Clinical trial NCT04456699
Conditions: Metastatic Colorectal Cancer
Keywords: colorectal cancer CRC Olaparib Bevacizumab FOLFOX 5-FU fluorouracil folinic acid oxaliplatin CAPOX capecitabine
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-08-19; Completion date: 2023-11-06
Enrollment: 335 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an efficacy and safety study of olaparib alone or in combination with bevacizumab being compared to bevacizumab with a fluoropyrimidine in participants with unresectable or metastatic colorectal cancer who have not progressed following first-line induction. The primary hypotheses are: Olaparib + Bevacizumab is superior to a fluoropyrimidine + Bevacizumab with respect to progression-free survival (PFS) using Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1) as assessed by blinded independent central review (BICR); Olaparib is superior to a fluoropyrimidine + Bevacizumab with respect to PFS using RECIST 1.1 as assessed by BICR. As of amendment 5 study enrollment is being discontinued and study participants randomized to one of the two experimental arms (olaparib plus bevacizumab or olaparib monotherapy) must discontinue study intervention. Participants who are still on study treatment will no longer have tumor response assessments by BICR.

Detailed description:

Arms: arm 1: Participants will receive olaparib (300 mg twice daily \[BID\] oral) + Bevacizumab (5 mg/kg intravenous \[IV\] once every 2 weeks \[Q2W\]) until progressive disease or end of study. arm 2: Participants will receive olaparib (300 mg BID) oral, until progressive disease or end of study. arm 3: Participants will receive investigator's choice of either bevacizumab (7.5 mg/kg IV once every three weeks (Q3W)) + capecitabine (1000 mg/m\^2 BID for 14 days, then 7 days off, Q3W) or bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours Q2W; bolus 5-FU (400 mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator's discretion). Leucovorin or levoleucovorin 400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) Q2W IV infusion may be added per investigator's discretion. Treatment will continue until progressive disease or end of study.
Interventions: intervention 1: Olaparib intervention 2: 5-FU intervention 3: Bevacizumab intervention 4: Capecitabine intervention 5: Leucovorin/ levoleucovorin
Intervention descriptions: intervention 1: 300 mg BID, oral until progressive disease or end of study intervention 2: 2400 mg/m\^2 over 46 to 48 hours Q2W IV infusion until disease progression or end of study; bolus 5-FU (400mg/m2) can be added prior to infusional 5-FU, per local standards and at the investigator's discretion intervention 3: 5 mg/kg or 7.5 mg/kg Q2W or Q3W IV infusion until progressive disease or end of study intervention 4: 1000 mg/m\^2 oral capsule BID for 14 days, then 7 days off, Q3W) until progressive disease or end of study intervention 5: 400 mg/m\^2 (leucovorin) or 200 mg/m\^2 (levoleucovorin) may be added to Bevacizumab + 5-FU per investigator's discretion Q2W IV infusion until progressive disease or end of study

Protocol documents:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy 
and Safety of Olaparib Alone or in Combination With Bevacizumab 
Compared to Bevacizumab with a Fluoropyrimidine in Participants 
with Unresectable or Metastatic Colorectal Cancer who Have Not 
Progressed Following First-line Induction (LYNK-003)
NCT04456699
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TitlePage
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and 
Safety of Olaparib Alone or in Combination With Bevacizumab Compared to Bevacizumab 
with a Fluoropyrimidine in Participants with Unresectable or Metastatic Colorectal Cancer 
who Have Not Progressed Following First-line Induction (LYNK-003)
Protocol Number: 003-05
Compound Number: MK-7339
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
141,560
EudraCT
2019-000698-22
Approval Date: 08 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 05
08-SEP-2022
Protocol is amended consistent with recommendations of the eDMC after an interim 
review of the data; specifically, to discontinue the study enrollment due to futility. 
Study participants randomized to one of the two experimental arms (olaparib plus 
bevacizumab [Arm 1] or olaparib monotherapy [Arm 2]) must discontinue the 
therapy. No crossover from either experimental arm to Standard of Care (SOC) arm 
(Arm 3A and Arm 3B) within the study is allowed. Participants on SOC have the 
option to continue receiving study intervention until criteria for discontinuation are 
met.
Amendment 04
29-NOV-2021
Update 5-FU information in Schedule of Activities table
Amendment 03
14-OCT-2021
Addition of CAPOX as allowed induction therapy; require BICR confirmation of 
non-PD prior to randomization; allow use of leucovorin
Amendment 02
13-APR-2020
Response to agency request for protocol changes
Amendment 01
28-AUG-2019
Response to agency request for protocol changes
Original Protocol
05-JUL-2019
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendments:
Protocol is amended consistent with recommendations of the eDMC after an interim review of the data; specifically, to discontinue the 
study enrollment due to futility. Study participants randomized to one of the two experimental arms (olaparib plus bevacizumab 
[Arm1] or olaparib monotherapy [Arm 2]) must discontinue the therapy. No crossover from either experimental arm to SOC arm (Arm 
3A and Arm 3B) within the study is allowed. Participants on SOC have the option to continue receiving study intervention until 
criteria for discontinuation are met.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
5 Study Population
6.1 Study 
Intervention(s) 
Administered
9.1 Statistical Analysis 
Plan Summary
Added statement:
“As of Amendment 05, study enrollment is being stopped for 
futility. Study participants randomized to one of the two 
experimental arms (olaparib plus bevacizumab [Arm 1] or olaparib 
monotherapy [Arm2]) must discontinue study intervention. No 
crossover from either experimental arm to SOC arm (Arm 3A and 
Arm 3B) within the study is allowed. Participants on SOC have the 
option to continue receiving study intervention until criteria for 
discontinuation is met at the discretion of the investigator.”
To clarify that participants 
randomized to one of the two 
experimental arms (olaparib plus 
bevacizumab [Arm 1] or olaparib 
monotherapy [Arm2]) must 
discontinue and participants on 
SOC may continue to receive 
treatment 
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Section # and Name
Description of Change 
Brief Rationale 
2.3 Benefit/Risk 
Assessment
4.1 Overall Design
Added statement that as of Amendment 05, the study enrollment is 
being stopped due to futility.
The prespecified analyses (IA 2, 3, 4 and FA) described in the SAP 
will not be performed.
In Section 2.3, added that selected analyses of safety endpoints will 
be performed at the end of the study.
To inform of the decision to stop 
this clinical study
1.1 Synopsis -
Hypotheses, Objectives, 
and Endpoints
3 Hypotheses, 
Objectives, and 
Endpoints
The following statement was added:
“NOTE: As of Amendment 05, participants who are still on study 
treatment will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue as per
local institutional guidelines. In addition, PRO assessments will no 
longer be performed. Blood for RNA analysis and serum and plasma 
biomarker analysis will no longer be collected. Updated analyses are 
described in Section 9. Post-treatment follow-up visits are no longer 
required except for safety and efficacy follow-up requirements (refer 
to Sec 8.11.4). The section below is retained for reference.”
As the result of the efficacy IA 
indicated futility, further tumor 
scans and response assessments by 
BICR, and PRO assessments, and 
collection of blood for RNA 
analysis and serum and plasma 
biomarker analysis are considered 
unnecessary.
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities (SoA)
In Sections 1.3.1, 1.3.2, and 1.3.3, added Statement:
“NOTE: As of Amendment 05, participants who are still on study 
treatment will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue as per
local institutional guidelines. In addition, PRO assessments (EORTC 
QLQ-C30, EORTC QLQ-CR29, EQ-5D-5L) will no longer be 
performed. Blood for RNA analysis and serum and plasma biomarker 
analysis will no longer be collected. Updated analyses are described in 
Section 9. Post-treatment follow-up visits are no longer required 
except for safety and efficacy follow-up requirements (refer to Section
8.11.4). The section below is retained for reference.”
As of Amendment 05, these 
assessments and sample 
collections are considered 
unnecessary.
Title page
10.1.1 Code of Conduct 
for Clinical Trials
Throughout
Sponsor entity name and address change
Merck Sharp & Dohme Corp. 
underwent an entity name and 
address change to Merck Sharp & 
Dohme LLC, Rahway, NJ, USA. 
This conversion resulted only in 
an entity name change and update 
to the address.
5.1 Inclusion Criteria
For Criterion #10, updated the time needed for male participants to 
continue contraception after the last dose of each individual study 
intervention.
For Criterion #11, updated the time needed for female participants 
to continue contraception after the last dose of each individual 
study intervention, and clarified that the contraceptive methods 
should be consistent with local regulations.
To correct the time required for 
contraception after the last dose of 
each study intervention for males 
and females
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Section # and Name
Description of Change 
Brief Rationale 
7.1 Discontinuation of 
Study Intervention
Under the bullet “Documented radiographic disease progression 
outlined in Section 8.2.1”, added a note to clarify the criteria for 
participants remaining on SOC to discontinue
To clarify the criteria for 
participants on SOC arm to 
discontinue from study 
intervention after Amendment 05
8.2.1 Tumor Imaging 
and Assessment of 
Disease
Added text:
“As of Amendment 05, central tumor response assessments will be 
discontinued. Imaging scans will no longer be submitted to iCRO 
nor read by BICR. The subsections below are retained for 
reference.
However, for participants who are still receiving and will continue
receiving SOC treatment until criteria for discontinuation are met, 
local tumor imaging should continue per local institutional 
guidelines.”
To clarify that as of Amendment 
05, further efficacy assessments 
are considered unnecessary. 
Participants who are still receiving 
SOC at the time of this 
amendment will continue with 
local tumor imaging as per local 
institutional guidelines.
8.4.1 Time Period and 
Frequency for 
Collecting AE, SAE, 
and Other Reportable 
Safety Event 
Information
In bullet “All AEs meeting serious criteria”, changed the time 
period required for SAE reporting from 90 to 30 days after the last 
dose of study intervention
To be consistent with Section 4.1
where the time period required for 
AE and SAE reporting is 30 days
8.6 Pharmacokinetics
Added statements that as of Amendment 05, sample collection for 
PK has been completed and is no longer applicable
To update that this analysis is 
complete
8.8 Biomarkers
Added statements that as of Amendment 05, sample collections for 
biomarkers (blood for RNA analysis, serum and plasma biomarker 
analysis) will be discontinued.
As of Amendment 05, collection 
of these samples is considered 
unnecessary.
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Section # and Name
Description of Change 
Brief Rationale 
8.9 Future Biomedical 
Research Sample 
Collection
Clarified the types of specimens that will be obtained for future 
biomedical research
To be consistent with Section 8.8
8.10 Medical Resource 
Utilization and Health 
Economics
Added statement:
“As of Amendment 05: medical resource utilization and health 
economics data collection will be discontinued. The section below 
is retained for reference.”
As of Amendment 05, assessment 
of these data is considered 
unnecessary.
8.10 Medical Resource 
Utilization and Health 
Economics
Changed the time period required for all-cause hospitalization and 
emergency room visits be reported in the eCRF (90 days to 30 
days).
For correction
8.11.4.1 Safety Follow-
up Visit
Added a statement to clarify that once the safety follow-up is 
completed, all participants will be discontinued from the study.
To clarify the requirement for 
safety follow-up 
8.11.4.2 Follow-up 
Visits
8.11.4.3 PFS2 Follow-
up
Added statement that as of Amendment 05, efficacy follow-up 
visits and PFS2 follow-up visits will be discontinued for all 
participants, and all participants will move into survival follow-up 
phase.
As of Amendment 05, these 
assessments are considered 
unnecessary.
8.11.4.4 Survival 
Follow-up
Added statement to clarify the time period for survival follow-up 
visits.
To clarify the periods for survival 
follow-up visits for all participants 
and for participants on SOC.
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Section # and Name
Description of Change 
Brief Rationale 
9 Statistical Analysis 
Plan
9.1 Statistical Analysis 
Plan Summary
9.6 Statistical Methods
9.7 Interim Analyses
9.7.2 Safety Interim 
Analyses
9.8 Multiplicity
9.9 Sample Size and 
Power Calculations
In Sections 9 and 9.1, updated text with the status of data 
unblinding.
In Section 9.1, a note was added describing the results of the safety 
and efficacy IA1 that led to the decision to stop the study 
enrollment due to futility.
In Sections 9.1, and 9.6, added statement:
“Selected analyses of safety endpoints will be performed at the end 
of the study; there will be no further analyses of efficacy and PRO 
endpoints.”
In Sections 9.1, 9.6, 9.7, 9.8, and 9.9, a statement was added that 
the prespecified interim analyses 2, 3, 4, and final analysis of the 
study described in the SAP will not be performed.
In Section 9.7.2, a note was added to indicate that no further 
analysis to the eDMC is warranted as of Amendment 05.
To describe the results of the IA1 
and to specify which analyses will 
be conducted as of Amendment 05
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Section # and Name
Description of Change 
Brief Rationale 
4.4 Beginning and End-
of-Study Definition
5 Study Population
6.1 Study 
Intervention(s)
Administered
8.4 Adverse Events, 
Serious Adverse Events, 
and Other Reportable 
Safety Events
10.3 Appendix 3: 
Adverse Events: 
Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting
In Section 4.4, clarified when the overall study ends for analysis 
and reporting, and the local start of the study in the EEA
In Section 5, second paragraph, added additional text to clarify the 
collection and use of demographic data provided by the participants
In Section 6.1, Table 2 Study Interventions, in the “Use” column, 
changed “Experimental” to “Test Product”; changed the column 
heading from “IMP/NIMP” to “IMP or NIMP/AxMP”
In Section 6.1 Table 2, added abbreviations EEA, IMP, 
NIMP/AxMP, and added clarifications that the classification of 
IMP and NIMP/AxMP in this table is based on guidance issued by 
the European Commission and applies to countries in the EEA
In Section 8.4, added that investigators need to document when an 
SAE is associated with a medication error, misuse, or abuse
Added Section 10.3.1 Definitions of Medication Error, Misuse, and 
abuse
To align with EU CTR
1.1 Synopsis
In the Table Intervention Groups and Duration, in the “Use” 
column, changed “Experimental” to “Test Product”
To be consistent with Section 6.1 
Table 2
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study 
Intervention(s) 
Administered
Added reference to Appendix 7 country-specific differences
To align with PMDA regulation
6.1 Study 
Intervention(s) 
Administered
In Table 2, changed the dose formulation for capecitabine from 
capsule to tablet
To correct a typographical error
8.3.5 Pregnancy test
To clarify the requirements for pregnancy testing 
To clarify the timeline 
requirements for pregnancy testing
and be consistent with Section 5.1 
Inclusion Criterion #11.
8.8.1 Planned Genetic 
Analysis Sample 
Collection
Stated the time point and acceptable window for collection of 
planned genetic analysis samples
For clarification of genetic 
analysis sample collection
10.2 Appendix 2 
Clinical Laboratory 
Tests
In Table 16, added a reference to the footnote next to Reticulocytes 
to clarify that test is only performed if it is considered as local SOC
To comply with local regulation
10.7 Country-specific 
Requirements
Deleted 10.7.2 Argentina
For correction, given that the study 
was not conducted in Argentina
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Section # and Name
Description of Change 
Brief Rationale 
10.7 Country-specific 
Requirements
10.7.1 France
For Section 1.3 Schedule of Activities, clarified when pregnancy 
testing must be performed 
For Section 5.2 Exclusion Criteria, added additional exclusion 
criteria related to dihydropyrimidine dehydrogenase deficient 
participants and brivudine administration
Added 10.7.2 Japan
For Section 6.1 Study Intervention(s) Administered, clarified the 
classification of study intervention (bevacizumab) in Japan
Added 10.7.4 Germany
For Section 1.3 Schedule of Activities, added requirements for 
dihydropyrimidine dehydrogenase deficiency testing at screening
For Section 5.2 Exclusion Criteria, added additional exclusion 
criteria related to dihydropyrimidine dehydrogenase deficient 
participants and brivudine administration
For Section 6.5.3 Rescue Medications and Supportive Care, 
clarified the requirements for live vaccines administration
Clarified that all references to a participant’s “legally acceptable 
representative” in the protocol are not applicable for participants in 
Germany
To update based on local health 
authority feedbacks for similar 
studies
Throughout Document
Minor administrative, formatting, grammatical, and typographical 
changes were made throughout the document
To ensure clarity and accurate 
interpretation of the intent of the 
protocol
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................22
1.1
Synopsis.................................................................................................................22
1.2
Schema ..................................................................................................................26
1.3
Schedule of Activities (SoA)................................................................................27
1.3.1
Arm 1 (Olaparib + Bevacizumab) & Arm 3a (Bevacizumab + 5-FU) ........27
1.3.2
Arm 2 Olaparib Monotherapy......................................................................37
1.3.3
Arm 3b Bevacizumab + Capecitabine .........................................................46
2
INTRODUCTION..........................................................................................................54
2.1
Study Rationale....................................................................................................54
2.2
Background ..........................................................................................................56
2.2.1
Olaparib........................................................................................................56
2.2.2
Pharmaceutical and Therapeutic Background .............................................57
2.2.2.1
Inhibition of PARP as a Target for Cancer........................................57
2.2.2.2
PARP Inhibition in Platinum-sensitive Cancers................................57
2.2.2.2.1
Rationale for PARP Inhibition in CRC....................................58
2.2.2.2.2
Rationale for Combining Olaparib and Bevacizumab in 
CRC..........................................................................................59
2.2.3
Preclinical and Clinical Studies ...................................................................59
2.2.4
Ongoing Clinical Studies.............................................................................61
2.3
Benefit/Risk Assessment......................................................................................62
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................62
4
STUDY DESIGN............................................................................................................65
4.1
Overall Design......................................................................................................65
4.2
Scientific Rationale for Study Design.................................................................68
4.2.1
Rationale for Endpoints ...............................................................................68
4.2.1.1
Efficacy Endpoints.............................................................................68
4.2.1.1.1
RECIST 1.1..............................................................................69
4.2.1.2
Safety Endpoints................................................................................69
4.2.1.3
Patient-reported Outcomes.................................................................69
4.2.1.3.1
EORTC QLQ-C30 ...................................................................69
4.2.1.3.2
EORTC QLQ-CR29.................................................................70
4.2.1.3.3
EQ-5D-5L ................................................................................70
4.2.1.4
Pharmacokinetic Endpoints ...............................................................70
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4.2.1.5
Planned Exploratory Biomarker Research.........................................70
4.2.1.6
Future Biomedical Research..............................................................72
4.2.2
Rationale for the Use of Comparator...........................................................72
4.3
Justification for Dose...........................................................................................72
4.3.1
Rationale for Olaparib Dosing.....................................................................72
4.3.2
Rationale for 5-FU Dosing Regimen...........................................................72
4.3.3
Rationale for Capecitabine Dosing Regimen...............................................73
4.3.4
Rationale for Bevacizumab Dosing Regimen..............................................73
4.3.4.1
Rationale for Combination Dosing Regimen of Olaparib + 
Bevacizumab......................................................................................73
4.4
Beginning and End of Study Definition .............................................................73
4.4.1
Clinical Criteria for Early Study Termination .............................................73
5
STUDY POPULATION ................................................................................................74
5.1
Inclusion Criteria.................................................................................................74
5.2
Exclusion Criteria................................................................................................79
5.3
Lifestyle Considerations......................................................................................82
5.3.1
Meals and Dietary Restrictions....................................................................82
5.3.2
Driving or Operating Machinery .................................................................82
5.3.3
Pregnancy.....................................................................................................82
5.4
Screen Failures.....................................................................................................83
5.5
Participant Replacement Strategy......................................................................83
6
STUDY INTERVENTION............................................................................................83
6.1
Study Intervention(s) Administered...................................................................83
6.2
Preparation/Handling/Storage/Accountability .................................................86
6.2.1
Dose Preparation..........................................................................................86
6.2.2
Handling, Storage, and Accountability........................................................86
6.3
Measures to Minimize Bias: Randomization and Blinding..............................87
6.3.1
Intervention Assignment..............................................................................87
6.3.2
Stratification.................................................................................................87
6.3.3
Blinding........................................................................................................87
6.4
Study Intervention Compliance..........................................................................87
6.5
Concomitant Therapy..........................................................................................88
6.5.1
Leucovorin/Levoleucovorin.........................................................................88
6.5.2
Prohibited Concomitant Medications ..........................................................88
6.5.3
Rescue Medications and Supportive Care ...................................................90
6.6
Dose Modification Guidelines.............................................................................90
6.6.1
Olaparib Dosing Modifications....................................................................90
6.6.1.1
Management of Hematological Toxicities.........................................91
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6.6.1.2
Management of Prolonged Hematological Toxicities .......................92
6.6.1.3
Management of Non-hematologic Toxicity.......................................93
6.6.1.3.1
Management of New or Worsening Pulmonary Symptoms ....93
6.6.1.3.2
Management of Nausea and Vomiting ....................................93
6.6.1.3.3
Management of Renal Impairment ..........................................94
6.6.1.3.4
Dose Reductions for Concurrent CYP3A4 Inhibitor Use........94
6.6.1.4
Interruptions for Non-toxicity Related Events...................................95
6.6.2
Bevacizumab, Capecitabine, Leucovorin, and 5-FU Dose Modifications...95
6.7
Intervention After the End of the Study............................................................95
6.8
Clinical Supplies Disclosure................................................................................95
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................95
7.1
Discontinuation of Study Intervention...............................................................95
7.2
Participant Withdrawal From the Study...........................................................96
7.3
Lost to Follow-up .................................................................................................97
8
STUDY ASSESSMENTS AND PROCEDURES........................................................97
8.1
Administrative and General Procedures ...........................................................98
8.1.1
Informed Consent.........................................................................................98
8.1.1.1
General Informed Consent.................................................................98
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................99
8.1.2
Inclusion/Exclusion Criteria ........................................................................99
8.1.3
Participant Identification Card.....................................................................99
8.1.4
Demographics and Medical History ............................................................99
8.1.5
Prior and Concomitant Medications Review...............................................99
8.1.5.1
Prior Medications...............................................................................99
8.1.5.2
Induction History .............................................................................100
8.1.5.3
Concomitant Medications................................................................100
8.1.6
Submitting Prior Radiographic Images......................................................100
8.1.7
Assignment of Screening Number.............................................................100
8.1.8
Assignment of Treatment/Randomization Number...................................100
8.1.9
Study Intervention Administration ............................................................101
8.1.9.1
Timing of Dose Administration.......................................................101
8.1.9.1.1
Olaparib..................................................................................101
8.1.9.1.2
Bevacizumab and 5-FU..........................................................101
8.1.9.1.3
Capecitabine...........................................................................102
8.1.10
Discontinuation and Withdrawal ...............................................................102
8.1.10.1
Withdrawal From Future Biomedical Research ..............................102
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08-SEP-2022
8.1.11
Participant Blinding/Unblinding................................................................102
8.1.12
Calibration of Equipment...........................................................................102
8.2
Efficacy Assessments .........................................................................................103
8.2.1
Tumor Imaging and Assessment of Disease..............................................103
8.2.1.1
Tumor Imaging During Screening...................................................103
8.2.1.2
Tumor Imaging During the Study....................................................104
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging ...........................104
8.3
Safety Assessments.............................................................................................105
8.3.1
Physical Examinations...............................................................................105
8.3.2
Vital Signs..................................................................................................105
8.3.3
Electrocardiograms ....................................................................................105
8.3.4
Clinical Safety Laboratory Assessments ...................................................106
8.3.4.1
Bone Marrow or Blood Cytogenetic Samples .................................106
8.3.5
Pregnancy Test...........................................................................................106
8.3.6
ECOG Performance Scale..........................................................................107
8.3.7
Safety Considerations With Capecitabine and 5-FU .................................107
8.3.7.1
Photosensitivity................................................................................107
8.3.7.2
Ophthalmologic Complications Due to Capecitabine......................107
8.3.7.3
Severe Skin Reactions Due to Capecitabine....................................107
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................108
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................108
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....111
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.111
8.4.4
Regulatory Reporting Requirements for SAE ...........................................111
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................111
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................112
8.4.7
Events of Clinical Interest (ECIs)..............................................................112
8.5
Treatment of Overdose......................................................................................112
8.6
Pharmacokinetics...............................................................................................113
8.7
Pharmacodynamics............................................................................................113
8.8
Biomarkers .........................................................................................................113
8.8.1
Planned Genetic Analysis Sample Collection............................................114
8.9
Future Biomedical Research Sample Collection.............................................114
8.10
Medical Resource Utilization and Health Economics.....................................114
8.11
Visit Requirements.............................................................................................114
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8.11.1
Screening....................................................................................................115
8.11.2
Treatment Period........................................................................................115
8.11.3
Discontinuation Visit .................................................................................115
8.11.4
Post-treatment Visits..................................................................................115
8.11.4.1
Safety Follow-up Visit.....................................................................115
8.11.4.2
Follow-up Visits...............................................................................116
8.11.4.3
PFS2 Follow-up ...............................................................................116
8.11.4.4
Survival Follow-up ..........................................................................116
8.11.5
Survival Status ...........................................................................................117
9
STATISTICAL ANALYSIS PLAN ...........................................................................117
9.1
Statistical Analysis Plan Summary...................................................................117
9.2
Responsibility for Analyses/In-house Blinding ...............................................120
9.3
Hypotheses/Estimation ......................................................................................120
9.4
Analysis Endpoints.............................................................................................120
9.4.1
Efficacy Endpoints.....................................................................................120
9.4.2
Safety Endpoints........................................................................................121
9.4.3
PRO Endpoints...........................................................................................121
9.5
Analysis Populations..........................................................................................121
9.5.1
Efficacy Analysis Population.....................................................................121
9.5.2
Safety Analysis Population........................................................................122
9.5.3
PRO Analysis Population ..........................................................................122
9.6
Statistical Methods.............................................................................................122
9.6.1
Statistical Methods for Efficacy Analyses.................................................122
9.6.1.1
Progression-free Survival (PFS) ......................................................122
9.6.1.2
Overall Survival (OS) ......................................................................124
9.6.1.3
Objective Response Rate (ORR) .....................................................124
9.6.1.4
Duration of Response (DOR)...........................................................125
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................125
9.6.2
Statistical Methods for Safety Analyses ....................................................126
9.6.3
Statistical Methods for Patient-reported Outcomes ...................................128
9.6.4
Summaries of Baseline Characteristics......................................................128
9.7
Interim Analyses ................................................................................................128
9.7.1
Efficacy Interim Analyses..........................................................................128
9.7.2
Safety Interim Analyses.............................................................................130
9.8
Multiplicity .........................................................................................................130
9.8.1
Progression-free Survival...........................................................................131
9.8.2
Overall Survival.........................................................................................132
9.9
Sample Size and Power Calculations ...............................................................133
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9.10
Subgroup Analyses.............................................................................................134
9.11
Compliance (Medication Adherence)...............................................................135
9.12
Extent of Exposure.............................................................................................135
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................136
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......136
10.1.1
Code of Conduct for Clinical Trials...........................................................136
10.1.2
Financial Disclosure...................................................................................138
10.1.3
Data Protection...........................................................................................138
10.1.3.1
Confidentiality of Data ....................................................................139
10.1.3.2
Confidentiality of Participant Records.............................................139
10.1.3.3
Confidentiality of IRB/IEC Information..........................................139
10.1.4
Committees Structure.................................................................................139
10.1.4.1
Executive Oversight Committee......................................................139
10.1.4.2
External Data Monitoring Committee .............................................139
10.1.5
Publication Policy......................................................................................140
10.1.6
Compliance with Study Registration and Results Posting Requirements .140
10.1.7
Compliance with Law, Audit, and Debarment ..........................................141
10.1.8
Data Quality Assurance .............................................................................141
10.1.9
Source Documents .....................................................................................142
10.1.10
Study and Site Closure...............................................................................142
10.2
Appendix 2: Clinical Laboratory Tests............................................................143
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................145
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................145
10.3.2
Definition of AE ........................................................................................145
10.3.3
Definition of SAE ......................................................................................146
10.3.4
Additional Events Reported in the Same Manner as SAE.........................148
10.3.5
Recording AE and SAE .............................................................................148
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................151
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................153
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................154
10.5.1
Definitions..................................................................................................154
10.5.2
Contraception Requirements......................................................................155
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................157
10.7
Appendix 7: Country-specific Requirements..................................................162
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10.7.1
France.........................................................................................................162
10.7.2
Japan ..........................................................................................................162
10.7.3
Germany.....................................................................................................162
10.8
Appendix 8: Abbreviations ...............................................................................164
11
REFERENCES.............................................................................................................167
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PRODUCT: MK-7339  
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LIST OF TABLES
Table 1
Adequate Organ Function Values....................................................................76
Table 2
Study Interventions..........................................................................................84
Table 3
Management of Anemia Attributed to Olaparib..............................................91
Table 4
Management of Neutropenia, Leukopenia, and Thrombocytopenia 
Attributed to Olaparib......................................................................................92
Table 5
Dose Reduction of Olaparib to Manage Moderate Renal Impairment ............94
Table 6
Dose Reduction of Olaparib with a Strong or Moderate CYP3A Inhibitor.....94
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................110
Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS.....................124
Table 9
Censoring Rules for Duration of Response ...................................................125
Table 10
Analysis Strategy for Key Efficacy Variables...............................................126
Table 11
Analysis Strategy for Safety Parameters........................................................127
Table 12
Operating Characteristics of the Futility Interim Analysis (IA1)..................129
Table 13
Summary of Interim and Final Analyses .......................................................129
Table 14
Efficacy Boundaries and Properties for PFS Analyses..................................132
Table 15
Efficacy Boundaries and Properties for OS Analyses ...................................133
Table 16
Protocol-required Safety Laboratory Assessments........................................143
Table 17
Highly Effective Contraception Methods......................................................156
08HF0N


PRODUCT: MK-7339  
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................26
Figure 2
Multiplicity Diagram for Type-I Error Control .............................................131
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Randomized, Open-label Study to Evaluate the Efficacy and 
Safety of Olaparib Alone or in Combination With Bevacizumab Compared to Bevacizumab 
with a Fluoropyrimidine in Participants with Unresectable or Metastatic Colorectal Cancer 
who Have Not Progressed Following First-line Induction (LYNK-003)
Short Title: Olaparib ± bevacizumab in CRC with SD/PR/CR from FOLFOX or CAPOX
with bevacizumab
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
NOTE: As of Amendment 05, participants who are still on study treatment will no longer 
have tumor response assessments by BICR. However, local tumor imaging assessments 
should continue as per local institutional guidelines. In addition, PRO assessments will no 
longer be performed. Blood for RNA analysis and serum and plasma biomarker analysis will
no longer be collected. Updated analyses are described in Section 9. Post-treatment follow-up 
visits are no longer required except for safety and survival follow-up requirements (refer to 
Section 8.11.4). The section below is retained for reference.
In male or female participants with unresectable or metastatic CRC who have not progressed 
following prior FOLFOX + bevacizumab or CAPOX + bevacizumab induction.
The study is considered to have met its primary objective if at least 1 primary hypothesis test 
is significant.
Primary Objectives
Primary Endpoints

To compare PFS using RECIST 1.1 as 
assessed by BICR between the 
following treatments:
-
Olaparib + Bevacizumab versus a 
fluoropyrimidine + Bevacizumab
-
Olaparib versus A fluoropyrimidine 
+ Bevacizumab
Hypotheses:
H1 – Olaparib + Bevacizumab is superior 
to a fluoropyrimidine + Bevacizumab with 
respect to PFS using RECIST 1.1 as 
assessed by BICR.
H2 – Olaparib is superior to a 
fluoropyrimidine + Bevacizumab with 
respect to PFS using RECIST 1.1 as 
assessed by BICR.

PFS: the time from randomization to first 
documented disease progression (PD) or 
death due to any cause, whichever occurs 
first
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Secondary Objectives
Secondary Endpoints

To compare OS between the following 
treatments:
-
Olaparib + Bevacizumab versus a 
fluropyrimidine + Bevacizumab
-
Olaparib versus a fluoropyrimidine 
+ Bevacizumab
Hypotheses:
H3 – Olaparib + Bevacizumab is superior 
to a fluoropyrimidine + Bevacizumab with 
respect to OS.
H4 – Olaparib is superior to a 
fluorpyrimidine + Bevacizumab with 
respect to OS.

OS: the time from randomization to death 
due to any cause

To evaluate ORR, and DOR using 
RECIST 1.1 as assessed by BICR 
following administration of:
-
Olaparib + Bevacizumab
-
Olaparib
-
Fluoropyrimidine + Bevacizumab

OR: CR or PR

DOR: the time from first response (CR or 
PR) to subsequent disease progression or 
death due to any cause, whichever occurs 
first

To evaluate the safety and tolerability 
of:
-
Olaparib + Bevacizumab
-
Olaparib

AEs

Study intervention discontinuation due to 
AEs
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
The treatment of participants with unresectable or 
metastatic CRC that has not progressed following an 
induction course of FOLFOX + bevacizumab or CAPOX + 
bevacizumab
Population
Participants with unresectable or metastatic CRC that has
not progressed following an induction course of FOLFOX 
+ bevacizumab or CAPOX + bevacizumab
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
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Type of Control
Active Control Without Placebo
Study Blinding
Unblinded Open-label
Masking
Outcomes Assessor
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 6 years from the time the first participant 
provides documented informed consent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 525 participants with CRC that has not progressed following prior CAPOX + 
bevacizumab or FOLFOX + bevacizumab induction will be enrolled in this study.
Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion Group 
Name
Drug
Dose Strength
Dose 
Frequency
Route of 
Administra-
tion
Regimen/
Treatment 
Period
Use
Arm 1
Olaparib
300 mg
Twice daily
Oral
Until 
progressive 
disease or 
end of 
study
Test 
Product
Bevacizumaba
5 mg/kg
Q2W
IV Infusion
Arm 2
Olaparib
300 mg
Twice daily
Oral
Arm 3a
Arm 3b
Leucovorinb
or
Levoleucovorin
400 mg/m2
(leucovorin) or 
200 mg/m2
(levoleucovorin)
Q2W
IV Infusion
Until 
progressive 
disease or 
end of 
study
Comparator
Bevacizumaba
5-FU
5 mg/kg
2400 mg/m2 over 
46 to 48 hoursc
Q2W
Q2W
IV Infusion
IV Infusion
Capecitabine
Bevacizumaba
1000 mg/m2
7.5 mg/kg
BID 14 days 
on, 7 days 
off Q3W
Q3W
Oral
IV Infusion
Abbreviations: 5-FU: 5-Fluorouracil, BID: Twice daily, IV: Intravenous, QXW: Every X weeks
a. Participants who begin study treatment with bevacizumab must remain on bevacizumab throughout the study. 
Participants who begin study treatment with biosimilar bevacizumab must remain on the same biosimilar 
throughout the study.
b. Leucovorin/levoleucovorin may be added to Arm 3a per investigator’s discretion.
c. 5-FU regimen may include a bolus of 5-FU prior to infusion: 400mg/m2 IV infusion on Day 1 based on local 
standards, investigator preference, and participant experience with the bolus during the induction phase.
Total Number 3 Arms
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Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-
specified contact.
After a Screening phase of up to 28 days, each participant will be 
randomized to receive study intervention until disease progression is 
radiographically documented, unacceptable AEs, intercurrent illness that
prevents further administration of study intervention, investigator’s 
decision to discontinue the participant, or administrative reasons requiring 
cessation of treatment.
After the end of study treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.1.
Participants who discontinue study intervention for reasons other than 
radiographically documented disease progression will have post-treatment 
follow-up imaging for disease status until disease progression is 
documented radiographically per RECIST 1.1.
All participants will then be followed for disease status until second 
disease progression during reintroduction of investigator-choice of 
anticancer therapy. All participants will be followed for OS until death, 
withdrawal of consent, or the end of the study.
Once the participant has achieved all study objectives or the study has 
ended, the participant is discontinued from this study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The design for the study is depicted in Figure 1.
Figure 1
Study Schema
Abbreviations: CR = complete response; CRC = colorectal cancer; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; FOLFOX = folinic 
acid/fluorouracil (5-FU)/oxaliplatin; mut = mutant; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; R = randomization; 
SD = stable disease; wt = wildtype.
Note: For the purpose of this study a cycle of FOLFOX is given every 2 weeks, and a cycle of CAPOX is given every 3 weeks, such that 1 administration of oxaliplatin is 1 cycle.
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1.3
Schedule of Activities (SoA)
1.3.1
Arm 1 (Olaparib + Bevacizumab) & Arm 3a (Bevacizumab + 5-FU)
NOTE: As of Amendment 05, participants who are still on study treatment will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue as per local institutional guidelines. In addition, PRO assessments 
(EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D-5L) will no longer be performed. Blood for RNA analysis and serum and plasma 
biomarker analysis will no longer be collected. Updated analyses are described in Section 9. Post-treatment follow-up visits are no 
longer required except for safety and survival follow-up requirements (refer to Section 8.11.4). The section below is retained for 
reference.
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Administrative Procedures
ICF
X
Consent must be obtained prior 
to performing any protocol-
specific procedures. 
FBR ICF
X
Participation in FBR is optional 
and consent must be obtained 
before collection of samples.
Inclusion/Exclusion 
Criteria
X
Participant ID card
X
X
At the time of Visit 1, site 
personnel should add the 
randomization number to the 
Participant ID card.
Demographics and 
medical history
X
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Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Cancer history
X
Prior/concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
Induction history
X
Including history of response 
while on or after completing the 
regimen as well as documented 
reason for discontinuation of 
oxaliplatin. 
Provide 
radiographic 
image(s) from 
induction
X
Sites must submit to the iCRO 1 
set of radiographic images 
including chest/abdomen/pelvis 
taken before or during the 
induction period and at least 42 
days prior to the imaging taken 
during Screening. The site must 
receive the iCRO’s 
determination that the images 
are of diagnostic quality and 
confirmation of non-PD by 
BICR prior to randomization.
Randomization 
number/study 
treatment 
assignment using
IRT
X
Visit 1 study treatment must be 
administered within 3 days after 
obtaining randomization 
number.
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Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Subsequent 
anti-neoplastic 
therapy status
including disease 
status
X
X
X
X
PFS2 assessment will be 
performed by the investigator 
and defined according to local 
standard clinical practice and 
may involve radiological or 
symptomatic progression or 
death. Subsequent therapy will 
be collected for participants 
from the time of study 
intervention discontinuation 
until second progression.
Survival status
-------------------------------------------------------------------------------------
X
Continue after investigator 
determined PD or start of post-
maintenance investigator-choice 
anticancer therapy. In addition, 
upon Sponsor request, 
participants may be contacted 
for survival status at any time 
during the course of the study.
Administration of Study Treatment
Olaparib dispensed
X
X
X
Arm 1. Continuous daily dose of 
300 mg BID. 
Olaparib container 
returned
X
X
X
Day 1 of every Cycle starting in 
Cycle 2
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Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Bevacizumab
Administration
X
X
X
X
X
X
Arms 1 and 3. Participants who 
begin study treatment with 
bevacizumab must remain on 
bevacizumab throughout the 
study. Participants who begin 
study treatment with biosimilar 
bevacizumab must remain on the 
same biosimilar throughout the 
study.
5-FU 
Administration
X
X
X
X
X
X
Arm 3a only.
08HF0N


PRODUCT:  MK-7339  
31
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Efficacy Procedures
Imaging should continue to be 
performed until PD is 
documented, withdrawal of 
consent, or death, whichever 
occurs first.
Tumor imaging
X
X
X
X
Images will be performed every 
56 days (8 weeks, ± 7 days) for 
the first 12 months, and every 84 
days (12 weeks, ± 7 days) 
thereafter.
Imaging timing should be 
calculated from the date of 
randomization, should follow 
calendar days, and should not 
be adjusted for delays in cycle 
starts.
For participants who have an 
outcome of a confirmed curative 
surgery (Section 4.1), imaging 
must be performed at a 
minimum of (no less than) 4 
weeks after surgery and no more 
than 8 weeks prior to the next 
treatment cycle. Subsequent 
post-operative images will be 
assessed every 8 weeks (56 days 
± 7 days) for 12 months and 
every 12 weeks (84 days ± 7 
days) thereafter
08HF0N


PRODUCT:  MK-7339  
32
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Safety Procedures
AE monitoring
X
X
X
X
X
X
X
X
X
X
New diagnoses of MDS and 
AML should be reported 
throughout the study, including 
follow-up phase.
Height
X
Weight
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
Directed physical 
examination
X
X
X
X
X
X
Vital Signs (HR, 
DBP, SBP, RR, 
temperature)
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
12-lead ECG performed using 
local standard procedures. 
Additional ECGs performed as 
clinically indicated.
Hematology
X
X
X
X
X
X
X
X
X
Screening samples must be 
collected within 10 days of 
treatment initiation.
Chemistry
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Perform 24-hour urine protein 
analysis if dipstick is ≥2+.
Screening samples must be 
collected within 10 days of 
treatment initiation.
CEA testing
X
X
X
X
Perform every other cycle
HBV, HCV, and 
HIV testing
X
Not required unless mandated by 
local health authority.
08HF0N


PRODUCT:  MK-7339  
33
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Urine or Serum
β-hCG - WOCBP 
only
X
X
X
X
X
X
WOCBP require a negative urine 
test within 24 hours prior to the 
first dose of study treatment. 
Serum test is only required if 
urine test is positive or is not 
evaluable.
During the Treatment Period, 
pregnancy testing is conducted 
every 4 weeks.
Additional urine pregnancy 
testing can be conducted if 
required by local regulations or 
clinically indicated.
PT/INR and aPTT
X
Screening samples collected 
within 10 days of treatment 
initiation. PT/INR and aPTT
should be monitored more 
closely in participants receiving 
anticoagulant therapy during 
treatment and safety follow-up 
period. 
ECOG performance 
status
X
X
X
X
X
Screening assessment must be 
performed within 10 days of 
randomization. 
08HF0N


PRODUCT:  MK-7339  
34
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Patient-reported Outcomes
PROs are to be administered 
in the order listed
EQ-5D-5L
X
X
X
X
X
During the Treatment Period, 
PROs will be assessed at Cycles 
1 through 3, 5, 7, and every 3 
cycles thereafter (C10, C13, etc).
EORTC QLQ-C30
X
X
X
X
X
EORTC QLQ-CR29
X
X
X
X
X
Pharmacokinetics
Blood for olaparib 
pharmacokinetics
X
X
At Visit 1 (Day 1), the PK 
sample will be collected at 2 
hours (±1 hour) postdose.
At Visit 2 (Day 1), PK samples 
will be collected predose (30 
minutes prior to the planned 
dose [±15 min]) and at 30 min 
(±15 min) and 2 hours (±1 hour) 
postdose.
08HF0N


PRODUCT:  MK-7339  
35
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Biomarkers
Blood for Genetic 
Analysis (DNA)a
X
Blood for RNA 
analysis
X
X
X
X*
X*
Cycles 1 through 3 only.
*Final samples for RNA, serum, 
plasma, and ctDNA analysis 
should be collected at the time of 
PD. Collect at 
Discontinuation/EOT if 
participant discontinues study 
intervention due to PD, or at 
final visit in follow-up if 
participant discontinues follow-
up due to PD. Sample is not 
collected at every follow-up 
visit. 
Blood for serum 
biomarker analysis
X
X
X
X*
X*
Blood for plasma 
biomarker analysis
X
X
X
X*
X*
Blood for ctDNA
Analysis
X
X
X
X
X*
X*
Mandatory Tissue 
collection (New or 
Archival)
X
A new tumor specimen is 
preferred to archival samples.
08HF0N


PRODUCT:  MK-7339  
36
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 28 days
EOT
Post-Treatment
Notes
Cycle 
Number/Visit Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-
up Visitsb
PFS2
Follow-upb
Survival 
Follow-up
Cycle Day
1
15
1
15
1
15
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration 
unless otherwise indicated.
If the DC visit occurs ≥30 
days from last dose of study 
intervention, a Safety Follow-
up Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Scheduling 
Window (Days):
–28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
At 
time 
of 
DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 
months 
and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Ras/BRAF 
Mutation Testing
X
Only perform if status is not 
already known. Perform at the 
local laboratory unless it does 
not have this capability. Results 
must be obtained by the site 
prior to randomization.
Abbreviations: 5-FU = fluorouracil; AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = β-human chorionic gonadotropin; ctDNA = circulating tumor DNA; BID = twice 
daily; CEA = carcinoembryonic antigen; DBP = diastolic blood pressure; DC = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Cancer Group; EORTC QLQ-C29= European 
Organisation for Research and Treatment of Cancer Quality of Life Core 29; EORTC QLQ-C30= European Organisation for Research and Treatment of Cancer Quality of Life Core 30; EOT = end of 
therapy; FBR = Future Biomedical Research; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HR = heart rate; HRT = 
hormone replacement therapy; ICF = informed consent form; iCRO = imaging contract research organization; ID = identification; INR = International Normalized Ratio; interactive response 
technology (IRT) = interactive response system; PD = progressive disease; PK = pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; PFS2 
= second progression-free survival; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory rate; SBP = 
systolic blood pressure; SOC = standard of care; WOCBP = women of childbearing potential.
a.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is either a local law 
or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover extracted DNA will be stored for future 
biomedical research. If the planned genetic analyses are not approved, but future biomedical research is approved and consent is given, this sample will be collected for the purpose of future 
biomedical research.
b.
Participants who discontinue treatment for reasons other than disease progression will be monitored in the follow-up phase and will then move into the PFS2 follow-up period after progression is 
documented. Participants who discontinue treatment due to disease progression will move directly into the PFS2 follow-up period.
08HF0N


PRODUCT:  MK-7339  
37
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
1.3.2
Arm 2 Olaparib Monotherapy
NOTE: As of Amendment 05, participants who are still on study treatment will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue as per local institutional guidelines. In addition, PRO assessments 
(EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D-5L) will no longer be performed. Blood for RNA analysis and serum and plasma 
biomarker analysis will no longer be collected. Updated analyses are described in Section 9. Post-treatment follow-up visits are no 
longer required except for safety and survival follow-up requirements (refer to Section 8.11.4). The section below is retained for 
reference.
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Administrative Procedures
ICF
X
Consent must be obtained prior to 
performing any protocol-specific 
procedures.
FBR ICF
X
Participation in FBR is optional 
and consent must be obtained 
before collection of samples.
Inclusion/Exclusion 
Criteria
X
Participant ID card
X
X
At the time of Visit 1, site 
personnel should add the 
randomization number to the 
Participant ID card.
Demographics and 
medical history
X
Cancer history
X
08HF0N


PRODUCT:  MK-7339  
38
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Prior/concomitant 
medication review
X
X
X
X
X
X
X
Induction history
X
Including history of response while 
on or after completing the 
induction regimen as well as 
documented reason for 
discontinuation of oxaliplatin.
Provide radiographic 
image(s) from during 
induction
X
Sites must submit to the iCRO 1 
set of radiographic images 
including chest/abdomen/pelvis 
taken before or during the 
induction period and at least 42 
days prior to the imaging taken 
during Screening. The site must 
receive the iCRO’s determination 
that the images are of diagnostic 
quality and confirmation of non-
PD by BICR prior to 
randomization.
Obtain randomization 
number and study 
treatment assignment 
using interactive 
response technology 
(IRT)
X
Visit 1 study treatment must be 
administered within 3 days after
obtaining randomization number.
08HF0N


PRODUCT:  MK-7339  
39
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Subsequent 
anti-neoplastic therapy 
status including disease 
status
X
X
X
X
PFS2 assessment will be 
performed by the investigator and 
defined according to local standard 
clinical practice and may
involve radiological or 
symptomatic progression or death. 
Subsequent therapy will be 
collected for participants from the 
time of study intervention
discontinuation until second 
progression.
Survival status
---------------------------------------------------------
X
Continue after investigator 
determined PD or start of post-
maintenance investigator-choice 
anticancer therapy. In addition, 
upon Sponsor request, participants 
may be contacted for survival 
status at any time during the course 
of the study.
Administration of Study Treatment
Olaparib dispensed
X
X
X
Continuous daily dose of 300 mg 
BID.
Olaparib container 
returned
X
X
X
Day 1 of every cycle starting in 
Cycle 2
08HF0N


PRODUCT:  MK-7339  
40
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Efficacy Procedures
Imaging should continue to be 
performed until PD is 
documented, withdrawal of 
consent, or death, whichever 
occurs first.
Tumor imaging
X
X
X
X
Images will be performed every 
56 days (8 weeks, ± 7 days) for the 
first 12 months, and every 84 days 
(12 weeks, ± 7 days) thereafter.
Imaging timing should be 
calculated from the date of 
randomization, should follow 
calendar days, and should not be 
adjusted for delays in cycle starts.
For participants who have an 
outcome of a confirmed curative 
surgery (described in Section 4.1), 
imaging must be performed at a 
minimum of (no less than) 4 weeks 
after surgery and no more than 8 
weeks prior to the next treatment 
cycle. Subsequent post-operative 
images will be assessed every 8 
weeks (56 days ± 7 days) for 12 
months and every 12 weeks (84 
days ± 7 days) thereafter
08HF0N


PRODUCT:  MK-7339  
41
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Safety Procedures
AE monitoring
X
X
X
X
X
X
X
New diagnoses of MDS and AML 
should be reported throughout the 
study, including follow-up phase.
Height
X
Weight
X
X
X
X
X
Complete physical 
examination
X
X
Directed physical 
examination
X
X
X
Vital Signs (HR, DBP, 
SBP, RR, temperature)
X
X
X
X
X
X
12-lead ECG
X
X
12-lead ECG performed using 
local standard procedures. 
Additional ECGs performed as 
clinically indicated.
Hematology
X
X
X
X
X
X
Screening samples must be 
collected within 10 days of 
treatment initiation.
Chemistry
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Perform 24-hour urine protein 
analysis if dipstick is ≥2+.
Screening samples must be 
collected within 10 days of 
treatment initiation.
CEA testing
X
X
X
X
Perform every other cycle.
HBV, HCV, and HIV 
testing
X
Not required unless mandated by 
local health authority.
08HF0N


PRODUCT:  MK-7339  
42
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Urine or Serum
β-hCG – WOCBP only
X
X
X
X
X
X
WOCBP require a negative urine 
test within 24 hours prior to the 
first dose of study treatment.
Serum test is only required if urine 
test is positive or is not evaluable.
During the Treatment Period, 
pregnancy testing is conducted 
every 4 weeks.
Additional urine pregnancy testing 
can be conducted if required by 
local regulations or clinically 
indicated.
PT/INR and aPTT
X
Screening samples collected within 
10 days of treatment initiation. 
PT/INR and aPTT should be 
monitored more closely in 
participants receiving 
anticoagulant therapy during 
treatment and safety follow-up 
period. 
ECOG performance 
status
X
X
X
X
X
Screening assessment must be 
performed within 10 days of 
randomization. 
08HF0N


PRODUCT:  MK-7339  
43
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Patient-Reported Outcomes
PROs are to be administered in 
the order listed
EQ-5D-5L
X
X
X
X
X
During the Treatment Period, 
PROs will be assessed at Cycles 1
through 3, 5, 7, and every 3 cycles
thereafter (C10, C13, etc).
EORTC QLQ-C30
X
X
X
X
X
EORTC QLQ-CR29
X
X
X
X
X
Pharmacokinetics
Blood for olaparib 
pharmacokinetics
X
X
At Visit 1 (Day 1), the PK sample 
will be collected at 2 hours (±1 
hour) postdose.
At Visit 2 (Day 1), PK samples 
will be collected predose (30 
minutes prior to the planned dose 
[±15 min]) and at 30 min (±15 
min) and 2 hours (±1 hour) 
postdose.
Biomarkers
Blood for Genetic 
Analysis (DNA)a
X
08HF0N


PRODUCT:  MK-7339  
44
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Blood for RNA 
analysis
X
X
X
X*
X*
Cycles 1 through 3 only.
*Final samples for RNA, serum, 
plasma, and ctDNA analysis 
should be collected at the time of 
PD. Collect at 
Discontinuation/EOT if participant 
discontinues study intervention due 
to PD, or at final visit in follow-up 
if participant discontinues follow-
up due to PD. Sample is not 
collected at every follow-up visit.
Blood for serum 
biomarker analysis
X
X
X
X*
X*
Blood for plasma 
biomarker analysis
X
X
X
X*
X*
Blood for ctDNA
Analysis
X
X
X
X
X*
X*
Mandatory Tissue 
collection (New or 
Archival)
X
A new tumor specimen is preferred 
to archival samples.
08HF0N


PRODUCT:  MK-7339  
45
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Period
1 Cycle = 28 Days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+ 3
± 3
± 3
At time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months 
and Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days
Q12W
(± 14 days)
Ras/BRAF Mutation 
Testing
X
Only perform if status is not 
already known. Perform at the 
local laboratory unless it does not 
have this capability. Results must 
be obtained by the site prior to 
randomization.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-hCG = β-human chorionic gonadotropin; ctDNA = circulating tumor DNA; BID = twice 
daily; DBP = diastolic blood pressure; DC = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Cancer Group; EORTC QLQ-C29= European 
Organisation for Research and Treatment of Cancer Quality of Life Core 29; EORTC QLQ-C30= European Organisation for Research and Treatment of Cancer Quality of Life 
Core 30; EOT = end of therapy; FBR = Future Biomedical Research; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; HR = heart rate; HRT = hormone replacement therapy; ICF = informed consent form; iCRO = imaging contract research organization; ID = 
identification; INR = International Normalized Ratio; IRT = interactive response system; PD = progressive disease; PK = pharmacokinetics; PRO = patient-reported outcome; 
PT = prothrombin time; PTT = partial thromboplastin time; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in 
Solid Tumors; RR = respiratory rate; SBP = systolic blood pressure; SOC = standard of care; WOCBP = women of childbearing potential.
a.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research. If the planned genetic analyses are not approved, but future biomedical research is approved and 
consent is given, this sample will be collected for the purpose of future biomedical research.
b.
Participants who discontinue treatment for reasons other than disease progression will be monitored in the follow-up phase and will then move into the PFS2 follow-up 
period after progression is documented. Participants who discontinue treatment due to disease progression will move directly into the PFS2 follow-up period.
08HF0N


PRODUCT:  MK-7339  
46
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
1.3.3
Arm 3b Bevacizumab + Capecitabine
NOTE: As of Amendment 05, participants who are still on study treatment will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue as per local institutional guidelines. In addition, PRO assessments 
(EORTC QLQ-C30, EORTC QLQ-CR29, EQ-5D-5L) will no longer be performed. Blood for RNA analysis and serum and plasma 
biomarker analysis will no longer be collected. Updated analyses are described in Section 9. Post-treatment follow-up visits are no 
longer required except for safety and survival follow-up requirements (refer to Section 8.11.4). The section below is retained for 
reference.
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Administrative Procedures
ICF
X
Consent must be obtained prior to 
performing any protocol-specific 
procedures. 
FBR ICF
X
Participation in FBR is optional 
and consent must be obtained 
before collection of samples.
Inclusion/Exclusion 
Criteria
X
Participant ID card
X
X
At the time of Visit 1, site 
personnel should add the 
randomization number to the 
Participant ID card.
Demographics and 
medical history
X
Cancer history
X
08HF0N


PRODUCT:  MK-7339  
47
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Prior/concomitant 
medication review
X
X
X
X
X
X
X
Induction history
X
Including history of response 
while on or after completing the 
induction regimen as well as 
documented reason for 
discontinuation of oxaliplatin. 
Provide radiographic 
image(s) from 
induction
X
Sites must submit to the iCRO 1 
set of radiographic images 
including chest/abdomen/pelvis 
taken before or during the 
induction period and at least 42 
days prior to the imaging taken 
during Screening. The site must 
receive the iCRO’s determination 
that the images are of diagnostic 
quality and confirmation of non-
PD by BICR prior to 
randomization.
Randomization 
number/study 
treatment assignment 
using IRT
X
Visit 1 study treatment must be 
administered within 3 days after 
obtaining randomization number.
08HF0N


PRODUCT:  MK-7339  
48
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Subsequent 
anti-neoplastic therapy 
status including 
disease status
X
X
X
X
PFS2 assessment will be 
performed by the investigator and 
defined according to local 
standard clinical practice and may 
involve radiological or 
symptomatic progression or death. 
Subsequent therapy will be 
collected for participants from the 
time of study intervention 
discontinuation until second 
progression.
Survival status
-------------------------------------------------------------------------------------
X
Continue after investigator 
determined PD or start of post-
maintenance investigator-choice 
anticancer therapy. In addition, 
upon Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study.
Administration of Study Treatment
Bevacizumab
administration
X
X
X
Bevacizumab 7.5mg/kg IV on 
Day 1 Q3W.
Capecitabine 
administration
X
X
X
Capecitabine 1000mg/m2 BID for 
14 days, then 7 days off, Q3W. 
08HF0N


PRODUCT:  MK-7339  
49
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Efficacy Procedures
Imaging should continue to be 
performed until PD is 
documented, withdrawal of 
consent, or death, whichever 
occurs first.
Tumor imaging
X
X
X
Images will be performed every 
56 days (8 weeks, ± 7 days) for the 
first 12 months, and every 84 days 
(12 weeks, ± 7 days) thereafter.
Imaging timing should be 
calculated from the date of 
randomization, should follow 
calendar days, and should not be 
adjusted for delays in cycle starts.
For participants who have an 
outcome of a confirmed curative 
surgery (Section 4.1), imaging 
must be performed at a minimum 
of (no less than) 4 weeks after 
surgery and no more than 8 weeks 
prior to the next treatment cycle. 
Subsequent post-operative images 
will be assessed every 8 weeks 
(56 days ± 7 days) for 12 months 
and every 12 weeks (84 days ± 7 
days) thereafter
08HF0N


PRODUCT:  MK-7339  
50
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Safety Procedures
AE monitoring
X
X
X
X
X
X
X
New diagnoses of MDS and AML 
should be reported throughout the 
study, including follow-up phase.
Height
X
Weight
X
X
X
X
X
Complete physical 
examination
X
X
Directed physical 
examination
X
X
X
Vital Signs (HR, DBP, 
SBP, RR, 
temperature)
X
X
X
X
X
X
12-lead ECG
X
X
12-lead ECG performed using 
local standard procedures. 
Additional ECGs performed as 
clinically indicated.
Hematology
X
X
X
X
X
X
Screening samples must be 
collected within 10 days of 
treatment initiation.
Chemistry
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Perform 24-hour urine protein 
analysis if dipstick is ≥2+.
Screening samples must be 
collected within 10 days of 
treatment initiation.
CEA testing
X
X
X
X
Perform every other cycle
HBV, HCV, and HIV 
testing
X
Not required unless mandated by 
local health authority.
08HF0N


PRODUCT:  MK-7339  
51
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Urine or Serum
β-hCG - WOCBP only
X
X
X
X
X
X
WOCBP require a negative urine 
test within 24 hours prior to the 
first dose of study treatment.
Serum test is only required if 
urine test is positive or is not 
evaluable.
During the Treatment Period, 
pregnancy testing is conducted 
every 4 weeks.
Additional urine pregnancy 
testing can be conducted if 
required by local regulations or 
clinically indicated.
PT/INR and aPTT
X
Screening samples collected 
within 10 days of treatment 
initiation. PT/INR and aPTT
should be monitored more closely 
in participants receiving 
anticoagulant therapy during 
treatment and safety follow-up 
period. 
ECOG performance 
status
X
X
X
X
X
Screening assessment must be 
performed within 10 days of 
randomization. 
08HF0N


PRODUCT:  MK-7339  
52
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Patient-Reported Outcomes
PROs are to be administered in 
the order listed
EQ-5D-5L
X
X
X
X
X
During the Treatment Period, 
PROs will be assessed at Cycles 
1, 2, 4, 6, 9 and every 4 cycles 
thereafter (C13, C17, etc).
EORTC QLQ-C30
X
X
X
X
X
EORTC QLQ-CR29
X
X
X
X
X
Biomarkers
Blood for Genetic 
Analysis (DNA)a
X
Blood for RNA 
analysis
X
X
X
X*
X*
Cycles 1 through 3 only.
*Final samples for RNA, serum, 
plasma, and ctDNA analysis 
should be collected at the time of 
PD. Collect at 
Discontinuation/EOT if 
participant discontinues study 
intervention due to PD, or at final 
visit in follow-up if participant 
discontinues follow-up due to PD. 
Sample is not collected at every 
follow-up visit. 
Blood for serum 
biomarker analysis
X
X
X
X*
X*
Blood for plasma 
biomarker analysis
X
X
X
X*
X*
Blood for ctDNA
Analysis
X
X
X
X
X*
X*
Mandatory Tissue 
collection (New or 
Archival)
X
A new tumor specimen is 
preferred to archival samples.
08HF0N


PRODUCT:  MK-7339  
53
PROTOCOL/AMENDMENT NO.:  003-05  
MK-7339-003-05 FINAL PROTOCOL
08-SEP-2022
Trial Period
Screening
Treatment Cycle = 21 days
EOT
Post-Treatment
Notes
Cycle Number/Visit 
Title
Screening
1
2
3+
DC
Safety 
Follow-up
Follow-up 
Visitsb
PFS2
Follow-upb
Survival 
Follow-up
General Notes:
All assessments/ procedures 
should be performed prior to 
treatment administration unless 
otherwise indicated.
If the DC visit occurs ≥30 days 
from last dose of study 
intervention, a Safety Follow-up 
Visit is not required.
Follow-up visits may be 
scheduled to coincide with 
follow-up imaging.
Cycle Day
1
1
1
Scheduling Window 
(Days):
–28 to -1
+3
± 3
± 3
At 
time 
of DC
30 Days 
After Last 
Dose
(+ 7 days)
Q8W for
12 months and 
Q12W 
thereafter
(± 7 days)
Q8W
(± 14 days)
Q12W
(± 14 days)
Ras/BRAF Mutation 
Testing
X
Only perform if status is not 
already known. Perform at the 
local laboratory unless it does not 
have this capability. Results must 
be obtained by the site prior to 
randomization.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; β-HCG = β-human chorionic gonadotropin; ctDNA = circulating tumor DNA; BID = twice daily; CEA = 
carcinoembryonic antigen; DBP = diastolic blood pressure; DC = discontinuation; ECG = electrocardiogram; ECOG = Eastern Cooperative Cancer Group; EORTC QLQ-C29= European 
Organisation for Research and Treatment of Cancer Quality of Life Core 29; EORTC QLQ-C30= European Organisation for Research and Treatment of Cancer Quality of Life Core 30; EOT = end 
of therapy; FBR = Future Biomedical Research; FSH = follicle stimulating hormone; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HR = heart rate; 
HRT = hormone replacement therapy; ICF = informed consent form; iCRO = imaging contract research organization; ID = identification; INR = International Normalized Ratio; interactive response 
technology (IRT) = interactive response system; PD = progressive disease; PK = pharmacokinetics; PRO = patient-reported outcome; PT = prothrombin time; PTT = partial thromboplastin time; 
PFS2 = second progression-free survival; Q3W = every 3 weeks; Q8W = every 8 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RR = respiratory rate; 
SBP = systolic blood pressure; SOC = standard of care; WOCBP = women of childbearing potential.
a.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. This sample will not be collected at that site if there is either a local 
law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes. If the sample is collected, leftover extracted DNA will be stored for 
future biomedical research. If the planned genetic analyses are not approved, but future biomedical research is approved and consent is given, this sample will be collected for the purpose of 
future biomedical research.
b.
Participants who discontinue treatment for reasons other than disease progression will be monitored in the follow-up phase and will then move into the PFS2 follow-up period after progression 
is documented. Participants who discontinue treatment due to disease progression will move directly into the PFS2 follow-up period.
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2
INTRODUCTION
This clinical trial will study the PARP inhibitor, olaparib, alone or in combination with 
bevacizumab compared to bevacizumab with 5-FU in participants with unresectable or 
metastatic CRC that has not progressed following prior CAPOX + bevacizumab or FOLFOX 
+ bevacizumab.
2.1
Study Rationale
Human cancers show genomic instability and an increased mutation rate due to underlying 
defects in DNA repair. The deficiencies render cancer cells more dependent on the remaining 
DNA repair pathways, and targeting these pathways is expected to have much greater impact 
on the survival of the tumor cells than on normal cells. PARP1 and PARP2, the most 
abundant of the PARP enzymes, play a crucial role in repairing single-strand DNA breaks. 
The cells with inhibited PARP activity heavily depend on other DNA repair pathways, 
mainly HRR of DNA double strand breaks. A subset of patients with CRC have HRD and 
may be more sensitive to PARP inhibitors. Platinum-based chemotherapy regimens are the 
predominant first-line option for patients with advanced/metastatic CRC, similar to ovarian 
cancer. It is well documented that platinum sensitivity in ovarian cancer predicts sensitivity 
to PARP inhibition possibly related to the need for similar repair mechanism to repair their 
drug-induced DNA damage. This study will evaluate the antitumor effect of maintenance 
therapy with olaparib in participants with unresectable or metastatic CRC that has not 
progressed following prior CAPOX + bevacizumab or FOLFOX + bevacizumab.
Platinum-based regimens, specifically CAPOX or FOLFOX, with or without bevacizumab, 
are the most frequently used standard of care in metastatic CRC as frontline therapy. CAPOX 
and FOLFOX are considered interchangeable in the NCCN guidelines, and equivalent
efficacy has been shown in several clinical trials [Zhang, C., et al 2012] [Buchler, T., et al 
2014]. Historically, these regimens are given until disease progression or unacceptable 
toxicity. However, long exposure to oxaliplatin results in significant treatment-limiting 
associated toxicity, specifically neuropathy. Oxaliplatin toxicity is cumulative and regressive 
to some degree after drug discontinuation although it can be disabling and persistent [Esin, E. 
2016]. A stop-and-go approach, employing shorter durations of oxaliplatin containing 
regimens, interrupted by periods of oxaliplatin-free therapy, has been shown to have 
equivalent efficacy to continuous treatment with oxaliplatin, with reduced toxicity [Seymour, 
M. 2012] [Berry, S. R., et al 2015]. Maintenance treatment options aiming to enhance clinical 
benefit and reduce the associated toxicity derived from long exposures to oxaliplatin are an 
attractive modality in the management of first-line metastatic CRC.
In general, this approach involves intensive first-line therapy, followed by less intensive 
therapy until progression in patients who did not progress during the first-line induction 
chemotherapy [Aprile, G., et al 2016]. This concept is gaining credibility, and recent data in 
the literature suggest that maintenance treatment may play a key role in different cancer types 
such as CRC, lung, breast, and ovarian carcinomas [Fidias, P. M., et al 2009] [Paz-Ares, L. 
G., et al 2013] [Gligorov, J., et al 2014] [Burger, R. A., et al 2011] [Perren, T. J., et al 2011].
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Currently there are no approved drugs as maintenance after first-line therapy in metastatic
CRC. However, both NCCN and ESMO guidelines recommend that oxaliplatin may be 
discontinued after 12 weeks of therapy with FOLFOX (six 2-week cycles) or CAPOX (four 
3-week cycles) when subjects experience unacceptable neurotoxicity. In clinical practice, 
after discontinuation of oxaliplatin patients are switched to a maintenance regimen of 
fluoropyrimidine and bevacizumab based on the results from clinical trials such as CAIRO3, 
PRODIGE 9, and AIO KRK 0207 [Goey, K. K. H., et al 2017] [Hegewisch-Becker, S., et al 
2015] [Aparicio, T., et al 2018]. These trials showed a significant PFS benefit and a trend in 
OS benefit when maintenance was adopted.
The CAIRO3 study was an open-label, Phase 3, multicenter randomized controlled trial 
assessing maintenance therapy with capecitabine/bevacizumab versus observation (no drug) 
in 558 patients with metastatic CRC and with SD or better after first-line treatment with 
CAPOX/bevacizumab [Goey, K. K. H., et al 2017]. After first progression, both groups were 
to receive CAPOX/bevacizumab again until PFS2. After a median follow-up of 48 months, 
the primary endpoint of PFS2 was significantly better in the maintenance arm (8.5 vs. 11.7 
months; HR, 0.67; 95% CI, 0.56 to 0.81; p<0.0001), with 54% of patients overall receiving 
CAPOX/bevacizumab the second time. A nonsignificant trend toward improved OS was seen 
in the maintenance arm (18.1 vs. 21.6 months; adjusted HR, 0.83; 95% CI, 0.68 to 1.01; 
p=0.06).
The AIO 0207 trial was an open-label, noninferiority, randomized Phase 3 trial that 
randomized 472 patients whose disease did not progress on induction FOLFOX/bevacizumab 
or CAPOX/bevacizumab to no maintenance therapy or to maintenance therapy with 
fluoropyrimidine/bevacizumab or with bevacizumab alone [Hegewisch-Becker, S., et al 
2015]. The planned protocol included reintroduction of primary therapy after first 
progression. The primary endpoint was time to failure of strategy, defined as time from 
randomization to second progression, death, and initiation of treatment with a new drug. 
After a median follow-up of 17 months, the median time to failure of strategy was 6.4 
months (95% CI, 4.8 to 7.6) for the no treatment group, 6.9 months (95% CI, 6.1 to 8.5) for 
the fluoropyrimidine/bevacizumab group, and 6.1 months (95% CI, 5.3 to 7.4) for the 
bevacizumab alone group. Compared with fluoropyrimidine/bevacizumab, bevacizumab 
alone was noninferior, whereas the absence of maintenance therapy was not. However, only 
approximately one-third of trial participants received the reinduction therapy, thus limiting 
the interpretation of results. Overall survival was one of the secondary endpoints of the trial, 
and no relevant difference was seen between the arms.
The randomized Phase 3 noninferiority SAKK 41/06 trial provides historical data regarding 
bevacizumab monotherapy as maintenance after first-line treatment [Koeberle, D., et al 
2015]. In this study, the primary endpoint of time to progression was not met (4.1 months for 
bevacizumab continuation vs. 2.9 months for no continuation; HR, 0.74; 95% CI, 0.58 to 
0.96), and no difference in OS was observed (25.4 vs. 23.8 months; HR, 0.83; 95% CI, 0.63
to 1.1; p=0.20). Therefore, the value of bevacizumab monotherapy as maintenance was not 
demonstrated.
PRODIGE 9 trial is a randomized Phase 3 open-label trial that assessed bevacizumab 
maintenance versus no maintenance during CFI chemotherapy-free intervals in metastatic 
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CRC [Aparicio, T., et al 2018]. The primary endpoint was TCD, defined as the time elapsed 
between randomization and tumor progression during a chemotherapy sequence. The study 
randomized 494 participants assigned to either FOLFIRI plus bevacizumab induction 
chemotherapy followed by bevacizumab maintenance during CFI (n=247) or to the same 
induction chemotherapy followed by observation during CFI (n=247). The median TCD was 
15 months in both arms (HR, 1.07; 95% CI, 0.85 to 1.34; p=0.57). The median PFS was 
9.2 months in the maintenance arm and 8.9 months in the observation arm (HR, 0.91; 
95% CI, 0.76 to 1.09; p=0.316). The 12-month PFS was 30.2% (± 2.9) in the maintenance 
arm and 21.0% (± 2.6) in the observation arm. The median time to treatment failure was 
11.1 months in the maintenance arm and 12.1 months in the observation arm (HR, 1.17; 
95% CI, 0.97 to 1.40; p=0.092). The trial failed to demonstrate a treatment difference in TCD 
between the 2 treatment strategies of administering and not administering bevacizumab 
monotherapy during the maintenance period.
The current study (MK-7339-003) aims to compare the combination of fluoropyrimidine and 
bevacizumab to olaparib or olaparib plus bevacizumab as a maintenance strategy following 
discontinuation of CAPOX or FOLFOX in patients with CRC with the goal to improve the 
overall outcome in terms of efficacy and safety of first-line therapy in metastatic CRC.
2.2
Background
2.2.1
Olaparib
Olaparib (AZD2281, KU-0059436) is a potent PARP inhibitor (PARP1, 2, and 3) that is 
being developed as an oral anticancer therapy, both as monotherapy (including maintenance) 
and for combination with chemotherapy and other anticancer agents.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA SSBs. Inhibiting PARPs leads 
to the persistence of SSBs, which are then converted to the more serious DNA DSBs during 
the process of DNA replication. During the process of cell division, DSBs can be efficiently 
repaired in normal cells by HRR. Tumors with HRD, such as ovarian cancers in patients with 
BRCAm, cannot accurately repair the DNA damage, which may become lethal to cells as it 
accumulates. In such tumor types, olaparib may offer a potentially efficacious and less toxic 
cancer treatment compared with currently available chemotherapy regimens.
Olaparib traps the inactive form of PARP on DNA at sites of SSBs, thereby preventing their 
repair [Helleday, T. 2011] [Murai, J., et al 2012]. Olaparib has demonstrated efficacy in 
ovarian, prostate, and pancreatic tumors with BRCA1 and BRCA2 mutations and has shown 
proof of concept in tumors with ATM and other indicators of HRD. The specificity of 
olaparib for binding PARP at the replication fork during DNA replication is believed to have 
applicability to tumors associated with mutations in HRR.
Refer to the IB/approved labeling for detailed background information on olaparib.
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2.2.2
Pharmaceutical and Therapeutic Background
2.2.2.1
Inhibition of PARP as a Target for Cancer
PARP1 and PARP2 are zinc-finger DNA-binding enzymes that play a critical role in DNA 
repair [Ame, J. C., et al 2004] by sensing single-strand DNA damage and converting it into 
intracellular signals that activate the BER and SSB repair pathways. When a break in DNA 
occurs, PARP enzymes are recruited to, and bind at, the end of the broken DNA strands, 
activating their enzymatic activity. PARP subsequently catalyzes the addition of long 
polymers of ADP-ribose onto several other proteins associated with chromatin (eg, PARP, 
histones, DNA repair proteins), resulting in chromatin relaxation, rapid recruitment of DNA 
repair proteins, and efficient repair of the break. In the absence of repair of SSBs, during
subsequent DNA replication these breaks are converted to double strand breaks [Fong, Peter 
C., et al 2009].
Under normal conditions, HRR is the preferred pathway for repairing double strand DNA 
damage as it is associated with a lower rate of errors compared with other forms of DNA 
repair [Prakash, R., et al 2015]. Cells unable to perform HRR (eg, due to inactivation of 
genes required for homologous recombination, such as occur with deleterious mutations of 
BRCA1 or BRCA2) are more likely to use the error-prone NHEJ or alternative NHEJ 
pathways to repair these DSBs and risk accumulating multiple lesions or LOH due to an 
increase in deletions and accompanying genomic instability. Over time, the accumulation of 
excessive DNA errors in combination with the inability to complete S phase (ie, because of 
stalled replication forks due to PARP inhibitor administration), leads to cell death 
demonstrating that PARP inhibition is synthetic lethal in the context of BRCA mutations
[Farmer, H., et al 2005] [Bryant, H. E., et al 2005]. Cells without SSBs or with intact HRR, 
such as somatic tissue, replicate normally in the presence of a PARP inhibitor, thereby 
minimizing toxicity.
2.2.2.2
PARP Inhibition in Platinum-sensitive Cancers
Cisplatin, carboplatin and oxaliplatin are the backbone of platinum-based therapy for several 
malignancies, such as lung, ovarian, head and neck, colorectal, breast, genitourinary, and 
pancreatic cancers [Kelland, Lloyd 2007]. General mechanisms of action that are common 
among platinum agents are the formation of DNA cross-links, induction of DNA replicative 
stress, mitotic arrest, and ultimate cell death [Dilruba, S. 2016]. Hence, cancers with 
deficiencies in DNA damage repair pathways are particularly sensitive to platinum-based 
chemotherapies.
These cancer types are also sensitive to PARP inhibitors. PARP inhibitors have been shown 
to be effective in ovarian, prostate, breast, and pancreatic cancers [Ledermann, J., et al 2012] 
[Moore, K., et al 2018] [Robson, M., et al 2017] [Mirza, M. R., et al 2016] [Swisher, E. M., 
et al 2017]. See the olaparib IB for more information.
Sensitivity to platinum-based chemotherapy is a good predictor of response to PARP 
inhibition as demonstrated by these trials and therefore, it has been used as a biomarker for 
patient selection in PARP inhibitor maintenance clinical trials [Gelmon, K. A., et al 2011]. 
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Olaparib is approved as maintenance therapy for patients with platinum-sensitive relapsed 
ovarian cancer. Pancreatic cancer is another malignancy where platinum sensitivity is used as 
a selection criterion for testing PARP inhibitor efficacy in patients with gBRCA mutant 
cancers (POLO trial; NCT02184195).
The cross-sensitivity between PARP inhibitors and platinum-based chemotherapies is 
predicted to be due to similar repair mechanisms being used to repair the DNA damage 
resulting from exposure to both classes of drugs.
Correlating platinum sensitivity to response to PARP inhibition is also being explored in 
other malignancies, such as breast cancer. Germline BRCA1/2 mutations are frequent in 
HER2-negative breast cancers, particularly the TNBC subtype. TNBC’s biology, like in 
ovarian cancer, features high frequency of TP53 mutations, genomic instabilities and HRD 
signatures [Paik, S., et al 2012]. These similarities with ovarian cancer led to a number of 
clinical trials exploring PARP inhibitor’s efficacy in HER2-negative breast cancer and 
TNBC. Olaparib has been recently approved for the treatment of patients with gBRCAm
HER2-negative metastatic breast cancer who have been treated with chemotherapy 
(neoadjuvant, adjuvant or metastatic setting). In the OlympiAD trial (NCT02000622), an 
open-label, multicenter study evaluating olaparib monotherapy efficacy in patients with 
gBRCAm, HER2-negative metastatic breast cancer, the median PFS was significantly longer 
in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; HR
0.58; 95% CI, 0.43 to 0.80; p<0.001) [Robson, M., et al 2017]. Approximately 30% of the 
participants in this trial were previously treated with platinum-based chemotherapy.
In SCLC, a Phase 1 trial testing the PARP inhibitor talazoparib in participants with multiple
indications (NCT01286987) demonstrated preliminary efficacy in participants with platinum-
sensitive cancers. In this cohort of 23 participants, 2 participants (9%) had a PR and 
4 participants (17%) had stable disease [de Bono, J., et al 2017]. A Phase 2 trial is currently 
exploring talazoparib in combination with low-dose temozolomide in platinum-sensitive 
participants (NCT03672773).
2.2.2.2.1
Rationale for PARP Inhibition in CRC
Similar to ovarian cancer, platinum-based chemotherapy is the standard of care in CRC as 
the frontline treatment. In numerous clinical studies (eg, PAOLA-1, SOLO, PROfound as 
monotherapy and in combination with bevacizumab) evaluating the PARP inhibitors’ 
efficacy in ovarian cancer patients, platinum sensitivity was a valuable predictor of response 
to PARP inhibition. Hence, the patient selection was based on participants whose CRC had
not progressed following prior CAPOX or FOLFOX induction with bevacizumab. The 
oxaliplatin-free interval of ≥6 months in CRC patients is associated with better ORR, PFS,
and OS, and often this patient subpopulation responds well to second-line platinum treatment
[Venook, A. P. 2015]. Given that the platinum efficacy is the highest in tumors with defects 
in DNA damage repair pathways, it was not surprising that the ovarian cancer patients with 
platinum-sensitive tumors responded well to PARP inhibition in the maintenance setting.
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2.2.2.2.2
Rationale for Combining Olaparib and Bevacizumab in CRC
There are several data suggesting that olaparib and bevacizumab may be synergistic. One 
mechanism of bevacizumab resistance is hypoxia induction as a response to vessel regression 
caused by the anti-angiogenic agent, resulting in an increase of DNA damage and genetic 
instability [Chan, N., et al 2010]. This observation that tumor cells exposed to chronic 
hypoxia acquire defects in HR and increased sensitivity to PARP inhibition [Hegan, D. C., et 
al 2010] is an example of ‘contextual synthetic lethality’ in which hypoxia-induced repair-
deficient tumor cells can be targeted by disrupting backup pathways. Therefore, the premise 
of combining olaparib and bevacizumab is based on the rationale that direct targeting of 
PARP by olaparib and indirect sensitization to olaparib by acquisition of HR defects by 
bevacizumab will be therapeutically beneficial.
The potential synergy between olaparib and anti-VEGF therapy has been recently supported 
by the results of randomized Phase 2 trial showing that the combination of the antiangiogenic 
cediranib (30 mg daily po) plus olaparib (200 mg capsules BID) for the treatment of 
recurrent platinum-sensitive HGSOC compared to olaparib alone prolonged PFS from a 
median of 8.2 months to 16.5 months (HR 0.50; 95% CI, 0.30 to 0.83, p=0.007) [Liu, J. F., et 
al 2017]. However, the combination treatment elicited frequent toxicities leading to dose 
modifications in 77% of participants (compared to 24% in the single-agent arm), with 
increased occurrence of severe hypertension, fatigue and diarrhea which were previously 
reported toxicities for cediranib.
A Phase 1 study established the safety and tolerability of olaparib alone and in combination 
with bevacizumab. Participants with advanced solid tumors received oral olaparib (100 mg, 
200 mg, or 400 mg BID) in combination with bevacizumab (5 mg/kg IV Q2W). In the 
12 participants treated, the most common AEs related to olaparib were Grade 1/2 nausea and 
fatigue. No serious drug-related AEs or DLTs were reported. This study demonstrated that 
the combination of olaparib with bevacizumab was generally well tolerated with no DLTs 
observed and that it warranted additional investigations [Dean, E., et al 2012]. The PAOLA 
trial (NCT02477644) is evaluating the combination of olaparib (300 mg BID) and 
bevacizumab as maintenance therapy after response to first platinum-based therapy of 
advanced ovarian cancer.
2.2.3
Preclinical and Clinical Studies
The preclinical experience with olaparib is fully described in the IB.
SOLO1
SOLO1 is a randomized, double-blinded, placebo-controlled trial designed to evaluate the 
efficacy and safety of olaparib (tablets, 300 mg BID) as maintenance monotherapy in newly
diagnosed BRCAm ovarian cancer patients that are platinum-sensitive. Compared to placebo, 
olaparib significantly reduced the risk of disease progression. The median total treatment 
duration in the olaparib arm (106.9 weeks [approximately 25 months], reflecting the 2-year
treatment cap) was almost double that of the placebo arm (60.3 weeks [approximately 
14 months], reflecting median PFS in the placebo arm); equating to an exposure advantage 
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for patients in the olaparib arm of approximately 47 weeks (approximately 11 months). At 41
months follow-up, the median PFS for the olaparib-treated cohort was not reached, compared 
to 13.8 months for the placebo control (HR 0.30; 95% CI, 0.23 to 0.41; p<0.0001). At the 3-
year timepoint, 60.4% of patients in the olaparib-treated group had no disease progression 
versus 26.9% in the placebo group. Olaparib as maintenance monotherapy led to a substantial 
improvement in PFS in patients with newly diagnosed advanced BRCA mutant ovarian 
cancer patients, with a difference in median PFS for olaparib versus placebo of 
approximately 3 years [Moore, K., et al 2018].
SOLO2
SOLO2 is a randomized, double-blind, placebo-controlled Phase 3 study that evaluated
olaparib (300 mg BID) for the maintenance treatment of platinum-sensitive, relapsed ovarian 
cancer in patients with gBRCAm. Compared to placebo, olaparib significantly improved 
investigator-assessed median PFS from 5.5 months to 19.1 months (HR 0.30; 95% CI, 0.22
to 0.41; p<0.0001). Overall survival data were immature at the data cutoff [Pujade-Lauraine, 
E., et al 2017].
Study 19
Study 19 is a Phase 2, randomized, double-blind, multicenter study that assessed the efficacy 
of olaparib monotherapy in the maintenance treatment of patients with platinum-sensitive 
serous ovarian cancer, following treatment with 2 or more platinum containing regimens 
[Friedlander, M., et al 2018]. Thirty-two patients (24%) in the study continued receiving 
olaparib maintenance for over 2 years, and 15 patients (11%) received olaparib maintenance 
for over 6 years. Long-term treatment with olaparib was demonstrated to be well tolerated, 
with no new safety signals observed.
OlympiAD
OlympiAD was a randomized, open-label, Phase 3 study that evaluated olaparib
monotherapy (300 mg BID) versus TPC chemotherapy for the treatment of metastatic, 
HER2-, gBRCAm breast cancer in patients who had received no more than 2 previous 
chemotherapy regimens. Compared to TPC, olaparib significantly improved mPFS as 
assessed by BICR (7.0 months vs. 4.2 months; HR= 0.58; 95% CI, 0.43 to 0.80; p<0.001). 
Additionally, olaparib significantly improved the median PFS2 (13.2 months vs. 9.3 months; 
HR: 0.57; 95% CI, 0.40 to 0.83; p=0.003). Finally, the ORR for olaparib was 59.9% (95% 
CI: 52.0 to 67.4; 9% CR) compared to 28.8% (95% CI: 18.3 to 41.3; 1.5% CR) for TPC 
[Robson, M., et al 2017].
TOPARP
TOPARP was an open-label, multicenter, Phase 2 investigator-initiated single arm study
(NCT01682772) of olaparib (400 mg BID) for the treatment of mCRPC in patients who had 
progressed after 1 or 2 prior treatment regimens. All patients must have received prior 
docetaxel. The primary endpoint, composite RR, was defined as an OR by RECIST 1.1, a 
reduction in PSA ≥50%, or a decrease in the number of CTC from ≥5 to <5 per 7.5 mL
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blood. The secondary endpoints included safety, tolerability, PFS, and OS. Of 49 evaluable 
patients, 16 (32.7%) responded to olaparib (95% CI: 20.0 to 47.5), and 12 patients remained 
on treatment for greater than 6 months. Six of 32 patients with RECIST 1.1-measurable 
disease had radiological responses (18.8 %) and 11 patients had a biochemical response 
(≥50% decrease in PSA). Four responses lasted more than 1 year. Next generation 
sequencing identified homozygous deletions and/or deleterious mutations in DNA repair 
genes in 16/49 (32.7%) cases, including 7 patients with BRCA2 mutations and 5 patients with 
ATM alterations. Of the 16 patients with DNA repair mutations, 14 patients (87.5%) 
responded to olaparib by RR including all 7/7 patients with BRCA2 loss (4 bi-allelic somatic 
loss; 3 germline mutations) and 4/5 patients with ATM aberrations. Few responses were 
observed in biomarker-negative patients (2/33 = 6% ORR). Median PFS of the 16 biomarker-
positive patients was 9.8 months with a median OS of 13.8 months. In contrast, in the 
biomarker-negative group, mPFS was 2.7 months and median OS was 7.5 months [Mateo, J., 
et al 2015].
Study 42
Study 42 was a nonrandomized, open-label, multicenter, Phase 2 study of olaparib in patients 
with advanced ovarian, breast, pancreatic, or prostate cancers and gBRCAm. The ORRs 
reported were 26.2% (78/298, 95% CI, 21.3 to 31.6) for the total study population, 31.1% 
(60/193; 95% CI, 24.6 to 38.1) for ovarian, 12.9% (8/62; 95% CI, 5.7 to 23.9) for breast, 
21.7% (5/23; 95% CI, 7.5 to 43.7) for pancreas, and 50.0% (4/8; 95% CI, 15.7 to 84.3) for
prostate cancer [Kaufman, B., et al 2015].
In summary, olaparib monotherapy treatment has resulted in favorable ORRs in a variety of 
HRRm advanced solid tumors including breast, ovarian, and prostate cancers. This broad 
response suggests that a strong association between HRRm and olaparib response may be 
tumor-agnostic.
2.2.4
Ongoing Clinical Studies
The Phase 3 PROfound clinical trial (NCT02987543) is evaluating olaparib in participants
with mCRPC who progressed on prior nonhormonal treatments. Participants are randomly 
assigned based on mutations in genes associated with HRD by the Lynparza™HRR assay to 
Cohort A (BRCA1, BRCA2, or ATM mutations) or Cohort B (men with a mutation in 1 of the 
12 other HRR genes). Participants are randomly assigned (2:1) to receive either olaparib or 
physician’s choice of enzalutamide or abiraterone. The primary endpoint is radiographic 
PFS, and secondary efficacy endpoints include ORR, time to pain progression, and OS.
The Phase 3 POLO clinical trial (NCT02184195) is evaluating olaparib as monotherapy in 
participants with metastatic pancreatic cancer with gBRCAm and whose tumors have not 
progressed on at least 16 weeks of platinum-base chemotherapy. Participants are randomly 
assigned in a 3:2 ratio to either olaparib (300 mg BID) or placebo. The primary endpoint is 
PFS, and secondary efficacy endpoints include OS, time from randomization to PFS2, TFST, 
TSST, TDT, ORR, and DCR.
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The Phase 3 SOLO3 clinical trial (NCT02282020) is evaluating olaparib in participants with 
relapsed gBRCAm ovarian cancer who have progressed at least 6 months after their last 
platinum treatment and have received at least 2 prior platinum treatments. Participants are 
randomly assigned to either olaparib 300 mg BID or physician’s choice of chemotherapy. 
The primary endpoint is ORR, and secondary efficacy endpoints include OS, PFS2, time to 
earliest progression by RECIST 1.1, CA-125, or death, time to deterioration of HRQoL, 
TFST, TSST, and TDT.
The Phase 3 PAOLA-1 clinical trial (NCT02477644) is evaluating olaparib in maintenance 
therapy in participants with high-grade serous or endometrioid advanced ovarian cancer 
(including patients with primary peritoneal and/or fallopian tube cancer) who have responded 
following first-line platinum-paclitaxel based chemotherapy plus bevacizumab concomitant 
with chemotherapy and in maintenance (planned for 15 months). Participants must have 
completed a minimum of 6 and maximum of 9 cycles of first-line platinum-paclitaxel based 
chemotherapy, including a minimum of 3 cycles of bevacizumab in combination with the 3 
last cycles of chemotherapy. Participants were randomly assigned in 2:1 ratio to olaparib 300 
mg BID or placebo. The primary endpoint is PFS, and secondary efficacy endpoints include: 
PFS2, time to earliest progression (by RECIST 1.1) or CA-125, TFST, TSST, OS, effects of 
olaparib maintenance compared to placebo, and safety/tolerability.
For a summary of ongoing clinical study data and results for olaparib, refer to the IB.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
As olaparib has been found to be well tolerated across various tumor types, a positive 
benefit/risk profile is anticipated.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
NOTE: Based on the data from IA1 of safety and efficacy for LYNK-003 (data cutoff 10-
MAY-2022), the eDMC recommended stopping the study enrollment for futility based on 
prespecified futility boundary of IA1. The prespecified final analysis of the study described 
in the SAP will not be performed.
Selected analyses of safety endpoints will be performed at the end of the study. There will be 
no further analyses of efficacy and PRO endpoints.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
NOTE: As of Amendment 05, participants who are still on study treatment will no longer 
have tumor response assessments by BICR. However, local tumor imaging assessments 
should continue as per local institutional guidelines. In addition, PRO assessments will no 
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longer be performed. Blood for RNA analysis and serum and plasma biomarker analysis will
no longer be collected. Updated analyses are described in Section 9. Post-treatment follow-up 
visits are no longer required except for safety and survival follow-up requirements (refer to 
Section 8.11.4). The section below is retained for reference.
In male or female participants with unresectable or metastatic CRC who have not progressed 
following prior FOLFOX + bevacizumab or CAPOX + bevacizumab induction.
The study is considered to have met its primary objective if at least 1 primary hypothesis test 
is significant.
Objectives
Endpoints
Primary
•
To compare PFS using RECIST 1.1 as 
assessed by BICR between the 
following treatments:
-
Olaparib + Bevacizumab versus a 
fluoropyrimidine + Bevacizumab
-
Olaparib versus A fluoropyrimidine
+ Bevacizumab
Hypotheses:
H1 – Olaparib + Bevacizumab is 
superior to a fluoropyrimidine +
Bevacizumab with respect to PFS using 
RECIST 1.1 as assessed by BICR.
H2 – Olaparib is superior to a 
fluoropyrimidine + Bevacizumab with 
respect to PFS using RECIST 1.1 as 
assessed by BICR.
•
PFS: the time from randomization to 
first documented disease progression 
(PD) or death due to any cause, 
whichever occurs first
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Objectives
Endpoints
Secondary
•
To compare OS between the following 
treatments:
-
Olaparib + Bevacizumab versus a 
fluropyrimidine + Bevacizumab
-
Olaparib versus a fluoropyrimidine
+ Bevacizumab
Hypotheses:
H3 – Olaparib + Bevacizumab is 
superior to a fluoropyrimidine +
Bevacizumab with respect to OS.
H4 – Olaparib is superior to a 
fluorpyrimidine + Bevacizumab with 
respect to OS.
•
OS: the time from randomization to 
death due to any cause
•
To evaluate ORR, and DOR using 
RECIST 1.1 as assessed by BICR
following administration of:
-
Olaparib + Bevacizumab
-
Olaparib
-
Fluoropyrimidine + Bevacizumab
•
OR: CR or PR
•
DOR: the time from first response (CR 
or PR) to subsequent disease 
progression or death due to any cause, 
whichever occurs first
•
To evaluate the safety and tolerability 
of:
-
Olaparib + Bevacizumab
-
Olaparib
•
AEs
•
Study intervention discontinuation due 
to AEs
Tertiary/Exploratory
•
To evaluate progression-free survival 2 
(PFS2) by investigator assessment
following administration of:
-
Olaparib + Bevacizumab
-
Olaparib
-
5-FU + Bevacizumab
•
PFS2: the time from randomization to 
second documented disease progression
(PD2) or death due to any cause, 
whichever occurs first
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Objectives
Endpoints
•
To evaluate DCR using RECIST 1.1 as 
assessed by BICR following 
administration of:
-
Olaparib + Bevacizumab
-
Olaparib
-
Fluoropyrimidine + Bevacizumab
•
Disease control: stable disease (SD), PR 
or CR
•
To evaluate mean changes from 
baseline in HRQoL scores and 
characterize health utilities
•
The global health status/QoL scores of 
the EORTC QLQ-C30 (items 29 and 
30)
•
The multi-item and single-item scales of 
the EORTC QLQ-C30
•
The multi-item and single-item scales of 
the EORTC QLQ-CR29
•
Health utilities as assessed using the 
EQ-5D 5L
•
To identify molecular (genomic, 
metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamics activity, and or the 
mechanism of action of olaparib with 
or without bevacizumab
•
Germline genetic variation
•
To evaluate pharmacokinetics of 
olaparib in the following treatment 
groups:
-
Olaparib + Bevacizumab
-
Olaparib
•
Olaparib plasma concentrations (Cmax
and Ctrough)
4
STUDY DESIGN
4.1
Overall Design
NOTE: Based on the data from IA1 of safety and efficacy for LYNK-003 (data cutoff 10-
MAY-2022), the eDMC recommended stopping the study enrollment for futility based on 
prespecified futility boundary of IA1. As a result the study team was unblinded and study 
enrollment was stopped (as of 18-JUL-2022). The prespecified analysis (IA 2,3,4 and FA) of 
the study described in the SAP will not be performed. Study participants randomized to one 
of the two experimental arms (olaparib plus bevacizumab [Arm 1] or olaparib monotherapy 
[Arm 2]) must discontinue study intervention. No crossover from either experimental arm to 
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SOC arm (Arm 3A and Arm 3B) within the study is allowed. Participants on SOC have the 
option to continue receiving study intervention until criteria for discontinuation is met at the 
discretion of the investigator. Participants on SOC will no longer have tumor response 
assessments by BICR. However, local tumor imaging assessments should continue as per local 
institutional guidelines.
This is a Phase 3 randomized, open-label study of olaparib alone or in combination with 
bevacizumab compared to bevacizumab + 5-FU or capecitabine in participants with 
unresectable or metastatic CRC that has not progressed following an induction course of 
CAPOX + bevacizumab or FOLFOX + bevacizumab. Approximately 525 participants will 
be enrolled and randomized to 1 of 3 intervention arms in a 1:1:1 ratio as follows:

Arm 1: Olaparib (300 mg BID) + bevacizumab (5 mg/kg IV Q2W)

Arm 2: Olaparib (300 mg BID)

Arm 3: Bevacizumab (5 mg/kg IV Q2W) + 5-FU (2400 mg/m2 IV over 46 to 48 hours 
Q2W) (Arm 3a) or bevacizumab (7.5mg/kg IV Q3W) + capecitabine (1000mg/m2 BID
for 14 days, then 7 days off, Q3W) (Arm 3b). The 5-FU regimen may include a bolus of 
5-FU prior to infusion: 400mg/m2 IV infusion on Day 1 based on local standards, 
investigator preference, and participant experience with the bolus during the induction 
phase.
Participants who begin study treatment with bevacizumab must remain on bevacizumab 
throughout the study. Participants who begin study treatment with biosimilar bevacizumab 
must remain on the same biosimilar throughout the study.
Randomization will be stratified based on whether the participant experienced SD versus a 
PR or CR to prior CAPOX + bevacizumab or FOLFOX + bevacizumab whether they have 
BRAF and/or Ras mutations versus wild type for both, and whether they received 4 to 6
cycles or >6 cycles of CAPOX + bevacizumab or 6 to 8 cycles or >8 cycles of FOLFOX + 
bevacizumab.
The study includes a non-binding futility analysis (Interim Analysis 1, IA1) to determine 
whether there is sufficient evidence to continue the experimental arms. If the PFS HR of 
either Arm 1 or Arm 2 compared to the control arm is less than the prespecified futility 
boundary, the study will continue as planned. Additional details regarding interim analyses 
can be found in Section 9.7.
Efficacy will be evaluated using PFS as the primary endpoint using RECIST 1.1 as 
determined by BICR. OS, ORR, DOR, and PFS2 will also be assessed. Participants will be 
evaluated with radiographic imaging to assess response to intervention at regular intervals. 
On study imaging will be assessed every 8 weeks (56 days ± 7 days) for 12 months and every 
12 weeks (84 days ± 7 days) thereafter. After documented PD, participants will receive 
investigator-choice anticancer therapy and will continue to be followed for disease status 
until a PFS2 event is recorded.
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All imaging obtained on study, including imaging showing investigator-assessed PD, will be 
submitted to the iCRO for BICR, which will assess the images using RECIST 1.1 for the 
determination of efficacy (Section 8.2.1). The iCRO will also collect scans taken before and 
during Screening and must determine the prior scans are of diagnostic quality and 
confirmation of non-PD by BICR prior to randomization.
Participants may undergo resection of the primary tumor and/or metastasectomy with 
curative intent after achieving a response to trial therapy that converts previously 
unresectable disease to resectable disease if deemed eligible per the investigator’s discretion 
in a multidisciplinary approach according to his/her institutional standard and with Sponsor 
consultation. After surgery, participants may resume the same therapy that they were 
receiving pre-operatively, when clinically appropriate and after the surgical wound is fully 
healed.
The first post-operative tumor imaging should be performed at a minimum of (no less than) 4 
weeks after surgery and no more than 8 weeks prior to the next treatment cycle (Section 
8.2.1.2). If treatment does not resume within 8 weeks after surgery the investigator should 
consult with the Sponsor.
For participants who undergo surgery with curative intent, a new baseline of tumor burden
will be established as described in Section 8.2.1.2.
Adverse event monitoring will be ongoing throughout the trial and AEs will be graded in 
severity according to the guidelines outlined in the NCI CTCAE v5. Adverse events and
SAEs will be reported by the investigator or delegate from allocation through 30 days 
following cessation of study intervention, or until initiation of reintroduction of investigator-
choice of anticancer therapy, whichever is earlier.
Study intervention will continue until documented PD, unacceptable AEs, intercurrent illness 
that prevents further administration of study intervention, investigator’s decision to 
discontinue the participant, participant withdrawal of consent, pregnancy of the participant, 
or administrative reasons requiring cessation of study intervention (Section 7.1).
Participants who discontinue study intervention for reasons other than documented PD will 
have post-treatment follow-up for disease status (including imaging) until PD. All 
participants will then be followed for disease status until second documented PD, 
withdrawing consent for study participation, or becoming lost to follow-up. Investigator 
assessment of disease status as part of routine clinical practice during the reintroduction of 
investigator-choice of anticancer therapy will be reported to assess for PFS2. No imaging 
will be collected as part of the study to assess or verify PFS2. Investigators will also provide 
information regarding all anticancer therapies given during the PFS2 follow-up period.
After second documented PD, each participant will be contacted (eg, by telephone)
approximately every 12 weeks (84 ± 7 days) for survival until withdrawal of consent to 
participate in the study, becoming lost to follow-up, death, or end of the study, whichever 
occurs first.
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CAPOX is a permitted induction regimen. Participants who received CAPOX/bevacizumab 
as induction, and who are subsequently randomized to the control arm, will receive 
capecitabine and bevacizumab as maintenance. The rationale for this change is based on the 
high utilization of CAPOX as an induction regimen in the community, to the point where 
allowing only FOLFOX/bevacizumab does not represent real-world practice.
FOLFOX and CAPOX are used interchangeably in CRC, both in the adjuvant and the 
metastatic setting. The NCCN guidelines recommend both of these regimens for first-line 
therapy as equivalent.
BICR confirmation of non-PD: the inclusion criteria in this study require a response of SD or 
better to first-line induction. In order to maintain population homogeneity, reduce 
interobserver variability, and ensure all participants enter the trial with the same clinical 
status, BICR confirmation of non-PD is required prior to randomization.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use PFS based on RECIST 1.1 criteria as assessed by BICR as the primary 
endpoint. Progression-free survival is an acceptable measure of clinical benefit for a late 
stage study that demonstrates superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of BICR and RECIST 1.1 to assess PFS is typically considered acceptable by regulatory 
authorities. Images will be submitted to an imaging CRO (iCRO) and read by an independent 
central review blinded to treatment assignment to minimize bias in the response assessments.  
In addition, the final determination of radiologic progression will be based on the central 
assessment of progression, rather than a local site investigator/radiology assessment. 
Expedited verification of radiologic progression as determined by central review will be 
communicated to the site.
Overall survival will be assessed as a key secondary endpoint, and ORR and DOR will be 
assessed as additional secondary efficacy endpoints. PFS2 and DCR will be assessed as 
exploratory efficacy endpoints.
Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies and will therefore 
be assessed as a key secondary endpoint in the study. However, the anticipated duration
needed to collect adequate OS data to make an accurate conclusion precludes the use of OS 
as the primary endpoint in this study.
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Objective response rate, DOR, and DCR together are considered acceptable measures of 
clinical benefit and will be assessed. PFS2 is an additional measure of clinical benefit and is 
most useful in a disease setting where most participants go on to receive similar subsequent 
therapies. It is expected for this study that most participants will be restarted on a platinum-
based chemotherapy regimen at progression on study therapy. However, all participants will 
be followed for PFS2 regardless of subsequent therapy.
4.2.1.1.1
RECIST 1.1
RECIST 1.1, which allows a maximum of 5 target lesions in total (2 per organ), will be used 
by the BICR and the local site when assessing images for efficacy measures and when 
determining eligibility and for all protocol guidelines related to disease status (eg, 
discontinuation of study intervention) (Section 8.2.1).
4.2.1.2
Safety Endpoints
Safety parameters frequently used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/SAEs; and changes in vital signs and laboratory values. 
Adverse events will be assessed as defined by NCI CTCAE v5.0.
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. As part of the
analyses for this trial, HRQoL and disease-related symptoms will be investigated among all 
participants via the following assessment tools:

EORTC QLQ C30

EORTC QLQ CR29

EQ-5D-5L
These measures are not pure efficacy or safety endpoints because they are affected by both 
disease progression and study intervention tolerability. EQ-5D-5L will also be used to 
calculate health utilities for health economic models.
4.2.1.3.1
EORTC QLQ-C30
The EORTC QLQ-C30 was developed to assess the QoL of participants with cancer. It has 
been translated and validated in over 100 languages and used in more than 3000 studies 
worldwide. It contains 5 functional scales (physical, role, cognitive, emotional, and social), 
3 symptom scales (fatigue, nausea, and pain), and 6 single symptom items (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact) [Aaronson, N. K., et 
al 1993]. It is scored on a 4-point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). 
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The EORTC QLQ-C30 instrument also contains 1 global health status/QoL scale that uses 7-
point scale scoring with anchors (1=very poor and 7=excellent).
4.2.1.3.2
EORTC QLQ-CR29
The EORTC QLQ-CR29, a supplemental colorectal cancer-specific module, comprises 
multi-item and single-item measures of colorectal cancer-associated symptoms and impact. It 
includes 4 scales assessing urinary frequency, fecal seepage, stool consistency, and body 
image, and single items assessing other common problems following colorectal cancer 
therapy.
4.2.1.3.3
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome. The 
EQ-5D-5L will provide data for use in economic models and analyses including developing 
health utilities or quality-adjusted life-years [Rabin, R. and de Charro, F. 2001]. The 5 health 
state dimensions addressed in this instrument are mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The EQ-5D-5L also 
includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or 
her general state of health at the time of the assessment. The EQ-5D-5L will always be 
completed by participants first, prior to completing any other PRO instruments. This 
instrument has been used extensively in cancer studies and published results from these 
studies support its validity and reliability [Pickard, A. S., et al 2007].
4.2.1.4
Pharmacokinetic Endpoints
Collection of olaparib PK samples in a limited number of patients (n = 50 in Arm 1 and n =
50 in Arm 2) is proposed to determine the exposure to olaparib. Exposure data along with 
other participant factors can be used to evaluate any potential differences compared to 
established olaparib PK.
4.2.1.5
Planned Exploratory Biomarker Research
PARP inhibitors represent an important class of antitumor agents. However, the mechanism 
of action of these new therapies is not completely understood and much remains to be 
learned regarding how best to leverage these new drugs in treating patients. Thus, to aid 
future patients, it is important to investigate the determinants of response or resistance to 
cancer therapy and other treatments administered, as well as determinants of AEs in the 
course of our clinical studies. These efforts may identify novel predictive/PD biomarkers and 
generate information that may better guide single-agent and combination therapy. To identify 
novel biomarkers, biospecimens (ie, blood components, tumor material) will be collected to 
support analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other 
circulating molecules. Investigations of biomarkers that correlate with response or resistance 
to treatment may include but are not limited to:
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Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). To conduct this type of research, it is important to identify 
tumor-specific mutations that occur across all genes in the tumor genome. Thus, genome-
wide approaches may be used for this effort. 
 
 
 
 
 
irculating tumor DNA and/or RNA may also be evaluated 
from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment. 
 
 
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses to identify tumor 
or blood-derived proteins that may also correlate with response. Therefore, tumor tissue may 
be subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays and liquid chromatography/mass spectrometry. This approach could 
identify novel protein biomarkers that could aid in patient selection.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, other tumor derived proteins can be shed from 
tumor and released into the blood. Assays such as enzyme-linked immunoassay (ELISA) 
measure such proteins in serum. Correlation of expression with response to therapy may 
identify new approaches for predictive biomarkers in blood, representing a major advance 
CCI
CCI
CCI
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from today’s reliance on assessing tumor biomarkers. This research would serve to develop 
such assays for future clinical use.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Maintenance therapy with bevacizumab and a fluoropyrimidine is frequently used for 
patients with unresectable or metastatic CRC who do not progress following an induction 
course of CAPOX or FOLFOX with or without bevacizumab. Both the ESMO consensus 
guidelines and NCCN practice guidelines for unresectable or metastatic CRC recommend the 
consideration of active maintenance with a fluoropyrimidine and bevacizumab for patients 
with a good response following first-line chemotherapy and who are experiencing 
unacceptable neurotoxicity due to oxaliplatin . Refer to the approved labeling for 
bevacizumab, 5-FU, and capecitabine for more information.
4.3
Justification for Dose
4.3.1
Rationale for Olaparib Dosing
The dose of olaparib used in this study is 300 mg BID (tablet formulation), which is the 
currently approved dose.
4.3.2
Rationale for 5-FU Dosing Regimen
5-FU will be administered at an approved dose and schedule (2400 mg/m2 IV over 46 to 48 
hours Q2W). The 5-FU regimen may include a bolus of 5-FU prior to infusion: 400mg/m2 IV 
infusion on Day 1 based on local standards, investigator preference, and participant 
experience with the bolus during the induction phase. Refer to its approved labeling for more 
information.
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4.3.3
Rationale for Capecitabine Dosing Regimen
Capecitabine will be administered at an approved dose and schedule (1000 mg/m2 BID 2 
weeks on, 1 week off, Q3W). Refer to its approved labeling for more information.
4.3.4
Rationale for Bevacizumab Dosing Regimen
Bevacizumab will be administered at an approved dose and schedule (5 mg/kg IV Q2W with 
5-FU or 7.5 mg/kg IV Q3W with capecitabine). Refer to its approved labeling for more 
information.
4.3.4.1
Rationale for Combination Dosing Regimen of Olaparib + Bevacizumab
In a Phase 1 study to assess the safety and tolerability of the combination of olaparib with 
bevacizumab, 12 participants with advanced solid tumors received increasing doses of 
continuous oral olaparib (100, 200, and 400 mg BID) in combination with bevacizumab 
(10 mg/kg Q2W) [Dean, E., et al 2012]. No SAEs related to treatment or DLTs were 
reported. The authors concluded the combination of olaparib 400 mg BID (capsule 
formulation) with bevacizumab 10 mg/kg Q2W was generally well tolerated with no DLTs
and could be considered for future clinical investigation. This study will treat participants 
with 300 mg olaparib BID, the current approved dose for olaparib, and 5 mg/kg of 
bevacizumab Q2W as this is the standard recommended dose in combination with FOLFOX 
for unresectable or metastatic CRC. It is expected that combination treatment at these dose 
levels should be safe as they are lower doses than those previously tested.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory test result or at 
the time of final contact with the last participant, whichever comes last. If the study includes 
countries in the European Economic Area (EEA), the local start of the study in the EAA is 
defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
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5
STUDY POPULATION
As of Amendment 05, study enrollment is being stopped for futility. Study participants 
randomized to one of the two experimental arms (olaparib plus bevacizumab [Arm 1] or 
olaparib monotherapy [Arm 2]) must discontinue study intervention. No crossover from 
either experimental arm to SOC arm (Arm 3A and Arm 3B) within the study is allowed. 
Participants on SOC have the option to continue receiving study intervention until criteria for 
discontinuation is met at the discretion of the investigator.
As stated in the Code of Conduct for Clinical Trials (Appendix 1, Section 10.1.1) this study 
includes participants of varying age (as applicable), race, ethnicity, and sex (as applicable). 
The collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Male/Female participants of at least 18 years of age with unresectable or metastatic CRC
who have not progressed following prior CAPOX + bevacizumab or FOLFOX + 
bevacizumab will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant is eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has a histologically-confirmed metastatic or unresectable (Stage IV as defined by AJCC 
eighth edition) colorectal adenocarcinoma (NCCN 2018).
2. Has not progressed (ie, achieved a SD, PR, or CR) after a first-line induction course of at 
least 6 cycles of FOLFOX + bevacizumab or 4 cycles of CAPOX + bevacizumab as first-
line therapy.

Participants must not have received an investigational agent during their induction 
course.

Determination of best overall response (SD/PR/CR) will be made by the investigator.

Non-PD will be verified by BICR prior to randomization based on the images 
submitted to iCRO as described in inclusion criterion 4.

“First-line therapy” is defined as the first systemic chemotherapy regimen given for 
the diagnosis of unresectable or metastatic CRC. Participants may have received prior 
adjuvant/neoadjuvant chemotherapy for CRC as long as it was completed at least 6 
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months prior to initiation of first-line CAPOX + bevacizumab or FOLFOX + 
bevacizumab induction treatment. 
3. Has experienced unacceptable toxicity to oxaliplatin that, in the opinion of the treating 
physician, requires/required the discontinuation of oxaliplatin. Note: As an example, 
unacceptable toxicity may include (but is not limited to) severe or prolonged 
neurotoxicity.

Participants must be randomized within a minimum of 2 weeks and a maximum of 
6 weeks after their last dose of CAPOX + bevacizumab or FOLFOX + bevacizumab
(last dose is the day of the last infusion that contained oxaliplatin).
4. Has provided to the iCRO 1 set of baseline radiographic images taken before or during 
the CAPOX + bevacizumab or FOLFOX + bevacizumab induction period and at least 42 
days prior to the imaging performed during Screening. Tumor imaging at Screening must 
be performed within 28 days prior to the date of randomization. 
5. Has an ECOG performance status of 0 to 1 within 10 days prior to randomization.
6. Has the ability to swallow and retain oral medication and not have any clinically 
significant gastrointestinal abnormalities that might alter absorption.
7. Has adequate organ function, as detailed in Table 1; all Screening laboratory tests should 
be performed within 10 days of randomization.
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Table 1
Adequate Organ Function Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥10.0 g/dL or ≥5.6 mmol/La
Renal
Estimated creatinine clearance using the Cockcroft-
Gault equationb
≥51 mL/min
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); ULN=upper limit of normal.
a Criteria must be met without packed red blood cell (pRBC) transfusion within last 2 weeks.
b Estimated creatinine clearance using Cockcroft-Gault:
(140-age [years] × weight [kg])
(× F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
8. Has provided a tumor tissue sample to the central lab for biomarker analysis.

If a sample is not available at Screening, a new tissue sample is required to be 
collected during Screening.
Demographics
9. Is male or female, at least 18 years of age, at the time of providing documented informed 
consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods
of contraception for those participating in clinical studies.
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10. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention is:
-
Olaparib: 90 days
-
5-FU: 90 days
-
Capecitabine: 90 days
-
Leucovorin/levoleucovorin: 90 days.
-
Bevacizumab: none.
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
•
Male participants must also agree to use male condom when engaging in any activity 
that allows for passage of ejaculate to another person of any sex.
Female Participants
11. Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies:
•
Is not a WOCBP
OR
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•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and 
persistent basis), as described in Appendix 5 during the intervention period and for at 
least the time needed to eliminate each study intervention ) after the last dose of study 
intervention. The participant agrees not to donate eggs (ova, oocytes) to others or 
freeze/store eggs during this period for the purpose of reproduction. The length of 
time required to continue contraception for each study intervention is:. 
-
Olaparib: 180 days
-
5-FU: 180 days
-
Capecitabine: 180 days
-
Leucovorin/levoleucovorin: 180 days.
-
Bevacizumab: 120 days.
•
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. If 
the contraception requirements in the local label for any of the study interventions are 
more stringent than the requirements above, the local label requirements are to be 
followed.
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as 
required by local regulations within 72 hours (serum) or 24 hours (urine) before the 
first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 2.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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Informed Consent
12. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has known hypersensitivity to the components and/or excipients in bevacizumab, 5-FU, 
capecitabine, or olaparib.
2. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable (ie, without evidence of progression for at least 28 days by repeat imaging - note 
that the repeat imaging should be performed during study Screening), clinically stable 
and without requirement of steroid intervention for at least 14 days prior to first dose of 
study intervention.
3. Has an active infection requiring systemic therapy.
4. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
5. Has a known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C 
(HCV RNA [qualitative] is detected).
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority.
6. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
7. Has MDS/AML or with features suggestive of MDS/AML.
8. Has hemoptysis or hematemesis within 28 days prior to randomization.
9. Has evidence of bleeding diathesis or significant coagulopathy (in the absence of 
anticoagulation).
10. Has clinically significant bleeding within 28 days prior to randomization.
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11. Is considered a poor medical risk due to a serious, uncontrolled medical disorder, non-
malignant systemic disease or active, uncontrolled infection. Examples include, but are 
not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial 
infarction, uncontrolled major seizure disorder, unstable spinal cord compression, 
superior vena cava syndrome, extensive interstitial bilateral lung disease on HRCT scan 
or any psychiatric disorder that prohibits obtaining informed consent.
12. Has 1 or more conditions that, in the opinion of the treating physician, make the 
participant ineligible for treatment with bevacizumab. These conditions may include:

Uncontrolled hypertension (SBP >150 mm Hg or DBP >100 mm Hg) or a history of 
hypertensive crisis or hypertensive encephalopathy

Arterial thromboembolic events (eg, myocardial infarction, cerebral infarction)

History of nephrotic syndrome or moderate proteinuria

History of gastrointestinal perforation

History of non-gastrointestinal fistula formation

History of RPLS
Prior/Concomitant Therapy
13. Has received prior systemic anticancer therapy (other than CAPOX + bevacizumab or 
FOLFOX + bevacizumab induction) including investigational agents within 28 days prior 
to randomization.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with persistent alopecia or Grade ≤3 neuropathy are
eligible.
14. Has received prior therapy with olaparib or with any other PARP inhibitor.
15. Is currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, telaprevir) or moderate (eg, ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil) inhibitors of CYP3A4 that cannot be discontinued for the 
duration of the study. The required washout period prior to randomization is 2 weeks.
16. Is currently receiving either strong (phenobarbital, enzalutamide, phenytoin, rifampicin, 
rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate (eg,
bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be discontinued for the 
duration of the study. The required washout period prior to randomization is 5 weeks for 
phenobarbital and 3 weeks for other agents.
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Note: A current list of strong/moderate inhibitors or inducers of CYP3A4 can be found at 
the following website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
17. Has undergone major surgery within 2 weeks of randomization or has not recovered 
adequately from toxicities and/or complications from any major surgery prior to 
randomization.
18. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis. A 1-week washout is permitted for palliative 
radiation (≤2 weeks of radiotherapy) to non-CNS disease.
Prior/Concurrent Clinical Study Experience
19. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 28 days prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 28 days after the last dose of the previous investigational 
agent.
Diagnostic Assessments
20. Has a known additional malignancy that is progressing or has required active therapy
within the past 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
21. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
22. Has clinically significant (eg, active) cardiovascular disease, including:

Myocardial infarction or unstable angina within ≤6 months of randomization

CHF ≥Grade 2 (as per New York Heart Association)

The presence of uncontrolled, potentially reversible cardiac conditions, as judged by 
the investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, 
congestive heart failure, QTcF prolongation >450 ms on 2 or more time points within 
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a 24 hour period, electrolyte disturbances, etc), or patients with congenital long QT 
syndrome 

Peripheral vascular disease ≥Grade 3 (eg, symptomatic and interfering with activities 
of daily living requiring repair or revision)
23. Has known dihydropyrimidine dehydrogenase (DPD) deficiency
Other Exclusions
24. This criterion was removed as a result of updates to the pregnancy and contraception 
language in Inclusion Criteria #10 and #11.
25. Received a live or live-attenuated vaccine within 30 days before the first dose of study 
intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5.2 for information on COVID-19 vaccines.
Refer to Appendix 7 for country-specific requirements.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants receiving olaparib should avoid grapefruit, grapefruit juice, Seville oranges, 
Seville orange juice, and St. John’s Wort (tablet or tea) while receiving study intervention. 
Otherwise, participants should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea, or vomiting.
5.3.2
Driving or Operating Machinery
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, participants
receiving olaparib should be advised to use caution while driving or operating machinery if 
these symptoms occur.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant during the study, the participant will be 
immediately discontinued from study intervention. The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to the Sponsor without delay 
and within 24 hours if the outcome is an SAE (eg, death, abortion, congenital anomaly, or 
other disabling or life-threatening complication to the mother or newborn). The study 
investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male 
participant impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy must be reported to the Sponsor and followed as described in 
Section 8.4.5.
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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized 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 AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention will not be replaced.
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.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
As of Amendment 05, study enrollment is being stopped for futility. Study participants 
randomized to one of the two experimental arms (olaparib plus bevacizumab [Arm 1] or 
olaparib monotherapy [Arm 2]) must discontinue study intervention. No crossover from
either experimental arm to SOC arm (Arm 3A and Arm 3B) within the study is allowed. 
Participants on SOC have the option to continue receiving study intervention until criteria for 
discontinuation is met at the discretion of the investigator. 
The study interventions to be used in this study are outlined in Table 2.
Country-specific requirements are noted in Appendix 7.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP
or 
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Olaparib
Drug
Tablet
150 mg
300 mg
Oral
Twice Daily
Test 
Product
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 1
Experi-
mental
Bevacizumab
Drug
Vial
Variable
5 mg/kg
IV 
Infusion
Q2W
Test 
Product
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 2
Experi-
mental
Olaparib
Drug
Tablet
150 mg
300 mg
Oral
Twice Daily
Test 
Product
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 
3a/3b
Active 
Compar-
ator
Bevacizumab
Drug
Vial
Variable
5 mg/kg or 
7.5 mg/kg
IV 
Infusion
Q2W or 
Q3W
Compa-
rator
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
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Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admini-
stration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP
or 
NIMP/
AxMP
Sourcing
Arm 3a
Active 
Compar-
ator
5-FU
Drug
Vial
Variable
2400 mg/m2 
over 46 to 
48 hours
IV 
Infusion
Q2W
Compa-
rator
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 3b
Active 
Compar-
ator
Capecitabine
Drug
Tablet
Variable
1000mg/m2
Oral
BID 14 days 
on, 7 days 
off Q3W
Compa-
rator
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
Arm 3a
Active 
Compar-
ator
Leucovorin/ 
levoleucovorin
Drug
Vial
Variable
400 mg/m2
(leucovorin) 
or 200 
mg/m2 (levo-
leucovorin)
IV 
Infusion
Q2W
Compa-
rator
IMP
Centrally by the 
Sponsor, or 
locally by the 
trial site, 
subsidiary, or 
designee
5-FU=fluorouracil; BID=twice daily; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
Q2W=every 2 weeks; Q3W=every 3 weeks.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: 100 mg olaparib tablets will also be made available and are to be used only in the event of dose modifications.
Participants who received CAPOX will receive a dose of 7.5 mg/kg of bevacizumab (Arm 3b), while those who received FOLFOX will receive 5 mg/kg of bevacizumab (Arm 3a).
5-FU regimen may include a bolus of 5-FU prior to infusion: 400mg/m2 IV infusion on Day 1 based on local standards, investigator preference, and participant experience with the bolus during the 
induction phase
Participants who begin study treatment with bevacizumab must remain on bevacizumab throughout the study. Participants who begin study treatment with biosimilar bevacizumab must remain on the 
same biosimilar throughout the study.
Leucovorin/levoleucovorin may be added to Arm 3a per investigator’s discretion.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Bevacizumab, leucovorin, and 5-FU should be prepared per local and institutional guidelines 
according to the approved product labels. Refer to the Pharmacy Manual for more details 
regarding olaparib administration.
Capecitabine will be given at 1000 mg/m2 po BID for Days 1-14 only of a 21-day cycle.
As capecitabine is an oral drug available in fixed doses, the dose administered may not 
exactly match the calculated dose. Determination of the rounding of capecitabine doses for 
administration should be made according to local institutional practices, with documentation 
of both the calculated and administered dose.
Capecitabine should be prepared and administered per instructions in the package insert. 
Capecitabine will be administered po based on instructions provided by the investigator. Per 
package insert, it is recommended that capecitabine be administered with food.
The rationale for selection of doses to be used in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
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 authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
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investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 3 study intervention arms. Participants will be assigned 
randomly in a 1:1:1 ratio to Arm 1 (olaparib + bevacizumab), Arm 2 (olaparib monotherapy), 
or Arm 3a/Arm 3b (bevacizumab + fluoropyrimidine [5-FU or capecitabine]).
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. SD versus PR/CR to prior FOLFOX + bevacizumab or CAPOX + bevacizumab induction
2. BRAFmut and/or Rasmut versus BRAFwt + Raswt
3. Number of induction cycles

For FOLFOX-based induction, 6 to 8 cycles versus >8 cycles

For CAPOX-based induction, 4 to 6 cycles versus >6 cycles
Note: Stratification is based on the number of cycles of FOLFOX or CAPOX with or 
without bevacizumab.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for ≥4 weeks (28 days) require 
consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on participant management.
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Participants should be given clear instructions on how and when to take their study 
intervention. Participants will self-administer olaparib except when a clinic visit is scheduled. 
Study site staff will make tablet counts at regular intervals during treatment. After the tablet 
count has been performed, the remaining tablets will not be returned to the participant but 
will be retained by the investigative site until reconciliation is completed by the study 
monitor. Olaparib compliance will be calculated by the Sponsor based on the drug 
accountability documented by the site staff and monitored by the Sponsor/designee. All 
participants must return their bottle(s) of olaparib at the appropriate scheduled visit, when a 
new bottle will be dispensed. Participants will be instructed to notify study site personnel of 
missed doses.
6.5
Concomitant Therapy
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered >30 days after the last dose of study intervention
should be recorded for SAEs and ECIs as defined in Section 8.4.7.
Based on limited in vitro data, olaparib may increase the exposure to substrates of CYP3A4, 
organic-anion-transporting polypeptide (OATP)1B1, organic cation transporter (OCT)1/2/3, 
and multidrug and toxic compound extrusion (MATE)1/2 and reduce exposure to substrates 
of CYP2B6. Caution should be observed if substrates of these isoenzymes or transporter 
proteins are co-administered. A current list of substrates can be found at the following 
website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
6.5.1
Leucovorin/Levoleucovorin
Leucovorin (calcium folinate/folinic acid/calcium leucovorin, 400 mg/m2, IV infusion Q2W) 
or levoleucovorin (200 mg/m2, IV infusion, Q2W) may be used in Arm 3a with 5-FU at the 
investigator’s discretion, and in accordance with local standards.
6.5.2
Prohibited Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria (Section 5.2) are 
not allowed during Screening and during the study intervention phase of the ongoing study. 
If there is a clinical indication for any medication or vaccination specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
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questions regarding this with the Sponsor Clinical Director. The final decision on any 
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.

Investigational agents other than olaparib.

Radiation therapy for disease control.
Note: Radiation therapy to symptomatic lesions or to the brain may be allowed following 
Sponsor consultation.

Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. 
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.

Anticancer hormonal therapy (eg, androgen deprivation, androgen receptor blockade, 
anti-estrogens)
Note: Hormonal replacement therapy is allowed.

Strong and moderate inducers or inhibitors of CYP3A4 that cannot be discontinued for 
the duration of the study.
Note: a current list of strong/moderate inducers/inhibitors of CYP3A4 can be found 
at the following website:
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
Note: Exceptions are outlined in Section 6.6.1.3.4.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment but 
continue in trial for assessment of disease status and survival.
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There are no prohibited therapies during the post-treatment follow-up phase.
For participants being treated with capecitabine, bevacizumab, leucovorin or 5-FU, refer to 
their approved labeling for additional prohibited therapies.
6.5.3
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
6.6
Dose Modification Guidelines
NCI CTCAE v5.0 must be used to grade the severity of AEs. If appropriate, the investigator 
may attribute each toxicity event to olaparib, bevacizumab, capecitabine or 5-FU alone, or to 
any combination of these agents, and follow the dose modification guidelines accordingly 
below. If a participant experiences several toxicities and there are conflicting 
recommendations, following the most conservative dose adjustment is recommended (dose 
reduction appropriate for the most severe toxicity).
Reduction or holding of 1 agent and not the other agents is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to 1 of the study drugs. If, in the opinion of the 
investigator, the toxicity is related to a combination of agents, both drugs should be held 
according to recommended dose modifications.
If toxicity does not revolve to Grade 0 or 1 within 12 weeks after the last dose, study 
treatment should be discontinued after consultation with the Sponsor. With investigator and 
Sponsor agreement, participants with a laboratory AE still at Grade 2 after 12 weeks may 
continue treatment in the study if the AE is asymptomatic and controlled. After any Grade 4 
drug-related AE, participants should not restart study treatment without consultation with the 
Sponsor.
6.6.1
Olaparib Dosing Modifications
Any toxicity observed during the course of the study that the investigator believes 
attributable to olaparib could be managed by interruption of olaparib treatment or dose 
reduction. Repeated interruptions, not exceeding 4 weeks (28 days) duration, are allowed as 
required. If the interruption is any longer, it must be agreed to by the Sponsor.
The dose of olaparib can be reduced to 250 mg BID initially and then to 200 mg BID as 
needed (except in specific instances as described in Sections 6.6.1.1 through 6.6.1.3). If the 
200 mg BID dose is not tolerable, no further dose reduction is allowed, and study 
intervention should be discontinued. Once the dose has been reduced, escalation is not 
permitted (except following concomitant treatment with CYP3A4 inhibitors – see Section 
6.6.1.3.4).
All dose reductions and interruptions (including any missed doses) and the reason(s) for the 
dose interruption/reduction should be captured on the appropriate eCRF.
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In Arm 1, if olaparib is discontinued due to toxicity the participant must discontinue study 
treatment and enter the follow-up phase of the study. If bevacizumab is discontinued due to 
toxicity, the participant may remain on study treatment receiving olaparib alone.
In Arm 3a/Arm 3b, if 5-FU or capecitabine is discontinued due to toxicity the participant 
must discontinue study treatment and enter the follow-up phase of the study. If bevacizumab 
is discontinued due to toxicity, the participant may remain on study treatment receiving 5-FU 
or capecitabine alone.
6.6.1.1
Management of Hematological Toxicities
Dose modification guidelines and supportive care guidelines for hematological toxicities that 
are attributed to olaparib by the investigator are in Table 3 and Table 4.
Table 3
Management of Anemia Attributed to Olaparib
Toxicity
NCI CTCAE Grade
Action Taken
Hemoglobin 
(Hb)
Grade 2
(<10 but ≥8 g/dL)
First Occurrence:
Give appropriate supportive treatment and investigate causality.

Investigator judgment to either continue olaparib with 
supportive treatment (eg, transfusion) or interrupt olaparib 
dosing for a maximum of 4 weeks (28 days). Treatment can 
be restarted if Hb has recovered to >9 g/dL.
Subsequent Recurrence:

Hb <10 but ≥9 g/dL: Investigator judgment to either 
continue olaparib with supportive treatment (eg, 
transfusion) or interrupt olaparib dosing for maximum of 
4 weeks (28 days). Upon recovery, a dose reduction to 
250 mg BID as a first step or 200 mg BID as a second step 
may be considered.

Hb <9 but ≥8 g/dL: Interrupt olaparib for a maximum of 4 
weeks (28 days) until Hb improves to >9 g/dL. Upon 
recovery, reduce the dose of olaparib to 250 mg BID. A
second dose reduction to 200 mg BID may be considered if 
additional decreases in Hb occur.
Grade 3
(<8 g/dL)
Give appropriate supportive treatment (eg, transfusion) and 
investigate causality.

Interrupt olaparib, for a maximum of 4 weeks (28 days), 
until Hb improves to ≥9 g/dL.

Upon recovery, reduce the dose of olaparib to 250 mg BID. 
A second dose reduction to 200 mg BID may be considered 
if additional decreases in Hb occur.
Abbreviations: BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; Hb = hemoglobin; 
NCI = National Cancer Institute.
Note: Common treatable causes of anemia (eg, iron, vitamin B12 or folate deficiencies and hypothyroidism) should be 
investigated and appropriately managed. In some cases, management of anemia may require blood transfusions. The 
management of prolonged hematological toxicities is detailed in Section 6.6.1.2.
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Table 4
Management of Neutropenia, Leukopenia, and Thrombocytopenia Attributed to 
Olaparib
Toxicity
NCI CTCAE Grade
Action Taken
Neutropenia, 
Leukopenia, or 
Thrombocytopenia
Grades 1 or 2
Investigator judgment to either continue olaparib or 
interrupt dosing for a maximum of 4 weeks (28 days). 
Give appropriate supportive treatment and investigate 
causality.
Grades 3 or 4

Interrupt olaparib, for a maximum of 4 weeks (28 
days), until event recovers to ≤Grade 1.

Repeated incidence: reduce the dose of olaparib to 
250 mg BID. A second dose reduction to 200 mg 
BID may be considered if additional Grade 3 or 4 
events occur.
Abbreviations: AE = adverse event; BID = twice daily; CTCAE = Common Terminology Criteria for Adverse Events; G-
CSF = granulocyte colony-stimulating factor; NCI = National Cancer Institute.

AEs of neutropenia and leukopenia should be managed as deemed appropriate by the investigator with close follow-
up and interruption of study intervention if CTCAE Grade 3 or worse neutropenia occurs.

Primary prophylaxis with G-CSF is not recommended; however, if a participant develops febrile neutropenia, study 
intervention should be stopped and appropriate management including G-CSF should be given according to local 
hospital guidelines. Please note that G-CSF should not be used within at least 24 hours (7 days for PEGylated G-
CSF) of the last dose of study intervention unless absolutely necessary.

Platelet transfusions, if indicated, should be done according to local hospital guidelines.

The management of prolonged hematological toxicities is detailed in Section 6.6.1.2.
6.6.1.2
Management of Prolonged Hematological Toxicities
If a participant develops prolonged hematological toxicity such as:

≥2 week interruption/delay in study intervention due to Grade 3 or worse anemia and/or 
the development of blood transfusion dependence

≥2 week interruption/delay in study intervention due to Grade 3 or worse neutropenia 
(absolute neutrophil count <1 × 109/L)

≥2 week interruption/delay in study intervention due to Grade 3 or worse 
thrombocytopenia and/or development of platelet transfusion dependence (platelets 
<50 × 109/L)
Differential blood count, including reticulocytes and peripheral blood smear, should be 
checked weekly. If any blood parameters remain clinically abnormal after the dosing of 
olaparib has been interrupted for ≥4 weeks (≥28 days), the participant should be referred to a 
hematologist for further investigations. Bone marrow analysis and/or blood cytogenetic 
analysis should be considered, according to local regulation and/or standard institutional 
hematological practice. Study intervention should be discontinued if blood counts do not 
recover to NCI CTCAE v5 Grade 1 or better within 4 weeks (28 days) of dose interruption.
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Development of confirmed MDS or other clonal blood disorder should be reported as an SAE 
and full reports must be provided by the investigator to the Sponsor as outlined in 
Section 8.4.4. Olaparib intervention should be discontinued for confirmed MDS and/or AML 
(Section 7.1).
6.6.1.3
Management of Non-hematologic Toxicity
Repeated dose interruptions, not exceeding 4 weeks (28 days) duration, are allowed as 
required. If toxicity reoccurs following rechallenge with study intervention, and where 
further dose interruptions are considered inadequate for management of toxicity, either a 
dose reduction should be considered (Section 6.6.1) or the participant must permanently 
discontinue study intervention.
Treatment must be interrupted if any Grade 3 or 4 AE occurs that the investigator considers 
to be related to administration of olaparib.
6.6.1.3.1
Management of New or Worsening Pulmonary Symptoms
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormalities occur 
in the absence of a clear diagnosis, an interruption in study intervention dosing is 
recommended and further diagnostic workup (including a high-resolution CT scan) should be 
performed to exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then study intervention can be restarted, if deemed appropriate by the 
investigator. If significant pulmonary abnormalities are identified, these must be discussed 
with the Sponsor.
6.6.1.3.2
Management of Nausea and Vomiting
Events of nausea and vomiting are known to be associated with olaparib intervention. These 
events are generally mild to moderate (Grade 1 or 2) in severity, intermittent, and
manageable on continued treatment. The first onset generally occurs in the first month of 
intervention for nausea and within the first 6 months of intervention for vomiting. For 
nausea, the incidence generally plateaus at around 9 months, and for vomiting at around 6 to 
7 months.
No routine prophylactic anti-emetic treatment is required at the start of study intervention; 
however, participants should receive appropriate anti-emetic treatment at the first onset of 
nausea or vomiting and as required thereafter, in accordance with local regulations or 
institutional guidelines. Alternatively, olaparib tablets can be taken with a light meal/snack 
(ie, 2 pieces of toast or a couple of biscuits).
As per international guidance on anti-emetic use in cancer patients, generally a single agent 
anti-emetic should be considered (eg, dopamine receptor antagonist, antihistamines, or 
dexamethasone).
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6.6.1.3.3
Management of Renal Impairment
If after study entry and/or while still on study therapy, a participant’s estimated CrCl falls 
below the threshold for study inclusion (≥50 mL/min), retesting should be performed 
promptly.
A dose reduction is recommended for participants who develop moderate renal impairment 
(calculated CrCl between 31 and 50 mL/min as calculated by Cockcroft-Gault equation) for 
any reason during the course of the study (Table 5).
Table 5
Dose Reduction of Olaparib to Manage Moderate Renal Impairment
Initial Dose
Moderate Renal Impairmenta
300 mg BID
200 mg BID
Abbreviation: BID = twice daily.
a.
Creatinine clearance of 31 to 50 mL/min as calculated by Cockcroft-Gault equation.
Because the CrCl determination is only an estimate of renal function, in instances where the 
CrCl falls to between 31 and 50 mL/min, the investigator should use his or her discretion in 
determining whether a dose change or discontinuation of therapy is warranted.
Olaparib has not been studied in participants with severe renal impairment 
(CrCl ≤30 mL/min) or end-stage renal disease; if participants develop severe impairment or 
end-stage disease, it is recommended that olaparib be discontinued.
6.6.1.3.4
Dose Reductions for Concurrent CYP3A4 Inhibitor Use
Strong or moderate CYP3A inhibitors should not be taken with olaparib. If there is no 
suitable alternative concomitant medication, then the dose of olaparib should be reduced for 
the period of concomitant administration as described in Table 6. After the washout of the 
inhibitor is complete (Section 5.2), the olaparib dose can be re-escalated. Note: After 
washout of the CYP3A4 drug, dosing of olaparib can immediately resume at the normal 
dosing level – no step-wise titration needed). The dose reduction of olaparib should be 
recorded in the eCRF with the reason documented as concomitant CYP3A4 inhibitor use.
Table 6
Dose Reduction of Olaparib with a Strong or Moderate CYP3A Inhibitor
Initial Dose
Strong CYP3A Inhibitor
Moderate CYP3A Inhibitor
300 mg BID
100 mg BID
150 mg BID
Abbreviations: BID = twice daily; CYP = cytochrome P450.
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6.6.1.4
Interruptions for Non-toxicity Related Events
Olaparib dose interruptions for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart study treatment within 4 weeks for resolution
of intercurrent conditions not related to disease progression or toxicity, the case should be
discussed with the Sponsor’s clinical director. All dose reductions and interruptions 
(including any missed doses), and the reasons for the reductions/interruptions, per drug 
accountability and participant feedback reconciliation, are to be recorded in the eCRF. Study 
treatment should be stopped at least 3 days prior to planned surgery. After surgery, study 
treatment can be restarted when the wound has healed. Study treatment should be 
discontinued for a minimum of 3 days before a participant undergoes radiation treatment. 
Study treatment should be restarted within 4 weeks as long as any bone marrow toxicity has 
recovered.
6.6.2
Bevacizumab, Capecitabine, Leucovorin, and 5-FU Dose Modifications
Bevacizumab, capecitabine, leucovorin, and 5-FU doses may be modified in accordance with 
their approved labeling and local practice guidelines.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or
for administrative and/or other safety reasons. Specific details regarding procedures to be 
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performed at study intervention discontinuation are provided in Section 8.1.10 and Section 
8.11.3.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Documented radiographic disease progression outlined in Section 8.2.1.
Note: As of Amendment 05, participants remaining on SOC (Arm 3A and Arm 3B) 
should be discontinued from study intervention based on investigator assessment of 
radiographic disease progression.
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy, that requires treatment.
•
Bone marrow findings consistent with MDS or AML.
•
The participant interrupts study intervention administration for more than 28 consecutive 
days without Sponsor consultation.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive pregnancy test.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.10. The procedures to be performed should a participant repeatedly 
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fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician .
•
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 ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
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•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
can be found in the Laboratory Manual. Repeat or unscheduled samples may be taken for 
safety reasons or for technical issues with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Demographics and Medical History
Detailed participant demographics and medical history will be obtained by the investigator or 
qualified designee. The medical history will collect all active conditions and any condition 
diagnosed within the prior 10 years that the investigator considers to be clinically significant. 
In addition, significant and potentially relevant conditions that occurred >10 years previously 
should be collected. Details regarding the disease for which the participant has enrolled in 
this study will be recorded separately and not listed as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study medication. Additionally, all prior chemotherapies
administered (including neoadjuvant, adjuvant and first-line induction), their duration and 
reason for discontinuation (ie, disease progression, discontinuation of therapy for reason 
other than progression, completion of planned program without progression and toxicity) will 
be documented.
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8.1.5.2
Induction History
The investigator or qualified designee will review and record the participant’s prior induction 
history with CAPOX + bevacizumab or FOLFOX + bevacizumab including the participant’s 
history of response while on or after completing the CAPOX + bevacizumab or FOLFOX + 
bevacizumab regimen.
8.1.5.3
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
8.1.6
Submitting Prior Radiographic Images
The investigator must review all prestudy (induction) imaging per RECIST 1.1 and confirm 
that the participant has not progressed (ie, SD, PR or CR) prior to entering the study.
The site must submit to the iCRO 1 set of radiographic images including 
chest/abdomen/pelvis taken before or during the CAPOX + bevacizumab or FOLFOX + 
bevacizumab induction period and at least 42 days prior to the imaging taken during 
Screening. The site must receive the iCRO’s determination that the images are of diagnostic 
quality and confirmation of non-PD by BICR prior to randomization.
8.1.7
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original Screening number 
assigned at the initial Screening visit.
Specific details on the Screening visit requirements (Screening/rescreening) are provided in 
Section 8.11.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
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8.1.9
Study Intervention Administration
Chemotherapy will be administered according to the specifications within the Pharmacy 
Manual.
Olaparib will be administered by the investigator and/or study staff on Day 1 of each cycle 
according to the specifications within the Pharmacy Manual. Participants will then self-
administer olaparib orally for the remainder of the study intervention period.
Study intervention can be administered within ± 3 days of the targeted Day 1 for each cycle, 
except Cycle 1, when intervention can only be administered within + 3 days of the targeted 
Day 1.
8.1.9.1
Timing of Dose Administration
8.1.9.1.1
Olaparib
Olaparib will be administered at a dose of 300 mg po BID.
Olaparib tablets should be taken with one glass of water twice a day at the same time each 
day, approximately 12 hours (±2h) between doses. The tablets should be swallowed whole 
and not chewed, crushed, dissolved, or divided. Olaparib tablets can be taken with or without 
food. If vomiting occurs shortly after olaparib tablets are swallowed, the dose should only be 
replaced if all the intact tablets can be seen and counted. Should any participant enrolled on 
the study miss a scheduled dose for any reason (eg, because of forgetting to take the tablets 
or vomiting), the participant will be allowed to take the scheduled dose up to a maximum of 
2 hours after that scheduled dose time. If it is more than 2 hours after the scheduled dose 
time, the missed dose is not to be taken, and the participant should take their allotted dose at 
the next scheduled time.
Participants must be instructed that if they miss a dose or vomit at any time after taking a 
dose, they should take their next dose at its scheduled time. The site will validate compliance 
with study intervention (including missed or vomited doses) at each site visit according to its 
standard operating procedure. If doses are missed or vomited, this must be indicated in the 
source documents and CRFs.
8.1.9.1.2
Bevacizumab and 5-FU
Bevacizumab will be administered at a dose of 5 mg/kg IV Q2W. 5-FU will be administered 
at a dose of 2400 mg/m2 IV over 46 to 48 hours Q2W. The 5-FU regimen may include a 
bolus of 5-FU prior to infusion: 400mg/m2 IV infusion on Day 1 based on local standards, 
investigator preference, and participant experience with the bolus during the induction phase.
Bevacizumab and 5-FU will be administered after all predose assessments and procedures 
have been completed. The participant should self-administer olaparib at home prior to the 
infusion of bevacizumab. Detailed information regarding the dose regimen/
administration/modification is in the approved labeling for bevacizumab and 5-FU.
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8.1.9.1.3
Capecitabine
Capecitabine will be administered at a dose of 1000 mg/m2 BID 14 days on, 7 days off,
Q3W. Detailed information regarding the dose regimen/administration/modification is in the 
approved labeling for capecitabine.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the end of treatment should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4 and Section 8.11.4.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
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Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
As of Amendment 05, central tumor response assessments will be discontinued. Imaging 
scans will no longer be submitted to iCRO nor read by BICR. The subsections below are 
retained for reference.
However, for participants who are still on SOC treatment and will continue receiving SOC 
treatment until criteria for discontinuation are met, local tumor imaging should continue per
local institutional guidelines. .
The process for image collection and transmission to the iCRO is given in the SIM.
Tumor imaging should be acquired by CT of the chest, abdomen and pelvis, or contrast-
enhanced MRI when CT is contraindicated or when mandated by local practice (CT is 
strongly preferred). MRI is the strongly preferred modality for imaging the brain. The same 
imaging modality, ideally the same scanner, and the use of contrast should be used in a 
participant throughout the study to optimize reproducibility of assessment of existing and 
new tumor burden and improve accuracy of assessment of response or progression based on 
imaging. Tumor imaging by CT (or MRI) of the chest, abdomen, and pelvis is required at 
every scheduled imaging time point. Brain imaging should only be performed as clinically 
indicated.
All scheduled images for all participants from the sites will be submitted to the iCRO. In 
addition, images (including via other modalities) obtained at an unscheduled time point to 
determine disease progression, as well as imaging obtained for other reasons but that
demonstrate radiologic progression, should be submitted to the iCRO.
When the investigator identifies radiographic progression, the iCRO will perform expedited 
verification of radiologic PD and communicate the results to the study site and Sponsor. 
Study intervention should continue until PD has been verified. Images should continue to be 
submitted to the iCRO. In clinically stable participants, imaging should continue until PD has 
been verified by BICR (if initial site-assessed PD was not verified by BICR, each subsequent 
scan must be submitted to the iCRO for verification of PD until PD has been verified by 
BICR).
Assessment of treatment response will be according to RECIST 1.1 (some limitation is 
described in Section 8.2.1.2).
8.2.1.1
Tumor Imaging During Screening
Tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. Tumor imaging performed as part of routine clinical management is 
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acceptable for use in place of the Screening tumor imaging if it is of diagnostic quality and 
was performed within 28 days prior to the date of randomization and can be assessed by the 
iCRO.
Upon completion of the Screening tumor imaging, the investigator must confirm that the 
participant’s disease did not progress prior to randomization. Non-PD must be verified by 
BICR prior to randomization, based on the images submitted to iCRO as described in 
inclusion criterion 4.
Participants who do not have measurable disease per RECIST 1.1 at Screening because of a 
CR or PR to the induction regimen are still eligible for the study.
8.2.1.2
Tumor Imaging During the Study
In the first year, on study imaging assessments must be performed every 8 weeks (56 days, 
± 7 days) from the date of randomization. After the first year, imaging assessments must be 
performed every 12 weeks (84 days, ± 7 days). All supplemental imaging must also be 
submitted to the iCRO.
Timing of imaging should follow calendar days from the date of randomization and should 
not be adjusted for delays in cycle starts.
For participants who undergo surgery with curative intent, imaging must be performed at a 
minimum of (no less than) 4 weeks after surgery and no more than 8 weeks prior to the next 
treatment cycle. The last set of imaging prior to restart of treatment will be used to establish a 
new baseline of tumor burden. Subsequent imaging will be compared to this new baseline 
and the visit responses will be limited to PD, non-PD, or not evaluable; these new post-
operative images will be assessed every 8 weeks (56 days ± 7 days) for 12 months and every 
12 weeks (84 days ± 7 days) thereafter. After documented PD, participants will receive 
investigator-choice anticancer therapy and will continue to be followed for disease status 
until a PFS2 event is recorded.
8.2.1.3
End-of-treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (± 4-week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, imaging at treatment discontinuation is 
not mandatory.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging with the 
same schedule used while on treatment until the start of new anticancer treatment, disease 
progression, death, withdrawal of consent, or the end of the study, whichever occurs first.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. After the first dose of study intervention, new clinically significant abnormal 
findings should be recorded as AEs. Height and weight will also be measured and recorded.
At visits that do not require a full physical examination (Section 1.3), brief directed physical 
examination will be conducted by an investigator or medically qualified designee (consistent 
with local requirements) per institutional standard. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be measured with the participant in a sitting, semirecumbent, or supine 
position after 5 minutes of rest, and will include temperature, systolic and diastolic BP, heart 
rate, and respiratory rate.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed at the Screening visit and again at the 
Discontinuation Visit using local standard procedures.
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8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Laboratory Manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
Bone Marrow or Blood Cytogenetic Samples
Bone marrow or blood cytogenetic samples may be collected for participants with prolonged 
hematological toxicities as defined in Section 6.6.1.2.
Bone marrow analysis should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity. If it is not 
possible to conduct cytogenetic analysis or flow cytometry on the bone marrow aspirate, then 
attempts should be made to perform the tests on a blood sample.
8.3.5
Pregnancy Test
Pregnancy testing (urine or serum) should be conducted according to Section 1.3 (SoA) and 
at the end of relevant systemic exposure for all arms.

Pregnancy testing requirements for study inclusion are described in Section 5.1.

Pregnancy testing (urine or serum) should be conducted at monthly intervals during 
intervention.
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
Pregnancy testing (urine or serum) should be conducted for the time required to eliminate 
systemic exposure after the last dose of study intervention and should correspond with 
the time frame for the participant’s contraception, as noted in Section 5.1. The length of 
time required to continue pregnancy testing for each study intervention is:
-
Olaparib:180 days
-
5-FU: 180 days
-
Capecitabine: 180 days
-
Leucovorin/levoleucovorin: 180 days.
-
Bevacizumab: 120 days.

Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator, or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study.
8.3.6
ECOG Performance Scale
The investigator or qualified designee will assess ECOG performance status as specified in 
the SoA.
8.3.7
Safety Considerations With Capecitabine and 5-FU
8.3.7.1
Photosensitivity
Investigators are advised to counsel participants assigned to receive capecitabine or 5-FU 
about the risk of photosensitivity and to take sun protection measures accordingly.
8.3.7.2
Ophthalmologic Complications Due to Capecitabine
Participants should be carefully monitored for ophthalmological complications such as 
keratitis and corneal disorders, especially if they have a prior history of eye disorders. 
Treatment of eye disorders should be initiated as clinically appropriate.
8.3.7.3
Severe Skin Reactions Due to Capecitabine
Capecitabine can induce severe skin reactions such as Stevens-Johnson syndrome and toxic 
epidermal necrolysis. Capecitabine should be permanently discontinued in participants who 
experience a severe skin reaction during treatment.
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8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days 
following cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 30 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 180 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
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•
Any SAE of MDS/AML or new primary malignancy occurring 30 days after the last dose 
of olaparib should be reported regardless of the investigator’s assessment of causality or 
knowledge of the treatment arm.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of olaparib’s safety profile and require close monitoring and rapid 
communication by the investigators to the Sponsor. Adverse events of special interest for 
olaparib comprise the Important Identified Risk of MDS/AML and the Important Potential
Risks of new primary malignancy (other than MDS/AML) and pneumonitis.
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of 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 and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
•
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
•
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).

Any event of MDS/AML, new primary malignancy, or pneumonitis should be reported 
whether it is considered a non-serious AE (eg non-melanoma skin cancer) or SAE and 
regardless of Investigator’s assessment of causality.
8.5
Treatment of Overdose
Olaparib must only be used in accordance with the dosing recommendations in this protocol. 
Any dose or frequency of dosing that exceeds the dosing regimen specified in this protocol 
should be reported as an overdose.
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No specific information is available on the treatment of overdose of olaparib. In the event of 
overdose, the study intervention should be discontinued, and the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
Refer to the approved labeling for capecitabine, leucovorin, bevacizumab, and 5-FU 
regarding the definition of an overdose and recommended treatment for an overdose.
The Sponsor’s medical monitor must be contacted in the event of a study intervention 
overdose.
8.6
Pharmacokinetics
As of Amendment 05, the collection of blood samples for PK was completed and is no longer 
applicable. The section below is retained for reference.
A minimum of 100 PK samples are anticipated to be collected. Pharmacokinetic sample 
collections are currently planned in a limited number of participants (n = 50 in Arm 1 and n = 
50 in Arm 2). Based on known non-overlapping clearance pathways for bevacizumab and 
olaparib, PK drug-drug interaction is not expected. The PK of olaparib in combination with 
bevacizumab has been evaluated in patients with advanced solid tumors and no impact on PK 
of olaparib was seen in this study [Dean, E., et al 2012]. The PK profile of olaparib is well 
characterized and additional PK data will be available from ongoing studies in solid tumor 
indications (eg, SOLO3, PROfound, and LYNK-002).
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
As of Amendment 05, blood collections for RNA analysis and serum and plasma biomarker 
analysis will be discontinued. The section below is retained for reference.
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for RNA analysis
•
Blood for serum and plasma biomarker analysis
•
Blood for ctDNA analysis
•
Tumor Tissue 
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Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant 
provides documented informed consent for future biomedical research. If the planned genetic
analysis is not approved, but future biomedical research is approved and consent is given, 
this sample will be collected for the purpose of future biomedical research.
The planned genetic analysis sample should be obtained predose on Day 1 but may be 
collected at the next scheduled blood draw, if needed. Sample collection, storage, and 
shipment instructions for planned genetic analysis samples will be in the 
Operations/Laboratory Manual.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
Leftover sample listed in Section 8.8 (including any extracted material from samples).
8.10
Medical Resource Utilization and Health Economics
As of Amendment 05: medical resource utilization and health economics data collection will 
be discontinued. The section below is retained for reference.
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from 
the time of treatment allocation/randomization through 30 days following cessation of 
study intervention or if the participant initiates new anticancer therapy, whichever is 
earlier. 
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1
Screening
Approximately 28 days prior to intervention randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Screening procedures may be repeated after consultation with the Sponsor.
All Screening procedures are to be completed within 28 days prior to the date of 
randomization except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of study 
intervention. An exception is HBV, HCV, and HIV testing which may be performed up 
to 28 days prior to the date of randomization if testing is required by local regulations. 
Refer to Appendix 7 for country-specific requirements.

Evaluation of ECOG performance status is to be performed within 10 days prior to 
randomization.

The radiographic images submitted to the iCRO during Screening must have been 
performed before or during the CAPOX + bevacizumab or FOLFOX + bevacizumab
induction period and at least 42 days prior to the imaging performed during Screening.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.3
Discontinuation Visit
The Discontinuation Visit should occur at the time when study intervention is discontinued. 
If the Discontinuation Visit occurs 30 days after the last dose of study intervention, at the 
time of the mandatory Safety Follow-up Visit, procedures do not need to be repeated. Visit 
requirements are outlined in the SoA (Section 1.3). Specific procedure-related details are 
provided in Section 8.
8.11.4
Post-treatment Visits
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Once the Safety Follow-up Visit is completed, all participants will be discontinued from the 
study.
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8.11.4.2
Follow-up Visits
As of Amendment 05, follow-up visits for assessment of efficacy will be discontinued for all 
participants. All participants will move into survival follow-up phase (Section 8.11.4.4). The 
section below is retained for reference.
Participants who discontinue study intervention for a reason other than BICR-verified disease 
progression will move into the follow-up phase and should be assessed every 8 weeks
(56 days ± 7 days) for the first year and every 12 weeks (84 days ± 7 days) thereafter, from 
the date of randomization, to coincide with the imaging schedule at the time of 
discontinuation from study intervention. to monitor disease status. Every effort should be 
made to collect information regarding disease status until the start of new anticancer therapy, 
disease progression, death, or the end of study, whichever occurs first. Information regarding 
post-study anticancer treatment will be collected if new treatment is initiated.
8.11.4.3
PFS2 Follow-up
As of Amendment 05, PFS2 follow-up visits will be discontinued for all participants. All 
participants will move into survival follow-up phase (Section 8.11.4.4). The section below is 
retained for reference.
After disease progression, sites should continue to provide updates regarding the participant’s 
disease status until subsequent disease progression occurs, death, withdrawal of consent, or 
the end of the study, whichever occurs first.
Participants will be assessed every 8 weeks for a second progression (using the participant’s 
status at first progression as the reference for assessment of second progression). A 
participant’s progression status is defined according to local standard clinical practice and 
may involve radiological or symptomatic progression or death. Copies of the participants 
radiological scans are not required to be sent to the iCRO and RECIST measurements will 
not be collected for assessment of PFS2. The date of PFS2 assessment and investigator 
determination of progression status (progressed or non-progressed) at each assessment will 
be recorded in the eCRF.
8.11.4.4
Survival Follow-up
As of Amendment 05, for all participants, survival follow-up visits will continue until the
final efficacy evaluation.. Those participants remaining on SOC (Arm 3A and Arm 3B) at the 
time of Amendment 05 should continue to be monitored in the study through the AE 
reporting period (Section 8.4). The section below is retained for reference. 
Participants who experience second disease progression will move into the survival follow-
up phase and should be contacted (eg, by telephone) approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first. Investigators will be directed to ask during the regular follow-up for OS if the 
participant has developed MDS/AML or a new primary malignancy and will be prompted to 
report any such cases.
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8.11.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an eDMC 
review, interim and/or final analysis. Upon Sponsor notification, all participants who do 
not/will not have a scheduled study visit or study contact during the Sponsor defined time 
period will be contacted for their survival status (excluding participants that have a 
previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. The study
team has been unblinded (as of 18-JUL-2022). Changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses that occurred 
prior to Amendment 05 were documented in previous protocol amendments(s) (consistent 
with ICH Guideline E9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in an sSAP and referenced in the CSR for the study. A separate biomarker 
analysis plan will be provided. Post hoc exploratory analyses will be clearly identified in the 
CSR. The PRO analysis plan will also be included in the sSAP.
9.1
Statistical Analysis Plan Summary
As of Amendment 05: The SAP is amended as follows:
NOTE: Based on the data from IA1, an interim safety and efficacy analysis for LYNK-003 
(data cutoff 10-MAY-2022), eDMC recommended stopping the study enrollment for futility 
based on prespecified futility boundary of IA1. Based upon the recommendation of the 
eDMC, the study team was unblinded (as of 18-JUL-2022). The prespecified interim 
analyses 2, 3, 4, and final analysis of the study described in the SAP will not be performed. 
Selected analyses of safety endpoints will be performed at the end of the study; there will be 
no further analyses of efficacy and PRO endpoints. The SAP summary has been updated 
accordingly.
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
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Study Design Overview
A Phase 3 randomized, open-label study to evaluate the efficacy and safety
of olaparib alone or in combination with bevacizumab compared to 
bevacizumab with a fluoropyrimidine in participants with unresectable or 
metastatic CRC who have not progressed following first-line induction.
Treatment Assignment
Approximately 525 participants will be randomized in a 1:1:1 ratio to 3
treatment groups (1) olaparib + bevacizumab, (2) olaparib and (3) 
bevacizumab + 5-FU or bevacizumab + capecitabine (Control). 
Stratification factors are 1) SD versus PR/CR to prior FOLFOX + 
bevacizumab or CAPOX + bevacizumab induction, 2) BRAFmut and/or 
Rasmut versus BRAFwt + Raswt, and 3) 6 to 8 cycles of induction versus >8 
cycles for FOLFOX-based induction, and 4 to 6 cycles versus >6 cycles for 
CAPOX-based induction.
This is an open-label study.
As of Amendment 05, study enrollment is being stopped for futility. Study 
participants randomized to one of the two experimental arms (olaparib plus 
bevacizumab [Arm 1] or olaparib monotherapy [Arm 2]) must discontinue 
study intervention. No crossover from either experimental arm to SOC arm 
(Arm 3A and Arm 3B) within the study is allowed. Participants on SOC 
have the option to continue receiving study intervention until criteria for 
discontinuation is met at the discretion of the investigator.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoint
Progression-free survival (PFS) based on RECIST 1.1 as assessed by BICR.
Key Secondary Endpoint
OS
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary and secondary hypotheses will be evaluated by comparing 
olaparib + bevacizumab versus 5-FU + bevacizumab or capecitabine + 
bevacizumab and olaparib versus 5-FU + bevacizumab or capecitabine + 
bevacizumab with respect to PFS and OS using a stratified log-rank test. 
The HR will be estimated using a stratified Cox regression model. Event 
rates over time will be estimated within each treatment group using the 
Kaplan-Meier method.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach. The tiers differ 
with respect to the analyses that will be performed. There is no Tier 1 safety 
endpoint for this study. Tier 2 parameters will be assessed via point 
estimates with 95% CIs provided for between arm comparisons; only point 
estimates by treatment arm will be provided for Tier 3 safety parameters. 
The 95% CIs for the between-treatment differences in percentages will be 
provided using the Miettinen and Nurminen method [Miettinen, O. and 
Nurminen, M. 1985].
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Interim Analyses
As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final 
analysis described in the SAP will not be performed.
The study includes a non-binding futility analysis (IA1) to determine 
whether there is sufficient evidence to continue the experimental arms.
Three IAs beyond IA1 are planned in addition to the final analysis.
•
Interim analysis 1 (IA1): non-binding futility analysis (~ 119 PFS
events have been observed for both treatment comparisons [119 events 
in Arm 1 plus Control; and 119 events in Arm 2 plus Control], 
expected to occur ~ 19 months after study start):
-
If the PFS HR of either Arm 1 or Arm 2 compared to the control 
arm is less than the prespecified futility boundary, the study may 
continue as planned.
•
Interim analysis 2 (IA2): ~ 238 PFS events have been observed for at 
least one treatment comparison (238 events in Arm1 plus Control or 
238 events in Arm 2 plus Control), ~ 117 deaths are expected in these
2 arms (Arm 1 plus Control or Arm 2 plus Control) when ~ 238 PFS
events are observed, expected to occur ~ 30 months after study start.
-
Interim PFS and OS analyses
•
Interim analysis 3 (IA3): ~297 PFS events have been observed for both 
treatment comparisons (297 events in Arm 1 plus Control; and 297
events in Arm 2 plus Control), ~ 174 deaths are expected for both 
treatment comparisons, expected to occur ~42 months after study start.
-
Final PFS analysis
-
Interim OS analysis
•
Interim analysis 4 (IA4): ~ 228 deaths have occurred for at least 1
treatment comparison (228 deaths in Arm 1 plus Control or 228 deaths 
in Arm 2 plus Control), expected to occur ~ 58 months after study start
-
Interim OS analysis
•
Final analysis: ~ 268 deaths have occurred for both treatment 
comparisons (268 deaths in Arm 1 plus Control; and 268 deaths in 
Arm 2 plus Control), expected to occur ~ 78 months after study start
-
Final OS analysis 
Multiplicity
The Type-I error rate over the multiple treatment comparisons and primary 
and key secondary efficacy endpoints will be controlled at 2.5% (1-sided).
A small alpha penalty of 0.01% will be paid for the futility analysis (split 
equally between the 2 treatment comparisons). The remaining alpha will be 
initially equally split between the 2 treatment comparisons to test PFS 
(1.245% for each treatment comparison: Arm 1 vs. Control and Arm 2 vs. 
Control). If a test for PFS is significant, then the secondary OS endpoint 
will be tested for that arm. The graphical approach of Maurer and Bretz
[Bretz, F., et al 2009] will be applied to re-allocate alpha among the
hypotheses of PFS and OS. Lan-DeMets O’Brien-Fleming group sequential
methods will be used to allocate alpha among the interim and final 
analyses. The study will be considered positive if the PFS hypothesis test is 
positive for either treatment comparison (Arm 1 vs. Control, and/or Arm 2 
vs. Control).
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Sample Size and Power 
As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final 
analysis of the study described in the SAP will not be performed.
The planned sample size is approximately 525 participants. For PFS, based 
on 297 events at IA3, the study has 88% power to detect an HR of 0.65 at 
α=1.245% (1-sided) for each treatment comparison (Arm 1 vs. Control, or 
Arm 2 vs. Control), with assumed PFS median of 7 months in the control 
arm. For OS, based on 268 events at the final analysis, the study has 53% 
(73%) power to detect an HR of 0.75 (0.70) at α=1.245% (1-sided) for each 
treatment comparison, with assumed OS median of 24 months in the 
control arm.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
This study is being conducted as an open-label study; therefore, participants, investigators, 
and Sponsor personnel will be aware of participant treatment assignments after each 
participant is enrolled and treatment is assigned. Although the study is open-label, analyses 
or summaries generated by randomized intervention assignment, or actual intervention 
received will be limited and documented. In addition, the independent radiologist(s) will 
perform the central imaging review without knowledge of intervention group assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
Primary Endpoint:
•
PFS: the time from randomization to the first documented PD per RECIST 1.1 as 
assessed by BICR or death due to any cause, whichever occurs first. See Section 9.6.1 for 
the definition of censoring.
Key Secondary Endpoint:
•
OS: the time from randomization to death due to any cause.
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Secondary Endpoint:
•
ORR: the proportion of the participants in the analysis population who have a confirmed 
CR or PR per RECIST 1.1 as assessed by BICR.
•
DOR: the time from first documented evidence of CR or PR until PD per RECIST 1.1 as 
assessed by BICR or death due to any cause, whichever occurs first, in participants who 
demonstrate CR or PR.
Exploratory Endpoint:
•
PFS2: the time from randomization to second documented disease progression or death 
due to any cause, whichever occurs first, by investigator assessment.
•
DCR: the proportion of the participants in the analysis population who have a confirmed 
CR or PR or SD per RECIST 1.1 as assessed by BICR.
The analysis of PFS2 and DCR will be described in the sSAP.
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific 
events will be collected and designated as ECIs as described in Section 8.4.7.
9.4.3
PRO Endpoints
The following exploratory PRO endpoints will be evaluated as described in Section 4.2.1.3:
•
Global health status/QoL of the EORTC QLQ-C30 (items 29 and 30)
•
The multi-item and single-item scales of the EORTC QLQ-C30
•
The multi-item and single-item scales of the EORTC QLQ-CR29
•
Health utilities as assessed using the EQ-5D-5L
These analyses will be described in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
Analyses of the primary efficacy endpoint are based on the ITT population. All randomized 
participants will be included in this population. Participants will be analyzed in the treatment 
arm to which they are randomized. Details of the approach to handling missing data are 
provided in Section 9.6.
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Participants who enter the study without measurable disease will be excluded from the ORR 
and DCR analysis.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed in the treatment arm corresponding to the study 
treatment they actually received. For most participants, this will be the treatment group to 
which they are randomized. Participants who receive incorrect study treatment for the entire 
treatment period will be included in the treatment arm corresponding to the study treatment 
actually received. 
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO FAS population, defined as participants who have at 
least 1 PRO assessment available and have received at least 1 dose of study treatment.
9.6
Statistical Methods
NOTE: As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final analysis of 
the study described in the SAP will not be performed. Selected analyses of safety endpoints 
will be performed at the end of study; there will be no further analyses of efficacy and PRO 
endpoints. The subsections below are retained for reference.
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy 
objectives. Methods related to exploratory objectives will be described in the sSAP. Efficacy 
results that will be deemed to be statistically significant after consideration of the Type-I 
error control strategy are described in Section 9.8. Nominal p-values will be computed for 
other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity.
9.6.1.1
Progression-free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie-handling will be 
used to assess the magnitude of the treatment difference (ie, the HR) between the treatment 
arms (Arm 1 vs. Control, and Arm 2 vs. Control). The HR and its 95% CI from the stratified 
Cox model with Efron’s method of tie-handling and with a single treatment covariate will be 
reported. The stratification factors used for randomization (Section 6.3.2) will be applied to 
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both the stratified log-rank test and the stratified Cox model. Descriptive statistics of the 
treatment difference (ie, the HR, 95% CI, and nominal p-value) between Arm 1 and Arm 2 
will also be provided.
Since disease progression is assessed periodically, PD can occur any time in the interval 
between the last assessment when PD is not documented and the assessment when PD is 
documented. The true date of disease progression will be approximated by the date of the 
first assessment at which PD is objectively documented per RECIST 1.1 by BICR. Death is 
always considered as a confirmed PD event. Participants who do not experience a PFS event 
will be censored at the last disease assessment. A sensitivity analysis will be performed for a 
comparison of PFS based on the investigator’s assessment. 
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 1 primary 
and 2 sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are immediately after more than 1 missed 
disease assessment, the data are censored at the last disease assessment prior to the missed 
visits. Data after new anticancer therapy are censored at the last disease assessment prior to 
the initiation of new anticancer therapy. The first sensitivity analysis follows the ITT
principle. That is, PDs/deaths are counted as events regardless of missed study visits or 
initiation of new anticancer therapy. The second sensitivity analysis considers 
discontinuation of treatment due to reasons other than CR or initiation of new anticancer
treatment, whichever occurs later, to be a PD event for participants without documented PD 
or death. If a participant meets multiple criteria for censoring, the censoring criterion that 
occurs earliest will be applied. The censoring rules for primary and sensitivity analyses are 
summarized in Table 8.
For participants who have a surgery with curative intent (described in Section 4.1), PFS will 
be defined using time from randomization to the disease recurrence after the surgery.
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Table 8
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented after ≤1 
missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death 
documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anticancer
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessments and 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; 
new anticancer
treatment is not initiated
Censored at last disease 
assessment
Censored at last disease 
assessment
Progressed at treatment 
discontinuation due to 
reasons other than CR; 
otherwise censored at last 
disease assessment if 
participant is still 
receiving study treatment 
or has completed study 
treatment
No PD and no death; 
new anticancer
treatment is initiated
Censored at last disease 
assessment before new 
anticancer treatment
Censored at last disease 
assessment
Progressed at date of new 
anticancer treatment
Abbreviations: CR = complete response; PD = progressive disease; PFS = progression-free survival.
9.6.1.2
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test. A stratified 
Cox proportional hazard model with Efron’s method of tie-handling will be used to assess the 
magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date of last known alive date.
9.6.1.3
Objective Response Rate (ORR)
Stratified Miettinen and Nurminen method will be used for the comparison of the ORR 
between 2 treatment arms. The difference in ORR and its 95% CI from the stratified 
Miettinen and Nurminen method with strata weighting by sample size will be reported. The 
stratification factors used for randomization (Section 6.3.2) will be applied to the analysis. 
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Participants who enter the study without measurable disease will be excluded from the ORR 
analysis.
9.6.1.4
Duration of Response (DOR)
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until PD or death due to any cause, whichever occurs 
first. Censoring rules for DOR are summarized in Table 9.
For each DOR analysis, a corresponding summary of the reasons for which responding 
participants are censored will also be provided. Responses in participants who are alive, have 
not progressed, have not initiated new anticancer treatment (reintroduction of investigator-
choice of anticancer therapy), have not been determined to be lost to follow-up, and have had 
a disease assessment within approximately 5 months of the data cutoff date, are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
If the sample size permits, DOR will be summarized descriptively using Kaplan-Meier
medians and quartiles. Only the subset of participants with a confirmed CR or PR will be 
included in this analysis. 
Table 9
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anticancer 
therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anticancer 
therapy initiated
Last adequate disease assessment 
before new anticancer therapy was 
initiated
Censor
(non-event)
Death or progression immediately after ≥2 
consecutive missed disease assessments or 
after new anticancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anticancer 
therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed disease 
assessments and before new anticancer
therapy if any
PD or death
End of response
(Event)
Abbreviation: PD = progressive disease.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 10.
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Table 10
Analysis Strategy for Key Efficacy Variables 
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
PFS (RECIST 1.1) 
by BICR
Testing: stratified log-rank 
test
Estimation: stratified Cox 
model with Efron’s tie-
handling method
ITT
Censored according to rules 
in Table 8
Secondary Analyses
OS
Testing: stratified log-rank 
test
Estimation: stratified Cox 
model with Efron’s tie-
handling method
ITT
Censored at last known alive 
date
ORR (RECIST 1.1) 
by BICR
Estimation:
Stratified Miettinen and 
Nurminen method
Participants who 
enter the study 
with measurable 
disease in ITT
Participants with missing 
data are considered 
nonresponders
DOR (RECIST 1.1) 
by BICR
Summary statistics using 
Kaplan-Meier method
All responders in 
ITT
Censored according to rules 
in Table 9
Abbreviations: BICR = blinded independent central review; DOR = duration of response; ITT = intention-to-treat; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumors Version 1.1.
Sensitivity analyses will be performed for PFS, ORR, and DOR based on investigator’s assessment.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters, including 
AEs, laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 11). The tiers differ with 
respect to the analyses that will be performed. Adverse events are either pre-specified as 
Tier 1 events or will be classified as belonging to Tier 2 or Tier 3 based on the number of 
events observed.
Tier 1 Events
Safety parameters or AEOSIs that are identified a priori constitute Tier 1 safety events that 
will be subject to inferential testing for statistical significance. Based on a review of historic 
chemotherapy data in CRC and data from ongoing olaparib clinical studies, there are no AEs 
that warrant inferential testing between treatment groups; therefore, there are no Tier 1 events 
for this protocol.
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Tier 2 Events
Tier 2 events will be assessed via point estimates with 95% CIs provided for differences in 
the proportion of participants with events using the Miettinen and Nurminen method 
[Miettinen, O. and Nurminen, M. 1985], an unconditional, asymptotic method.
Membership in Tier 2 requires that at least 10% of participants in any treatment group show
the event; all other AEs will belong to Tier 3. The threshold of at least 10% of participants 
was chosen for Tier 2 events because the population enrolled in this study is in critical 
condition and usually experiences various AEs of similar types regardless of treatment; 
events reported less frequently than 10% of participants would obscure the assessment of the 
overall safety profile and add little to the interpretation of potentially meaningful treatment 
differences. In addition, Grade 3 to 5 AEs (≥5% of participants in 1 of the treatment groups) 
and SAEs (≥5% of participants in 1 of the treatment groups) will be considered Tier 2 
endpoints. Because many 95% CIs may be provided without adjustment for multiplicity, the 
CIs should be regarded as a helpful descriptive measure to be used in safety review, not as a 
formal method for assessing the statistical significance of the between-group differences.
Tier 3 Events
Safety events that are not Tier 1 or Tier 2 events will be considered Tier 3 events. Only point 
estimates by treatment arm will be provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital sign, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment arm in table format.
Table 11
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Specific AEs (incidence ≥10% in at least 1 treatment 
group) 
X
X
Specific Grade 3 to 5 AEs (incidence ≥5% in at least 1 
treatment group)
X
X
Specific Serious AEs (incidence ≥5% in at least 1 
treatment group)
X
X
Tier 3
Safety events that are not (Tier 1 or Tier 2)
X
Change from baseline results (laboratory tests, vital 
signs, ECGs)
X
Abbreviations: AE = adverse event; CI = confidence interval; ECG = electrocardiogram; X = results will be provided.
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9.6.3
Statistical Methods for Patient-reported Outcomes
Details of PRO analyses will be included in the sSAP.
9.6.4
Summaries of Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
randomized and the primary reason for discontinuation will be displayed. Demographic 
variables (such as age) and baseline characteristics will be summarized by treatment either by 
descriptive statistics or categorical tables. The reasons for exclusion from the ITT population 
(if any) will be summarized.
9.7
Interim Analyses
Note: As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final analysis of 
the study described in the SAP will not be performed. This section is retained for reference.
An eDMC will serve as the primary reviewer of the unblinded results of the IAs and will 
make recommendations for discontinuation of the study or protocol modifications to an EOC
of the Sponsor. Depending on the recommendation of the eDMC, the Sponsor may prepare a 
regulatory submission. If the eDMC recommends modifications to the design of the protocol 
or discontinuation of the study, this EOC (and potentially other limited additional Sponsor
personnel) may be unblinded to results at the study intervention level in order to act on these 
recommendations. Additional logistical details will be provided in the eDMC Charter.
Treatment-level results from the interim analysis will be provided to the eDMC by the 
unblinded statistician. Prior to final study unblinding, the unblinded statistician will not be 
involved in any discussions regarding modifications to the protocol, statistical methods, 
identification of protocol deviations, or data validation efforts after the interim analyses.
9.7.1
Efficacy Interim Analyses
The study includes a non-binding futility analysis (IA1) to determine whether there is 
sufficient evidence to continue the experimental arms. The analysis will occur approximately 
19 months after study initiation at 40% information fraction for the PFS analysis. This 
analysis will compare PFS between Arm 1 and the control arm (Arm 3a/Arm 3b) as well as 
Arm 2 and the control arm (Arm 3a/Arm 3b). The study may be stopped if both arms are 
deemed futile; otherwise, the study may continue as planned. The operating characteristics of 
the futility interim analysis for each comparison are shown in Table 12.
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Table 12
Operating Characteristics of the Futility Interim Analysis (IA1)
Futility HR 
Boundary
IA1 Information 
Fraction (%)
Prob arm is 
futile based on 
HR=1.0
Prob arm is 
futile based on 
HR=0.65
IA1 Timing 
(Month)
0.85
40
81.2%
7.2%
19
Abbreviations: HR = hazard ratio; IA1 = Interim Analysis 1.
Three IAs beyond IA1 are planned in addition to the final analysis. The timing and purpose 
of analyses are summarized in Table 13.
Table 13
Summary of Interim and Final Analyses
Analyses
Timing
Estimated Time after First 
Participant Randomized 
Primary Purpose of 
Analysis
IA1
~ 119 PFS events have been observed
for both treatment comparisons (119 
events in Arm 1 plus Control; and 119 
events in Arm 2 plus Control).
~ 19 months
PFS futility analysis 
IA2
~ 238 PFS events have been observed
for at least 1 treatment comparison (238 
events in Arm 1 plus Control or 238 
events in Arm 2 plus Control).
~ 117 deaths are expected in these 2 
arms (Arm 1 plus Control or Arm 2 plus 
Control) where ~ 238 PFS events are 
observed.
~ 30 months
Interim PFS and OS 
analysis
IA3
~ 297 PFS events have been observed
for both treatment comparisons (297 
events in Arm 1 plus Control; and 297 
events in Arm 2 plus Control).
~ 174 deaths are expected for both 
treatment comparisons.
~ 42 months
Final PFS analysis
Interim OS analysis
IA4
~ 228 deaths have occurred for at least 
one treatment comparison (228 deaths 
in Arm 1 plus Control or 228 deaths in 
Arm 2 plus Control).
~ 58 months
Interim OS analysis
Final 
Analysis
~ 268 deaths have occurred for both 
treatment comparisons (268 deaths in 
Arm 1 plus Control; and 268 deaths in 
Arm 2 plus Control).
~ 78 months
Final OS analysis
Abbreviations: IA = Interim Analysis; OS = overall survival; PFS = progression-free survival.
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9.7.2
Safety Interim Analyses
Note: As of Amendment 05, no further analysis to the eDMC is warranted as the eDMC has 
recommended at IA1 that study participants randomized to one of the two experimental arms 
(olaparib plus bevacizumab [Arm1] or olaparib monotherapy [Arm2]) must discontinue study 
intervention.
The eDMC conducted regular safety monitoring. The timing of the safety monitoring was 
specified in the DMC charter. No further analysis is warranted.
The eDMC has responsibility for assessment of overall risk:benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. DMC review of efficacy 
data to assess the overall risk:benefit to study participants will not require a multiplicity 
adjustment typically associated with a planned efficacy IA. However, to account for any 
multiplicity concerns raised by the eDMC review of unplanned efficacy data when prompted 
by safety concerns, a sensitivity analysis for PFS and OS adopting a conservative multiplicity 
adjustment will be prespecified in the sSAP. This analysis will be performed if requested by 
the eDMC.
9.8
Multiplicity
Note: As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final analysis of 
the study described in the SAP will not be performed. This section is retained for reference.
The Type-I error rate over the multiple treatment comparisons and primary and key 
secondary efficacy endpoints will be controlled at 2.5% (1-sided). A small alpha penalty of 
0.01% will be paid for the futility analysis. The study will use the graphic method of Maurer 
and Bretz to control multiplicity for multiple hypotheses as well as IAs [Bretz, F., et al 2009]. 
According to this approach, study hypotheses may be tested more than once, and, when a 
particular null hypothesis is rejected, the α allocated to that hypothesis can be reallocated to 
other hypothesis tests.
Figure 2 shows the initial 1-sided α allocation for each hypothesis in the ellipse representing 
the hypothesis. The weights for reallocation from each hypothesis to the others are 
represented in the boxes on the lines connecting hypotheses.
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Figure 2
Multiplicity Diagram for Type-I Error Control
Abbreviations: OS = overall survival; PFS = progression-free survival.
9.8.1
Progression-free Survival
PFS will be tested at IA2 and IA3. The study allocates α=0.0249, 1-sided, to test PFS for 
Arm 1 versus Control and Arm 2 versus Control (α=0.01245 for each comparison). If the null 
hypothesis for PFS in 1 comparison is rejected, Figure 2 shows that its α=0.01245 is 
essentially fully reallocated to the OS hypothesis in the same treatment comparison. If the 
null hypotheses for OS is rejected, the alpha will be reallocated to the PFS in the other 
treatment comparison. Thus, each PFS comparison may be tested at α=0.01245 (initial α), or 
at α=0.0249 (if the null hypotheses for the other PFS comparison and OS comparison are 
rejected) (Table 14). For each comparison, the actual boundaries will be calculated based on 
the observed number of PFS events at the interim and final PFS analyses using the Lan-
DeMets O’Brien-Fleming spending function accordingly. For PFS interim analysis, the same 
alpha spend will be used for both comparisons (Arm 1 vs. Control and Arm 2 vs. Control), 
based on the lower number of observed PFS events from both comparisons.
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Table 14
Efficacy Boundaries and Properties for PFS Analyses
Analyses
Value
α=0.01245
α=0.0249
IA2: 80%a
N:350
Events: 238
Months: 30
Z
2.5594
2.2500
p (1-sided)b
0.0052
0.0122
HR at boundc
0.7176
0.7470
P(Cross) if HR = 1d
0.0052
0.0122
P(Cross) if HR = 0.65e
0.7616
0.8324
IA3:100%a
N:350
Events: 297
Months: 42
Z
2.2943
2.0270
p (1-sided)b
0.0109
0.0213
HR at boundc
0.7662
0.7904
P(Cross) if HR = 1d
0.01245
0.0249
P(Cross) if HR = 0.65e
0.8817
0.9047
Abbreviations: HR = hazard ratio; IA = Interim Analysis; PFS = progression-free survival.
a.
Percentage of total number of required events needed at each interim analysis.
b.
The nominal α for testing.
c.
The approximate HR required to reach an efficacy bound.
d.
The probability of crossing a bound under the null hypothesis.
e.
The probability of crossing a bound under the alternative hypothesis.
Note that if the α-reallocation from OS hypothesis testing occurs at the final analysis after 
hypothesis testing for PFS has been completed, the previously computed PFS test statistic for 
the PFS analysis may be re-evaluated versus the updated bounds.
9.8.2
Overall Survival
No initial alpha is allocated to the OS hypothesis. The OS hypothesis will only be tested if 
the test for PFS for the same treatment comparison is significant. If the test for PFS is not 
significant at the final analysis for PFS, the study may not continue for test of OS.
If the study continues based upon the IA1 futility criterion, OS will be tested at IA2 only if 
the test for PFS for the same treatment comparison is significant at IA2; and tested at IA3, 
IA4 and final analysis only if the final analysis of PFS (IA3) for the same treatment 
comparison is significant. Each OS comparison (Arm 1 vs. Control and Arm 2 vs. Control) 
may be tested at α=0.01245 (if the null hypothesis for the PFS in the same treatment 
comparison is rejected), or at α=0.0249 (if the null hypotheses for both PFS comparisons and 
OS for the other comparison are rejected). Table 15 shows the boundary properties for OS
interim analyses and final analysis for each treatment comparison, which were derived using 
a Lan-DeMets O’Brien-Fleming spending function.
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Table 15
Efficacy Boundaries and Properties for OS Analyses
Analyses
Value
α=0.01245
α=0.0249
IA2: 44%a
N:350
Events: 117
Months: 30
Z
3.6062
3.2000
p (1-sided)b
0.0002
0.0007
HR at boundc
0.5134
0.5534
P(Cross) if HR = 1d
0.0002
0.0007
P(Cross) if HR = 0.75e
0.0202
0.0501
IA3: 65%a
N:350
Events: 174
Months: 42
Z
2.8988
2.5655
p (1-sided)b
0.0019
0.0052
HR at boundc
0.6443
0.6778
P(Cross) if HR = 1d
0.0019
0.0054
P(Cross) if HR = 0.75e
0.1595
0.2547
IA4: 85%a
N:350
Events: 228
Months: 58
Z
2.5046
2.2160
p (1-sided)b
0.0061
0.0133
HR at boundc
0.7177
0.7456
P(Cross) if HR = 1d
0.0067
0.0150
P(Cross) if HR = 0.75e
0.3770
0.4931
Final:100%a
N:350
Events: 268
Months: 78
Z
2.3145
2.0511
p (1-sided)b
0.0103
0.0201
HR at boundc
0.7537
0.7784
P(Cross) if HR = 1d
0.01245
0.0249
P(Cross) if HR = 0.75e
0.5332
0.6396
Abbreviations: HR = hazard ratio; IA = Interim Analysis; OS = overall survival.
a.
Percentage of total number of required events needed at each interim analysis.
b.
The nominal α for testing.
c.
The approximate HR required to reach an efficacy bound.
d.
The probability of crossing a bound under the null hypothesis.
e.
The probability of crossing a bound under the alternative hypothesis.
Alpha spending for OS at IA2 and IA3 is provided for regulatory purposes since it will be summarized in conjunction 
with PFS analyses.
9.9
Sample Size and Power Calculations
Note: As of Amendment 05, the prespecified interim analyses 2, 3, 4, and final analysis of 
the study described in the SAP will not be performed. This section is retained for reference.
The study will randomize approximately 525 participants in a 1:1:1 ratio into Arm 1 olaparib 
+ bevacizumab, Arm 2 olaparib, and Arm 3 bevacizumab + fluoropyrimidine (5-FU in Arm 
3a or capecitabine in Arm 3b). PFS is the primary endpoint for the study, with OS as the key 
secondary endpoint. For PFS, based on a target number of 297 events at IA3, the study has 
88% power to detect a HR of 0.65 at α=1.245% (1-sided) for each treatment comparison 
(Arm 1 vs. Control, or Arm 2 vs. Control). If PFS is positive for the same treatment 
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comparison, then for OS, based on a target number of 268 events, the study has 53% (73%) 
power to detect an HR of 0.75 (0.70) at α=1.245% (1-sided) for each treatment comparison 
(Arm 1 vs. Control, or Arm 2 vs. Control). The above sample size and power calculations for 
PFS and OS assume the following. 
 
 
9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect (Arm 1 vs. Control, and Arm 2 vs. Control) for PFS and OS 
(with a nominal 95% CI) will be estimated and plotted by treatment group within each 
category of the following classification variables:

Stratification factors
-
SD versus PR/CR to prior FOLFOX (or CAPOX) + bevacizumab induction
-
BRAFmut and/or Rasmut versus BRAFwt + Raswt
-
Number of induction cycles

For FOLFOX-based induction, 6 to 8 cycles versus >8 cycles

For CAPOX-based induction, 4 to 6 cycles versus >6 cycles

Age category (<70 years; ≥70 years)

Sex (female; male)

Geographic region (Asia vs. Western Europe/North America vs. Rest of World)

Hepatic or pulmonary metastases versus other metastases

ECOG performance status (0, 1)
CCI
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
Site (colon, rectum)

Number of metastatic sites (1, >1)

Induction regimen
-
FOLFOX + bevacizumab
-
CAPOX + bevacizumab
For subgroup analysis to take place, a given subgroup must include ≥10% of the total sample
size in the 2 treatment arms to be compared.
9.11
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of days in which the participant 
receives olaparib, and the number of cycles in which the participant receives the study 
treatment infusion for bevacizumab and/or 5-FU (or capecitabine). Summary statistics will be 
provided on the extent of exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
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 that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide upon any recommendations made by the DMC regarding the study.
10.1.4.2
External Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study.
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The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (Section 9.7) and 
recommend to the EOC whether the study should continue in accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study governance structure; and requirements for and proper documentation 
of DMC reports, minutes, and recommendations will be described in the DMC charter that is 
reviewed and approved by all the DMC members.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, 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.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized 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 documented informed consent, 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.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 16 will be performed by the local laboratory.
•
Results of predose laboratory procedures must be reviewed by the investigator or 
qualified designee and found acceptable prior to study intervention administration at 
study visits.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytesa
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN) or urea
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic Oxaloacetic
Transaminase 
(SGOT)
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is 
elevated above 
the upper limit of 
normal)
Albumin
Bicarbonate or CO2 a
Chloride
Phosphorous
Creatinine or 
creatinine clearance
Sodium
Alanine 
Aminotransferase 
(ALT)/ Serum 
Glutamic Pyruvic 
Transaminase (SGPT)
Total Protein
Glucose (nonfasting)
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
by dipstick

Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other Tests

Urine (or serum) β-human chorionic gonadotropin (β-hCG) pregnancy test (as needed 
for WOCBP)

Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) if required by local regulations

Prothrombin time (PT)/International normalized ratio (INR) and activated partial 
thromboplastin time (aPTT)

Carcinoembryonic antigen (CEA) levels
a.
Performed only if considered local standard of care.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
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•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not considered a reportable event unless it results in hospitalization or death.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
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An SAE is defined as any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
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-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?

If yes, did the AE resolve or improve?
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
If yes, this is a positive dechallenge.

If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?

If yes, did the AE recur or worsen?

If yes, this is a positive rechallenge.

If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:

There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
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
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
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Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.

Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following for the minimum protocol-defined time frame in Section 5.1 
or the time frame detailed in the approved product label per local requirements:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method (LAM).

Male condom with cap, diaphragm, or sponge with spermicide.

Male and female condom cannot be used together.
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception as described in
Table 17 during the protocol-defined time frame in Section 5.1.
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Table 17
Highly Effective Contraception Methods
•
Contraceptives allowed during the study includea:
•
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc
•
Nonhormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review 
of the participant’s medical records, medical examination, or medical history interview.
•
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to female participant hormonal contraception.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:

The biology of how drugs/vaccines work

Biomarkers responsible for how a drug/vaccine enters and is removed by the body

Other pathways drugs/vaccines may interact with

The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study visit 
by the investigator or his or her designate. Informed consent for future biomedical 
research should be presented to the participants on the visit designated in the SoA. If 
delayed, present consent at next possible Participant Visit. Consent forms signed by the 
participant will be kept at the clinical study site under secure storage for regulatory 
reasons.
A template of each study site’s approved informed consent will be stored in the Sponsor’s 
clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured in 
the eCRFs. Any specimens for which such an informed consent cannot be verified will be 
destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined in 
the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the investigator for the main study. If medical records 
for the main study are still available, the investigator will contact the Sponsor using the 
designated mailbox (clinical.specimen.management@msd.com). Subsequently, the 
participant's specimens will be flagged in the biorepository and restricted to main study 
use only. If specimens were collected from study participants specifically for future 
biomedical research, these specimens will be removed from the biorepository and 
destroyed. Documentation will be sent to the investigator confirming withdrawal and/or 
destruction, if applicable. It is the responsibility of the investigator to inform the 
participant of completion of the withdrawal and/or destruction, if applicable. Any 
analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3,4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@msd.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
France
Section 1.3 Schedule of Activities
Pregnancy testing must be performed prior to study intervention administration at each cycle 
during the treatment period as well as before the last dose of study intervention, and 180 days 
after the last dose of olaparib, at the end of study intervention.
Section 5.2 Exclusion Criteria
Dihydropyrimidine dehydrogenase deficient participants who are treatment-naïve to 5-FU 
and 5-Fluoropyrimidin containing drugs
Received the last dose of brivudine within the past 4 weeks or is currently receiving 
brivudine
Section 8.11.1 Screening
All participants at study sites in France must be tested for hepatitis B and hepatitis C at
Screening prior to randomization.
10.7.2
Japan
Section 6.1 Study Intervention(s) Administered
Bevacizumab in combination with other anti-cancer agents for CRC has been approved in 
Japan with the same dosage and administration as in this study, and authorization 
application/submission of bevacizumab is not planned based on the results of this study.
Bevacizumab used in Arm1 in this study is categorized as “product(s) used in the clinical 
trial other than test product(s)” in Japan local regulation.
10.7.3
Germany
Section 1.3 Schedule of Activities (SoA)
Dihydropyrimidine dehydrogenase deficiency testing is required at screening for participants.
Section 5.2 Exclusion Criteria
•
Dihydropyrimidine dehydrogenase deficient participants who are treatment-naïve to 5-FU 
and 5-Fluoropyrimidin containing drugs
•
Received the last dose of brivudine within the past 4 weeks or is currently receiving 
brivudine
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6.5.3 Rescue Medications and Supportive Care
Live vaccines must not be administered until 90 days after the last dose of study intervention.
Legally Acceptable Representative protocol sections 
For a participant to be eligible to participate in Germany, they must be capable of providing 
documented informed consent; therefore, all references to a participant’s “legally acceptable
representative” in the protocol are not applicable for participants in Germany.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
5-FU
fluorouracil
AML
acute myeloid leukemia
APaT
All Participants as Treated
BICR
blinded independent central review
BID
twice daily
CAPOX
capecitabine and oxaliplatin
CEA
carcinoembryonic antigen
CFI
chemotherapy-free interval
CI
confidence interval
CRC
colorectal cancer
CRO
contract research organization
CT
computed tomography
ctDNA
circulating tumor DNA
DBP
diastolic blood pressure
DCR
disease control rate
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DPD
dihydropyrimidine dehydrogenase
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDMC
external data monitoring committee
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
ESMO
European Society for Medical Oncology
FAS
full analysis set
FDAAA
Food and Drug Administration Amendments Act
FOLFIRI
fluorouracil/leucovorin/irinotecan
FOLFOX
folinic acid/fluorouracil/oxaliplatin
FSH
follicle stimulating hormone 
gBRCA
germline breast cancer susceptibility gene
GCP
Good Clinical Practice 
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HER2-
human epidermal growth factor receptor 2 negative
HGSOC
high-grade serous ovarian cancer
HIV
human immunodeficiency virus
HR
hazard ratio
HRCT
high-resolution computed tomography
HRD
homologous recombination deficiency
HRQoL
health-related quality of life
HRR
homologous recombination repair
HRRm
homologous recombination repair mutation
HRT
hormone replacement therapy
IA
interim analysis
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Council for Harmonisation
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Abbreviation
Expanded Term
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
IRT
interactive response technology
ITT
intention-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhea method
LOH
loss of heterozygosity
mCRPC
metastatic castrate-resistant prostate cancer
MDS
myelodysplastic syndrome
mPFS
median PFS
MRI
magnetic resonance imaging
mut
mutant
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHEJ
non-homologous end-joining
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PARP
polyadenosine 5′-diphosphoribose polymerase
PD
progressive disease
PFS
progression-free survival
PFS2
second progression-free survival
PK
pharmacokinetic
po
by mouth/orally
PR
partial response
PRO
patient-reported outcomes
PSA
prostate-specific antigen
Q2W
every 2 weeks
Q3W
every 3 weeks
QLQ
Quality of Life Questionnaire
RECIST 1.1
Response Evaluation Criteria In Solid Tumors version 1.1
RNA
ribonucleic acid
RPLS
reversible posterior leukoencephalopathy syndrome
RR
response rate
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SCLC
small cell lung cancer
SD
stable disease
SIM
Site Imaging Manual
SLAB
supplemental laboratory test(s)
SoA
Schedule of Activities
sSAP
supplemental statistical analysis plan
SSB
single-strand break
SUSAR
suspected unexpected serious adverse reaction
TCD
tumor control duration
TDT
time from randomization to discontinuation or death
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Abbreviation
Expanded Term
TFST
time from randomization to first subsequent therapy or death
TNBC
triple-negative breast cancer
TPC
treatment of physician’s choice
TSST
time from randomization to second subsequent therapy or death
VEGF
vascular endothelial growth factor
WOCBP
woman/women of childbearing potential 
wt
wild type
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