and sent to Parexel Informatics for central analysis. For each 
participant, the BICR will define the overall visit response (i.e. the response obtained overall at each 
visit by assessing TLs, NTLs and new lesions) data and no programmatic derivation of visit response 
is necessary.  (For participants with TLs at baseline: CR, PR, SD, PD, NE; for participants with NTLs 
only: CR, SD, PD, NE).  If a participant has had a tumour assessment that cannot be evaluated, then 
the participant will be assigned a visit response of NE (unless there is evidence of progression in 


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which case the response will be assigned as PD).  RECIST assessments/scans contributing towards a 
particular visit may be performed on different dates and for the central review the date of progression 
for each reviewer will be provided based on the earliest of the scan dates of the component that 
triggered the progression. 
If adjudication is performed, the reviewer that the adjudicator agreed with will be selected as a single 
reviewer (note in the case of more than one review period, the latest adjudicator decision will be 
used).  In the absence of adjudication, the records for all visits for a single reviewer will be used.  The 
reviewer selected in the absence of adjudication will be the reviewer who read the baseline scan first.  
The records from the single selected reviewer will be used to report all BICR RECIST information 
including dates of progression, visit response, censoring and changes in target lesion dimensions.  
Endpoints (of ORR, PFS, DCR and DoR) will be derived programmatically from this information. 
Results of this independent review will not be communicated to investigators and the management of 
participants will be based solely upon the results of the RECIST 1.1 assessment conducted by the 
investigator.
A BICR of all participants will be performed up to the primary database lock, which will cover all of 
the scans up to the DCO. After the primary analysis DCO, images will no longer need to be collected 
centrally. Ongoing collection of site reviewed tumour assessment is required and must be recorded in 
the eCRF. Radiological examinations performed in the conduct of this study should be retained at site 
as source data.
Further details of the BICR will be documented in the BICR Charter.
3.3
Efficacy Variables
3.3.1
Objective Response Rate
The ORR is defined as follows:

The ORR is the proportion (%) of participants with measurable disease at baseline who have a
confirmed complete response (CR) or partial response (PR), as determined by BICR per 
RECIST v1.1. The denominator is defined as the subset of all treated participants with 
measurable disease at baseline per BICR.
ORR will also be defined similarly based on site investigator assessments. The denominator for 
investigator assessment based ORR is defined as the subset of all treated participants with measurable 
disease at baseline per investigator.
Data obtained up until progression, or the last evaluable assessment in the absence of progression, 
will be included in the assessment of the ORR. Responses that occur after the start of subsequent anti-
cancer therapy must be excluded from the derivation of ORR (ie, only responses that occur prior to
receiving subsequent therapy will be included in the numerator). Radiotherapy is not considered as 
subsequent cancer therapy while calculating ORR.
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed 
by repeat imaging not less than 4 weeks after the visit when the response was first observed with no 
evidence of progression between the initial and CR/PR confirmation visit. Summaries of ORR for the 
primary analysis will be based on BICR.


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3.3.2
Best Objective Response
Best objective response (BoR) is calculated based on the overall visit responses from each RECIST 
assessment, described in Section 3.2. It is the best response a participant has had following first 
treatment administration, but prior to starting any subsequent cancer therapy and up to and including
RECIST progression or the last evaluable assessment in the absence of RECIST progression. 
Categorisation of BoR will be based on RECIST using the following response categories: CR, PR, 
SD, NED (applies only to those participants entering the study with no disease at baseline), PD and 
NE.
CR or PR must be confirmed. For CR/PR, the initial overall visit assessment which showed a response 
will use the latest of the dates contributing towards a particular overall visit assessment. 
For determination of a best response of SD, the earliest of the dates contributing towards a particular 
overall visit assessment will be used.  SD should be recorded at least 6 weeks minus 1 week, i.e. at 
least 35 days (to allow for an early assessment within the assessment window), after first dose of 
study treatment.  
BoR will be determined programmatically based on RECIST from the overall visit response using all 
BICR data up until the first progression event.  It will also be determined programmatically based on 
RECIST using all site investigator data up until the first progression event.  The denominators for 
each case will be consistent with those used in the ORR analysis.
For participants whose progression event is death, BoR will be calculated based upon all evaluable 
RECIST assessments prior to death.
For participants who die with no evaluable RECIST assessments, if the death occurs ≤49 days (i.e. 
6 weeks + 1 week to allow for a late assessment within the assessment window) after first dose, then 
BoR will be assigned to the progression (PD) category.  For participants who die with no evaluable 
RECIST assessments, if the death occurs > 49 days after start of treatment then BoR will be assigned 
to the NE category.
A participant will be classified as a responder if the RECIST criteria for a CR or PR are satisfied at 
any time following first dose of study treatment, prior to RECIST progression and prior to starting 
any subsequent cancer therapy.
3.3.3
Duration of Response
DoR is defined as the time from the date of first documented response (which is subsequently 
confirmed) until the first date of documented progression or death in the absence of disease 
progression

DoR = (date of PFS event or censoring) – (date of start of response) +1
The end of response should coincide with the date of progression or death from any cause used for 
the PFS endpoint (see Section 3.3.5). The time of the initial response will be defined as the latest of 
the dates contributing towards the first visit that was CR or PR that was subsequently confirmed. If a 


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participant does not progress following a response, then their DoR will use the PFS censoring time.
Duration of response will be presented in months. 
3.3.4
Depth of Response
Depth of response is defined as the best percentage change from baseline in Target Lesions.
The absolute change and percentage change from baseline in the sum of tumour size at each 
assessment will be calculated. Tumour size is the sum of the longest diameters of the TLs.
Percent changes in tumour size from baseline will be determined for participants with measurable 
disease at baseline and is derived at each visit as percent change in the sum of the diameters of TLs.

% change = [(post baseline TL sum – baseline TL sum) / baseline TL sum] *100. 
The best change in tumour size (i.e. depth of response) is the largest decrease from baseline or the 
smallest increase from baseline in the absence of a reduction and will include all assessments prior to 
the earliest of death in the absence of progression, any evidence of progression, the start of subsequent 
anti-cancer or the last evaluable RECIST assessment if the participant has not died, progressed or 
started subsequent anti-cancer therapy.
Baseline for RECIST v1.1 is defined as the last evaluable assessment prior to the start of treatment. 
If a participant with missing baseline data, best percentage change from baseline will be kept as 
missing. If best percentage change cannot be calculated due to missing data, a value of +20% will be 
imputed as the best percentage change from baseline in the following situations (otherwise best 
percentage change will be left as missing):

If a participant has no post-baseline assessment and has died

If a participant has new lesions or progression of NTLs or TLs

If a participant has withdrawn due to PD and has no evaluable TL data before or at PD
3.3.5
Progression-Free Survival (PFS)
Progression-free survival is defined as the time from the date of first dose until the date of objective 
disease progression or death (by any cause in the absence of progression) regardless of whether the 
participant discontinues adavosertib or receives another anticancer therapy prior to progression.

PFS (days) = (date of PFS event or censoring) – (date of first dose of adavosertib) + 1.
Participants who have not progressed or died at the time of analysis will be censored at the date of 
their last evaluable RECIST v1.1 assessment.
If the participant progresses or dies after 2 or more missed visits, the participant will be censored at 
the date of the latest evaluable RECIST v1.1 assessment prior to the missed visits.  
If the participant has no evaluable visits or does not have baseline data, he/she will be censored at 
Day 1 unless he/she dies within 2 visits of baseline, in which case the date of death is the event date.
Given the scheduled visit assessment scheme (i.e. six-weekly for the first 48 weeks and then nine-
weekly thereafter) the definition of 2 missed visits will change. 


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1. If the previous RECIST assessment is <= study day 35 (i.e. week 5) then two missing visits 
will equate to 13 weeks since the previous RECIST assessment, allowing for a late visit (i.e. 
2 x 6 weeks + 1 week for a late assessment = 13 weeks).
2. If the previous RECIST assessment is >35 and < study day 287 (i.e. week 41) then two missing 
visits will equate to 14 weeks since the previous RECIST assessment, allowing for early and 
late visits (i.e. 2 x 6 weeks + 1 week for an early assessment + 1 week for a late assessment = 
14 weeks).
3. If the two missed visits occur over the period when the scheduled frequency of RECIST 
assessments changes from six-weekly to nine-weekly this will equate to 17 weeks (i.e. take 
the average of 6 and 9 weeks which gives 7.5 weeks and then apply same rationale, hence 2 
x 7.5 weeks + 1 week for an early assessment + 1 week for a late assessment = 17 weeks).  
The time period for the previous RECIST assessment will be from study days 288 to 329 (i.e. 
week 41 to week 47).
4. From week 47 onwards (when the scheduling changes to nine-weekly assessments), two 
missing visits will equate to 20 weeks (i.e. 2 x 9 weeks + 1 week for an early assessment + 1 
week for a late assessment = 20 weeks).
3.3.6
Progression-Free Survival at 6 months (PFS6)
PFS6 is the proportion of participants alive and progression-free at 6 months (PFS6). It is defined as 
the Kaplan-Meier estimate of PFS (per RECIST v1.1) at 6 months.
3.3.7
Overall Survival
The Overall Survival (OS) is defined as the time from the date of first dose of adavosertib until death 
due to any cause, regardless of whether the participant discontinues adavosertib or receives another
anticancer therapy.

OS (days) = (date of death or censoring) (date of first dose of adavosertib) + 1
Any participant not known to have died at the time of analysis will be censored at the last recorded 
date at which the participant was known to have been alive.
The date that an individual participant was last known to be alive will be identified using the data 
recorded within the SURVIVE and DEATH modules of the eCRF.
Note: Survival calls will be made in the week following the date of DCO for the analysis, and if 
participants are confirmed to be alive or if the death date is after the DCO date these participants will 
be censored at the date of DCO. The status of ongoing, withdrawn (from the study) and “lost to 
follow-up” participants at the time of the primary analysis should be obtained by the site personnel 
by checking the participant’s notes, hospital records, contacting the participant’s general practitioner 
and checking publicly available death registries. In the event that the participant has actively 
withdrawn consent to the processing of their personal data, the vital status of the participant can be 
obtained by site personnel from publicly available resources where it is possible to do so under 
applicable local laws.
It may be necessary to use all relevant CRF fields to determine the last recorded date on which the 
patient was known to be alive for those patients still on treatment. The last date for each individual 
patient is defined as the latest among the following dates recorded on the case report forms (CRFs):

AE start and stop dates


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
Admission and discharge dates of hospitalization

Study treatment date

End of treatment date

Laboratory test dates

Date of vital signs

Disease assessment dates on RECIST CRF

Start and stop dates of alternative anticancer treatment

Date last known alive on survival status CRF

End of study date
3.3.8
Disease control rate
Disease control rate is defined as the proportion of participants with best response of confirmed CR, 
confirmed PR, or who have stable disease at least 5 weeks after first dose (to allow for an early 
assessment within the assessment window).
3.4
3.4.1
CCI
CCI
CCI
CCI


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CCI


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3.4.2
CCI
CCI
CCI


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3.4.3
CCI
CCI
CCI


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3.4.4
3.5
Other Variables
3.5.1
Prior and Concomitant Medications and Therapies
All therapies (drug or non-drug), including herbal preparations, whether prescribed or over-the-
counter, that are used during the study will be recorded in the eCRF. Details include generic and/or 
brand names of medications, WHO drug dictionary encoding, reason for use, route, dose, dosing 
frequency, and start and stop dates. 

Prior medications are those taken prior to study treatment with a stop date prior to the first 
dose of study treatment.
CCI
CCI
CCI


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
Concomitant medications are those with a stop date on or after the first dose date of study 
treatment (and could have started prior to or during treatment).

Post-treatment medications are those with a start date after the last dose date of study 
treatment.
Missing start and stop dates for medications will be imputed using the rules described in 
Section 4.1.1.
3.6
Safety Variables
Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory assessments,
ECGs, and AEs leading to dose interruptions, dose reductions, and dose discontinuations.
3.6.1
Exposure and dose interruptions
The total and actual exposure calculations make no adjustment for any dose reductions that may have 
occurred. 
Exposure will also be measured by the number of cycles received. A cycle corresponds to a period of 
21 days. If a cycle is prolonged due to toxicity, it should still be counted as one cycle. A cycle will 
be counted if treatment is started even if the full dose is not delivered.
3.6.1.1
Dose calculations
Duration of adavosertib exposure (or intended) is calculated as follows:

Total (or intended) exposure = min (last dose date where dose > 0 mg, date of death, date of 
data cut off) – first dose date + 1 
Actual exposure of study treatment 

Actual exposure = intended exposure – total duration of dose interruptions, where intended 
exposure will be calculated as above and a dose interruption is defined as any length of time 
where the participant has not taken any of the planned dose.
Number of treatment cycles received

Exposure will also be measured by the number of cycles received.  A cycle corresponds to a 
period of 21 days. If the last dose is in Cycle 1, the number of cycles received will be 1.  If 
a cycle is prolonged due to toxicity, this should still be counted as one cycle.  A cycle will 
be counted if treatment is started even if the full dose is not delivered.
Missed or forgotten doses

Missed and forgotten doses should be recorded on the exposure form as a dose interruption 
with the reason recorded as “Patient forgot to take dose”.  These missed or forgotten doses 
will not be included as dose interruptions in the summary tables but the information will 
appear in the listing for dosing.  However, these missed and forgotten doses will be 
considered in the derivation of actual exposure.


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Participants who permanently discontinue during a dose interruption

If a participant permanently discontinues study treatment during a dose interruption, then the 
date of last administration of study medication recorded on Discontinuation of study drug
will be used in the programming.
3.6.1.2
Dose Intensity 
Dose intensity will be addressed by considering relative dose intensity (RDI). and percentage 
intended dose (PID). 

Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. This is derived as:

RDI = 100% * d/ Dc, where d is the actual cumulative dose delivered up to the earlier 
of progression (or a censoring event) or the actual last day of dosing and Dc is the 
intended cumulative dose up to the earlier of progression (or a censoring event) or the 
actual last day of dosing.

Percentage intended dose (PID) is the percentage of the actual dose delivered relative to the 
intended dose through to progression.  The PID is derived as:

PID= 100% * d/Dp, where d is the actual cumulative dose delivered up to progression 
(or a censoring event).  Dp is the total dose that would be delivered, if there were no 
modification to dose or schedule.
Please note the calculation of Dcand Dp will not change when investigator modified the dose level of 
individual participants. If a participant received the planned dose at the scheduled time at every cycle, 
then RDI = 1.
3.6.2
Adverse events
Details of all AEs and SAEs will be collected for a participant from the signing of the Informed 
Consent Form (ICF) up to 30 days after the last dose of adavosertib. If an event starts after this period 
and the Investigator considers that it is possible that it is due to a late onset toxicity to adavosertib, 
then it should be reported as an AE or SAE.
All AEs will be coded using the latest version of Medical Dictionary for Regulatory Activities 
(MedDRA) providing the System Organ Class (SOC) and Preferred Term (PT). 
In addition, all AEs will also be graded according to the National Cancer Institute (NCI) Common 
Terminology Criteria for AEs (CTCAE Version 5.0) allocating grades from Grade 1 to Grade 5 which 
will be used for the reporting. The meaning of these categories are as follows:  

Grade 1: Mild AE

Grade 2: Moderate AE

Grade 3: Severe AE

Grade 4: Life-threatening or disabling AE

Grade 5: Death related to AE
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs and ECG 
abnormalities should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the 


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reason for discontinuation of treatment with the investigational product or are considered to be 
clinically relevant as judged by the investigator.
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 nonmandated parameters should be reported 
as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should not be 
reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to the 
disease under study.
Treatment Emergent Adverse Events
The following events will be considered treatment emergent:

Adverse events with an onset date on or after first dose of adavosertib and within 30 days
after last dose of adavosertib

Worsening of pre-existing events on or after first dose of adavosertib and within 30 days
after last dose of adavosertib. Latest grade prior to first dose will be considered as the 
baseline of pre-existing events.
Missing start and stop dates for AEs will be imputed using the rules described in Section 4.1.1.
3.6.3
Hy’s law
Cases where a participant shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 x ULN together with total bilirubin ≥2 x ULN will need to be 
reported as SAEs if criteria are met for a Potential Hy’s Law case. Please refer to Protocol Appendix 
H for further instruction on cases of increases in liver biochemistry and evaluation of Hy’s Law.
3.6.4
ECG changes
These measurements will be recorded as detailed in the study schedule (See Appendix A). 
At Screening, and as clinically indicated throughout the study, ECGs will be obtained after the 
participant has been in a supine position for at least 10 minutes and recorded while the participant
remains in that position. Any clinically significant abnormalities detected require triplicate ECG 
results. At each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, within 5 minutes. If there is a clinically significant abnormal unscheduled 
ECG finding during the treatment period, this should be recorded as the AE. 


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3.6.5
Vital sign changes
Vital signs will be collected as outlined in Appendix A. Measurements will include SBP (mmHg), 
DBP (mmHg), pulse rate, heart rate (bpm) and body temperature (degrees Celsius). Change from 
baseline in vital signs variables will be calculated for each post-dose visit on treatment. For derivation 
of post-baseline visit values, considering visit window, and handling multiple records, derivation 
rules as described in section 3.1 will be used.
3.6.6
Laboratory data
Laboratory data (clinical chemistry, haematology and urinalysis) will be collected as detailed in the 
Schedule of Assessment (Appendix A). Coagulation and urinalysis will be collected at screening and 
as clinically indicated. Haematology and clinical chemistry parameters will be collected at screening, 
at Day 1 and Day 8 of each cycle, at study treatment discontinuation, 30 days after last dose and at 
other times if clinically indicated. For the definition of baseline and the derivation of post baseline 
visit values considering visit windows and how to handle multiple records, derivation rules as 
described in section 3.1 will be used.
Women of childbearing potential must have a negative urine or serum pregnancy test during screening 
and a confirmatory negative test prior to dosing on Day 1 of each treatment cycle. In the event of 
suspected pregnancy during the study, the test should be repeated prior to dosing and, if positive, the 
participant discontinued from study treatment immediately.
The laboratory parameters presented in Table 9 will be measured as a minimum. 
Table 9
Laboratory Safety Variables
Haematology
Clinical Chemistry
B-Haemaglobin
S/P-Albumin
B-Leukocyte
S/P-Alanine aminotransferase (ALT)
B-Haematocrit
S/P-Aspartate aminotransferase (AST)
B-Red blood cell count
S/P-Alkaline phosphatase (ALP)
B-Absolute leukocyte differential count
S/P-Bilirubin, total
B-Neutrophils
S/P-Calcium, total
B-Lymphocytes
S/P-Creatinine
B-Monocytes
S/P-Chloride
B-Basophils
S/P-Potassium
B-Eosinophils
S/P-Sodium
B-Platelet counts
S/P-Urea nitrogen or blood urea nitrogen
B-Absolute neutrophil count 
Coagulation
Pregnancy test (blood or urine)
B-PT or INR with PTT


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Urinalysis 
U-Hb/erythrocytes/blood
U-Protein/albumin
U-Glucose
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, blood; Hb, 
haemoglobin; INR, International Normalised Ratio; P, plasma; PT, prothrombin time; PTT, partial thromboplastin time; 
S, serum; U, urine.
Laboratory data will be from local laboratories and units will be entered into the CRF. The 
Investigator should make an assessment of the available results with regard to clinically relevant 
abnormalities. 
Change from baseline in clinical chemistry and haematology variables will be calculated for each 
post-dose visit on treatment. 
Absolute values will be compared to the local reference range and classified as low (below range), 
normal (within range or on limits of range) and high (above range). As applicable, values will be 
converted to standard units. The assessment of haematology, clinical chemistry and coagulation that 
deviate above or below the normal range will be classified by Common Terminology Criteria (CTC) 
grade (NCI CTCAE v5) taking values: Grade 0, 1, 2, 3, or 4.
The maximum (or minimum) on-treatment value (depending on the direction of an adverse effect) 
will be defined for each laboratory parameter as the maximum (or minimum) post-dose value up until 
treatment discontinuation.
3.6.7
ECOG Performance Status
ECOG PS will be assessed at the times specified in the schedule of assessments (Appendix A) based 
on the following:
0.
Normal activity. Fully active, able to carry out all usual activities without restrictions
1.
Symptoms, but ambulatory. Restricted in strenuous activity, but ambulatory and able to 
carry out work of a light or work of sedentary nature (eg, light housework or office work)
2.
In bed <50% of the time. Ambulatory and capable of self-care, but unable to carry out 
any work activities; up and about more than 50% of waking hours
3.
In bed >50% of the time. Capable of only limited self-care; confined to bed or chair more 
than 50% of waking hours
4.
100% bedridden. Completely disabled. Cannot carry on any self-care and totally confined 
to bed or chair
5.
Dead.
Any significant change from baseline or screening must be reported as an AE.


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3.7
Pharmacokinetic Variables
3.7.1
Pharmacokinetics
Blood sample for measurement of plasma concentration will be collected as the following timepoints:

Cycle 1, Day 5 (-1 day): pre-dose and 2 hours post-dose

Cycle 2, Day 5 (-1 day): pre-dose and 2 hours post-dose 
All PK samples need to be collected within 10% of the nominal time (± 6 minutes for a 60-minute
sample) to be protocol compliant. Pre-dose samples should be collected within 60 minutes prior to 
dosing. Samples may be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor (eg, for safety reasons).
Pharmacokinetic parameters will be estimated from the plasma concentration data by Covance 
Pharmacokinetic Alliance (CPKA). The following PK parameters will be determined at cycle 1 day 
5 and cycle 2 day 5 (steady-state): Cmax and Ctrough (as data allows). 
Cmax and Ctrough, will be obtained directly from the observed plasma concentration. 
4
ANALYSIS METHODS
4.1
General Principles
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, 
minimum, maximum and number of observations, unless otherwise stated. Continuous data that are 
expected to be skewed will be presented in terms of the maximum, upper quartile, median, lower 
quartile, minimum and number of observations.  The minimum and maximum will be reported to the 
same number of decimal places as the raw data recorded in the database.  The mean, median, lower 
quartile and upper quartile will be reported to one more decimal place than the raw data recorded in 
the database.  The SD will be reported to two more decimal places than the raw data recorded in the 
database.  In general, the maximum number of decimal places reported shall be four for any summary 
statistic.
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts and percentages.  
Percentages will be presented to one decimal place. Unless otherwise stated, percentages will be 
calculated out of the population total. Percentages will not be presented for zero counts.  
Exact CIs for proportions will be calculated using the Clopper-Pearson method.
For percentiles of survival times based on the Kaplan-Meier method (eg, median survival), CIs will 
be calculated using the default method available in the SAS LIFETEST procedure (ie, the Klein and 
Moeschberger extension of the Brookmeyer-Crowley method).
For point-estimates of survival based on the Kaplan-Meier method (eg, for PFS6), CIs will be 
calculated using the default method available in the SAS LIFETEST procedure (ie, using 
Greenwood’s estimate of standard error and a log-log transformation).


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Confidence intervals will be presented to one more decimal place than the raw data.
Due to Covid-19 some participants were screen failed in the first instance but later rescreened. For 
summary tables only data from the rescreening will be presented for the rescreened participants. For 
listings both original screen failure data and rescreened data will be presented for the rescreened 
participants.
4.1.1
Handling of Dropouts or Missing Data
Summary statistics will be based on non-missing values. Missing safety data will generally not be 
imputed. However, safety assessment values (vital signs, laboratory assessments) of the form of 
“<x” (ie, below the lower limit of quantification) or >x (ie, above the upper limit of quantification) 
will be imputed as “x” in the calculation of summary statistics but displayed as “<x” or “>x” in the 
listings.
For missing diagnostic dates, if day and/or month are missing use 01 and/or Jan. If year is missing, 
put the complete date to missing.
For missing or partial missing start dates for AEs and concomitant medications/procedures, the 
following will be applied:

Missing day - Impute the 1st of the month unless month and year are same as month and year of 
first dose of study drug then impute first dose date

Missing day and month – impute 1st January unless year is the same as first dose of study drug 
then impute first dose date.

Completely missing date – impute to first dose date unless the end date is less than the first dose 
date, in which case impute to 1st January of the same year as the end date. 
When imputing a start date ensure that the new imputed date is sensible e.g. is prior to the end date 
of the AE.
For missing or partial missing stop dates of AEs or concomitant medications/procedures, the 
following will be applied:

Missing day - Impute the last day of the month unless month is the same as month of the last dose 
of study drug then impute last dose date.

Missing day and month – impute 31st December unless year is the same as last dose date then 
impute last dose date.

Completely missing date - Impute the stop dates of AEs to the date of cut-off for the patients with 
AE still is on-going, when the date of cut-off applies to the analysis. Do not impute it for the all 
the other situation.
For missing first dosing time for exposure data, impute the first dosing time as 00:00. For missing 
last dosing time for exposure data, impute the last dosing time as 23:59. 
The imputation of dates will be used to decide if an observation is treatment emergent for adverse 
events or concomitant medications. The imputed dates are not used to calculate durations.


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It is not expected to have missing dates for unscheduled laboratory, ECG, diagnostics data. However, 
if there are missing dates, for any derivations, the dates should be imputed following the rules for 
concomitant medications and AEs
If a participant is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive +1 from the database and the 
death date using the available information provided:

For Missing day only – using the 1st of the month 

For Missing day and Month – using the 1st of January
If relevant for the study, the following will be included due to the COVID-19 pandemic: participants 
affected by the COVID-19 pandemic will be listed including category for study disruption due to the 
pandemic and details of the disruption. If required, the study disruptions due to the pandemic will 
also be summarised. Subject disposition will be summarised including number (%) of participants 
who discontinued treatment due to the pandemic and who withdrew from study due to the pandemic. 
Important protocol deviations will be summarised including number (%) of participants with at least 
one important protocol deviation related to the pandemic.
4.2
Analysis Methods
4.2.1
Disposition, Demography and Baseline Characteristics
4.2.1.1
Participant Disposition
A clear accounting of the disposition of all participants who enter the study will be provided, from 
screening to study completion.
The following participant disposition summaries will be produced:

The number and percentage of participants, enrolled participants (i.e. those providing 
informed consent), and who received adavosertib will be summarised for all participants.

Discontinuation from adavosertib and/or discontinuation from study, together with reason 
for discontinuation (including the reason due to COVID-19 pandemic) will be summarised 
using the FAS.
4.2.1.2
Analysis Sets
The following summaries will be provided:

A summary of the number and percentage of participants in each analysis set. Exclusions 
from each analysis population will also be summarized by reason.
By-participant listings of participants excluded from each analysis set will be provided.


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4.2.1.3
Protocol Deviations
Programmable PDs will be detected from the data recorded in the clinical database and will be 
reviewed at regular PD review meetings. At this meeting, the programmatically derived PDs will be 
checked to ensure that they have been correctly classified as important or not important PDs. 
On an ongoing basis throughout the study, monitoring notes or summaries will also be reviewed to 
determine any important post-entry deviations that are not identifiable via programming. 
The final classification of IPDs will be made prior to database lock (DBL) or data cut-off for primary
analysis. The number and percentage of participants with important protocol deviations in each 
deviation category, Number of subjects with at least 1 COVID-19 related important protocol 
deviation and Number of subjects with at least 1 important protocol deviation, excluding COVID-19 
related IPDs will be summarized.  Important protocol deviations will be listed. Any other relevant 
deviations from monitoring notes or reports will be reported in the CSR as required.
4.2.1.4
Demography and baseline characteristics
Demographic and other baseline characteristics will be listed for all participants and summarised for 
the FAS, as:

Demographics (age (years), age group [<50, ≥50-< 65, ≥65-<75, and ≥75 years], sex, race 
(if collected) and ethnicity)

Participant characteristics at baseline (height (cm), weight (kg), weight groups [<40, ≥40-< 
75, ≥75-<90, ≥90-<120, and  ≥120 kg], body mass index (BMI), and BMI groups 
[Underweight (<18.5), Normal weight (=18.5 - <25.0), Overweight (=25.0 - <30.0), Obese 
(≥30.0)]

A summary and a list of participants by country will be provided.
4.2.1.5
Disease diagnosis and staging
The number and percentage of participants with the corresponding categorical values in disease 
diagnosis and staging will be summarised for all participants in the FAS including:  

Primary Tumour Location

Histology Type

Primary Tumour

Regional Lymph Nodes

Distant Metastases  

Tumour Grade

International Federation of Gynecology and Obstetrics (FIGO) Stage
The extent of disease at entry of study will be summarised including:

Site of local/metastatic disease

Metastatic/Locally Advanced


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
ECOG performance status
4.2.1.6
Prior therapies
The following categorical summaries will be presented for all participants in the FAS:

The number and percentage of participants with prior therapy class will be summarised by 
category (e.g. immunotherapy, Hormonal, etc.).

Number of regimens

Treatment Status

Treatment Outcome

Oncology Response Assessment Result
4.2.1.7
Concomitant medications
Concomitant medications and procedures will be listed for all participants in the FAS.
World Health Organization (WHO) Drug Global Mar 2020, B3 will be used for coding medication 
terms.  
Partial dates will be handled as follows to determine whether a medication is treatment emergent:  
Missing day only (assume Day 1 of each respective month), missing day and month (assume 1st 
January unless year is the same as first dose date then impute first dose date),  completely missing  
(assume first dose date unless the end date suggests it could have started prior to this in which case 
impute the 1st January of the same year as the treatment start date). Imputed dates are not to be used 
to calculate durations.
Concomitant medications will be summarized (frequency and percentage of participants) by ATC 
dictionary text and generic term.  Each unique drug will be counted once per participant.  The 
summary will be ordered by decreasing total frequency of use. Disallowed concomitant medications
and all-allowed concomitant medications will be summarized in the same table with * to indicate the 
disallowed concomitant medications.
A by-participant listing of all medications will be provided.
4.2.1.8
Medical history
Medical history and relevant surgical history will be coded using MedDRA version 23.0 or later 
version.  The frequency and percentage of participants with each condition will be summarised by 
SOC and PT.  Participants with multiple unique terms will be counted once per each unique PT and 
unique SOC.  Each summary will be sorted alphabetically by SOC and PT.  
4.2.2
Tumour response and efficacy
Tumour assessments using computed tomography (CT)/magnetic resonance imaging (MRI) will be 
performed at the times specified in the schedule of assessment (Appendix A). These will be every 6 
weeks (±7 days) for the first 48 weeks, then every 9 weeks (±7 days) thereafter until radiological 
progression.  RECIST 1.1 measurements as assessed by the Investigator will be used to derive the 
primary variable of ORR, and secondary variables of PFS, PFS6 and DOR. The categorisation of 
objective tumour response assessment into complete response (CR), partial response (PR), stable


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disease (SD), progressive disease (PD) or not evaluable (NE) will be based on RECIST 1.1.
Summaries for the primary analysis will be based on the BICR.
All RECIST assessments, whether scheduled or unscheduled, and regardless of whether a participant
discontinues adavosertib treatment or receives another anti-cancer therapy will be included in the 
calculation of the efficacy variables.
All efficacy analyses will be performed separately in the FAS and CCAS.
4.2.2.1
Objective Response Rate and Best Objective Response
Summaries of ORR for the primary analysis will be based on BICR. ORR and its 90% and 95% CI 
(Clopper-Pearson) will be summarised. ORR per investigator review will be a sensitivity analysis.
ORR and number of participants with a confirmed response of CR or PR will be analysis at interim 
data cut off and primary data cut off. 
Best objective response (BoR) will be summarised by n (%) for each category (CR, PR, SD, PD and 
NE).  No formal statistical analyses are planned for BoR.
All summaries of ORR and BoR will be performed in the FAS and CCAS separately.
4.2.2.2
Duration of Response
If there are sufficient numbers of responders, and sufficient numbers of responders that have
progressed by the point of the analysis, Kaplan-Meier plots of DoR in the responding participants 
will be produced, and appropriate descriptive summary statistics will be presented (n, number of 
responses that have progressed or died, median, quartile, minimum and maximum DoR).
Summaries of DoR will be based on BICR; DoR per investigator review will be a sensitivity analysis.
Kaplan-Meier plots, summaries of DoR will be performed in the FAS and CCAS separately.
4.2.2.3
Depth of Response
Depth of response will be summarised using descriptive statistics. Waterfall plots showing the best 
percentage change from baseline in sum of the diameters of TLs will be produced. Spider plots
showing the percentage change from baseline in tumour size for each participant over time will be
produced.
Summaries of percentage change from baseline will be based on BICR.
Summaries and plots of depth of response will be performed in the FAS and CCAS separately. 
4.2.2.4
Progression-free Survival
Summaries of PFS (n, events, medians, quartiles, proportion progression free at 3, 6, 9 and 12 months 
and corresponding 95% CIs) and Kaplan-Meier plots will be provided.
Summaries of PFS will be based on BICR; PFS per investigator review will be a sensitivity analysis.
Summaries and plots of PFS will be performed in the FAS and CCAS separately.


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4.2.2.5
Progression-free survival at 6 months
The proportion of participants alive and progression free at 6 months (PFS6) will be defined as the 
Kaplan-Meier estimate of PFS (per RECIST v1.1) at 6 months.
Summaries of PFS6 will be based on BICR; PFS6 per investigator review will be a sensitivity
analysis.
4.2.2.6
Overall survival
Summaries of OS (n, events, medians, quartiles, proportion alive at 3, 6, 9 and 12 months and
corresponding 95% CIs) and a Kaplan-Meier plot will be provided.
Summaries and plots of OS will be performed in the FAS and CCAS separately.
4.2.2.7
Disease control rate
DCR and its 95% CI (Clopper-Pearson) will be summarised. Summaries of DCR will be based on 
BICR; DCR per investigator review will be a sensitivity analysis.
Summaries of DCR will be performed in the FAS and CCAS separately.
4.2.3
4.2.3.1
CCI
CCI
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4.2.3.2
4.2.3.3
4.2.4
Safety Analyses
Safety analyses will be performed using the FAS. Safety data will be presented using descriptive 
statistics unless otherwise specified.
4.2.4.1
Exposure
Exposure to adavosertib will be summarised in the following ways: 

Duration of adavosertib exposure (months) 

Total number of initiated cycles 

Cumulative actual dose of adavosertib (mg) 

Actual exposure to adavosertib (months) 

Relative dose intensity of adavosertib (%) 

Dose interruptions

Dose reductions

Dose discontinuations
Listings of treatment administration and treatment modifications will be provided.
4.2.4.2
Adverse Events/Serious Adverse Events
Adverse events will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA).
AEs will be presented by System Organ Class and/or Preferred Term covering number and percentage
of participants reporting at least one event and number of events where appropriate.
AEs occurring prior to start of adavosertib and treatment emergent AEs will be presented separately.
An overview of AEs will present the number and percentage of participants with any AE, AEs with 
outcome of death, serious AEs, and AEs leading to discontinuation of adavosertib, as well as AEs 
CCI
CCI
CCI
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leading to adavosertib dose interruptions, AEs leading to adavosertib dose reduction and AEs leading 
to withdrawal from study as well as the number of individual occurrences in those categories.
Separate AE tables will be provided taking into consideration relationship as assessed by the 
investigator, CTC grading, seriousness, death and events leading to discontinuation of adavosertib as 
well as other action taken related to adavosertib, and timing of events.
An additional table will present number and percentage of participants with most common AEs. Most
common (eg, frequency of >5%).
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of participants.
Key subject information will be presented for participants with AEs with outcome of death, serious 
AEs, and AEs leading to discontinuation of IP.
An AE listing for the safety analysis set will cover details for each individual AE.
Participants with multiple events in the same category are counted only once in that category.  
Participants with events in more than 1 category are counted once in each of those categories. Each 
participant is represented with the maximum reported intensity only for each preferred term. Each 
participant is represented by the maximum reported relationship for each preferred term.
Any AE occurring within the defined follow-up period after discontinuation of IP will be included in 
the AE summaries. Any AEs in this period that occur after a participant has received further therapy 
for cancer (following discontinuation of IP) will be flagged in the data listings. Adverse events 
occurring after the 30-day follow-up period after discontinuation of IP will be listed separately, but 
not included in the summaries.
4.2.4.3
Electrocardiographic (ECG) data
The listings with ECG overall qualitative conclusion per time point and the abnormal ECG findings 
will be provided. ECG measurements are taken during screening and as clinically indicated.
4.2.4.4
Vital signs assessment
Systolic and diastolic blood pressure, pulse rate, heart rate, weight and temperature will be collected 
at Screening and then on Day 1 and Day 8 of each treatment cycle. Measurements will be taken prior 
to dose administration. Height will only be collected at the screening visit and BMI will be calculated 
for each visit where weight is assessed. 
Summary statistics for continuous variables will include n, mean, SD, Min, Q1, median, Q3, and 
Max. Observed value, and change from baseline values for each visit-based parameter will be 
presented. 
The number (and percentage) of participants will be presented by laboratory status including change 
in abnormality (eg. Low, normal, high; abnormal-clinically significant, abnormal – clinically not 
significant) from baseline to:

Each scheduled time point


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
Maximum on-treatment value

Minimum on-treatment value

Maximum post-baseline value

Minimum post-baseline value
Frequency tables will present the number and percentage of subjects by abnormality status over time 
(by visit) and the number (and percentage) of subjects with at least one abnormal or clinically 
significant abnormality. 
Supportive vital signs listings will include observed values and change from baseline values, as well 
as abnormalities.
4.2.4.5
Laboratory data
All laboratory parameters will be summarized based on the FAS.
Assuming laboratory data on C1D1 were performed before first day administration of study therapy, 
the evaluations collected prior to (and including) C1D1 will be reported as baseline data. The 
evaluations collected after C1D1 will be reported as on-treatment. All laboratory tables will be 
restricted to the on-study measurements at protocol specified time points (no unscheduled visits). The 
laboratory listings will however include all measurements (whether on-treatment or not). If a visit 
falls outside the protocol specified timepoint, visit windowing as described in Section 3.1.1 will be 
used.
Laboratory parameters including clinical chemistry and haematology parameters will be presented. 
Summaries will include the observed value, change from baseline values over time.
Summary 
statistics for continuous variables include the number of participants included in summary, mean, SD, 
minimum, 1st quartile, median, 3rd quartile and maximum. The CTCAE grade including shift from
baseline to maximum post-baseline grade on treatment will be summarised.
The number (and percentage) of participants will be presented by laboratory status including change 
in abnormality (eg. Low, normal, high; abnormal-clinically significant, abnormal – clinically not 
significant) from baseline to:

Each scheduled time point, 

Maximum on-treatment value

Minimum on-treatment value

Maximum post-baseline value

Minimum post-baseline value.
The number (and percentage) of participants in abnormality status or clinically significant 
abnormalities in laboratory parameters over time will be provided.
The listings (haematology clinical chemistry and urinalysis separately), will include all the laboratory 
parameters as available in the data base (including laboratory tests codes as “Other”) with the 
corresponding relevant information. All laboratory data will be listed and values outside the normal 
ranges will be flagged.


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4.2.4.5.1 Hy’s Law  
Participants with potential Hy’s Law will be listed, it includes all participants who have ALT or AST
≥3 time of upper limit of normal (ULN) together with total bilirubin (TBL) ≥2 time of ULN at any 
point during the study following the start of study medication irrespective of an increase in Alkaline 
Phosphatase (ALP). In this table the value of individual ALT, AST and total bilirubin at each visit 
together with the upper limit of normal will be displayed.
4.2.4.6
Physical Examination
New or aggravated findings, as compared with baseline, on the physical examinations are to be 
reported as AEs.
4.2.4.7
ECOG Performance Status
Summaries of ECOG PS data will include all data obtained up until 30 days after the last dose of 
adavosertib.
A shift table will be produced comparing baseline value to maximum ECOG PS on-treatment value. 
The outputs will be presented based on the FAS.
4.2.5
Pharmacokinetic data
Blood samples for assessment of AZD1775 pharmacokinetics will be collected pre-dose and 2-hours 
post-dose on Day 5 for Cycle 1 and Cycle 2 only. 
The derived PK parameters Cmax and Ctrough will be summarised by cycle, day and time point as 
appropriate.  Concentrations and derived PK parameters will be summarised using descriptive 
statistics (geometric mean, geometric coefficient of variation, arithmetic mean, SD, minimum, 
maximum, number of samples/participants).
Concentrations below the lower limit of quantitation (BLQ) will be reported in the following way:

Individual BLQ concentrations will be reported as NQ (not quantifiable). 

For summary data:

If, at a given time point, 50% or less of the concentrations are not quantifiable (NQ), the 
geomean, coefficient of variation (CV), geoSD, arithmetic mean and standard deviation 
(SD) will be calculated by substituting the lower limit of quantification (LLOQ) for values 
which are NQ.

If more than 50%, but not all, of the concentrations are NQ, the geomean, CV, arithmetic 
mean and SD will be reported as not calculable (NC). The maximum value will be reported 
from the individual data, and the minimum and median will be set as NQ.

If all the concentrations are NQ, the geomean and arithmetic mean will be reported as NQ 
and the CV and SD as NC.


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
The number of values below LLOQ will be reported for each time point along with the 
total number of collected values.
Three values >LLOQ will be required as a minimum for a concentration or PK parameter to be 
summarised.  Two values will be presented as a minimum and maximum with the other summary 
statistics as NC. The lower limit of quantitation will be reported in the CSR and in PK tables, figures 
and listings.
4.2.6
Subgroup Analyses
Subgroup analysis will be performed in the subgroup of participants who have previously been 
exposed to PD-1/PD-L1 inhibitors. Subgroup analysis will perform for interim analysis and primary 
analysis.. For subgroup analysis, it will present as one separate column along with the overall 
participants in the tables.
The subgroup results will be provided for following where they are applicable: 
Patient disposition
Demography and baseline characteristics
Prior and post anti-cancer treatment
Exposure, including dose modifications (interruption, reduction, discontinuation)
Adverse Events
Laboratory measurements
Vital Signs/ECG/Physical examination, ECOG
Concomitant medications
Objective Response Rate
Duration of Response
Depth of Response
PFS
PFS6
OS
DCR
5
SAFETY REVIEW COMMITTEE
A Safety Review Committee will be formed to review safety data during the study conduct. SRC will 
include approximately 3 key study investigators, and AstraZeneca study personnel. All clinical data, 
including safety, tolerability, dose modifications, and available PK data will be reviewed periodically 
at an appropriate time interval (e.g. 8 weeks). When at least 6 participants have either received ≥2 
cycles of study treatment or have discontinued study treatment due to unacceptable toxicity, the 


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Safety Review Committee will convene. SRC will be empowered to make recommendations 
including the option to modify dosing regimen or stop the study.
Full details of SRC procedures and processes are provided in the SRC Charter.
6
INDEPENDENT DATA MONITORING COMMITTEE
The Independent Data Monitoring Committee (IDMC) will meet for the planned interim analysis 
when approximately 30 participants in the CCAS have had the opportunity to be treated for at least 4 
months, to provide a recommendation based on efficacy observed. 
The IDMC will review safety data and will make recommendations to continue, amend, or stop the 
study based on findings.  Serious AEs, AEs, and other safety data will be reviewed, and individual 
and aggregated safety data will be evaluated by the IDMC. 
Full details of the IDMC procedure and processes can be found in the IDMC Charter.
7
INTERIM ANALYSIS
An interim analysis is planned after approximately 30 participants in the CCAS have had the 
opportunity to be treated for at least 4 months. Recruitment will not be paused whilst the participants 
required for the interim analysis are evaluated. It may be considered futile to continue recruitment 
into the study if there is 
 probability for the ORR to be greater than 
This translates into observing  or fewer responders out of 30 participants; an ORR of 
 which 
has a 2-sided exact binomial 80% CI of 
 to 
 wherein the upper confidence limit is below 
The analysis will be performed on participants who had the opportunity to be treated for at least 4 
months. A sensitivity analysis will be performed on all participants who had the opportunity to be 
treated for at least 4 months, and those with a best overall response of CR, PR, and progressive disease. 
8
CHANGES OF ANALYSIS FROM PROTOCOL
Not applicable for this study.
9
REFERENCES
[1] McMeekin DS, Filiaci VL, Thigpen JT, Gallion HH, Fleming GF, Rodgers WH. The relationship 
between histology and outcome in advanced and recurrent endometrial cancer patients participating 
in first-line chemotherapy trials: a Gynecologic Oncology Group study. Gynecol Oncol 2007;106:16–
22.
[2] Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
[3] Greimel E, Nordin A, Lanceley A, Creutzberg CL, van de Poll-Franse LV, Radisic VB, et al. 
Quality of Life Group. Psychometric validation of the European Organisation for Research and 
CCI
CCI
C
C
I
CCI
CCI
CCI
CCI


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Treatment of Cancer Quality of Life Questionnaire-Endometrial Cancer Module (EORTC QLQ-
EN24). Eur J Cancer 2011;47:183-90.


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10 APPENDIX
10.1 Appendix A: Schedule of Assessments
Table 7 Schedule of Assessments for Screening and Treatment Period
Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Informed 
consent
X
Section 5.1 & 
Appendix C


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Inclusion/exclusi
on criteria
X
Recheck 
inclusion 
and 
exclusion 
criteria 
prior to 
first dose
Sections 5.1 & 5.2
Routine clinical procedures
Demography
X
Sections 5.1 & 5.2
CCI


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Medical/surgical 
history
X
Sections 5.1 & 5.2
Previous cancer 
therapy
X
Section 5.2
Concomitant 
medication
X
At every study visit
Section 6.5
ECOG 
performance 
status
X
X
X
X
X
Appendix B
Physical 
examination
X
X
X
X
X
Section 8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
Section 8.2.2
Height
X
Section 8.2.1


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Weight
X
X
X
X
X
Section 8.2.1
12-lead ECG
X
As clinically indicated
Section 8.2.3
General 
assessment 
through phone 
call
X
Day 3 
phone call 
for AE 
assessment
Section 8.3.13.3
Routine safety measurements
Adverse events
X
At every study visit
Section 8.3 & 
Appendix E
Pregnancy test 
(if applicable)
X
X
X
X
Section 8.2.4


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Haematology
X
X
X
X
X
X
X
X
X
C1/2 D5 
safety labs 
visit 
window ±1 
days
Section 8.2.4
Clinical 
chemistry
X
X
X
X
X
X
X
X
X
C1/2 D5 
safety labs 
visit 
window ±1 
days
Section 8.2.4
Coagulation
X
As clinically indicated
Section 8.2.4
Urinalysis
X
As clinically indicated
Section 8.2.4


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
FFPE tumour 
sample
X
Section 8.6.1
CCI
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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
CCI


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
CCI


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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Pharmacokinetic measurements
PK plasma 
samples
Pre-
dose 
and
2h 
post
-
dose
Section 8.5.1
Imaging and other assessments
RECIST v1.1 
tumour 
assessments (CT 
and/or MRI)
X
Every 6 weeks (±7 days) for the first 48 weeks and then every 9 weeks (±7 days) thereafter, 
from Day 1 to radiological progression by investigator assessment using RECIST v1.1.  
Participants who discontinue treatment prior to progression should continue to be scanned until 
progression.
Section 8.1.1 & 
Appendix A


Parexel International
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D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
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Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Subsequent 
cancer therapy 
following 
discontinuation 
of study 
intervention
X
X
Section 8.1.2.1
Survival status
X
Section 8.1.2
CCI


Parexel International
AstraZeneca
D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
Page 65 of 69
Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
CCI


Parexel International
AstraZeneca
D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
Page 66 of 69
Screen
Cycle 1 and 2
Cycle 3+
Discontinuation Progression 
Post-
treatment 
follow-up
Survival 
follow-up
Notes
Details in CSP 
section or 
appendix
Timing
-28 to -1 Day 
1
Day 
3
Day 
5
Day 
8
      
Day 
15
Day 1
Day 8
If the reason for 
discontinuation is disease 
progression, then only the 
discontinuation visit is 
required
30 days 
after last 
dose
Every 12 
weeks
Visit window 
(days)
0
0
±1
-1
+2
±1
+3
+2
+7
+7
±7
±14
C1/2 D5 
safety labs 
visit 
window 
±1 days
Adavosertib dispensing and administration
Adavosertib 
dispensing
X
X
Section 6.1.1
Adavosertib 
administration
Dosing on Days 1 to 5 and Days 8 to 12 of 
21-day cycle
A 
minimum 
of 9 days 
between 
the last 
dosing of a 
cycle and 
Day 1 of 
the next 
cycle is 
required.
Section 6.1.1


Parexel International
AstraZeneca
D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
Page 67 of 69
AE, adverse event; 
 CT, computed tomography; 
 
ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; 
 
MRI, magnetic resonance imaging; 
 ORR, objective response rate; OS, overall survival; 
PK, pharmacokinetics; 
 RECIST v1.1, Response 
Evaluation Criteria in Solid Tumors; 
 
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Parexel International
AstraZeneca
D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
Page 68 of 69
10.2 Appendix B: Study design and flow chart
Figure 1 Study Design
BICR, Blinded Independent Central Review; CT, computed tomography; DCO, data cut-off; ECOG, Eastern Cooperative Oncology Group; FFPE, formalin-fixed paraffin-embedded; 
HER2, Human epidermal growth factor receptor 2; LPFD, last participant first dose; mo, months; MRI, magnetic resonance imaging; ORR, objective response rate; USC, uterine 
serous carcinoma; VEGF, vascular endothelial growth factor.


Parexel International
AstraZeneca
D601HC00002
Statistical Analysis Plan
TP-GDO-WW-016-08
CONFIDENTIAL
Project Document Version No. 2.0
Effective Date:  26 Nov 19
Project Document Effective Date: 10 Sep. 21
Related to:  SOP-GDO-WW-019
Page 69 of 69
Figure 2 Study Flow Chart
QD, once daily; 
 RECIST v1.1, Response Evaluation Criteria in Solid Tumours.
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Statistical Analysis Plan Edition 2
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