An Open-label, Randomized, Phase 2/3 Study of Olaparib Plus Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction of Clinical Benefit With First-line Chemotherapy Plus Pembrolizumab in Participants With Locally Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) (KEYLYNK-009)
Phase: PHASE2
Conditions: Triple Negative Breast Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
An Open-label, Randomized, Phase 2/3 Study of Olaparib 
Plus Pembrolizumab Versus Chemotherapy Plus 
Pembrolizumab After Induction of Clinical Benefit With First-
line Chemotherapy Plus Pembrolizumab in Participants With 
Locally Recurrent Inoperable or Metastatic Triple Negative 
Breast Cancer (TNBC) (KEYLYNK-009)
NCT04191135
22-May-2023

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Title Page
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: An Open-label, Randomized, Phase 2/3 Study of Olaparib Plus 
Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction of Clinical 
Benefit With First-line Chemotherapy Plus Pembrolizumab in Participants With Locally 
Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) 
(KEYLYNK-009)
Protocol Number: 009-03
Compound Number: MK-7339
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as 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
140257
EudraCT
2019-001892-35
EU CT
2022-500418-24-00
Approval Date:  22 May 2023
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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 03
22-MAY-2023
Protocol amended consistent with recommendations of the internal DMC to discontinue
the study after a prespecified interim review of the data because the combination of 
pembrolizumab plus olaparib did not show an improvement in PFS compared with the 
combination of chemotherapy plus pembrolizumab. Participants who are still receiving 
study intervention (in post-induction or Second Course Retreatment phase) may have 
the option to continue on study treatment if they are deriving clinical benefit, until 
criteria for discontinuation are met.
Amendment 02
18-MAY-2022
Amendment 01
02-JUN-2021
To update the dose modification and toxicity management guidelines for immune-
related adverse events (irAEs). Additional minor corrections and clarifications were 
made throughout the protocol.
Original Protocol
24-JUL-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
4.1 Overall Design
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Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis, Estimated 
Duration of Study
Added that as of Amendment 03, the study is being discontinued 
based on the recommendation of the internal DMC, but participants 
who are still receiving study intervention may have the option of 
continuing with study treatment if they are deriving clinical benefit, 
and the study will remain open until the last participant who is 
continuing study treatment completes the Safety Follow-up visit.
To inform of the decision to 
discontinue this clinical study,
clarify that participants may 
continue to receive study 
treatment if deriving clinical 
benefit, and how long the 
study will remain open.
1.1 Synopsis, Duration of 
Participation
Added that as of Amendment 03, participants who are still on study 
treatment and deriving clinical benefit will no longer have tumor 
response assessments by BICR, but local tumor imaging assessments 
should continue per SOC schedule, and Survival Follow-up visits will 
no longer be conducted.
As of Amendment 03, further 
tumor scans and response 
assessments by BICR and 
Survival Follow-up visits are 
considered unnecessary.
1.1 Synopsis, Study 
Governance Committees
10.1.4 Committees 
Structure
Added that as of Amendment 03, the Steering Committee and internal 
DMC are no longer applicable.
These committees will no 
longer review the study data.
1.3.2 Post-induction
Added that as of Amendment 03, participants who are still receiving 
study intervention in post-induction may have the option of 
continuing with study treatment if they are deriving clinical benefit. If 
continuing on study treatment, participants will have local tumor 
imaging assessments per SOC schedule, but will no longer have 
ePRO assessments, biomarker samples, or tumor response 
assessments by BICR.
As of Amendment 03, further 
tumor scans and response 
assessments by BICR, ePRO 
assessments, and collection of 
additional samples for 
biomarker evaluation are 
considered unnecessary.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.3 End-of-Treatment 
and Follow-up After 
Treatment Discontinuation
Added that as of Amendment 03, participants who discontinue from 
study treatment should complete the End-of-Treatment and Safety 
Follow-up visits. Disease Status Follow-up and Survival Follow-up 
visits will no longer be conducted, ePRO assessments will no longer 
be performed, and biomarker samples will no longer be collected.
As of Amendment 03, further 
Disease Status and Survival 
Follow-up visits, ePRO 
assessments, and collection of 
additional samples for 
biomarker evaluation are 
considered unnecessary.
1.3.4 Second Course 
Retreatment
8.12.6 Second Course 
Retreatment
Added that as of Amendment 03, the study will be discontinued based 
on the recommendation of the internal DMC, and Second Course 
Retreatment is no longer an option for participants. 
Added that participants who are already receiving Second Course 
Retreatment and deriving clinical benefit may continue Second 
Course Retreatment, local tumor imaging assessments should 
continue per SOC schedule, until radiographic disease progression per 
RECIST 1.1 as determined by investigator/site/local radiology 
review, and no treatment beyond progression will be authorized.
To update the status of the 
Second Course Retreatment 
phase of the study.
4.1.3 End-of-Treatment
Clarified that after implementation of Amendment 03, disease 
progression will be determined by investigator/site/local radiology 
review and not verified by BICR.
As of Amendment 03, there 
will be no further response 
assessments by BICR.
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Section # and Name
Description of Change 
Brief Rationale 
4.1.4 Planned Analyses
Skipping IA1 and 
corresponding changes have 
been documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023.
To specify which analyses 
will be conducted and which 
will no longer be performed 
after implementation of 
Amendment 03.
4.4.1 Clinical Criteria for 
Early Study Termination
Added that in the event of Sponsor decision to no longer supply study 
interventions, ample notification will be provided.
Added that as of Amendment 03, the study will be discontinued based 
on the recommendation of the internal DMC.
Clarification regarding supply 
of study interventions.
To inform of the decision to 
discontinue this clinical study.
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Section # and Name
Description of Change 
Brief Rationale 
6.1 Study Intervention(s) 
Administered
Added that as of Amendment 03, the study is being discontinued 
based on the recommendation of the internal DMC. Participants who 
are still receiving study intervention may have the option of 
continuing on study treatment, if they are deriving clinical benefit, 
until radiographic disease progression per RECIST 1.1 as determined 
by investigator/site/local radiology review or other discontinuation 
criteria are met, and no treatment beyond progression will be 
authorized.
Added that participants who have experienced first disease 
progression by RECIST 1.1 in post-induction, who are continuing 
study treatment due to deriving clinical benefit and are being followed 
using the iRECIST criteria at the time of Amendment 03, may 
continue to receive study treatment only until the next confirmed 
disease progression (iCPD) by investigator/site/local radiology 
review, and no treatment beyond iCPD as determined by 
investigator/site/local radiology review will be authorized.
To inform of the decision to 
discontinue this clinical study 
and clarify that participants 
may continue to receive study 
treatment until radiographic 
disease progression per 
RECIST 1.1 if deriving 
clinical benefit.
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Section # and Name
Description of Change 
Brief Rationale 
7.1 Discontinuation of 
Study Intervention
Added the following to the notes regarding discontinuation due to 
radiographic disease progression:

As of Amendment 03, central tumor response assessments will no 
longer be performed. Participants who are continuing to receive 
study treatment will be assessed by investigator/site/local 
radiology review for disease progression per SOC schedule.

Treatment beyond progression (by RECIST 1.1 or iRECIST) will 
no longer be authorized after implementation of Amendment 03.
Participants who have experienced first disease progression by 
RECIST 1.1 in post-induction, who are continuing study 
treatment and are being followed using the iRECIST criteria at the 
time of Amendment 03, may continue to receive study treatment 
only until the next confirmed disease progression (iCPD) by 
investigator/site/local radiology review, and no treatment beyond 
iCPD as determined by investigator/site/local radiology review 
will be authorized.
To clarify that participants 
still on study treatment at the 
time of Amendment 03, 
because they are deriving 
clinical benefit, will be 
assessed by 
investigator/site/local 
radiology review for disease 
progression per SOC 
schedule, and that treatment 
beyond progression will no 
longer be authorized.
7.1 Discontinuation of 
Study Intervention
Added the following to the notes regarding completion of study 
intervention:

As of Amendment 03, Second Course Retreatment is no longer an 
option for participants.
To update the status of the 
Second Course Retreatment 
phase of the study.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.2 Tumor Scans and 
Assessment of Disease
Added that as of Amendment 03, central tumor response assessments 
will be discontinued. 
Added that participants deriving clinical benefit may continue on 
study treatment until criteria for discontinuation are met; local tumor 
imaging should continue per SOC schedule.
As of Amendment 03, further 
efficacy assessments are 
considered unnecessary.
To clarify that participants 
still receiving study treatment 
at the time of this amendment 
because they are deriving 
clinical benefit will continue 
with local tumor imaging per 
SOC schedule.
8.2.2.3.3 Determination of 
Radiographic Progression
Added that as of Amendment 03, central tumor response assessments 
will be discontinued, and participants with radiographically 
documented disease progression during post-induction as assessed by 
investigator/site/local radiology review according to RECIST 1.1 will 
be discontinued from study intervention.
As of Amendment 03, there 
will be no further response 
assessments by BICR.
8.2.2.6 iRECIST 
Assessment of Disease 
During Post-induction
10.9 Appendix 9: 
Description of the 
iRECIST Process for 
Assessment of Disease 
Progression During Post-
induction
Added that as of Amendment 03, iRECIST assessment of disease is 
no longer applicable for participants who have an initial PD evaluated 
by RECIST 1:1, and participants who are currently being assessed by 
iRECIST may continue to be assessed per iRECIST until iCPD is 
determined by investigator/site/local radiology review. 
As of Amendment 03, 
treatment beyond RECIST 1.1 
progression will not be 
authorized, therefore 
assessment using iRECIST 
criteria will no longer be 
applicable.
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Section # and Name
Description of Change 
Brief Rationale 
8.2.3 Patient-reported 
Outcomes
Added that PROs and Quality of Life assessments will be 
discontinued.
As of Amendment 03, PRO 
and Quality of Life 
assessments are considered 
unnecessary.
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
Removed requirement for investigators to document if an AE was 
associated with medication error, misuse, or abuse. This requirement 
is applicable only for SAEs. 
Clarification as per global 
Protocol Clarification Letter 
29-JUN-2022.
The updated Regulation (EU) 
No 36/2014 on clinical trials 
includes language on the 
reporting of SUSARs 
associated with medication 
errors and use outside of what 
is foreseen in the protocol 
(misuse and abuse); therefore, 
the event must meet the 
definition for an SAE, and 
hence “AE” was removed.
8.10 Biomarkers
Added that as of Amendment 03, biomarker sample collections will 
be discontinued, and biomarker samples already collected before 
implementation of Amendment 03 will be analyzed.
As of Amendment 03, 
collection of biomarker 
samples is considered 
unnecessary, but samples 
collected before Amendment 
03 will be analyzed.
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Section # and Name
Description of Change 
Brief Rationale 
8.11 Medical Resource 
Utilization and Health 
Economics
Added that as of Amendment 03, Medical Resource Utilization and 
Health Economics data collection will be discontinued.
As of Amendment 03, 
assessment of these data is 
considered unnecessary.
8.12.4.2 Disease Status 
Follow-up
Added that as of Amendment 03, Disease Status Follow-up Visits will 
be discontinued.
As of Amendment 03, these 
visits are considered 
unnecessary.
8.12.4.3 Survival Follow-
up Contacts
Added that as of Amendment 03, Survival Follow-up visits will be 
discontinued. Participants remaining on study treatment should 
continue to be monitored in the study through the AE reporting 
period.
Survival follow-up is only for 
participants remaining on 
study at the time of this 
amendment, and participants 
will be followed for the 
duration of the AE reporting 
period.
8.12.6.2 Treatment 
Requirements for Second 
Course Retreatment
In the last bullet point, updated “achieved or sustained a BICR-
verified SD or better” to “achieved or sustained an SD or better”.
To clarify that achieving SD 
or better after completing 35 
administrations of 
pembrolizumab is not verified 
by BICR as per global 
Protocol Clarification Letter 
03-MAR-2023.
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Section # and Name
Description of Change 
Brief Rationale 
8.12.6.9 Tumor Scans 
During Second Course 
Retreatment
Added that as of Amendment 03, central tumor response assessments 
will be discontinued, and participants who are continuing study 
treatment will continue with local tumor imaging per SOC schedule. 
Participants with radiographically documented disease progression 
during Second Course Retreatment as assessed by 
investigator/site/local radiology review according to RECIST 1.1 will 
be discontinued from study intervention. Participants who are 
currently being assessed by iRECIST during Second Course 
Retreatment may continue to be assessed per iRECIST until iCPD is 
determined by investigator/site/local radiology review. Treatment 
beyond RECIST 1.1 progression or iCPD will no longer be authorized 
after implementation of Amendment 03.
Clarified that tumor scans in Second Course Retreatment should be 
assessed using RECIST 1.1 criteria and do not need to be submitted to 
or reviewed by BICR.
To clarify that participants 
still receiving Second Course 
Retreatment at the time of this 
amendment because they are 
deriving clinical benefit will 
continue with local tumor 
imaging per SOC schedule. 
As of Amendment 03, 
treatment beyond RECIST 1.1 
progression or iCPD will not 
be authorized.
Clarification per global 
Protocol Clarification Letter 
03-MAR-2023.
9 Statistical Analysis Plan
Added that based on the data from a prespecified interim safety and 
efficacy analysis, the internal DMC recommended discontinuing the 
study.
Added that the prespecified final analysis of the study described in the 
SAP will not be performed. Selected safety analyses will be 
performed at the end of the study. 
To inform of the decision to 
discontinue this clinical study. 
To specify which analyses 
will be conducted and which 
will no longer be performed 
after implementation of 
Amendment 03. 
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Section # and Name
Description of Change 
Brief Rationale 
9.1 Statistical Analysis 
Plan Summary
To specify which analyses 
will be conducted and which 
will no longer be performed 
after implementation of 
Amendment 03. 
Skipping IA1 and 
corresponding changes have 
been documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023.
To clarify that participants 
may continue to receive study 
treatment if deriving clinical 
benefit.
9.7 Interim Analyses
Added that the prespecified final analysis of the study described in the 
SAP will not be performed.
To specify which analyses 
will be conducted and which 
will no longer be performed 
after implementation of 
Amendment 03.
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Section # and Name
Description of Change 
Brief Rationale 
9.7.1 Efficacy Interim 
Analyses
Skipping IA1 and 
corresponding changes have 
been documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023. 
The changes align the 
protocol with sSAP 
Amendment 01 and finalized 
efficacy IA.
9.8.1 Progression-free 
Survival
Removed IA1 and IA2 from efficacy boundaries and properties for 
PFS analyses in Table 16.
Only a single PFS analysis is
performed due to skipping 
IA1, as documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023. 
The changes align the 
protocol with sSAP 
Amendment 01 and finalized 
efficacy IA.
9.8.2 Overall Survival
Added that if the actual number of OS events at the interim analyses 
differs from those specified in the table, the bounds will be adjusted 
by the spending function accordingly, and if the PFS null hypothesis 
is rejected at PFS final analysis, OS interim and final analysis test 
may be compared to its updated bounds, considering the α 
reallocation from the PFS hypothesis.
To clarify alpha spending due 
to skipping IA1, as 
documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023. 
The changes align the 
protocol with sSAP 
Amendment 01 and finalized 
efficacy IA.
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Section # and Name
Description of Change 
Brief Rationale 
9.9 Sample Size and 
Power Calculations
Updated the HR at the boundary for success from 0.73 to 0.74 and 
updated the assumption of improvement over control from 2.2 to 2.1 
months. 
Due to skipping IA1, as 
documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023, the 
boundary and alpha changed.
The changes align the 
protocol with sSAP 
Amendment 01 and finalized 
efficacy IA.
9.10 Subgroup Analyses
Added subgroups by HRD status and for HRD combined with BRCA.
To fully explore the effect of 
these biomarkers, as 
documented in sSAP 
Amendment 01, which was 
finalized on 09-FEB-2023.
The changes align the 
protocol with sSAP 
Amendment 01 and finalized 
efficacy IA.
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Section # and Name
Description of Change 
Brief Rationale 
10.7.3 Japan
Added new section to clarify the category of drug of the clinical 
notification submitting to the regulatory authority.
Clarification as per Japan 
Protocol Clarification Letter 
25-MAY-2022.
Since carboplatin and 
gemcitabine are already 
approved for use in this study 
population in Japan, it is 
categorized as “product(s) 
used in the clinical trial other 
than test product(s)" 
following Japan regulation.
Throughout Document
Minor administrative, formatting, grammatical, and/or 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 ............................................................................................28
1.1
Synopsis.................................................................................................................28
1.2
Schema ..................................................................................................................35
1.3
Schedule of Activities (SoA)................................................................................36
1.3.1
Screening and Induction ..............................................................................36
1.3.2
Post-induction ..............................................................................................42
1.3.3
End-of-Treatment and Follow-up After Treatment Discontinuation...........48
1.3.4
Second Course Retreatment.........................................................................52
2
INTRODUCTION..........................................................................................................57
2.1
Study Rationale....................................................................................................57
2.2
Background ..........................................................................................................59
2.2.1
Olaparib........................................................................................................59
2.2.2
Pembrolizumab ............................................................................................60
2.2.3
Pharmaceutical and Therapeutic Background .............................................60
2.2.3.1
Inhibition of PARP as a Target for Cancer Therapy..........................60
2.2.3.2
Inhibition of PD-1 as a Target for Cancer Therapy ...........................61
2.2.4
Disease Background.....................................................................................61
2.2.4.1
Triple Negative Breast Cancer...........................................................61
2.2.5
Rationale for Combination Therapy ............................................................63
2.2.5.1
Chemotherapy in Combination With Pembrolizumab.......................63
2.2.5.2
Olaparib in Combination With Pembrolizumab ................................63
2.2.6
Preclinical and Clinical Studies ...................................................................65
2.2.7
Ongoing Clinical Studies.............................................................................65
2.2.8
Information on Other Study-related Therapy ..............................................65
2.3
Benefit/Risk Assessment......................................................................................65
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................66
4
STUDY DESIGN............................................................................................................71
4.1
Overall Design......................................................................................................71
4.1.1
Induction ......................................................................................................72
4.1.2
Post-induction ..............................................................................................72
4.1.3
End-of-Treatment.........................................................................................74
4.1.4
Planned Analyses.........................................................................................74
4.2
Scientific Rationale for Study Design.................................................................74
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4.2.1
Rationale for Endpoints ...............................................................................74
4.2.1.1
Efficacy Endpoints.............................................................................74
4.2.1.2
Safety Endpoints................................................................................75
4.2.1.3
Patient-Reported Outcomes ...............................................................75
4.2.1.4
Planned Exploratory Biomarker Research.........................................75
4.2.1.5
Future Biomedical Research..............................................................77
4.2.2
Rationale for the Use of Comparator...........................................................78
4.3
Justification for Dose...........................................................................................78
4.3.1
Rationale for Olaparib Dosing Regimen......................................................78
4.3.2
Rationale for Chemotherapy Dosing Regimens ..........................................78
4.3.3
Rationale for Pembrolizumab Dosing Regimen ..........................................78
4.3.4
Maximum Dose/Exposure for This Study ...................................................79
4.4
Beginning and End of Study Definition .............................................................79
4.4.1
Clinical Criteria for Early Study Termination .............................................79
5
STUDY POPULATION ................................................................................................80
5.1
Inclusion Criteria.................................................................................................80
5.2
Exclusion Criteria................................................................................................85
5.3
Lifestyle Considerations......................................................................................90
5.3.1
Meals and Dietary Restrictions....................................................................90
5.3.2
Contraception...............................................................................................90
5.3.3
Pregnancy.....................................................................................................90
5.3.4
Use in Nursing Women................................................................................90
5.3.5
Practical Considerations...............................................................................90
5.4
Screen Failures.....................................................................................................91
5.5
Participant Replacement Strategy......................................................................91
6
STUDY INTERVENTION............................................................................................91
6.1
Study Intervention(s) Administered...................................................................91
6.2
Preparation/Handling/Storage/Accountability .................................................95
6.2.1
Dose Preparation..........................................................................................95
6.2.2
Handling, Storage, and Accountability........................................................95
6.3
Measures to Minimize Bias: Randomization and Blinding..............................96
6.3.1
Intervention Assignment..............................................................................96
6.3.2
Stratification.................................................................................................96
6.3.3
Tumor Marker Status Blinding....................................................................96
6.3.4
Study Intervention Blinding.........................................................................97
6.4
Study Intervention Compliance..........................................................................97
6.4.1
Olaparib Compliance ...................................................................................97
6.4.2
Pembrolizumab, Carboplatin, and Gemcitabine Compliance......................97
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6.5
Concomitant Therapy..........................................................................................97
6.5.1
Acceptable Concomitant Medications .........................................................97
6.5.2
Prohibited Concomitant Medications ..........................................................98
6.5.3
Rescue Medications and Supportive Care .................................................100
6.5.3.1
Rescue Medication and Supportive Care for Olaparib ....................100
6.5.3.2
Rescue Medication and Supportive Care for Pembrolizumab.........100
6.5.3.3
Rescue Medication and Supportive Care for Chemotherapy 
(Carboplatin and Gemcitabine)........................................................100
6.6
Dose Modification (Escalation/Titration/Other).............................................101
6.6.1
Olaparib Dosing Modifications..................................................................101
6.6.1.1
Management of Hematological Toxicities.......................................101
6.6.1.2
Management of Prolonged Hematological Toxicities .....................103
6.6.1.3
Management of Non-hematologic Toxicity.....................................104
6.6.1.3.1
Management of New or Worsening Pulmonary Symptoms ..104
6.6.1.3.2
Management of Nausea and Vomiting ..................................104
6.6.1.3.3
Management of Renal Impairment ........................................105
6.6.1.4
Interruptions for Intercurrent Non-Toxicity-related Events ............105
6.6.1.5
Dose Reductions for Concurrent CYP3A4 Inhibitor Use................106
6.6.2
Pembrolizumab Dosing Modifications ......................................................106
6.6.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).....................................................................................106
6.6.2.2
Management of Infusion Reactions .................................................112
6.6.2.3
Interruptions for Intercurrent Non-Toxicity-related Events ............115
6.6.3
Management of Overlapping Toxicities of Olaparib and Pembrolizumab115
6.6.4
Chemotherapy (Carboplatin and Gemcitabine) Dosing Modifications .....115
6.6.5
Management of Overlapping Toxicities of Gemcitabine and 
Pembrolizumab ..........................................................................................116
6.7
Intervention After the End of the Study..........................................................116
6.8
Clinical Supplies Disclosure..............................................................................116
6.9
Standard Policies................................................................................................116
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................116
7.1
Discontinuation of Study Intervention.............................................................116
7.2
Participant Withdrawal From the Study.........................................................119
7.3
Lost to Follow-up ...............................................................................................119
8
STUDY ASSESSMENTS AND PROCEDURES......................................................119
8.1
Administrative and General Procedures .........................................................120
8.1.1
Informed Consent.......................................................................................120
8.1.1.1
General Informed Consent...............................................................120
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research...........................................................................................121
8.1.2
Inclusion/Exclusion Criteria ......................................................................121
8.1.3
Participant Identification Card...................................................................121
8.1.4
Medical History .........................................................................................122
8.1.4.1
Breast Cancer History......................................................................122
8.1.4.2
Prior Treatments for Breast Cancer .................................................122
8.1.4.3
Childbearing Potential .....................................................................122
8.1.5
Prior and Concomitant Medications Review.............................................122
8.1.5.1
Prior Medications.............................................................................122
8.1.5.2
Concomitant Medications................................................................123
8.1.5.3
Subsequent Anticancer Therapy ......................................................123
8.1.6
Assignment of Screening Number.............................................................123
8.1.7
Assignment of Treatment/Randomization Number...................................123
8.1.8
Study Intervention Administration ............................................................124
8.1.8.1
Timing of Dose Administration.......................................................124
8.1.8.1.1
Induction ................................................................................124
8.1.8.1.1.1
Pembrolizumab ............................................................125
8.1.8.1.1.2
Gemcitabine.................................................................125
8.1.8.1.1.3
Carboplatin...................................................................125
8.1.8.1.2
Post-induction ........................................................................126
8.1.8.1.2.1
Olaparib........................................................................127
8.1.8.1.2.2
Pembrolizumab ............................................................127
8.1.8.1.2.3
Gemcitabine.................................................................127
8.1.8.1.2.4
Carboplatin...................................................................127
8.1.9
Discontinuation and Withdrawal ...............................................................128
8.1.9.1
Withdrawal From Future Biomedical Research ..............................128
8.1.10
Blinding of Study Intervention ..................................................................128
8.1.11
Blinding of Tumor Marker Status..............................................................129
8.1.12
Calibration of Equipment...........................................................................129
8.1.13
Tumor Tissue Collection............................................................................129
8.2
Efficacy Assessments .........................................................................................130
8.2.1
Tumor Markers ..........................................................................................130
8.2.2
Tumor Scans and Assessment of Disease..................................................130
8.2.2.1
Tumor Scans During Screening.......................................................131
8.2.2.1.1
Scans of Target Lesions.........................................................131
8.2.2.1.2
Scans of Brain Metastases .....................................................132
8.2.2.2
Tumor Scans During Induction........................................................132
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8.2.2.2.1
Timing of Tumor Scans .........................................................132
8.2.2.2.2
Response Evaluation..............................................................132
8.2.2.2.3
Determination of Radiographic Progression..........................132
8.2.2.3
Tumor Scans During Post-induction................................................133
8.2.2.3.1
Timing of Tumor Scans .........................................................133
8.2.2.3.2
Response Evaluation..............................................................133
8.2.2.3.3
Determination of Radiographic Progression..........................133
8.2.2.4
Discontinuation and Follow-up Tumor Scans .................................134
8.2.2.5
RECIST 1.1 Assessment of Disease During Induction and Post-
induction ..........................................................................................134
8.2.2.6
iRECIST Assessment of Disease During Post-induction ................136
8.2.2.7
Tumor Scan Flow for Determination of Disease Progression .........136
8.2.3
Patient-Reported Outcomes .......................................................................138
8.2.3.1
Timing During Induction .................................................................139
8.2.3.2
Timing During Post-induction.........................................................139
8.2.4
Eastern Cooperative Oncology Group Performance Status.......................139
8.3
Safety Assessments.............................................................................................140
8.3.1
Physical Examinations...............................................................................140
8.3.2
Vital Signs..................................................................................................140
8.3.3
Electrocardiograms ....................................................................................140
8.3.4
Clinical Safety Laboratory Assessments ...................................................141
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................141
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................142
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....144
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.144
8.4.4
Regulatory Reporting Requirements for SAE ...........................................144
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................144
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................145
8.4.7
Events of Clinical Interest (ECIs)..............................................................145
8.5
Treatment of Overdose......................................................................................146
8.6
Pharmacokinetics...............................................................................................146
8.7
Pharmacodynamics............................................................................................146
8.8
Future Biomedical Research Sample Collection.............................................146
8.9
Planned Genetic Analysis Sample Collection..................................................146
8.10
Biomarkers .........................................................................................................147
8.11
Medical Resource Utilization and Health Economics.....................................147
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8.12
Visit Requirements.............................................................................................148
8.12.1
Screening....................................................................................................148
8.12.2
Treatment Visits.........................................................................................148
8.12.2.1
Induction ..........................................................................................149
8.12.2.2
Pre-randomization............................................................................149
8.12.2.3
Post-induction ..................................................................................150
8.12.3
Treatment Discontinuation.........................................................................150
8.12.4
Post-treatment Follow-up...........................................................................150
8.12.4.1
Safety Follow-up..............................................................................150
8.12.4.2
Disease Status Follow-up.................................................................151
8.12.4.3
Survival Follow-up Contacts ...........................................................151
8.12.5
Vital Status.................................................................................................152
8.12.6
Second Course Retreatment.......................................................................152
8.12.6.1
Conditions of Second Course Retreatment......................................152
8.12.6.2
Treatment Requirements for Second Course Retreatment...............153
8.12.6.3
Visit Requirements of Second Course Retreatment.........................153
8.12.6.4
Study Treatments During Second Course Retreatment ...................154
8.12.6.5
Concomitant Medications During Second Course Retreatment ......154
8.12.6.6
Laboratory Tests During Second Course Retreatment ....................154
8.12.6.7
Vital Signs During Second Course Retreatment..............................155
8.12.6.8
Adverse Events During Second Course Retreatment ......................155
8.12.6.9
Tumor Scans During Second Course Retreatment ..........................155
8.12.6.10
Discontinuation During Second Course Retreatment......................156
9
STATISTICAL ANALYSIS PLAN ...........................................................................156
9.1
Statistical Analysis Plan Summary...................................................................157
9.2
Responsibility for Analyses/In-house Blinding ...............................................158
9.3
Hypotheses/Estimation ......................................................................................159
9.4
Analysis Endpoints.............................................................................................159
9.4.1
Efficacy Endpoints.....................................................................................159
9.4.2
Safety Endpoints........................................................................................160
9.4.3
PRO Endpoints...........................................................................................160
9.5
Analysis Populations..........................................................................................161
9.5.1
Efficacy Analysis Population.....................................................................161
9.5.2
Safety Analysis Population........................................................................161
9.5.3
PRO Analysis Population ..........................................................................161
9.6
Statistical Methods.............................................................................................161
9.6.1
Statistical Methods for Efficacy Analyses.................................................161
9.6.1.1
Progression-free Survival (PFS) ......................................................162
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9.6.1.2
Overall Survival (OS) ......................................................................163
9.6.1.3
Analysis Strategy for Key Efficacy Endpoints................................164
9.6.2
Statistical Methods for Safety Analyses ....................................................164
9.6.3
Statistical Methods for Patient-reported Outcomes (PRO) Analyses........166
9.6.4
Summaries of Baseline Characteristics and Demographic ........................167
9.7
Interim Analyses ................................................................................................167
9.7.1
Efficacy Interim Analyses..........................................................................168
9.7.2
Safety Interim Analyses.............................................................................169
9.8
Multiplicity .........................................................................................................169
9.8.1
Progression-free Survival...........................................................................169
9.8.2
Overall Survival.........................................................................................170
9.9
Sample Size and Power Calculations ...............................................................170
9.10
Subgroup Analyses.............................................................................................171
9.11
Compliance (Medication Adherence)...............................................................172
9.12
Extent of Exposure.............................................................................................172
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................173
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......173
10.1.1
Code of Conduct for Clinical Trials...........................................................173
10.1.2
Financial Disclosure...................................................................................175
10.1.3
Data Protection...........................................................................................175
10.1.3.1
Confidentiality of Data ....................................................................176
10.1.3.2
Confidentiality of Participant Records.............................................176
10.1.3.3
Confidentiality of IRB/IEC Information..........................................176
10.1.4
Committees Structure.................................................................................176
10.1.4.1
Steering Committee .........................................................................176
10.1.4.2
Internal Data Monitoring Committee...............................................177
10.1.5
Publication Policy......................................................................................177
10.1.6
Compliance with Study Registration and Results Posting Requirements .177
10.1.7
Compliance with Law, Audit, and Debarment ..........................................178
10.1.8
Data Quality Assurance .............................................................................178
10.1.9
Source Documents .....................................................................................179
10.1.10
Study and Site Closure...............................................................................179
10.2
Appendix 2: Clinical Laboratory Tests............................................................181
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................183
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................183
10.3.2
Definition of AE ........................................................................................183
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10.3.3
Definition of SAE ......................................................................................184
10.3.4
Additional Events Reported in the Same Manner as SAE.........................186
10.3.5
Recording AE and SAE .............................................................................186
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................190
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................192
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................193
10.5.1
Definitions..................................................................................................193
10.5.2
Contraception Requirements......................................................................194
10.5.3
Pregnancy Testing......................................................................................195
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................196
10.7
Appendix 7: Country-specific Requirements..................................................201
10.7.1
France.........................................................................................................201
10.7.2
Germany.....................................................................................................201
10.7.3
Japan ..........................................................................................................202
10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status....203
10.9
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression During Post-induction.....................................................204
10.10 Appendix 10: Abbreviations .............................................................................209
11
REFERENCES.............................................................................................................214
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .................................................82
Table 2
Study Interventions..........................................................................................93
Table 3
Dose Modification Guidelines for Olaparib ..................................................101
Table 4
Management of Olaparib-related Anemia .....................................................102
Table 5
Management of Olaparib-related Neutropenia, Leukopenia, and 
Thrombocytopenia.........................................................................................103
Table 6
Dose Reduction of Olaparib to Manage Moderate Renal Impairment ..........105
Table 7
Dose Reduction of Olaparib With a Strong or Moderate CYP3A4 Inhibitor106
Table 8
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .............................................................108
Table 9
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ......................................................................................................113
Table 10
Dose Modification Guidelines for Chemotherapy (Carboplatin and 
Gemcitabine)..................................................................................................115
Table 11
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................143
Table 12
Censoring Rules for Primary and Sensitivity Analyses of PFS.....................163
Table 13
Analysis Strategy for Key Efficacy Endpoints..............................................164
Table 14
Analysis Strategy for Safety Parameters........................................................166
Table 15
Summary of Interim and Final Analyses .......................................................168
Table 16
Efficacy Boundaries and Properties for Progression-free Survival 
Analyses.........................................................................................................169
Table 17
Efficacy Boundaries and Properties for Overall Survival Analyses (H2) .....170
Table 18
Protocol-required Safety Laboratory Assessments........................................181
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................35
Figure 2
RECIST 1.1 Assessment During Post-induction for Clinically Stable 
Participants After First Radiologic Evidence of Disease Progression as 
Assessed by the Investigator..........................................................................137
Figure 3
iRECIST Assessment During Post-induction for Clinically Stable 
Participants.....................................................................................................138
Figure 4
Multiplicity Diagram .....................................................................................169
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-label, Randomized, Phase 2/3 Study of Olaparib Plus 
Pembrolizumab Versus Chemotherapy Plus Pembrolizumab After Induction of Clinical 
Benefit With First-line Chemotherapy Plus Pembrolizumab in Participants With Locally 
Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) 
(KEYLYNK-009)
Short Title: Olaparib Plus Pembrolizumab as Post-Induction Therapy in Triple Negative 
Breast Cancer
Acronym: KEYLYNK-009
Note: Based on the data from a prespecified interim safety and efficacy analysis for 
KEYLYNK-009 (data cutoff 15-DEC-2022), the internal DMC recommended discontinuing 
the study. The combination of pembrolizumab plus olaparib did not show an improvement in 
PFS compared with the combination of chemotherapy plus pembrolizumab. Participants who 
are still receiving study intervention (in post-induction or Second Course Retreatment phase) 
may have the option to continue on study treatment if they are deriving clinical benefit, until 
criteria for discontinuation are met. 
As of Amendment 03, participants who discontinue study treatment for any reason will 
complete the End-of-Treatment and Safety Follow-up visits, but no further data will be 
collected. If continuing on study treatment, participants will no longer have tumor response 
assessments by BICR, but local tumor imaging assessments should continue per SOC 
schedule. For all participants, ePRO assessments will no longer be performed, biomarker 
samples will no longer be collected, and Disease Status Follow-up and Survival Follow-up 
visits will no longer be conducted.
Hypotheses, Objectives, and Endpoints:
The Phase 2/3 2-in-1 adaptive design will not be pursued and the study is now a stand-alone 
Phase 2 study.
In males and females at least 18 years of age with locally recurrent inoperable or metastatic 
TNBC after induction of clinical benefit (objective response or stable disease [SD]) with 
first-line (1L) chemotherapy plus pembrolizumab:
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 refers to the modification of RECIST 1.1 to include a maximum of 10 target 
lesions and a maximum of 5 target lesions per organ. Refer to Section 4.2.1.1 for further 
details.
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Primary Objectives
Primary Endpoints
- Objective: To compare olaparib plus 
pembrolizumab to chemotherapy plus 
pembrolizumab with regards to progression-
free survival (PFS) according to RECIST 1.1 
by blinded independent central review 
(BICR).
Hypothesis (H1): Olaparib plus 
pembrolizumab is superior to chemotherapy 
plus pembrolizumab with respect to PFS 
according to RECIST 1.1 by BICR.
- PFS, the time from randomization until 
either the earliest date of documented 
disease progression or death due to any 
cause, whichever occurs first
- Objective: To compare olaparib plus 
pembrolizumab to chemotherapy plus 
pembrolizumab with regards to overall 
survival (OS).
Hypothesis (H2): Olaparib plus 
pembrolizumab is superior to chemotherapy 
plus pembrolizumab with respect to OS.
- OS, the time from randomization to death 
due to any cause
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate OS, and PFS 
according to RECIST 1.1 by BICR, in 
participants with PD-L1 positive tumors 
(CPS ≥10) following treatment with 
olaparib plus pembrolizumab or 
chemotherapy plus pembrolizumab.
- OS
- PFS
- Objective: To evaluate OS, and PFS 
according to RECIST 1.1 by BICR, in 
participants with BRCAm tumors following 
treatment with olaparib plus pembrolizumab 
or chemotherapy plus pembrolizumab.
- OS
- PFS
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- Objective: To evaluate health-related 
quality-of-life (HRQoL) and time to 
deterioration (TTD) using the European 
Organization for Research and Treatment of 
Cancer (EORTC) Quality of Life 
Questionnaire Core 30 (EORTC QLQ-C30) 
and the breast cancer module (EORTC QLQ-
BR23) in participants with BRCAm tumors 
and irrespective of BRCAm status following 
treatment with olaparib plus pembrolizumab 
or chemotherapy plus pembrolizumab.
- HRQoL, a change from baseline in 
Patient-Reported Outcomes (PRO) scores 
obtained in post-induction
- Time to Deterioration (TTD), the time 
from baseline to the first onset of a 
confirmed* ≥10-point deterioration from 
baseline in PRO scores
- For the following domains:
- EORTC QLQ-C30 global health 
status/QoL (Items 29 and 30)
- EORTC QLQ-C30 physical functioning 
(Items 1-5)
- EORTC QLQ-C30 emotional functioning 
(Items 21-24), and
- EORTC QLQ-BR23 systemic therapy 
side effects (Items 1-4, 6, 7, and 8)
*confirmed by a ≥10-point deterioration 
from baseline in the subsequent PRO score
- Objective: To evaluate visual analogue 
scale (VAS) using the EuroQoL 
5-dimension, 5-level questionnaire (EQ-5D-
5L) in participants with BRCAm tumors and 
irrespective of BRCAm status following 
treatment with olaparib plus pembrolizumab 
or chemotherapy plus pembrolizumab.
- Visual analogue scale (VAS), a change 
from baseline in EQ-5D-5L VAS score 
obtained in post-induction
- Objective: To evaluate the safety and 
tolerability of olaparib plus pembrolizumab 
or chemotherapy plus pembrolizumab.
- Adverse events (AEs)
- Study treatment discontinuation due to 
AEs
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Overall Design:
Study Phase
Phase 2*
Primary Purpose
Treatment
Indication
First-line treatment of locally recurrent inoperable or 
metastatic TNBC
Population
Females and males at least 18 years of age with 
previously untreated locally recurrent inoperable or 
metastatic TNBC
Study Type
Interventional
Intervention Model
Parallel
This is a randomized, 2-arm, multi-site study.
Type of Control
Active control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
As of Amendment 03, the study is being discontinued 
based on the recommendation of the internal DMC. 
However, participants who are still receiving study 
intervention (in post-induction or Second Course 
Retreatment phase) may have the option of continuing 
with study treatment if they are deriving clinical benefit.
The study will remain open until the last participant who 
is continuing study treatment completes the Safety 
Follow-up visit.
* Although the study title reflects the original Phase 2/3 2-in-1 adaptive design, following 
Amendment 02, the 2-in-1 adaptive design including the Phase 3 portion of the study will no 
longer be pursued and the study will be conducted as a stand-alone Phase 2 study with a 
revised SAP.
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Number of Participants:
Approximately 460 participants will be enrolled and treated with induction therapy, to ensure 
approximately 260 eligible participants being randomly assigned to post-induction therapy.
The approximations for enrollment into induction therapy are made from currently available 
efficacy and toxicity data.
Intervention Groups and Duration:
Intervention 
Groups
Induction 
All participants will receive the study interventions 
(carboplatin + gemcitabine + pembrolizumab) in the nonrandomized 
induction.

Carboplatin area under the concentration-time curve (AUC) 2 
intravenous (IV) on Days 1 and 8 (Cycles 1-6)

Gemcitabine 1000 mg/m2 IV on Days 1 and 8 (Cycles 1-6)

Pembrolizumab 200 mg every 3 weeks (Q3W) on Day 1 (Cycles 1-6)
Post-induction
Participants who achieve complete response (CR) or partial response (PR), or 
maintain SD, during induction after up to 6 cycles but not less than 4 cycles 
of treatment and meet the eligibility criteria for post-induction will be 
randomly assigned to Arm 1 (olaparib + pembrolizumab) or Arm 2 
(carboplatin + gemcitabine + pembrolizumab).
Arm 1

Olaparib 300 mg BID (twice daily) orally

Pembrolizumab 200 mg Q3W
Arm 2

Carboplatin AUC 2 IV on Days 1 and 8 

Gemcitabine 1000 mg/m2 IV on Days 1 and 8 

Pembrolizumab 200 mg Q3W on Day 1 
Olaparib, carboplatin, and gemcitabine may continue until a toxicity requires 
discontinuation or until disease progression.
Pembrolizumab may continue for up to 35 administrations, inclusive of 
induction administrations, until a toxicity requires discontinuation or until 
disease progression.
A summary of the study interventions, including dose strength, dose 
frequency, route of administration, treatment period, and use is presented in 
the table below.
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Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Treatment 
Period
Use
Induction
Carboplatin
AUC 2 
Days 1 
and 8 
IV 
infusion
Every 
21-day 
cycle
Test product
Gemcitabine
1000 
mg/m2
Days 1 
and 8 
IV 
infusion
Every
21-day 
cycle
Test product
Pembrolizumab
200 mg
Day 1 
IV 
infusion
Every 
21-day 
cycle
Test product
Post-
induction
Arm 1
Olaparib
300 mg
BID
Orally
Daily
Test product
Pembrolizumab
200 mg
Day 1 
IV 
infusion
Every
21-day 
cycle
Test product
Post-
induction
Arm 2
Carboplatin
AUC 2 
Days 1 
and 8 
IV 
infusion
Every 
21-day 
cycle
Test product
Gemcitabine
1000 
mg/m2
Days 1 
and 8 
IV 
infusion
Every
21-day 
cycle
Test product
Pembrolizumab
200 mg
Day 1 
IV 
infusion
Every
21-day 
cycle
Test product
Abbreviations: Admin = administration; AUC = area under the concentration-time curve; BID = twice 
daily; IV = intravenous.
Total 
Number
2 arms
Duration 
of 
Participa-
tion
Each participant will participate in the study for approximately 2 to 5 years 
from the time the participant provides documented informed consent through 
the final protocol-specified contact.
After the screening period of up to 28 days, each participant will begin 
induction therapy with carboplatin and gemcitabine plus pembrolizumab. 
Participants who achieve CR or PR, or maintain SD, after 4 to 6 cycles will 
be randomized to receive either olaparib plus pembrolizumab (Arm 1) or to 
continue carboplatin and gemcitabine plus pembrolizumab (Arm 2).
Discontinuation criteria are outlined in Section 7.1, including discontinuation 
from a specific study intervention.
During induction, participants who discontinue all study interventions for any 
reason, and are therefore ineligible for randomization to post-induction 
treatment, will enter the 30-day safety follow-up, as outlined in Section 1.3.3
and as described under Section 8.12.4.1 and will not enter disease status 
follow-up or survival follow-up.
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During post-induction, participants who discontinue all study interventions 
for reasons other than disease progression will enter the 30-day safety follow-
up and disease status follow-up, as outlined in Section 1.3.3 and as described 
under Section 8.12.4.2 and will have post-treatment follow-up imaging to 
evaluate disease status until disease progression according to RECIST 1.1 is 
radiographically documented and verified by BICR, initiating a new 
anticancer therapy, a documented complete withdrawal of consent from the 
study, becoming lost to follow-up, pregnancy, or death. Note: As of 
Amendment 03, participants who are still on study treatment and deriving 
clinical benefit will no longer have tumor response assessments by BICR. 
However, local tumor imaging assessments should continue per SOC 
schedule.
After all post-induction treatments are discontinued because of disease 
progression, each participant will enter the 30-day safety follow-up and the 
survival follow-up, as outlined in Section 1.3.3 and as described under 
Section 8.12.4.1 and Section 8.12.4.3, respectively. Participants who enter 
survival follow-up will be contacted by telephone to determine OS until 
death, a complete documented withdrawal of consent from the study, or the 
end of the study, whichever occurs first. Note: As of Amendment 03, 
Survival Follow-up visits will no longer be conducted.
Study Governance Committees:
Steering Committee
Yes
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
The DMC will be an internal DMC (see Section 10.1.4.2).
As of Amendment 03, the Steering Committee and internal DMC are no longer applicable.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
AUC=area under the concentration-time curve; BID=twice daily; BRCAm=breast cancer susceptibility gene 
mutation; BRCAwt=breast cancer susceptibility gene wild type; CNS=central nervous system; CPS=combined 
positive score; CR=complete response; ECOG=Eastern Cooperative Oncology Group; PD-L1=programmed cell 
death-ligand 1; PR=partial response; Q3W=every 3 weeks; SD=stable disease; TNBC=triple negative breast 
cancer.
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1.3
Schedule of Activities (SoA)
1.3.1
Screening and Induction 
Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
Administrative Procedures
Informed Consent
X
Screening Window does not apply for 
informed consent. Main study informed 
consent is required before screening 
procedures. Consent for FBR is optional
and can be provided before or after Cycle 1, 
Day 1.
Informed Consent
for FBR
X
Inclusion / Exclusion 
Criteria
X
Participant 
Identification Card
X
Demographics 
and Medical History 
X
Menopausal Status
X
Prior/Concomitant 
Medication
X
<--------------------------------------------------------------------------->
Quality of Life and Physical Performance Measures
ePROs
EORTC QLQ-C30
EORTC QLQ-BR23
EQ-5D-5L™
X
X
X
X
Should be completed in the order listed and 
within 3 days prior to visit dose 
administration. Illiterate participants are 
allowed to enroll in the study and are 
exempt from completing ePROs (refer to 
Section 8.2.3).
ECOG 
Performance Status 
X
X
X
X
X
X
X
Within 7 days prior to Cycle 1, Day 1; prior
to dosing on Day 1 in subsequent cycles.
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Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
Treatment Administration
Pembrolizumab
X
X
X
X
X
X
Participants should not be dosed after Week 
18 scan (see Section 8.2.2.2.1) during 
induction.
Gemcitabine
X
X
X
X
X
X
X
X
X
X
X
X
Carboplatin 
X
X
X
X
X
X
X
X
X
X
X
X
Tumor Tissue Collection
Recently or Newly 
Obtained Tumor 
Tissue Collection
X
Screening Window does not apply.
Efficacy Procedures
Tumor Scans –a -
Chest, Abdomen, 
and Pelvis
X*
X
X
X
* Tumor scans for screening should be done
within 28 days before Cycle 1, Day 1. 
Tumor scans should be performed at 
Week 6 (42+7 days), Week 12 (84±7 days), 
and Week 18 (126-7 days) during induction. 
Timing of on-study tumor scans is relative 
to Cycle 1, Day 1 during induction, should 
follow calendar days, and not be adjusted 
for any dose modifications.
The same scan technique and consistent use 
of contrast should be used throughout the 
study to optimize assessment of existing 
and new tumor burden.
See the SIM for details.
08BLRN

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Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
Brain Scan
X*
X*
X*
X*
*Brain scans (MRI is preferred) are
required at screening and during induction 
(at the same schedule as other tumor scans
for evaluation of disease status) ONLY for 
participants with known brain metastases 
and those with worsening and/or new 
neurological symptoms. Brain imaging CT 
scans will be acceptable if MRI is medically 
contraindicated.
See the SIM for details.
Bone Scan
X*
-------------------------- If clinically indicated------------------------------
*Bone scans are required at screening, 
ONLY if a participant has a history of bone 
metastases and/or has new bone pain or 
other symptoms/signs suggestive of bone 
metastases and if the bone scan is negative, 
a plain X-ray is also required.
During the study, a bone scan (and plain 
X-ray, if participant has signs/symptoms of 
bone metastases and bone scan is negative) 
will be performed if clinically indicated for 
evaluation of known, worsening and/or new 
bone pain or other symptoms/signs 
suggestive of bone metastases OR if the site 
believes a participant has attained a CR.
See the SIM for details.
Safety Procedures
Full Physical 
Examination 
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
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Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
12-lead 
Electrocardiogram
X
Vital Signs/Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs/weight should be measured
within 3 days before each dosing day.
AEs / SAEs
<-------------------------------------------------------------------------->
Laboratory Assessments – Analysis performed by local laboratories
Urine 
Pregnancy Test 
(WOCBP only) b
X
<-------------------------------------------------------------------------->
Pregnancy testing should be completed at 
screening and then monthly or if clinically 
indicated in WOCBP. 
Serum FSH 
and Estradiol 
(WOCBP only) b
X
Will be measured only if clinically 
indicated for determination of menopausal 
status
HIV, and
Hepatitis B and C 
screen c
X
Performed only if mandated by local health 
authority.
CBC with 
Differential c
X
X*
X
X
X
X
X
X
X
X
X
X
X
*If screening is performed within 10 days 
of Cycle 1, Day 1, there is no need to repeat 
on Cycle 1, Day 1.
Chemistry c
X
X*
X
X
X
X
X
Urinalysis c
X
PT/INR and 
aPTT/PTT c
X
Additional testing to be conducted as 
clinically indicated for participants taking 
anticoagulation therapy.
Vitamin D (serum)
X
Perform at screening and as clinically 
indicated.
T3 (or Free T3), Free 
T4, and TSH c
X
X
X
X
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Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
Other Tumor 
Markers
CA 15-3, CEA, 
CA 27.29
X*
X
X
X
Should be collected during screening and 
then according to the tumor scan schedule 
ie, Week 6 (+7 days), Week 12 (±7 days), 
and Week 18 (-7 days) (can be conducted at 
corresponding study visit) until study 
treatment discontinuation.
* Blood collection is required before 
Cycle 1 Day 1, but results are not required 
before dosing.
Laboratory Assessments (Tissue Samples) – Analysis performed by central laboratory
TNBC 
Tumor Markers 
(ER, PGR, HER2)
X
TNBC and PD-L1 status must be centrally 
confirmed prior to enrollment in the study.
PD-L1 
Tumor Marker
X
Other Tumor 
Markers 
(BRCA)
X
BRCA results must be available prior to 
randomization in post-induction 
(Section 1.3.2).
Laboratory Assessments (Blood Samples) – Analysis performed by central laboratory
Blood for Genetic 
Analysis
X
Drawn pre-dose.
Blood for ctDNA 
analyses
X
X
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Study Period:
Induction (21-Day Cycles)
Notes
Treatment 
Cycle/Title:
Scree-
ning
1
2
3
4
5
6
Scheduled Day:
-28 
to -1
1
8
1
8
1
8
1
8
1
8
1
8
Screening days are relative to Cycle 1, 
Day 1 of induction.
Scheduling Window 
(Days):
NA
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for tumor 
scans.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; BICR=blinded independent central review; BRCA=breast cancer susceptibility gene; 
CA=cancer antigen; CBC=complete blood count; CEA=carcinoembryonic antigen; CR=complete response; CT=computed tomography; ctDNA=circulating tumor 
deoxyribonucleic acid; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire 30; EORTC QLQ-BR23=European Organization for the Research and Treatment of Cancer Breast Cancer Specific Quality of Life Questionnaire; EQ-5D-
5L=EuroQoL-5 dimensions-5 levels; ePRO=electronic patient-reported outcomes; ER=estrogen receptor; FBR=future biomedical research; FSH=follicle-stimulating hormone; 
HER2=human epidermal growth factor receptor-2; HIV=human immunodeficiency virus; INR=international normalized ratio; MRI=magnetic resonance imaging; 
PD-L1=programmed cell death-ligand 1; PGR=progesterone receptor; PR=partial response; PT=prothrombin time; PTT=partial thromboplastin time; RECIST=Response 
Evaluation Criteria in Solid Tumors; SAE=serious adverse event; SD=stable disease; TNBC=triple negative breast cancer; TSH=thyroid stimulating hormone; 
WOCBP=women of childbearing potential.
a.
A participant with a tumor response at Week 18 (-7 days) of CR, PR, or SD, according to RECIST 1.1 as determined by BICR expedited review, is eligible regarding
tumor response for randomization to post-induction treatment. Participants with centrally verified disease progression based on tumor scans at any time point will be 
discontinued from study treatment.
b.
For WOCBP, a urine or serum pregnancy test should be performed within 24 hours prior to the first dose of study treatment. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. 
c.
Screening laboratory tests must be performed within 10 days prior to the start of study treatment. Thereafter, laboratory samples can be collected up to 72 hours prior to 
scheduled administration of study treatment.
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1.3.2
Post-induction
Note: Participants who are randomized to Arm 1 (olaparib + pembrolizumab) in post-induction will not require the Day 8 scheduled 
assessments.
Note: As of Amendment 03, participants who are still receiving study intervention in post-induction may have the option of continuing 
with study treatment if they are deriving clinical benefit. If continuing on study treatment, participants will no longer have tumor 
response assessments by BICR, but local tumor imaging assessments should continue per SOC schedule. In addition, ePRO 
assessments (EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L) will no longer be performed and biomarker samples (blood for 
ctDNA analysis) will no longer be collected. 
Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Administrative Procedures
Post-induction 
Inclusion / Exclusion 
Criteria
X
Prior/Concomitant 
Medication 
X
<----------------------------------------------------------------->
Randomization 1:1 
to Post-Induction
X
Randomization is performed after 
participant has met post-induction
eligibility criteria and no more than 3 
days before Cycle 1, Day 1.
Informed Consent 
Addendum (If Required)
<----------------------------------------------------------------->
If the investigator plans to continue 
post-induction study intervention 
beyond BICR-verified disease 
progression, Sponsor communication 
with documented SCF and an informed
consent addendum are required.
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Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Quality of Life and Physical Performance Measures
ePROs
EORTC QLQ-C30
EORTC QLQ-BR23
EQ-5D-5L™
X
X
X
X
X
X
Day 1 of the first 8 cycles, then every 
second cycle in Year 1 of post-induction 
and then every fourth cycle (every 12 
weeks) starting in Year 2 of 
post-induction until end of treatment, 
disease progression as determined by 
BICR, or death (whichever occurs first).
Should be completed in the order listed 
and within 3 days prior to visit dose 
administration. 
Illiterate participants are exempt from 
completing ePROs (refer to Section 
8.2.3).
ECOG 
Performance Status 
X
X
X
X
X
X
X
Within 7 days prior to Cycle 1, Day 1; 
prior to dosing on Day 1 in subsequent 
cycles.
Treatment Administration – Arm 1
Olaparib 
<----------------------------------------------------------------->
Self-administered 
Pembrolizumab
X
X
X
X
X
X
Treatment Administration – Arm 2
Carboplatin 
X
X
X
X
X
X
X
X
X
X
X
X
Gemcitabine 
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab 
X
X
X
X
X
X
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Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Efficacy Procedures
Tumor Scans - Chest, 
Abdomen, and Pelvis
X
X
Tumor scans should be performed at 
Week 6 (42+7 days), then every 6 
weeks (±7 days) for the first year. In the 
second year post-induction, tumor scans 
move to every 12 weeks (±7 days).
Timing of tumor scans is relative to 
randomization date of post-induction. 
Tumor scans should follow calendar 
days and not be adjusted for any dose 
modifications.
The same scan technique and consistent 
use of contrast should be used 
throughout the study to optimize 
assessment of existing and new tumor 
burden.
See the SIM for details.
Brain Scans
X*
X*
*Brain scans (MRI is preferred) are
required during post-induction (at the 
same schedule as other tumor scans for 
evaluation of disease status) ONLY for 
participants with known brain 
metastases and those with worsening 
and/or new neurological symptoms. 
Brain imaging CT scans will be 
acceptable if MRI is medically 
contraindicated.
See the SIM for details.
08BLRN

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Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Bone Scans
--------------------If clinically indicated---------------------
During the study, a bone scan (and plain 
X-ray, if participant has 
signs/symptoms of bone metastases and 
bone scan is negative) will be 
performed ONLY if clinically indicated 
for evaluation of known, worsening 
and/or new bone pain or other 
symptoms/signs suggestive of bone 
metastases OR if the site believes a 
participant has attained a CR.
See the SIM for details.
Safety Procedures
Full Physical 
Examination 
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
X
12-lead 
Electrocardiogram
X
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs/weight should be measured
within 3 days before each dosing day.
AEs / SAEs
X
<------------------------------------------------------------------>
Laboratory Assessments – Analysis performed by local laboratories
Urine Pregnancy Test 
(WOCBP only) a
X
<---------------------------------------------------------------->
Pregnancy testing should be completed 
monthly or if clinically indicated in 
WOCBP.
CBC with Differential b
X
Xc
X
X
X
X
X
X
X
X
X
X
X
Chemistry b
X
Xc
X
X
X
X
X
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Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
T3 (or Free T3), Free 
T4, 
and TSH b
X
X
Can be assayed based on local 
guidelines and practices. To be repeated 
every 2 cycles after Cycle 5, or as 
clinically indicated. The thyroid 
functions collected at the end of 
induction will be the Baseline for safety 
analyses.
Other Tumor Markers
(CA 15-3, CEA, 
CA 27.29)
X
X
Should be collected according to the 
tumor scan schedule ie, Week 6 (42+7 
days), then every 6 weeks (±7 days) for 
the first year, and every 12 weeks 
(±7 days) in the second year post-
induction (can be conducted at 
corresponding study visit, but must be 
collected within the same window 
specified for imaging) until study 
treatment discontinuation.
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Study Period:
Pre-
randomization
Visit
Post-induction (21-Day Cycles)
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Cycle 1, Day 1 may occur on the same 
day as randomization or at most 3 days 
post randomization.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Laboratory Assessments (Blood Samples) – Analysis performed by central laboratory
Blood for ctDNA 
analyses*
X
X
X
*Blood for ctDNA analyses to be 
collected pre-dose at C1D1, C2D1, 
C5D1 of Post-induction. After C5D1, 
collect blood for ctDNA every 6 weeks
during Year 1 of Post-induction, and 
every 12 weeks from Year 2 until the 
end of Year 5, or until discontinuation 
of study treatment, whichever is earlier.
ctDNA collections post-induction 
should be aligned with clinic visit 
closest to tumor scan visits. If a clinic 
visit is not feasible, blood for ctDNA 
collection will not be collected.
Abbreviations: AE=adverse event; C=cycle; CA=cancer antigen; CBC=complete blood count; CEA=carcinoembryonic antigen; CT=computed tomography; ctDNA=circulating 
tumor deoxyribonucleic acid; D=day; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for the Research and Treatment of Cancer 
Quality of Life Questionnaire 30; EORTC QLQ-BR23=European Organization for the Research and Treatment of Cancer Breast Cancer Specific Quality of Life Questionnaire; 
EQ-5D-5L=EuroQoL-5 dimensions-5 levels; MRI=magnetic resonance imaging; SAE=serious adverse event; SCF=Sponsor Consultation Form; TSH=thyroid stimulating 
hormone; WOCBP=women of childbearing potential.
a.
For WOCBP, a urine or serum pregnancy test should be performed within 24 hours prior to the first dose of study treatment. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. 
b.
Laboratory samples can be collected up to 72 hours prior to scheduled administration of study treatment.
c.
Laboratory samples do not have to be repeated if done within 72 hours of Cycle 1, Day 1.
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1.3.3
End-of-Treatment and Follow-up After Treatment Discontinuation
Note: As of Amendment 03, participants who discontinue from study treatment should complete the End-of-Treatment and Safety 
Follow-up visits. Disease Status Follow-up and Survival Follow-up visits will no longer be conducted. In addition, ePRO assessments 
(EORTC QLQ-C30, EORTC QLQ-BR23, EQ-5D-5L) will no longer be performed and biomarker samples (blood for ctDNA 
analysis) will no longer be collected. 
End-of-Treatment
Follow-up After Treatment Discontinuation
Notes
Last Dose, 
Disease Progression, 
or Other Reasons
Safety 
Follow-up a
Disease Status 
Follow-up b
Survival 
Follow-up c
Treatment Cycle/Title:
At Treatment 
Discontinuation
30 Days 
After Last Dose
Every 6 or 12 
Weeks After Last 
Dose
Every 12 
Weeks
Scheduling Window (Days):
NA
±3
±7
±7
Administrative Procedures
Prior/Concomitant 
Medication
X
X
Disease Status
X
X
Record other therapies administered for 
disease under study and outcomes. 
Refer to Section 8.12.4.2 for details.
Survival (Vital) Status
<--------------------------------------------------------------->
X
Survival (vital) status may be requested 
by the Sponsor at any time during the 
study. Telephonic every 12 weeks (or 
more often as needed) until death, 
withdrawal of consent, or the end of the 
study.
Quality of Life and Physical Performance Measures
ePROs
EORTC QLQ-C30
EORTC QLQ-BR23
EQ-5D-5L™
X
X
Should be completed in the order listed.
ePROs are not performed during 
Second Course Retreatment follow-up.
Illiterate participants are exempt from 
completing ePROs (refer to 
Section 8.2.3).
ECOG Performance Status
X
X
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End-of-Treatment
Follow-up After Treatment Discontinuation
Notes
Last Dose, 
Disease Progression, 
or Other Reasons
Safety 
Follow-up a
Disease Status 
Follow-up b
Survival 
Follow-up c
Treatment Cycle/Title:
At Treatment 
Discontinuation
30 Days 
After Last Dose
Every 6 or 12 
Weeks After Last 
Dose
Every 12 
Weeks
Scheduling Window (Days):
NA
±3
±7
±7
Tumor Tissue Collection
Optional 
Tumor Tissue Collection
X*
*If possible, collect tumor tissue at the 
end of treatment (ie, either induction or 
post-induction).
Participant must provide optional 
biopsy consent.
Efficacy Procedures
Tumor Scans – Chest, 
Abdomen, and Pelvis
X
Assessed according to the already 
followed tumor scan schedule during 
disease status follow-up for participants 
who discontinue study intervention 
during post-induction (ie, every 
6 weeks [+7 days] for the first year and
every 12 weeks [±7 days] in the second 
year post-induction, relative to 
randomization date of post-induction), 
see Section 8.12.4.2. 
The same scan technique and consistent 
use of contrast should be used 
throughout the study to optimize 
assessment of existing and new tumor 
burden.
Safety Procedures
Full Physical Examination 
X
Vital Signs and Weight 
X
X
12-lead Electrocardiogram
X
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End-of-Treatment
Follow-up After Treatment Discontinuation
Notes
Last Dose, 
Disease Progression, 
or Other Reasons
Safety 
Follow-up a
Disease Status 
Follow-up b
Survival 
Follow-up c
Treatment Cycle/Title:
At Treatment 
Discontinuation
30 Days 
After Last Dose
Every 6 or 12 
Weeks After Last 
Dose
Every 12 
Weeks
Scheduling Window (Days):
NA
±3
±7
±7
AEs / SAEs
X
X
AEs that occur within 30 days of the 
end of treatment should be recorded.
SAEs that occur within 90 days 
following the last dose of study 
intervention (or 30 days following the 
last dose if participant initiates a new 
anticancer therapy) should be reported, 
followed, and recorded.
Laboratory Assessments – Analysis performed by local laboratories
Urine Pregnancy Test 
(WOCBP only)
X
X
(X)
(X)
Pregnancy testing in WOCBP should 
be performed at treatment 
discontinuation, at the 30-day safety 
follow-up, and as required locally or if 
clinically indicated. Pregnancy testing 
should continue in posttreatment until 
120 days after the last dose of 
pembrolizumab and 180 days after last 
dose of olaparib or chemotherapy.
Refer to Appendix 7 for 
country-specific requirements. 
CBC with Differential 
X
X
Chemistry 
X
X
T3 (or Free T3), Free T4, and 
TSH 
X
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End-of-Treatment
Follow-up After Treatment Discontinuation
Notes
Last Dose, 
Disease Progression, 
or Other Reasons
Safety 
Follow-up a
Disease Status 
Follow-up b
Survival 
Follow-up c
Treatment Cycle/Title:
At Treatment 
Discontinuation
30 Days 
After Last Dose
Every 6 or 12 
Weeks After Last 
Dose
Every 12 
Weeks
Scheduling Window (Days):
NA
±3
±7
±7
Other Tumor Markers
(CA 15-3, CEA, CA 27.29)
X
Should be collected during disease 
status follow-up according to the tumor 
scan schedule (ie, every 6 weeks 
[+7 days] for the first year and every 12 
weeks [±7 days] in the second year 
post-induction). Must be collected
within the same window specified for 
imaging.
Laboratory Assessments – Analysis performed by central laboratory
Blood for ctDNA Analysis
X
Abbreviations: AE=adverse event; CA=cancer antigen; CBC=complete blood count; CEA=carcinoembryonic antigen; ctDNA=circulating tumor deoxyribonucleic acid; 
ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire 30; EORTC 
QLQ-BR23=European Organization for the Research and Treatment of Cancer Breast Cancer Specific Quality of Life Questionnaire; ePRO=electronic patient-reported 
outcomes; EQ-5D-5L=EuroQoL-5 dimensions-5 levels; SAE=serious adverse event; TSH=thyroid stimulating hormone; WOCBP=women of childbearing potential.
a.
Participants enter the 30-day safety follow-up after discontinuation of all study interventions for any reason during induction or post-induction. If the End of Treatment 
Visit occurs ≥30 days from last dose of study treatment, a separate Safety Follow-up visit is not required.
b.
Participants who discontinue all study interventions for any reason during induction and are not randomized to the post-induction phase will not enter disease status follow-
up. Participants enter disease status follow-up after discontinuation of all study interventions for reasons other than centrally verified disease progression during post-
induction.
c.
Participants who discontinue all study interventions for any reason during induction and are not randomized to the post-induction phase will not enter survival follow-up. 
Participants enter survival follow-up after discontinuation of all study interventions due to centrally verified disease progression during post-induction or after starting a 
new anticancer therapy, whichever occurs first.
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1.3.4
Second Course Retreatment
The Schedule of Activities (SoA) for Second Course Retreatment is provided in this section 
for eligible participants. Complete details regarding Second Course Retreatment are provided 
in Section 8.12.6.
Note: As of Amendment 03, the study will be discontinued based on the recommendation of
the internal DMC, and Second Course Retreatment is no longer an option for participants.
Participants who are already receiving Second Course Retreatment and deriving clinical 
benefit may continue Second Course Retreatment, and local tumor imaging assessments 
should continue per SOC schedule, until radiographic disease progression per RECIST 1.1 as 
determined by the investigator/site/local radiology review. No treatment beyond progression 
will be authorized.
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Note: Participants who receive olaparib + pembrolizumab during Second Course Retreatment will not require the Day 8 scheduled 
assessments.
Study Period:
Second Course Retreatment (21-Day Cycles)
Combination Treatment
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Administrative Procedures
Inclusion/Exclusion Criteria
X
Assess before starting second course 
retreatment.
Additional Informed Consent
X
Sponsor consultation with documented 
SCF, followed by reconsent to main 
study ICF, is required before starting 
second course retreatment.
Prior/Concomitant Medication 
<-------------------------------------------------------------------->
Quality of Life and Physical Performance Measures
ECOG Performance Status 
X
X
X
X
X
X
Within 7 days prior to Cycle 1, Day 1; 
prior to dosing on Day 1 in subsequent 
cycles.
Treatment Administration – Arm 1
Olaparib 
<------------------------------------------------------------------->
Self-administered if applicable to 
retreatment.
Pembrolizumab 
X
X
X
X
X
X
Treatment Administration – Arm 2
Pembrolizumab 
X
X
X
X
X
X
Gemcitabine 
X
X
X
X
X
X
X
X
X
X
X
X
Carboplatin 
X
X
X
X
X
X
X
X
X
X
X
X
If applicable to retreatment.
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Study Period:
Second Course Retreatment (21-Day Cycles)
Combination Treatment
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Efficacy Procedures
Tumor Scans – Chest, abdomen, and 
pelvis 
X*
X
X
*Tumor scans must be or must have 
been performed within 28 days prior to 
Cycle 1, Day 1 of Second Course 
Retreatment.
Subsequent tumor scans every 9 weeks
(±7 days); timing of tumor scans is 
relative to Cycle 1, Day 1 of Second 
Course Retreatment, should follow 
calendar days, and not be adjusted for 
any dose modifications.
See the SIM for details.
Brain Scans
X*
X*
X*
*Brain scans (MRI is preferred) are
required during Second Course 
Retreatment (at the same schedule as 
other tumor scans for evaluation of 
disease status) ONLY for participants 
with known brain metastases and those 
with worsening and/or new 
neurological symptoms. Brain imaging 
CT scans will be acceptable if MRI is 
medically contraindicated.
See the SIM for details.
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Study Period:
Second Course Retreatment (21-Day Cycles)
Combination Treatment
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
Bone Scans
-------------------If clinically indicated--------------------
During Second Course Retreatment, a 
bone scan (and plain X-ray, if 
participant has signs/symptoms of bone 
metastases and bone scan is negative) 
will be performed ONLY if clinically 
indicated for evaluation of known, 
worsening and/or new bone pain or 
other symptoms/signs suggestive of 
bone metastases OR if the site believes 
a participant has attained a CR.
See the SIM for details.
Safety Procedures
Full Physical Examination 
X
Assess before starting second course 
retreatment.
Directed Physical Examination
X
X
X
X
X
X
X
X
X
X
X
12-lead Electrocardiogram
X
Assess before starting second course 
retreatment.
Vital Signs and Weight 
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs/weight should be measured
within 3 days before each dosing day.
AEs / SAEs
<------------------------------------------------------------------->
Laboratory Assessments – Analysis performed by local laboratories
Urine Pregnancy Test (WOCBP only) a
X
<------------------------------------------------------------->
Pregnancy testing should be performed
within 24 hours prior to receiving the 
first retreatment dose and monthly 
thereafter or if clinically indicated in 
WOCBP.
CBC with Differential b
X c
X
X
X
X
X
X
X
X
X
X
X
Chemistry b
X c
X
X
X
X
X
Urinalysis b
X
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Study Period:
Second Course Retreatment (21-Day Cycles)
Combination Treatment
Notes
Treatment Cycle/Title:
1
2
3
4
5
6+
Scheduled Day:
1
8
1
8
1
8
1
8
1
8
1
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Different windows are applicable for 
tumor scans.
PT/INR and aPTT/PTT b
X
Coagulation tests should be conducted 
as clinically indicated for participants 
taking anticoagulation therapy
T3 (or Free T3), Free T4, and TSH b
X
X
X
Can be assayed based on local 
guidelines and practices. To be 
repeated every 2 cycles after Cycle 5.
Other Tumor Markers
(CA 15-3, CEA, CA 27.29)
X
X
X
X
Should be collected within 28 days 
prior to Cycle 1, Day 1 of second 
course retreatment and then according 
to the tumor scan schedule (can be 
conducted at corresponding study visit, 
but must be collected within the same 
window specified for imaging) until 
study treatment discontinuation.
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; CA=cancer antigen; CBC=complete blood count; CEA=carcinoembryonic antigen; 
CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; ICF=informed consent form; INR=international normalized ratio; MRI=magnetic resonance 
imaging; PT=prothrombin time; PTT=partial thromboplastin time; SAE=serious adverse event; SCF=Sponsor Consultation Form; SIM=Site Imaging Manual; TSH=thyroid 
stimulating hormone; WOCBP=women of childbearing potential.
a.
For WOCBP, a urine or serum pregnancy test should be performed within 24 hours prior to the first dose of study treatment. If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required. 
b.
Laboratory samples can be collected up to 72 hours prior to scheduled administration of study treatment. 
c.
CBC and chemistry laboratory tests should be performed within 10 days prior to the first retreatment dose of pembrolizumab to determine eligibility, but do not need to be 
repeated on Cycle 1, Day 1 if obtained within 10 days prior to the first retreatment dose. However, they will be performed within 72 hours prior to dosing on Day 1 of 
each subsequent cycle.
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2
INTRODUCTION
This clinical study will evaluate the combination of olaparib plus pembrolizumab versus 
chemotherapy (carboplatin + gemcitabine) plus pembrolizumab after 4 to 6 cycles of 
induction therapy with 1L chemotherapy (carboplatin + gemcitabine) plus pembrolizumab
that demonstrates clinical benefit (CR, PR, or SD per RECIST 1.1 as determined by BICR) in 
participants with locally recurrent inoperable or metastatic TNBC.
2.1
Study Rationale
Immunotherapy plus chemotherapy combinations for the first-line (1L) treatment of
participants with metastatic TNBC (mTNBC) have been explored in several Phase 3 clinical 
studies.
The Phase 3 IMpassion 130 trial enrolled 902 patients with mTNBC who had not received 
prior treatment for metastatic disease. Patients were randomly allocated to standard 
chemotherapy (nab-paclitaxel) plus atezolizumab, an antibody targeting the protein PD-L1, 
or to standard chemotherapy plus placebo. The 2 main objectives were to determine if the 
drug combination would improve PFS and prolong OS in all patients and in those with 
tumors expressing PD-L1. The median follow-up was 12.9 months. The combination therapy 
reduced the risk of disease worsening or death by 20% in all patients and 38% in the 
subgroup expressing PD-L1. In the entire study population, the median PFS was 7.2 months 
with the combination and 5.5 months with chemotherapy alone; the PFS hazard ratio (HR)
was 0.80 (95% confidence interval [CI]: 0.69, 0.92; p=0.002). In the PD-L1 positive group, 
the median PFS was 7.5 months with the combination and 5.0 months with chemotherapy 
alone; the PFS HR was 0.62 (95% CI: 0.49, 0.78, p<0.0001). More than half of patients were 
alive at the time of analysis, so this was an interim assessment of OS. In the entire 
population, the median OS was 21.3 months with the combination versus 17.6 months with 
chemotherapy alone; the OS HR was 0.84 (95% CI: 0.69 to 1.02; p=0.08). In patients with 
PD-L1 positive tumors, the median OS was 25.0 months with the combination compared to 
15.5 months with standard chemotherapy alone; the OS HR was 0.62 (95% CI: 0.45, 0.86). 
The proportion of patients responding to treatment (objective response rate [ORR]) was 
higher with the combination compared to chemotherapy alone for all patients (56.0% vs 
45.9%) and those with PD-L1 positive tumors (58.9% vs 42.6%) [Schmid, P., et al 2018].
Given the benefit demonstrated in the treatment subgroup with PD-L1 positive tumors in the
IMpassion 130 trial, the study population for this study will be stratified at randomization by 
PD-L1 tumor status. Recently, as atezolizumab plus nab-paclitaxel did not demonstrate a 
significant improvement in OS in IMpassion 130 and atezolizumab plus paclitaxel did not 
improve OS in IMpassion 131 [Miles, D. W., et al 2020], this combination was removed 
from the NCCN treatment guidelines as a preferred 1L treatment option for patients with 
mTNBC whose tumors express PD-L1 [National Comprehensive Cancer Network 2021].
Improved outcomes have been demonstrated for pembrolizumab plus chemotherapy (nab-
paclitaxel; paclitaxel; or gemcitabine plus carboplatin) versus placebo plus chemotherapy in 
1L mTNBC in study KEYNOTE-355. After median follow-up of 26 months, median PFS 
was 9.7 months with pembrolizumab-chemotherapy and 5.6 months with placebo-
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chemotherapy (HR: 0.65, 95% CI 0.49-0.86, p=0.012) in patients with CPS ≥10, 7.6 and 
5.6 months (HR: 0.74, 95% CI: 0.61-0.90, p=0.0014) in patients with CPS ≥1, and 7.5 and 
5.6 months (HR: 0.82, 95% CI: 0.69-0.97, not tested) among the ITT population [Cortes, J., 
et al 2020]. At the final analysis (after median follow-up of 44 months), the benefit of 
pembrolizumab + chemotherapy on PFS was consistent with the prior results. Median OS
was 23.0 months with pembrolizumab-chemotherapy and 16.1 months with placebo-
chemotherapy (HR: 0.73, 95% CI 0.55-0.95, p=0.0093) in patients with CPS ≥10, 17.6 and 
16.0 months (HR: 0.86, 95% CI: 0.72-1.04, p=0.0563) in patients with CPS ≥1, and 17.2 and 
15.5 months (HR: 0.89, 95% CI: 0.76-1.05, not tested) among the ITT population. In 
summary, pembrolizumab + chemotherapy showed a statistically significant and clinically 
meaningful improvement in PFS and OS versus chemotherapy alone in patients with PD-L1 
positive tumors (CPS ≥10) [Cortes, J., et al 2021]. The FDA granted accelerated approval to 
pembrolizumab in combination with chemotherapy for the treatment of patients with locally 
recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) in NOV-
2020, with conversion to full approval in JUL-2021.
The MK-7339-009 study seeks to investigate if olaparib plus pembrolizumab will maintain 
the clinical benefit achieved after induction therapy with a platinum-based regimen 
(carboplatin + gemcitabine) plus pembrolizumab and may predict and/or increase sensitivity 
to a polyadenosine 5diphosphoribose (polyADP ribose) polymerization (PARP) inhibitor 
(PARPi). There is a strong rationale for treating TNBC with DNA-damaging agents because 
of the similarities in the gene-expression profiles of breast cancer susceptibility gene 1 
(BRCA1)-deficient and sporadic TNBCs. Approximately 70% of BRCA1-mutated breast 
cancers are triple negative, and these tumors appear to be particularly sensitive to the 
cytotoxic effects of DNA interstrand cross-linking agents such as cisplatin and carboplatin 
[Rottenberg, S., et al 2007]. Some metastatic TNBCs are also responsive to platinum-based 
chemotherapies [Isakoff, S. J., et al 2012] [Chia, J. W., et al 2007] [Koshy, N., et al 2010]
[Baselga, J., et al 2013]. The carboplatin-plus-gemcitabine combination has been shown to be 
more potent against TNBC cells compared with non-TNBC cells [Hastak, K., et al 2010], and 
the regimen has been demonstrated to have clinical activity in metastatic breast cancer, with 
response rates of 26% to 34% [Chew, H. K., et al 2009] [Loesch, D., et al 2008] [Yardley, D. 
A., et al 2008].
An optimal duration of induction chemotherapy in TNBC has not been established. In other 
tumor types, such as advanced nonsquamous non-small cell lung cancer (NSCLC), current 
treatment guidelines recommend 4 to 6 cycles of platinum-based doublet as first-line or 
induction treatment [National Comprehensive Cancer Network 2016] [Novello, S., et al 
2016] [Park, J. O., et al 2007] [Rossi, A., et al 2014]. More than 6 cycles of treatment in this 
population demonstrated prolonged PFS, added no benefit in OS, and increased toxicities 
[Park, J. O., et al 2007] [Rossi, A., et al 2014]. Given these results in NSCLC, 6 cycles of 
carboplatin and gemcitabine were considered optimal for the duration of induction in this 
study. Pembrolizumab as background immunotherapy is planned for up to 
35 administrations.
Olaparib is now established as maintenance therapy for platinum-sensitive populations
regardless of BRCA status in the setting of other tumor types. However, there is no current 
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regimen that uses a maintenance agent(s) in the metastatic TNBC setting. Furthermore, 
preclinical and clinical data indicates that an olaparib and pembrolizumab combination have 
an improved therapeutic effect, showing synergistic benefits [Karzai, F., et al 2017]
[Vinayak, S., et al 2018]. Therefore, adding olaparib to pembrolizumab after induction 
treatment with a platinum-based regimen plus pembrolizumab will change and expand the 
treatment paradigm in this disease, particularly for those patients with platinum-sensitive 
TNBC tumors. Olaparib plus pembrolizumab has the potential for further treatment benefit in 
a chemo-sparing regimen.
2.2
Background
2.2.1
Olaparib
Olaparib (AZD2281, KU-0059436, LYNPARZA®) is a potent PARPi (PARP1, 2, and 3) that 
is being developed as a monotherapy as well as for combination with chemotherapy, ionizing 
radiation and other anticancer agents, including novel agents and immunotherapy.
PARP inhibition is a novel approach to targeting tumors with deficiencies in DNA repair 
mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). 
Inhibiting PARPs leads to the persistence of SSBs, which are then converted to the more 
serious DNA double strand breaks (DSBs) during the process of DNA replication. During the 
process of cell division, DSBs can be efficiently repaired in normal cells by homologous 
recombination repair (HRR). Tumors with HRR deficiency (HRD), such as ovarian cancers 
in patients with breast cancer susceptibility gene 1/2 (BRCA1/2) mutations (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 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 ataxia-telangiectasia mutated (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.
The Phase 3 OlympiAD trial enrolled 302 patients with germline BRCAm (gBRCAm)
human epidermal growth factor receptor-2 (HER2)-negative metastatic breast cancer who 
had received no more than 2 lines of prior chemotherapy. Patients were randomly assigned 
(2:1 ratio) to receive olaparib or physician’s choice of single-agent chemotherapy. Median 
PFS was longer in the 205 patients who received olaparib than in the 97 patients who 
received the chemotherapy regimen (7.0 months vs 4.2 months). The HR for disease 
progression or death was 0.58 (95% CI: 0.43 to 0.80; p<0.001). The response rate in the 
olaparib group was 59.9% versus 28.8% in the chemotherapy group. In addition, the rate of 
Grade 3 or higher AEs was lower in the olaparib group (36.6% vs 50.5%) as was the rate of 
treatment discontinuations (4.9% vs 7.7%, respectively) [Robson, M., et al 2017]. Olaparib is 
currently approved for use in the United States (US) in previously treated patients with 
deleterious or suspected deleterious gBRCAm HER2-negative metastatic breast cancer and 
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as adjuvant treatment for patients with gBRCAm HER2-negative high-risk early breast 
cancer. In the population with metastatic TNBC being studied in this MK-7339-009 study, 
the PFS in participants randomly assigned to receive olaparib or chemotherapy will be 
evaluated as a secondary objective in a subset of participants with BRCAm tumors.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on olaparib.
2.2.2
Pembrolizumab
Pembrolizumab (MK-3475, KEYTRUDA®) is a potent humanized immunoglobulin G4 
(IgG4) monoclonal antibody (mAb) with high specificity of binding to the PD-1 receptor, 
thus inhibiting its interaction with PD-L1 and programmed cell death-ligand 2 (PD-L2). 
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is 
in clinical development as an IV immunotherapy for advanced malignancies and is indicated 
for the treatment of patients across a number of indications.
Refer to the IB/approved labeling for detailed background information on pembrolizumab.
2.2.3
Pharmaceutical and Therapeutic Background
2.2.3.1
Inhibition of PARP as a Target for Cancer Therapy
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 DNA damage and converting it into intracellular 
signals that activate the base excision repair (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. 
Under normal conditions, HRR is the preferred pathway for repairing DNA damage as it is 
associated with a lower rate of errors compared with other forms of DNA repair [Prakash, R., 
et al 2015]. During DNA replication (S phase), pre-existing or chemotherapy-induced SSBs 
are converted to DSBs if not adequately repaired by intracellular mechanisms [Fong, Peter 
C., et al 2009] such as HRR. Cells unable to perform HRR (eg, due to inactivation of genes 
required for HR, such as BRCA1 or BRCA2) are more likely to use the error-prone non-
homologous end-joining (NHEJ) or alternative (alt)-NHEJ pathways to repair these DSBs 
and risk accumulating multiple lesions or loss of heterozygosity (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 BRCAm [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.
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Treatment with PARP inhibitors could represent a novel opportunity to selectively kill cancer 
cells with deficiencies in DNA repair pathways.
2.2.3.2
Inhibition of PD-1 as a Target for Cancer Therapy
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 8 
(CD8)+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) 
correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; 
and renal cell carcinoma. Tumor-infiltrating lymphocytes (TILs) can be expanded ex vivo 
and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
[Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are Type I transmembrane glycoproteins containing an Ig-variable-type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as cluster of differentiation 3
(CD3) zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein kinase 
(ZAP70), which are involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 
2001][Chemnitz, J. M., et al 2004] [Sheppard, K-A, et al 2004][Riley, J. L. 2009]. The 
mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from, 
that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
[Parry, R. V., et al 2005] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 
pathway is an attractive target for therapeutic intervention in TNBC.
2.2.4
Disease Background
2.2.4.1
Triple Negative Breast Cancer
Breast cancer is the most commonly diagnosed malignancy in women, excluding basal cell 
and squamous cell skin cancers, accounting for 30% of all new cancers. It is also the second 
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leading cause of cancer death (after lung cancer) among women. About 268,000 new cases of 
breast cancer and approximately 41,000 deaths due to breast cancer are expected in women 
in the US in 2019 [Siegel, R. L., et al 2019]. Breast cancer is the leading cause of cancer-
related death among females worldwide with an estimated 1.2 million cases and 521,900 
deaths reported in 2012. The highest mortality rates are found in Western Europe, the US,
and Israel (which has some of the highest rates), and the lowest rates are found in Africa and 
Asia [Torre, L. A., et al 2016].
TNBC is phenotypically defined by a lack of estrogen receptor and progesterone receptor 
(ER/PGR) expression and the absence of HER2 overexpression and/or amplification [Dent, 
R., et al 2007]. TNBC represents 15% to 20% of all breast cancers [Bauer, K. R., et al 2007]
and is overlapping, but not synonymous, with the basal-like subtype defined by gene 
expression, as about 70% of TNBCs have basal-like characteristics [Badve, S., et al 2011]
[Sorlie, T., et al 2001].
TNBC is a molecularly heterogeneous disease and includes tumor subsets with different 
prognoses. Recent gene expression profiling has identified up to 6 distinct TNBC subtypes 
(2 basal-like, an immunomodulatory, a mesenchymal, a mesenchymal stem-like, and a 
luminal androgen receptor [AR] subtype) [Lehmann, B. D., et al 2011].
TNBC is associated with younger age at diagnosis, premenopausal status, African American 
race, more advanced disease stage, higher grade, high mitotic indices, family history of 
breast cancer, BRCA1 mutations, and more aggressive behavior than other breast cancer 
subtypes [Bauer, K. R., et al 2007]. As reported in a seminal study on TNBC, 34% of all 
participants with TNBC experience distant recurrence with a median distant recurrence-free 
survival (DRFS) of 2.6 years, compared to a distant recurrence rate of 20% and a median 
DRFS of 5 years in other breast cancer subtypes; the peak of recurrence for TNBC is within 
1 to 3 years after initial diagnosis, and decreases significantly thereafter; participants with 
TNBC also have shorter median overall survival (OS) compared with participants with non-
TNBC (4.2 vs 6.0 years, respectively) [Dent, R., et al 2007]. Finally, participants with TNBC 
tend to relapse with distant metastases rather than local recurrences and are more likely to 
develop visceral metastases, including central nervous system (CNS) involvement [Lin, N. 
U., et al 2008].
Treatment of TNBC is challenging and represents an area of unmet medical need, as these 
tumors lack therapeutic targets, such as ER and HER2, and become rapidly resistant to 
chemotherapy upon local recurrence and/or metastasis (even though they are often sensitive 
to cytotoxic drugs at initial presentation) [Arnedos, M., et al 2012]. The majority of 
participants with metastatic TNBC have experienced relapse after neoadjuvant/adjuvant 
therapy for early or locally advanced disease. In a frequently referenced study, the median 
OS of all (at any line of therapy) participants with mTNBC was 13.3 months [Kassam, F., et 
al 2009]. Additionally, locally recurrent inoperable breast cancer is considered clinically 
similar to previously untreated metastatic disease [Cardoso, F., et al 2014], and thus the MK-
7339-009 study population includes participants with “early” advanced disease, requiring 1L 
treatment for locally recurrent inoperable or metastatic TNBC.
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With the exception of those patients with metastatic PD-L1 positive TNBC, no specific 
chemotherapy regimen is currently established as a standard-of-care for the treatment for 
TNBC in any setting. Similar to any advanced breast cancer, the recommended initial 
treatment for participants with locally recurrent inoperable or metastatic TNBC includes 
anthracyclines and taxanes. For participants previously treated with an anthracycline, or for 
whom anthracyclines are contraindicated or not considered the best treatment option, taxanes 
are most commonly used as a 1L treatment, when the time interval between completion of 
taxane-based neoadjuvant/adjuvant therapy and recurrence is at least 12 months [Andre, F. 
2012]. Participants with earlier (<12 months) local or distant disease recurrence are treated 
with chemotherapies not previously used in the neoadjuvant/adjuvant setting; in the case of 
aggressive disease and/or visceral crisis, combination, rather than single agent, chemotherapy 
is thus indicated and may include any one of different regimens, such as 
gemcitabine/carboplatin, capecitabine/vinorelbine, gemcitabine/cisplatin, etc. The PARP 
inhibitors, olaparib and talazoparib, are indicated for the treatment of patients with 
deleterious or suspected deleterious gBRCAm HER2-negative metastatic breast cancer. 
PARP inhibitors are a reasonable treatment option for patients with gBRCA mutations 
previously treated with an anthracycline and/or a taxane and provide improvements in PFS 
and QoL with an acceptable toxicity profile [National Comprehensive Cancer Network 2019]
[Cardoso, F., et al 2018]. 
2.2.5
Rationale for Combination Therapy
2.2.5.1
Chemotherapy in Combination With Pembrolizumab
The rationale behind combining chemotherapy with pembrolizumab is based on the 
immunomodulatory effects of the former [Zitvogel, L., et al 2008], which may in turn 
increase the antitumor activity of PD-1 pathway inhibition. Even though cytotoxic drugs, 
including taxanes and gemcitabine/carboplatin, have historically been considered 
immunosuppressive, they can also have immunopotentiating roles by 1) depleting 
immunosuppressive cells, such as regulatory T-cells and myeloid-derived suppressor cells, to 
enhance a latent antitumor immune response, 2) inducing an immunogenic cell death, 
3) enhancing tumor antigen presentation by upregulating the expression of tumor antigens 
themselves, or of the major histocompatibility complex (MHC) class I molecules to which 
the antigens bind, 4) upregulating co-stimulatory molecules (B7-1) or down regulating 
co-inhibitory molecules (PD-L1/B7-H1 or B7-H4) expressed on the tumor cell surface, thus 
enhancing the strength of effector T-cell activity, and 5) rendering tumor cells more sensitive 
to T-cell–mediated lysis through fas-, perforin-, and granzyme B–dependent mechanisms 
[Emens, L. A. and Middleton, G. 2015].
2.2.5.2
Olaparib in Combination With Pembrolizumab
PARP inhibition has both the immune-activating and immune-suppressive effects on cancer 
cells [Mouw, K. W. 2018]. Several reports demonstrated that PARPis may trigger an 
immune-activating interferon secretion via the cGAS-STING pathway activation in BRCA 
mutant and breast cancer susceptibility gene wildtype (BRCAwt) cells [Shen, J., et al 2019]
[Ding, L., et al 2018] [Wang, Z., et al 2019]. In addition, it has been demonstrated that the 
PARP inhibitor niraparib potentiates anti-PD-1 antibody efficacy through interferon 
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activation, resulting in synergistic effects and tumor shrinkage in animal models [Wang, Z., 
et al 2019]. Some recent studies demonstrated that PARP inhibition can trigger immune-
suppressive effects by increasing PD-L1 expression in cancer cells [Sato, H., et al 2017]
[Jiao, S., et al 2017]. Continuous treatment with olaparib results in increased PD-L1 
expression in BRCA2-depleted cancer cells [Sato, H., et al 2017]. This enhanced PD-L1 
expression driven by olaparib is suggested to be dependent on the ATM/CHK1 axis. The 
effect of olaparib on PD-L2 expression seems to be independent of BRCA status. It has been 
demonstrated that olaparib can upregulate PD-L1 in both BRCA-proficient and BRCA-
deficient breast cancer cells [Jiao, S., et al 2017].
Mechanistically, PARPis inactivated glycogen synthase kinase-3 beta (GSK3β), which in 
turn enhanced PARPis-mediated PD-L1 upregulation. PARPis attenuated anticancer 
immunity via upregulation of PD-L1, and blockade of PD-L1 re-sensitized PARPis-treated 
cancer cells to T-cell killing. The combination of PARPis and anti-PD-L1 therapy compared 
with each agent alone significantly increased the therapeutic efficacy. The cross-talk between 
PARPis and tumor-associated immunosuppression provides evidence to support the 
combination of PARPis and PD-L1 or PD-1 immune checkpoint blockade as a potential 
therapeutic approach in the treatment of breast cancer [Jiao, S., et al 2017].
Strickland et al demonstrated that ovarian cancers that have a higher neoantigen load were 
associated with improved OS and higher expression of immune genes associated with tumor
cytotoxicity, such as genes of the T-cell receptor (TCR), the interferon-gamma (IFNγ), and 
the tumor necrosis factor receptor (TNFR) pathways. Furthermore, immunohistochemistry 
(IHC) studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased 
CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in 
tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed 
that both BRCA1/2-mutation status and number of TILs were independently associated with 
outcome [Strickland, K. C., et al 2016].
In a Phase 1 dose escalation study, Lee et al tested durvalumab in combination with the 
PARPi olaparib or the vascular endothelial growth factor (VEGF) receptor 1-3 inhibitor 
cediranib in women’s cancers (NCT02484404). The recommended Phase 2 dose (RP2D) was 
reached with durvalumab at 1500 mg every 4 weeks in combination with olaparib 300 mg 
BID or cediranib 20 mg (5 days on/2 days off). No dose-limiting toxicity was recorded with 
durvalumab plus olaparib. The most common treatment-emergent AE with durvalumab plus
olaparib was hematologic toxicity, which was observed in frequencies greater than that 
reported for single agent olaparib. Two PRs (≥15 months and ≥11 months; ORR 17%) and 
8 SDs ≥4 months (median 8 months [range 4 to 14.5 months]) were seen in 12 patients
(10 ovarian and 2 TNBC; 11 germline BRCA wildtype (gBRCAwt) and 1 gBRCA-unknown 
with SD for 3 months) who received durvalumab plus olaparib, yielding an 83% disease 
control rate (DCR). A trend toward association of response with degree of PD-L1–positive 
TIL infiltration was observed [Lee, J. M., et al 2017].
In a Phase 2 study, Karzai et al combined the anti-PD-L1 antibody durvalumab with olaparib 
in patients with metastatic castration-resistant prostate cancer (mCRPC) who had received 
prior treatment with enzalutamide and/or abiraterone (NCT02484404). Since 25% to 30% of 
sporadic mCRPCs have defects in DNA repair pathways that may confer sensitivity to PARP 
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inhibition, immune checkpoint blockade is a promising avenue in mCRPC treatment. 
Durvalumab was administered at 1500 mg IV every 28 days in combination with olaparib at 
300 mg orally every 12 hours to 25 patients (the study is still open and active). Seven (of 16) 
patients (44%) on-study >2 months have had prostate-specific antigen (PSA) declines >50%. 
Six-month and 9-month PFS rates were 86.7% and 57.8%. Median PFS has not yet been 
reached. Grade 3/4 AEs included anemia (3/14, 21%), thrombocytopenia, lymphopenia, 
leukopenia, neutropenia, nausea, vomiting, hypertension, syncope, fatigue, urinary tract 
infection (UTI), and lung infection. Preliminary data show tolerability and synergistic 
activity in mCRPC patients without a gBRCAm [Karzai, F., et al 2018].
In an ongoing Phase 2 study in which patients with TNBC received the PARPi niraparib 
200 mg orally once daily (QD) plus pembrolizumab 200 mg Q3W, Vinayak et al reported 
interim results for 45 evaluable patients. Twenty-two (41%) had received prior platinum in 
the metastatic setting and 39 (72%) had received prior neoadjuvant/adjuvant therapy. 
Thirteen patients had received >6 months of treatment with the combination (6 BRCAm, 
5 BRCAwildtype(wt), and 2 BRCA status unknown). As of this reported analysis, the ORR 
was 29%, including 3 CRs (7%), 10 PRs (22%), 9 SDs (20%); the DCR was 49%. Of the 
45 evaluable patients, 12 had BRCAm tumors with 1 CR, 7 PRs, 1 SD, and 3 with 
progressive disease (PD) reported in this subpopulation. Median PFS in this BRCAm group 
was 8.1 months (95% CI 0.2-Not evaluable). The ORR for patients regardless of BRCA 
status was 33% in PD-L1 positive (combined positive score [CPS] ≥1) versus 15% in PD-L1 
negative patients. Responses were durable regardless of BRCA or PD-L1 status or prior 
platinum therapy. Adverse events of Grade 3 or higher occurred in 27 patients (50%), with 
thrombocytopenia (13%) and anemia (11%) most commonly reported. No new safety signals 
emerged as of this preliminary analysis [Vinayak, S., et al 2018].
2.2.6
Preclinical and Clinical Studies
For a summary of preclinical and clinical study data for olaparib and for pembrolizumab,
refer to their respective IBs.
2.2.7
Ongoing Clinical Studies
For a summary of ongoing clinical study data for olaparib and pembrolizumab, refer to the 
respective IBs.
2.2.8
Information on Other Study-related Therapy
For additional information on carboplatin and gemcitabine, refer to the respective approved 
product labels.
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.
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The rapid resistance to chemotherapy that develops upon local recurrence and/or metastasis 
[Arnedos, M., et al 2012] yields an unmet medical need for an effective and tolerable 
maintenance treatment regimen after tumor response is observed following initial treatment. 
Early phase studies conducted with combinations of olaparib and the PD-L1 inhibitor 
durvalumab showed tumor responses and no new safety signals for the combination 
(Section 2.2.5.2). In the ongoing KEYNOTE-162 study, the combination of pembrolizumab 
and a PARPi has shown preliminary efficacy and tolerability in previously treated 
participants with metastatic TNBC [Vinayak, S., et al 2018]. Given the early results from 
these studies, the combination of the PD-1 inhibitor pembrolizumab and the PARPi olaparib 
in participants with previously untreated locally recurrent inoperable or metastatic TNBC 
who demonstrate a tumor response following induction with carboplatin and gemcitabine 
plus pembrolizumab is expected in this study to demonstrate a favorable benefit/risk profile.
It is also expected that participants randomly assigned to receive olaparib plus 
pembrolizumab in Arm 1 of the study will have fewer side effects than those participants 
receiving carboplatin and gemcitabine plus pembrolizumab in Arm 2 of the study, as 
carboplatin and gemcitabine will have been discontinued after induction in participants 
randomized to Arm 1, resulting in essentially a de-escalation to a chemo-sparing regimen.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IBs and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
The Phase 2/3 2-in-1 adaptive design will not be pursued and the study is now a stand-alone 
Phase 2 study.
In males and females at least 18 years of age with locally recurrent inoperable or metastatic 
TNBC after induction of clinical benefit (objective response or stable disease [SD]) with 
first-line (1L) chemotherapy plus pembrolizumab:
Throughout this protocol, the term Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 refers to the modification of RECIST 1.1 to include a maximum of 10 target 
lesions and a maximum of 5 target lesions per organ. Refer to Section 4.2.1.1 for further 
details.
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Objectives
Endpoints
Primary

Objective: To compare olaparib plus 
pembrolizumab to chemotherapy plus 
pembrolizumab with regards to 
progression-free survival (PFS) 
according to RECIST 1.1 by blinded 
independent central review (BICR).
Hypothesis (H1): Olaparib plus 
pembrolizumab is superior to 
chemotherapy plus pembrolizumab with 
respect to PFS according to RECIST 1.1 
by BICR.

PFS, the time from randomization until 
either the earliest date of documented 
disease progression or death due to any 
cause, whichever occurs first

Objective: To compare olaparib plus 
pembrolizumab to chemotherapy plus 
pembrolizumab with regards to overall 
survival (OS).
Hypothesis (H2): Olaparib plus 
pembrolizumab is superior to
chemotherapy plus pembrolizumab with 
respect to OS.

OS, the time from randomization to 
death due to any cause
Secondary

Objective: To evaluate OS, and PFS 
according to RECIST 1.1 by BICR, in 
participants with PD-L1 positive tumors 
(CPS ≥10) following treatment with 
olaparib plus pembrolizumab or 
chemotherapy plus pembrolizumab.

OS

PFS

Objective: To evaluate OS, and PFS 
according to RECIST 1.1 by BICR, in 
participants with BRCAm tumors 
following treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

OS

PFS
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Objectives
Endpoints

Objective: To evaluate health-related 
quality-of-life (HRQoL) and time to 
deterioration (TTD) using the European 
Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life 
Questionnaire Core 30 
(EORTC QLQ-C30) and the breast 
cancer module (EORTC QLQ-BR23) in 
participants with BRCAm tumors and 
irrespective of BRCAm status following 
treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

HRQoL, a change from baseline in 
Patient-Reported Outcomes (PRO)
scores obtained in post-induction

Time to Deterioration (TTD), the time 
from baseline to the first onset of a 
confirmed* ≥10-point deterioration 
from baseline in PRO scores
For the following domains:

EORTC QLQ-C30 global health 
status/QoL (Items 29 and 30)

EORTC QLQ-C30 physical 
functioning (Items 1-5)

EORTC QLQ-C30 emotional 
functioning (Items 21-24), and

EORTC QLQ-BR23 systemic 
therapy side effects (Items 1-4, 6, 
7, and 8)
*confirmed by a ≥10-point deterioration 
from baseline in the subsequent PRO score

Objective: To evaluate visual analogue 
scale (VAS) using the EuroQoL 
5-dimension, 5-level questionnaire 
(EQ-5D-5L) in participants with BRCAm 
tumors and irrespective of BRCAm status 
following treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

Visual analogue scale (VAS), a change 
from baseline in EQ-5D-5L VAS score
obtained in post-induction

Objective: To evaluate the safety and 
tolerability of olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

Adverse events (AEs)

Study treatment discontinuation due to
AEs
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Objectives
Endpoints
Tertiary/Exploratory

Objective: To evaluate the objective 
response rate (ORR), duration of 
response (DOR), and disease control rate 
(DCR) according to RECIST 1.1 by 
BICR, in all-comers and in participants 
with PD-L1 positive tumors (CPS ≥10)
following treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

Objective response: complete response 
(CR) or partial response (PR)

DOR, the time from first documented 
evidence of CR or PR after 
randomization until disease 
progression or death due to any cause, 
whichever occurs first

Disease control, CR or PR after 
randomization; or stable disease (SD) 
after randomization and for at least 24 
weeks prior to any evidence of 
progression

Objective: To evaluate the ORR, DOR, 
and DCR according to RECIST 1.1 by 
BICR in participants with BRCAm 
tumors following treatment with olaparib 
plus pembrolizumab or chemotherapy 
plus pembrolizumab.

ORR

DOR

DCR

Objective: To evaluate PFS after next 
line treatment (PFS2) according to the 
local standard of clinical practice as 
determined by the investigator, in 
all-comers, in participants with PD-L1 
positive tumors (CPS ≥10), and in 
participants with BRCAm tumors
following treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

PFS2, the time from randomization 
until disease progression on next-line 
treatment or death due to any cause, 
whichever occurs first
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Objectives
Endpoints

Objective: To evaluate the time to first 
subsequent treatment (TFST), the time to 
second subsequent treatment (TSST), and 
the time until discontinuation of study 
treatment or death (TDT), in all-comers,
in participants with PD-L1 positive 
tumors (CPS ≥10), and in participants 
with BRCAm tumors following treatment 
with olaparib plus pembrolizumab or 
chemotherapy plus pembrolizumab.

TFST, the time from randomization 
until initiation of first subsequent 
anticancer therapy or death due to any 
cause, whichever occurs first

TSST, the time from randomization 
until initiation of second subsequent 
anticancer therapy or death due to any 
cause, whichever occurs first

TDT, the time from randomization to 
discontinuation of study treatment or 
death due to any cause, whichever 
occurs first

Objective: To evaluate HRQoL and TTD 
using the EORTC QLQ-C30 and the 
EORTC QLQ-BR23 in participants with 
PD-L1 positive tumors (CPS ≥10)
following treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

HRQoL, a change from baseline in 
PRO scores obtained in post-induction

TTD, the time from baseline to the first 
onset of a confirmed* ≥10-point 
deterioration from baseline in PRO 
scores
For the following domains:

EORTC QLQ-C30 global health 
status/QoL (Items 29 and 30)

EORTC QLQ-C30 physical 
functioning (Items 1-5)

EORTC QLQ-C30 emotional 
functioning (Items 21-24), and

EORTC QLQ-BR23 systemic 
therapy side effects (Items 1-4, 6, 
7, and 8)
*confirmed by a ≥10-point deterioration 
from baseline in the subsequent PRO score

Objective: To evaluate VAS using the 
EQ-5D-5L in participants with PD-L1 
positive tumors (CPS ≥10) following 
treatment with olaparib plus 
pembrolizumab or chemotherapy plus 
pembrolizumab.

VAS, a change from baseline in 
EQ-5D-5L VAS score obtained in 
post-induction
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Objectives
Endpoints

Objective: To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of study drug and 
other treatments.

Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue
4
STUDY DESIGN
4.1
Overall Design
Note: Based on the data from a prespecified interim safety and efficacy analysis for 
KEYLYNK-009 (data cutoff 15-DEC-2022), the internal DMC recommended discontinuing 
the study. The combination of pembrolizumab plus olaparib did not show an improvement in 
PFS compared with the combination of chemotherapy plus pembrolizumab. Participants who 
are still receiving study intervention (in post-induction or Second Course Retreatment phase)
may have the option to continue on study treatment if they are deriving clinical benefit, until 
criteria for discontinuation are met.
As of Amendment 03, participants who discontinue study treatment for any reason will 
complete the End-of-Treatment and Safety Follow-up visits, but no further data will be 
collected. If continuing on study treatment, participants will no longer have tumor response 
assessments by BICR, but local tumor imaging assessments should continue per SOC 
schedule. For all participants, ePRO assessments will no longer be performed, biomarker 
samples will no longer be collected, and Disease Status Follow-up and Survival Follow-up 
visits will no longer be conducted. The section below is retained for reference.
This is a Phase 2, multicenter, worldwide, randomized, open-label study in participants with 
previously untreated locally recurrent inoperable or metastatic TNBC who achieve CR, PR, 
or SD per RECIST 1.1 as determined by BICR after 4 to 6 cycles of induction therapy with 
carboplatin and gemcitabine plus pembrolizumab.
Prior treatment with chemotherapy in the neoadjuvant/adjuvant setting is allowed. For such 
participants, the period between completion of treatment with curative intent (eg, date of 
primary breast tumor surgery or date of last adjuvant chemotherapy administration, 
whichever occurred last) and first documented local or distant disease recurrence must be 
≥6 months. Participants who received platinum-based chemotherapy or gemcitabine in the 
neoadjuvant/adjuvant setting may be treated with carboplatin and gemcitabine in this study if 
≥12 months have elapsed between completion of treatment with curative intent and the first 
documented local or distant disease recurrence. Participants presenting with de novo 
metastatic TNBC are eligible for the study if anthracycline and/or a taxane is contraindicated 
or not considered the best treatment option for the participant in the opinion of the treating 
physician.
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This study will be conducted in 2 periods, an induction period and a post-induction period. 
4.1.1
Induction
Approximately 460 eligible participants will be enrolled in the induction portion of the study 
to receive both carboplatin (AUC 2) with gemcitabine (1000 mg/m2) on Days 1 and 8 of each 
21-day cycle in addition to pembrolizumab (200 mg) Q3W for a maximum of up to 6 cycles
but not less than 4 cycles of treatment. 
If either or both chemotherapy agents are withheld for toxicities, pembrolizumab may be 
continued until the chemotherapy toxicities resolve. Participants must receive up to 6 but not 
less than 4 cycles of one or both chemotherapy agents plus pembrolizumab to be eligible for 
post-induction. During induction, dose reductions of both carboplatin and/or gemcitabine are 
allowed. One of the 2 chemotherapeutic agents may be discontinued for toxicity; however, if 
both carboplatin and gemcitabine are discontinued due to toxicity, the participant must be 
discontinued from all study interventions. If the participant needs to be discontinued from 
pembrolizumab due to toxicity during induction, the participant must be discontinued from 
all study interventions. Participants who discontinue from all study interventions for any 
reason during induction, and are therefore not eligible to be randomized to receive post-
induction treatment, will enter the 30-day safety follow-up.
Tumor assessments and response during induction will be evaluated by tumor scans at 
Week 6 (+7 days), Week 12 (±7 days), and Week 18 (-7 days) (see Section 8.2.2.2.1). A 
participant with a tumor response at Week 18 (-7 days) of CR, PR, or SD, according to 
RECIST 1.1 as determined by BICR expedited review, is eligible for randomization to 
post-induction treatment if all other eligibility criteria are met. Participants with disease 
progression as determined by BICR at any timepoint during induction will be discontinued 
from study intervention. The Week 18 (-7 days) evaluation will determine eligibility for 
randomization to the Post-induction period (see Section 8.2.2.2.2) (see Sections 5.1 and 5.2 
for full eligibility criteria for post-induction). If there is an increase in the size of target 
lesion(s) and/or a worsening of non-target lesions at the Week 18 (-7 days) induction scan, 
but these changes do not meet the RECIST 1.1 guidelines for PD [Eisenhauer, E. A., et al 
2009], the participant may be discontinued from study intervention at the discretion of the 
investigator. Participants with dose interruption for toxicity resolution cannot be randomized 
into post-induction until after the Week 18 (-7 days) scan tumor response is confirmed by 
BICR.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) will not be used to 
determine tumor response during induction. If PD seen by the site during induction is not 
verified by BICR, disease assessments should still be performed by the site/investigator using 
RECIST 1.1 if the participant is stable and continues treatment at treating physician’s 
discretion.
4.1.2
Post-induction
Participants will be assessed during pre-randomization to ensure eligibility and should be 
randomized into and begin post-induction within approximately 14 to 21 days after the 
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Week 18 (-7 days) scan. This scan will also establish the baseline for post-induction tumor 
response assessments. An additional up to 3 weeks will be allowed for recovery from 
toxicities related to induction therapy (ie, the interval between the last dose of induction and 
first dose of post-induction should be no more than 6 weeks). The Eastern Cooperative 
Oncology Group (ECOG) performance status, safety, and laboratory studies conducted 
during pre-randomization and the electronic patient-reported outcomes (ePROs) conducted 
just before the Cycle 1, Day 1 dose of study medication will establish a baseline for each of 
these respective assessments. 
During randomization, participants will be stratified by (1) best overall response to induction 
therapy (CR or PR vs SD) at Week 18 (-7 days) as assessed by BICR; (2) PD-L1(+) versus 
PD-L1(-); and (3) genomic tumor status (BRCAm vs BRCAwt). For the purpose of 
stratification, PD-L1 positive (+) is defined as a combined positive score (CPS) ≥1, and 
PD-L1 negative (-) is defined as a CPS <1.
The Sponsor, investigators, participants, and other study site staff will be blinded to 
participant PD-L1 and BRCA tumor results. 
Approximately 260 participants will be randomly assigned in the post-induction portion of 
the study in a 1:1 ratio to Arm 1 or Arm 2 of treatment. 
Participants in Arm 1 will continue to receive pembrolizumab 200 mg Q3W and will begin a 
concurrent regimen of olaparib 300 mg orally BID. 
Participants in Arm 2 will continue to receive carboplatin and/or gemcitabine at the same 
dose and schedule administered at the last dose of the induction period plus pembrolizumab 
200 mg Q3W. Participants must be able to receive at least 1 dose of single-agent 
chemotherapy plus 1 dose of pembrolizumab at Cycle 1, Day 1 of post-induction. In addition, 
the same chemotherapy agent or agents that were administered as the last dose in induction 
must also be administered at the Cycle 1, Day 1 dose in post-induction.
Participants who complete 35 cycles of pembrolizumab (this includes induction cycles) and 
continue to demonstrate clinical benefit during post-induction may continue to receive 
olaparib or carboplatin and/or gemcitabine. Crossover of participants between treatment arms 
will not be permitted. 
Tumor assessments and response during post-induction will be evaluated by tumor scans
every 6 weeks (±7 days, except for the first Week 6 scan after randomization, which should 
be 6 weeks +7 days) for the first year and every 12 weeks (±7 days) thereafter, independent 
of any dose modifications. All tumor scans performed post-induction will be assessed by 
BICR as described in Section 8.2.2.5.
Tumor response assessed per iRECIST may be performed during post-induction only. 
Safety will be monitored according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE), version 5.0. Safety and efficacy data 
will be reviewed by an internal DMC (see Section 10.1.4.2).
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4.1.3
End-of-Treatment
Participants will continue with study treatment until any of the following occurs during 
induction or post-induction: verified disease progression as determined by BICR according to
RECIST 1.1 (after implementation of Amendment 03, this will be until disease progression 
according to RECIST 1.1 as determined by investigator/site/local radiology review);
unacceptable toxicity; intercurrent illness that necessitates discontinuation of study treatment; 
investigator’s decision to withdraw the participant; pregnancy; participant noncompliance 
with study treatment or procedure requirements; a documented complete withdrawal of 
consent from all further study treatment; death; end of the study; or other administrative 
reasons requiring cessation of study treatment (Section 7.1).
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.
4.1.4
Planned Analyses
Two IAs (IA1 and IA2) and a final analysis (FA) may be performed. 
Note: IA1 was skipped to proceed to IA2 (see Section 9.1 for details).
As of Amendment 03, the prespecified final analysis of the study described in the SAP will 
not be performed.
Details of the planned analyses are provided in Section 9.7.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use PFS and OS as dual-primary endpoints based on RECIST 1.1 criteria, as 
outlined in Section 3. Throughout this protocol, the term RECIST 1.1 refers to the adjustment
of RECIST 1.1 to include a maximum of 10 target lesions overall and a maximum of 5 target 
lesions per organ. 
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 assessed by BICR according to RECIST 1.1 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 assessed by BICR, will be 
communicated to the site. 
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Overall survival has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are safety endpoints including, but not limited to, the incidence, causality, and 
outcome of AEs/serious adverse events (SAE)s; and changes in vital sign measurements and 
laboratory values. Adverse events will be assessed, as defined by NCI CTCAE v5.0.
4.2.1.3
Patient-Reported Outcomes
Improvement in patient-reported outcomes is considered a clinical benefit and accepted by 
health authorities as additional evidence of the risk-benefit profile of any new treatment. 
The EORTC QLQ-C30 was developed to assess the HRQoL 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 functioning scales (physical, role, cognitive, emotional, and social), 
3 symptom scales (fatigue, nausea, pain) and additional single symptom items. It is scored on 
a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The EORTC QLQ-C30 
instrument also contains a global health status/QoL score derived from 2 items that use 
7-point scale scoring with anchors (1=very poor and 7=excellent).
The EORTC QLQ-BR23 is a breast cancer-specific quality-of-life questionnaire developed to 
assess the extent of symptoms or problems in subjects receiving treatment for breast cancer. 
The tool is used to supplement the EORTC QLQ-C30 and follows the same 4-point scale 
described above. The tool consists of 23 questions containing 4 functioning scales (body 
image, sexual functioning, sexual enjoyment, future perspective) and 4 symptom scales (arm 
symptoms, breast symptoms, systemic therapy side effects, upset by hair loss). It has been 
translated and validated in over 70 languages. 
The European Quality of Life 5-dimension 5-level (EQ-5D-5L) questionnaire 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. The 5 health state dimensions in this instrument include the following: 
mobility, self -care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5-point scale from 1 (no problem) to 5 (unable to/extreme problems). The 
EQ-5D-5L also includes a graded (0 to 100) vertical visual analog scale on which the patient 
rates his or her general state of health at the time of the assessment. The EQ-5D-5L will 
always be completed by patients after completing the EORTC QLQ-C30. The EQ-5D-5L is 
available in more than 130 languages, has been used extensively in cancer studies, and 
published results from these studies support its validity and reliability.
4.2.1.4
Planned Exploratory Biomarker Research
PARP inhibitors and cancer immunotherapies represent important classes of antitumor 
agents. However, the mechanism of action of these exciting new therapies is not completely 
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understood and much remains to be learned regarding how best to leverage these 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/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy. To identify novel biomarkers, biospecimens (ie, blood 
components, tumor material, tissue 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:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. In addition to studying variation 
across the human genome, mutations in DNA damage repair genes including, but not limited 
to BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, 
PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L as well as genome scars including
LOH may be investigated. Based on data from participants in several olaparib studies in 
multiple cancer types, known or suspected deleterious mutations in these genes and LOH 
may be predictive of a response to the combination of olaparib and pembrolizumab. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (eg, colorectal cancer).
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). Key molecular changes of interest to oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. 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. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and/or blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and/or in blood may be performed to define gene signatures that 
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correlate to clinical response to treatment. Specific immune-related gene sets (ie, those 
capturing interferon-gamma transcriptional pathways) may be evaluated and new signatures 
may be identified. Individual genes related to the immune system may also be evaluated (eg, 
IL-10). MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor, tissue, and/or blood samples from this study may undergo proteomic analyses (eg, 
PD-L1 IHC). PD-L1 protein level in tumor sections, assessed by IHC, has been shown to 
correlate with response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic 
(IVD) device has been developed for use with pembrolizumab in NSCLC. Preliminary data 
indicates that this association may also be true in additional cancer types (ie, triple negative 
breast cancer, head and neck, and gastric). Additional tumor or blood-derived proteins may 
also correlate with response to olaparib and pembrolizumab. 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 for olaparib (MK-7339) 
and pembrolizumab (MK-3475) therapy.
Other biomarkers
In addition to expression on the tumor tissue, other tumor derived cells, proteins and 
DNA/RNA can be shed from tumor and released into the blood. Assays such as enzyme-
linked immunoassay (ELISA) that measure proteins and assays that measure cell-free 
DNA/RNA (cfDNA/cfRNA) may also be evaluated from blood samples. Correlation of these 
biomarkers with response to treatments may identify new approaches for predictive 
biomarkers in blood, representing a major advance from today’s reliance on assessing tumor 
biomarkers. This research would serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
In addition to studying variation across the human genome, PD-L1 and BRCA gene variants 
will specifically be investigated for the relationship to tumor response.
4.2.1.5
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 
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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 future biomedical research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Carboplatin and gemcitabine have been shown to be an effective treatment option for 1L
treatment of metastatic TNBC [O'Shaughnessy, J., et al 2014].
4.3
Justification for Dose
4.3.1
Rationale for Olaparib Dosing Regimen
The dose of olaparib used in this study is 300 mg BID (tablet formulation), which is the
recommended dose in the current prescribing information.
4.3.2
Rationale for Chemotherapy Dosing Regimens
The planned starting dose of carboplatin in this study is AUC 2 on Days 1 and 8 of each 
21-day cycle. The dose and timing of carboplatin administration is based on the most 
common clinical practice. 
The planned starting dose of gemcitabine in this study is 1000 mg/m2 on Days 1 and 8 of 
each 21-day cycle. The dose and timing of gemcitabine administration is based on the most 
common clinical practice.
4.3.3
Rationale for Pembrolizumab Dosing Regimen
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5-fold exposure 
range (refer to IB, Section 5.2.2)

Population pharmacokinetic (PK) analysis showing that both fixed dosing and 
weight-based dosing provides similar control of PK variability with considerable 
overlap in the distributions of exposures, supporting suitability of 200 mg Q3W

Clinical data showing meaningful improvement in benefit-risk including OS at 
200 mg Q3W across multiple indications
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
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg Q3W
4.3.4
Maximum Dose/Exposure for This Study
There is no maximum duration of exposure for olaparib. Olaparib administration will 
continue until disease progression or until discontinuation from treatment for any reason.
The maximum duration of exposure for pembrolizumab is 35 total administrations 
(~2 years), inclusive of induction and post-induction administrations. Participants may be 
eligible for an additional 17 administrations (~1 year), as outlined in Section 8.12.6.
Carboplatin and gemcitabine will continue until disease progression or until discontinuation 
from treatment for any reason.
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 result or at the time of final contact with the last participant, whichever comes 
last.
If the study includes countries in the EEA, the local start of the study in the EEA is defined
as FSR in any Member State.
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
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 an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
In the event of Sponsor decision to no longer supply study interventions, ample notification 
will be provided so that appropriate adjustments to participant treatment can be made.
Note: Based on the data from a prespecified interim safety and efficacy analysis for 
KEYLYNK-009 (data cutoff 15-DEC-2022), the internal DMC recommended discontinuing
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the study. The combination of pembrolizumab plus olaparib did not show an improvement in 
PFS compared with the combination of chemotherapy plus pembrolizumab.
5
STUDY POPULATION
Male and female participants ≥18 years of age with locally recurrent inoperable or metastatic 
TNBC who are eligible for 1L therapy in the metastatic TNBC setting and are willing to 
participate in the study will be enrolled.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
INDUCTION PERIOD
Type of Participant and Disease Characteristics
1. Have locally recurrent inoperable centrally confirmed TNBC that has not previously been 
treated with chemotherapy in the metastatic setting and that cannot be treated with 
curative intent.
OR
Have metastatic TNBC that has not been previously treated with chemotherapy.
Note: Participants with a history of locally recurrent TNBC that was treated with curative 
intent may be eligible. Local or distant disease recurrence must be ≥6 months from the 
completion of the most recent treatment with curative intent either in the neo-adjuvant or 
adjuvant setting.
Note: Adjuvant radiation therapy is not considered treatment with curative intent for the 
purpose of calculating the ≥6 month interval requirement described above.
Note: First documentation of local or distant disease recurrence must be in the form of a 
dated biopsy, pathology, or imaging study report. A laboratory report indicating tumor 
marker elevation cannot be used as documentation of local or distant disease recurrence, 
unless accompanied by dated biopsy, pathology, or imaging study report.
Note: Participants who received platinum agents or gemcitabine in the 
neoadjuvant/adjuvant setting are eligible for this study if ≥12 months have elapsed 
between completion of most recent treatment with curative intent and the first 
documented local or distant disease recurrence.
2. Have been treated with anthracycline and/or a taxane in the neoadjuvant/adjuvant setting,
if they received systemic treatment in the neoadjuvant/adjuvant setting, unless 
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anthracycline and/or taxane was contraindicated or not considered the best treatment 
option for the participant in the opinion of the treating physician.
Note: Participants presenting with de novo metastatic TNBC are eligible for the study if 
anthracycline and/or a taxane is contraindicated or not considered the best treatment 
option for the participant, in the opinion of the treating physician.
3. Have measurable disease based on RECIST 1.1, as determined by local radiology
review.
Note: Lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
Note: Chest wall recurrence can be used as a target lesion only if a radiologically 
measurable lesion is identified by quality imaging modality (digital photography alone is 
not adequate).
4. Have provided a recently obtained or archival (no more than 3 years old) core or 
excisional biopsy of a tumor lesion not previously irradiated for central determination of 
TNBC, PD-L1, and BRCA status.
Note: TNBC and PD-L1 status must be centrally confirmed prior to enrollment in the 
study. 
Note: Adequacy of a biopsy specimen (fine needle aspiration is not adequate) for the 
above analyses must be confirmed by the central laboratory. Submission of another tumor 
specimen may be required if adequate tumor tissue was not provided the first time.
Note: An archival tumor specimen obtained before the diagnosis of locally recurrent 
inoperable or metastatic TNBC that is more than 3 years old may be submitted after 
consultation with the Sponsor with documented SCF, if neither a recently nor a newly 
obtained biopsy from a locally recurrent inoperable or a metastatic site is available.
Note: Participants initially diagnosed with hormone receptor-positive (HR+) or 
HER2-positive breast cancer in the neoadjuvant/adjuvant setting must have central 
confirmation of TNBC in a tumor biopsy obtained from a local recurrence or distant 
metastasis site.
Note: Newly obtained tissue may be obtained at any time prior to the administration of 
systemic cytotoxic treatment for the treatment of metastatic TNBC. Formalin-fixed 
paraffin-embedded (FFPE) tumor blocks are preferred to slides. Newly obtained biopsies 
are preferred to archived tissue. If submitting unstained cut slides, newly cut slides 
should be submitted to the testing laboratory within 14 days from the date the slides are 
cut (details pertaining to tumor tissue submission can be found in the Laboratory
Manual).
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Demographics
5. Be a male or female at least 18 years of age on the day of signing the informed consent. 
6. Have an ECOG performance status of 0 or 1 as assessed within 7 days prior to the start of 
induction study treatment.
7. Have a life expectancy ≥27 weeks from the day of first study treatment.
8. Demonstrate adequate organ function within 10 days prior to the start of study treatment
as defined in the following table (Table 1).
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500 cells/µL
Platelets
≥100 000 cells/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Estimated creatinine clearance using the 
Cockcroft-Gault equation2
≥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)/partial thromboplastin time (PTT)
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT/PTT 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); CrCl = creatinine clearance; GFR = glomerular 
filtration rate; ULN = upper limit of normal.
1.
Criteria must be met without erythropoietin dependency within the last 14 days and without packed red blood cell 
(pRBC) transfusions within last 28 days. 
2.
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.
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Male Participants
9. 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 as follows:
◦
Olaparib: 95 days
◦
Pembrolizumab: no contraception requirement
◦
Chemotherapy: 95 days

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.

Contraceptive use by men 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 is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Refer to Appendix 7 for country-specific requirements. 
Female Participants
10. 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 and agrees not to donate eggs (ova, oocytes) to others or freeze/store for 
her own use for the purpose of reproduction during this period. The length of time 
required to continue contraception for each study intervention is as follows:
◦
Olaparib: 180 days
◦
Pembrolizumab: 120 days
◦
Chemotherapy: 180 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
◦
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 24 hours 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 
in Appendix 5.
◦
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.

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 is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Refer to Appendix 7 for country-specific requirements. 
Informed Consent
11. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for Future Biomedical 
Research (FBR). However, the participant may participate in the study without 
participating in FBR.
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POST-INDUCTION PERIOD
Types of Participant and Disease Characteristics
12. Have received up to 6 cycles but not less than 4 cycles of induction therapy without 
permanently discontinuing from pembrolizumab or both carboplatin and gemcitabine.  
13. Have achieved CR, PR, or SD based on RECIST 1.1, as determined by BICR at the 
Week 18 evaluation. Radiographic eligibility will be determined solely based upon the 
Week 18 evaluation.  
14. Should be able to complete during post-induction at least the Cycle 1, Day 1 doses of 
olaparib and pembrolizumab (Arm 1) or the Cycle 1, Day 1 doses of at least one of the 
chemotherapy agents being administered at the end of induction (carboplatin and/or
gemcitabine in addition to pembrolizumab [Arm 2]).
Demographics
15. Have an ECOG performance status of 0 or 1, as assessed within 7 days prior to the start 
of post-induction study treatment.
16. Have no higher than Grade 1 toxicities related to induction therapy (excluding alopecia)
prior to randomization.
Note: Hemoglobin (Hb) levels ≥9.0 g/dL or ≥5.6 mmol/L will be allowed.
Note: Grade 2 hyperthyroidism or Grade 2 hypothyroidism will be allowed.
Note: Grade 2 hyperglycemia will be allowed.
Note: Recovery from toxicities related to induction therapy will be allowed for up to 
3 weeks prior to randomization.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
INDUCTION PERIOD
Medical Conditions
1. Has a known additional malignancy that is progressing or has required active treatment 
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, cervical cancer in situ) that have undergone potentially 
curative therapy are not excluded.
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2. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
3. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(eg, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
4. 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 4 weeks by repeat scan (note that 
the repeat scan should be performed during study screening), clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
5. Has myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features 
suggestive of MDS/AML.
6. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or current pneumonitis/interstitial lung disease.
7. Has active, or a history of, interstitial lung disease.
8. Has a known history of active tuberculosis.
9. Has an active infection requiring systemic therapy.
10. Has a known history of human immunodeficiency virus (HIV) infection.
Note: No HIV testing is required unless mandated by local health authority.
11. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
12. Has a history of class II-IV congestive heart failure or myocardial infarction within 
6 months of first study treatment.
13. Has neuropathy ≥Grade 2.
14. Has not recovered (eg, to ≤Grade 1 or to baseline) from AEs due to a previously 
administered therapy.
Note: Alopecia of any grade is an exception to this criterion.
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Note: Prior to first study treatment, the participant must have recovered adequately from 
any toxicity and/or complications associated with any recent procedure.
15. Has a known history of hypersensitivity or allergy to pembrolizumab, olaparib and any of 
its components, and/or to any of the study chemotherapies (eg, carboplatin or 
gemcitabine) and any of their components.
16. Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their 
excipients.
17. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
18. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 180 days (or 
longer as specified by local institutional guidelines) after the last dose of study treatment.
19. Is a WOCBP who has a positive urine pregnancy test within 24 hours prior to 
randomization or treatment allocation (Appendix 5). If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required.
Note: In the event that 24 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for the participant to start receiving study 
medication.
Prior/Concomitant Therapy
20. Has received prior therapy with either olaparib or any other PARP inhibitor.
21. Has received prior radiotherapy within 2 weeks of start of study treatment. 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.
22. Has received colony-stimulating factors (eg, granulocyte colony-stimulating factor 
[G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF] or recombinant 
erythropoietin) within 2 weeks prior to the first dose of study treatment.
23. Has had an allogenic tissue/solid organ transplant.
24. Has received previous allogenic bone marrow transplant or double umbilical cord 
transplantation (dUCBT).
25. Had major surgery within 2 weeks of starting study intervention or has not recovered 
from any effects of any major surgery.
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26. Has received a live or live-attenuated vaccine within 30 days prior to first study 
treatment. Administration of killed vaccines are allowed. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live-attenuated 
vaccines and are not allowed.
27. Is receiving any medication prohibited in combination with study chemotherapies as 
described in the respective product labels unless medication was stopped within 7 days 
prior to first study treatment.
Prior/Concurrent Clinical Study Experience
28. Has received prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent or with 
an agent directed to another co-inhibitory T-cell receptor (such as CTLA-4, OX-40, 
CD137) or has previously participated in a study evaluating pembrolizumab regardless of 
treatment received.
29. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note: Participants who have entered the follow-up of a clinical study may participate as 
long as 4 weeks have elapsed since the last dose of the investigational agent and/or 
removal of the device.
Diagnostic Assessments
30. Has presence of uncontrolled, potentially reversible cardiac conditions, as judged by the 
investigator (eg, unstable ischemia, uncontrolled symptomatic arrhythmia, congestive 
heart failure, QTcF prolongation >500 ms, electrolyte disturbances), or participant has 
congenital long QT syndrome.
31. Has a history or current evidence of any condition (eg, cytopenia, transfusion-dependent 
anemia, or thrombocytopenia), therapy, or laboratory abnormality that might confound 
the results of the study, interfere with the participant’s involvement for the full duration 
of the study, or is not in the best interest of the participant to be involved, in the opinion 
of the treating investigator.
Other Exclusions
32. Is either unable to swallow orally administered medication or has a gastrointestinal 
disorder affecting absorption (eg, gastrectomy, partial bowel obstruction, malabsorption).
33. Is, in the judgement of the investigator, unlikely to comply with the study procedures, 
restrictions, and requirements of the study.
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POST-INDUCTION PERIOD
Medical Conditions
34. Has severe hypersensitivity (≥Grade 3) to the study treatments and/or any of their 
excipients.
35. Has permanently discontinued from both carboplatin and gemcitabine during induction 
due to toxicity.
36. Has permanently discontinued from pembrolizumab during induction due to toxicity.
37. Has received less than 4 cycles of chemotherapy plus pembrolizumab during induction.
Prior/Concomitant Therapy
38. 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 cytochrome P450 (CYP)3A4 that cannot be 
discontinued for the duration of the study. The required washout period prior to starting 
olaparib is 2 weeks.
Note: A current list of FDA-approved strong/moderate inhibitors of cytochrome P450 
(3A4) (CYP3A4) can be found at the following website. This list is not all-inclusive. Any 
inhibitors not approved in the US will not appear in the list. The investigator should also 
refer to local approved product labels and use their best medical judgment.  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers 
39. 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 starting olaparib is 
5 weeks for phenobarbital and 3 weeks for other agents.
Note: A current list of FDA-approved strong/moderate inducers of CYP3A4 can be found 
at the following website. This list is not all-inclusive. Any inducers not approved in the 
US will not appear in the list. The investigator should also refer to local approved product 
labels and use their best medical judgment.  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
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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
during post-induction. Otherwise, participants should maintain a normal diet unless 
modifications are required to manage an AE, such as diarrhea, nausea, or vomiting.
5.3.2
Contraception
Olaparib, pembrolizumab, carboplatin, and gemcitabine may have adverse effects on a fetus 
in utero. Refer to Appendix 5 for approved methods of contraception.
Participants should be informed that taking the study treatment may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study treatment initiation (or 14 days prior to the 
initiation of study treatment for oral contraception) throughout the study period up to the time 
frame for participant contraception specified in Section 5.1. If there is any question that a 
participant of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study.
5.3.3
Pregnancy
If a participant inadvertently becomes pregnant during the study, the participant will be 
immediately discontinued from study treatment and will have an assessment of disease status 
by radiographic imaging. 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.
5.3.4
Use in Nursing Women
It is unknown whether any of the study medications are excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.3.5
Practical Considerations
Because the AEs related to olaparib may include asthenia, fatigue and dizziness, participants 
should be advised to use caution while driving or using machinery if these symptoms occur.
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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 entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
Participants who fail screening may be re-screened for eligibility following consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study 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 as described in Table 2 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 03, the study is being discontinued based on the recommendation of the 
internal DMC. However, participants who are still receiving study intervention (in post-
induction or Second Course Retreatment phase) may have the option of continuing with 
study treatment if they are deriving clinical benefit, until radiographic disease progression 
per RECIST 1.1 as determined by investigator/site/local radiology review or other 
discontinuation criteria are met. No treatment beyond progression will be authorized.
Participants who have experienced first disease progression by RECIST 1.1 in post-
induction, who are continuing study treatment due to deriving clinical benefit and are being 
followed using the iRECIST criteria at the time of Amendment 03, may continue to receive 
study treatment only until the next confirmed disease progression (iCPD) by 
investigator/site/local radiology review. No treatment beyond iCPD as determined by 
investigator/site/local radiology review will be authorized.
The study intervention(s) to be used in this study are outlined in Table 2, and will be
administered during induction and post-induction.
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During induction, up to 6 cycles but not less than 4 cycles of DNA-damaging background 
chemotherapy (carboplatin and gemcitabine) in combination with the PD-1 inhibitor 
pembrolizumab will be administered to establish a tumor sensitizing effect. 
Participants who achieve CR or PR or maintain SD at their Week 18 (-7 days) scan during 
induction, and who are otherwise eligible, will be randomized into 1 of 2 study arms to begin
post-induction. 
During post-induction, participants randomized to Arm 1 will continue to receive 
pembrolizumab and will begin olaparib; participants in Arm 2 will continue to receive at 
least one of the background chemotherapy agents (carboplatin and/or gemcitabine) plus 
pembrolizumab.
Refer to Appendix 7 for country-specific requirements.
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Table 2
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/ 
Treatment Period
Use
IMP or
NIMP/ 
AxMP
Sourcing
Induction 
(all 
participants)
Experi
mental
Pembrolizumab
Drug
Solution for 
Infusion
100 mg (25 
mg/mL × 4 
mL)
200 mg
IV Infusion
On Day 1 of each 
21-day cycle, 
6 cycles
Test 
Product
IMP
Central
Induction 
(all 
participants)
Experi
mental
Carboplatin
Drug
Solution for 
Infusion
600 mg 
(10 mg/mL 
× 60 mL)
AUC 2
IV Infusion
On Days 1 and 8 
of each 21-day 
cycle, 6 cycles
Test 
Product
IMP
Central 
or Local
Induction 
(all 
participants)
Experi
mental
Gemcitabine
Drug
Lyophilized 
Powder
1000 mg
1000 
mg/m²
IV Infusion
On Days 1 and 8 
of each 21-day 
cycle, 6 cycles
Test 
Product
IMP
Central 
or Local
Post-
induction 
Arm 1
Experi
mental
Pembrolizumab
Drug
Solution for 
Infusion
100 mg 
(25 mg/mL 
× 4 mL)
200 mg
IV Infusion
On Day 1 of each 
21-day cycle, for 
up to 35 
administrations 
(inclusive of 
induction 
administrations)
Test 
Product
IMP
Central
Post-
induction 
Arm 1
Experi
mental
Olaparib
Drug
Tablet
150 mg
100 mg
300 mg
Oral
BID until disease 
progression or 
prohibitive 
toxicity
Test 
Product
IMP
Central
Post-
induction 
Arm 2
Experi
mental
Pembrolizumab
Drug
Solution for 
Infusion
100 mg 
(25 mg/mL 
× 4 mL)
200 mg
IV Infusion
On Day 1 of each 
21-day cycle, for 
up to 35 
administrations 
(inclusive of 
induction 
administrations)
Test 
Product
IMP
Central
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Arm Name
Arm 
Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/ 
Treatment Period
Use
IMP or
NIMP/ 
AxMP
Sourcing
Post-
induction 
Arm 2
Experi
mental
Carboplatin
Drug
Solution for 
Infusion
600 mg 
(10 mg/mL 
× 60 mL)
AUC 2
IV Infusion
On Days 1 and 8 
of each 21-day 
cycle until disease 
progression or 
prohibitive 
toxicity
Test 
Product
IMP
Central 
or Local
Post-
induction 
Arm 2
Experi
mental
Gemcitabine
Drug
Lyophilized 
Powder
1000 mg
1000 
mg/m²
IV Infusion
On Days 1 and 8 
of each 21-day 
cycle until disease 
progression or 
prohibitive 
toxicity
Test 
Product
IMP
Central 
or Local
Abbreviations: AUC = area under the concentration-time curve; AxMP = auxiliary medicinal product; BID = twice daily; EEA = European Economic Area; IMP = investigational 
medicinal product; IV = intravenous; NIMP = non investigational medicinal product.
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/NIMP may exist. In these circumstances, local legislation is followed.
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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).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.  
Olaparib is a tablet for oral administration; no preparation is required. Olaparib will be 
provided in high-density polyethylene (HDPE) bottles with child-resistant closures. Each 
bottle will be labelled in accordance with Good Manufacturing Practice (GMP) Annex 13 
and per country regulatory requirement.
Carboplatin and gemcitabine should be prepared per local and institutional guidelines 
according to the approved product labels.
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 
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.
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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 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to olaparib plus pembrolizumab study intervention (Arm 1) or
carboplatin and gemcitabine plus pembrolizumab study intervention (Arm 2).
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factors:
1. Response (CR or PR vs SD) at Week 18 (-7 days) as assessed by BICR
2. PD-L1 positive (CPS ≥1) versus PD-L1 negative (CPS <1)
3. Genomic tumor status (BRCAm vs BRCAwt)
For the purpose of stratification, PD-L1 positive tumors are defined as those with a CPS of 
≥1 [Kulangara, K., et al 2018].
Participants with a BRCA status that is considered not-determined due to a test failure or 
insufficient tumor tissue will be stratified as BRCAwt.
Participants with tumor scan result of non CR/non PD per BICR will be stratified as the same 
category of SD, and participants with tumor scan result of no evidence of disease per BICR 
will be stratified as the same category of CR or PR.
6.3.3
Tumor Marker Status Blinding 
Participant-level tumor PD-L1 results and BRCA biomarker status will be masked in the 
database to the Sponsor (including clinical, statistical, statistical programming, and data 
management personnel), investigator, study site staff, and the participant throughout the 
study. 
Access to the PD-L1 results and BRCA participant-level biomarker results will be limited to 
a designated team at the Sponsor who will be responsible for data review to ensure validity of 
results but who will have no other responsibilities associated with the study.   
Unblinded BRCA participant-level biomarker results will be released to the investigator only 
after a request by the investigator and after consultation with the Sponsor with documented 
SCF if a participant is not eligible for randomization to post-induction therapy or following 
discontinuation from post-induction.
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6.3.4
Study Intervention Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
6.4.1
Olaparib Compliance
Participants will take their dose of olaparib BID without regard to food. Participants will 
self-administer olaparib except on Day 1 of each cycle, when the morning dose will be given 
at the study site clinic prior to the infusion of pembrolizumab. When Day 1 visits cannot be 
performed in the morning, participants should take their morning dose of olaparib at home 
prior to the clinic visit.
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 will be 
instructed to return their bottle 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.
Interruptions from the protocol-specified olaparib treatment plan for >28 consecutive days 
require consultation between the investigator and the Sponsor with documented SCF and 
written documentation of the collaborative decision on participant management.
6.4.2
Pembrolizumab, Carboplatin, and Gemcitabine Compliance
Administration of IV pembrolizumab, carboplatin, and gemcitabine will be performed by the 
investigator and/or study staff. Pembrolizumab and chemotherapy will be administered on an 
outpatient basis.
Interruptions from either the protocol-specified pembrolizumab or carboplatin/gemcitabine 
treatment plan require consultation between the investigator and the Sponsor with 
documented SCF and written documentation of the collaborative decision on participant 
management.
6.5
Concomitant Therapy
6.5.1
Acceptable Concomitant Medications
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 medications will be recorded on the electronic case report 
form (eCRF), including all prescription, over-the-counter (OTC), and IV medications and 
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fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
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 FDA-approved substrates can be found at the 
following website. This list is not all-inclusive. Any inducers or inhibitors not approved in 
the US will not appear in the list. The investigator should also refer to local approved product 
labels and use their best medical judgment.
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
All concomitant medications received within 30 days before the first dose of induction study 
medication, while on study treatment, and up to 30 days after the last dose of study treatment 
should be recorded. All concomitant medications administered during SAEs or ECIs are to be 
recorded. SAEs and ECIs are defined in Section 8.4.
6.5.2
Prohibited Concomitant Medications
Medications specifically prohibited in the exclusion criteria (Section 5.2) are not allowed 
during the ongoing study (ie, during screening, induction, and post-induction). If there is a 
clinical indication for any medications specifically prohibited, discontinuation from study
intervention may be required. If discontinuation of study intervention is required, then the 
participant should continue in the study for assessment of disease status and survival. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor. 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.
Additionally, the following restrictions apply to concomitant therapies. These therapies are 
not permitted during the study (exceptions are noted):
1. Antineoplastic systemic chemotherapy or biological therapy 
2. Immunotherapy not specified in this protocol
3. Investigational agents other than those under study in this trial
4. Anticancer hormonal therapy (eg, anti-estrogens)
Note: Hormone replacement therapy is allowed.
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5. Radiation therapy within 2 weeks prior to the start of study treatment for disease control
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with Sponsor with documented SCF (except during screening).
6. Herbal supplements
7. Live vaccines within 30 days prior to randomization, while participating in the study, and 
within 30 days of the last dose of study medication. Refer to Appendix 7 for country-
specific requirements.

Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella, herpes zoster, yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid (oral) vaccines.  

Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed. However, intranasal influenza vaccines (eg, FluMist®) are live-attenuated 
vaccines, and are not allowed.

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, replication-
incompetent 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.
8. Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
of suspected immunologic etiology or as premedication for chemotherapy.  
Note: Physiologic doses of corticosteroids not exceeding 10 mg daily of prednisone (or 
equivalent) may be used during the study. Inhaled steroids for the management of asthma
and prophylactic corticosteroids to avoid allergic reactions may be used during the study.
9. Prophylactic cytokines (eg, G-CSF or GM-CSF) should not be administered within 
2 weeks prior to the first dose of induction study intervention or during the first cycle of 
induction but may be administered in subsequent cycles according to country-specific 
guidelines or local standard of care. 
10. Strong and moderate inducers or inhibitors of CYP3A4 that cannot be discontinued for 
the duration of the study.
Note: A current list of FDA-approved strong/moderate inducers/inhibitors of CYP3A4 
can be found at the following website. This list is not all-inclusive. Any inducers or 
inhibitors not approved in the US will not appear in the list. The investigator should also 
refer to local approved product labels and use their best medical judgment.
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-
interactions-table-substrates-inhibitors-and-inducers
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11. Any medication prohibited in combination with chemotherapy as described in the 
respective product labels for olaparib and pembrolizumab, and according to 
country-specific guidelines for gemcitabine and carboplatin.
There are no prohibited therapies during safety, disease status, or survival follow-up.
6.5.3
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Note: If, after evaluation, the event is determined not to be related to olaparib or 
pembrolizumab, the investigator does not need to follow the treatment guidance.
Sponsor consultation with documented SCF is required prior to any planned surgical 
procedures.
6.5.3.1
Rescue Medication and Supportive Care for Olaparib
Suggested supportive care measures for the management of AEs related to olaparib are 
outlined along with the dose modification guidelines in Section 6.6.1.
6.5.3.2
Rescue Medication and Supportive Care for Pembrolizumab
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.2, Table 8. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Refer to Table 8 in Section 6.6.2 for guidelines regarding dose modification and supportive 
care.   
6.5.3.3
Rescue Medication and Supportive Care for Chemotherapy (Carboplatin 
and Gemcitabine)
Suggested supportive care measures for the management of AEs related to carboplatin and 
gemcitabine are outlined along with the dose modification guidelines in Section 6.6.4.
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6.6
Dose Modification (Escalation/Titration/Other)   
The NCI CTCAE v5.0 must be used to grade the severity of AEs. If appropriate, the 
investigator may attribute each toxicity event to olaparib, pembrolizumab, carboplatin, or 
gemcitabine. Dose modifications for individual study treatment(s) must be based on the 
maximum toxicity experienced during the previous treatment cycle. Dose reductions for 
olaparib (Table 3, Table 6, and Table 7), and carboplatin or gemcitabine (Table 10) must be 
performed in a stepwise manner. Dose reductions for pembrolizumab are not allowed.
Dose modifications for the overlapping toxicities of pneumonitis and renal impairment for 
olaparib and pembrolizumab are described in Section 6.6.3.
If any of the study medications are reduced, interrupted, or discontinued, the other study 
medications may be continued as scheduled.
The reason for any dose reduction, interruption, discontinuation (including missed doses)
should be captured on the appropriate eCRF.
6.6.1
Olaparib Dosing Modifications
The dose of olaparib can be reduced to 250 mg BID initially and then to 200 mg BID as 
needed. If the 200 mg BID dose is not tolerable, no further dose reduction is allowed and 
olaparib should be discontinued. Once the dose has been reduced due to toxicity or 
tolerability issues, escalation is not permitted.
Table 3
Dose Modification Guidelines for Olaparib
Study Treatment
Dose level 0
Dose level -1
Dose level -2
Dose level -3
Olaparib
300 mg/BID
250 mg/BID
200 mg/BID
Discontinue
6.6.1.1
Management of Hematological Toxicities
Any olaparib-related hematological toxicity observed during post-induction could be 
managed by a brief interruption of study intervention or a dose reduction of olaparib (Table 4
and Table 5). Repeated interruptions, not exceeding 3 weeks (21 days) duration, are allowed 
as required. If the interruption is any longer, the Sponsor must be informed.
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Table 4
Management of Olaparib-related Anemia
Toxicity
NCI CTCAE Grade
Action Taken
Hemoglobin 
(Hb)
Grade 2
(<9.0 but ≥8 g/dL)
First Occurrence:
Give appropriate supportive treatment and 
investigate causality.

Investigator judgement to either continue 
olaparib with supportive treatment (eg, 
transfusion) or interrupt olaparib dosing for a 
maximum of 3 weeks (21 days). Treatment 
can be restarted if Hb has recovered to 
>9.0 g/dL.
Subsequent Recurrence:

Hb <9.0 but ≥8 g/dL: Investigator judgement 
to either continue olaparib with supportive 
treatment (eg, transfusion) or interrupt 
olaparib dosing for maximum of 3 weeks (21
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 3 weeks (21 days) until Hb 
improves to >9.0 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 3 weeks 
(21 days) until Hb improves to ≥9.0 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 5
Management of Olaparib-related Neutropenia, Leukopenia, and 
Thrombocytopenia
Toxicity
NCI CTCAE 
Grade
Action Taken
Neutropenia, 
Leukopenia, or 
Thrombocytopenia
Grades 1 or 2
Investigator judgement to either continue olaparib 
or interrupt dosing for a maximum of 3 weeks (21
days). Give appropriate supportive treatment and 
investigate causality.
Grades 3 or 4

Interrupt olaparib for a maximum of 3 weeks 
(21 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.

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 granulocyte colony-stimulating factor (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 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 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 related to olaparib, such as:

≥2 week interruption/delay in olaparib due to NCI CTCAE Grade 3 or worse anemia 
and/or the development of blood transfusion dependence

≥2 week interruption/delay in olaparib due to NCI CTCAE Grade 3 or worse 
neutropenia (absolute neutrophil count <1 × 109/L)

≥2 week interruption/delay in olaparib due to NCI CTCAE 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 dose of 
olaparib has been interrupted for ≥3 weeks (≥21 days), the participant should be referred to a 
hematologist for further investigation. Bone marrow analysis and/or blood cytogenetic 
analysis should be considered according to local regulation and/or standard institutional 
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hematological practice. Olaparib should be discontinued if blood counts do not recover to 
NCI CTCAE Grade 1 or better within 3 weeks (21 days) of dose interruption.
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 of olaparib, not exceeding 3 weeks (21 days) duration, are 
allowed as required. If toxicity reoccurs following rechallenge with olaparib, and 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 
olaparib.
Olaparib must be interrupted if any NCI CTCAE Grade 3 or 4 AE occurs that the investigator 
considers to be related to its administration.
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 olaparib dosing is recommended and 
further diagnostic workup (including a high resolution computed tomography [CT] scan) 
should be performed to exclude pneumonitis.
Following investigation, if no evidence of abnormality is observed on CT imaging and 
symptoms resolve, then olaparib can be restarted, if deemed appropriate by the investigator. 
If significant pulmonary abnormalities are identified, these need to be discussed with the 
Sponsor.
Please refer to Table 8 as well, which outlines the Toxicity Management Guidelines for 
pembrolizumab as it can also cause pneumonitis.
6.6.1.3.2
Management of Nausea and Vomiting
Events of nausea and vomiting are known to be associated with olaparib. These events are 
generally mild to moderate (NCI CTCAE 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 olaparib; 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 
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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 (European Society for 
Medical Oncology [ESMO], National Comprehensive Cancer Network [NCCN]), generally a 
single agent anti-emetic should be considered (eg, dopamine receptor antagonist, 
antihistamines, or dexamethasone).
6.6.1.3.3
Management of Renal Impairment
If subsequent to the first dose of olaparib, a participant’s estimated creatinine clearance 
(CrCl) falls below the threshold for study inclusion (≥51 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 either Cockcroft-Gault equation 
or based on a 24-hour urine test) for any reason during the course of the study (Table 6).
Please refer to Table 8, as well, which outlines the Toxicity Management Guidelines for 
pembrolizumab as it can also cause nephritis.
Table 6
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 51 mL/min as calculated by either Cockcroft-Gault equation or based on 24-hour urine 
test.
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 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.
6.6.1.4
Interruptions for Intercurrent Non-Toxicity-related Events
Olaparib dose interruption for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart olaparib within 4 weeks (28 days) due to 
intercurrent conditions not related to disease progression or toxicity, the investigator and the 
Sponsor should discuss the case, and the collaborative decision on participant management
appropriately documented.
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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. 
Olaparib should be stopped at least 3 days prior to planned surgery and can be restarted when 
the wound has healed. Olaparib interruption is not required for any needle biopsy procedure.
Olaparib should be discontinued for a minimum of 3 days before a participant undergoes 
radiation treatment and should be restarted within 4 weeks (28 days) as long as any bone 
marrow toxicity has recovered.
6.6.1.5
Dose Reductions for Concurrent CYP3A4 Inhibitor Use
Strong or moderate CYP3A4 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 7. After the washout of the 
inhibitor is complete (Section 5.2), the olaparib dose can be re-escalated. The dose reduction 
of olaparib should be recorded in the eCRF with the reason documented as concomitant 
CYP3A4 inhibitor use.
Table 7
Dose Reduction of Olaparib With a Strong or Moderate CYP3A4 Inhibitor
Initial Dose
Strong CYP3A Inhibitor
Moderate CYP3A Inhibitor
300 mg BID
100 mg BID
150 mg BID
Abbreviation: BID = twice daily.
6.6.2
Pembrolizumab Dosing Modifications
Pembrolizumab may be interrupted or discontinued. Dose reductions of pembrolizumab are 
not permitted.
6.6.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 
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Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 8.
If pembrolizumab is discontinued during the induction period, all study treatment must be 
discontinued. If pembrolizumab is discontinued during post-induction, dosing with either 
olaparib or chemotherapy (carboplatin and gemcitabine) may continue if the criteria outlined 
in Section 6.6.1 and Section 6.6.4 have not been met.
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Table 8
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics for 
opportunistic infections
Monitor participants for signs and symptoms 
of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
in participants with 
hyperglycemia
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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6.6.2.2
Management of Infusion Reactions
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reactions are provided in Table 9.
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Table 9
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, nonsteroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate (eg, 
from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the participant should be premedicated for 
the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment.
Participant may be 
premedicated 1.5 hr (± 30 
minutes) prior to infusion of 
pembrolizumab with:
diphenhydramine 50 mg orally 
(PO) (or equivalent dose of 
antihistamine).
acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further study 
drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
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6.6.2.3
Interruptions for Intercurrent Non-Toxicity-related Events
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 3 weeks (21 days) of the originally 
scheduled dose and within 42 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for study intervention interruption is to be 
documented in the participant’s study record.
6.6.3
Management of Overlapping Toxicities of Olaparib and Pembrolizumab
Both olaparib and pembrolizumab treatment may be associated with the development of 
pneumonitis and renal toxicity.  
Treatment with olaparib must be held for any grade of pneumonitis. Treatment with 
pembrolizumab must be held for pneumonitis ≥Grade 2 (Table 8). When the pneumonitis 
resolves to <Grade 2, then pembrolizumab may be resumed as per the guidelines in Table 8. 
Olaparib may be restarted after pneumonitis has completely resolved. Pembrolizumab must 
be discontinued for recurrent Grade 2 pneumonitis (Section 7.1).
For renal dysfunction, follow the dose modification guidelines provided in Table 6 (olaparib) 
and Table 8 (pembrolizumab). A kidney biopsy is strongly recommended to help to 
determine etiology of renal dysfunction.
6.6.4
Chemotherapy (Carboplatin and Gemcitabine) Dosing Modifications
Carboplatin and gemcitabine may be reduced, interrupted, or discontinued at the 
investigator’s discretion per the approved product labels and local regulations. Missed doses
of carboplatin and gemcitabine should be skipped if not given within the allowed window of 
±3 days.
Carboplatin should be interrupted in participants who experience a hypersensitivity reaction. 
Participants may be desensitized to carboplatin per country guidelines and then restarted on 
carboplatin at the discretion of the investigator. Other study interventions may continue while 
the participant undergoes carboplatin desensitization. 
Suggested dose modifications for chemotherapy (carboplatin and gemcitabine) are detailed in 
Table 10.
Table 10
Dose Modification Guidelines for Chemotherapy (Carboplatin and Gemcitabine)
Study Treatment
Dose level 0
Dose level - 1
Dose level - 2
Dose level - 3
Gemcitabine
1000 mg/m2
~20% reduction
~20% reduction
Discontinue
Carboplatin
AUC 2
AUC 1.5
AUC 1
Discontinue
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6.6.5
Management of Overlapping Toxicities of Gemcitabine and Pembrolizumab
Both gemcitabine and pembrolizumab treatment may be associated with the development of 
pneumonitis.  
Gemcitabine may be reduced, interrupted, or discontinued at the investigator’s discretion per 
the approved product labels and local regulations (Table 10). Treatment with pembrolizumab 
must be held for pneumonitis ≥Grade 2 (Table 8). When the pneumonitis resolves to 
<Grade 2, then pembrolizumab may be resumed as per the guidelines in Table 8. 
Pembrolizumab must be discontinued for recurrent Grade 2 pneumonitis (Table 8).
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.
6.9
Standard Policies
For studies using controlled substances, all Federal, State, Province, Country, etc., 
regulations must be adhered to in regard to their shipping, storage, handling, and dispensing
of controlled substances. Additionally, the investigator should have the appropriate 
controlled drug license(s) as mandated by Federal, State, Province, Country, etc., laws in 
which the study is being conducted.
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 be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.12.3. unless the participant has 
withdrawn from the study (Section 7.2).
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 
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for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.12.3.
A participant must be discontinued from all 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.

Radiographic disease progression per RECIST 1.1 as verified by BICR.
Note: As of Amendment 03, central tumor response assessments will no longer be 
performed. However, participants who are still receiving study intervention (in post-
induction or Second Course Retreatment phase) and deriving clinical benefit who are 
continuing to receive study treatment, will be assessed by investigator/site/local radiology 
review for disease progression per SOC schedule. 
Note: During post-induction, an exception to continue study treatment beyond any 
confirmed PD per iRECIST (iCPD) may be considered after Sponsor communication
with documented SCF and obtaining informed consent addendum (Section 8.2.2.6).
As of Amendment 03, the note above regarding iRECIST is no longer applicable but 
retained for reference. Treatment beyond progression by iRECIST will no longer be 
authorized. Participants who have experienced first disease progression by RECIST 1.1 
in post-induction, who are continuing study treatment due to deriving clinical benefit and 
are being followed using the iRECIST criteria at the time of Amendment 03, may 
continue to receive study treatment only until the next confirmed disease progression 
(iCPD) by investigator/site/local radiology review. No treatment beyond iCPD as 
determined by investigator/site/local radiology review will be authorized.

Active systemic treatment is required for any progression or recurrence of any 
malignancy (excluding the cancer under treatment) or for any occurrence of another 
malignancy.

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 serum pregnancy test.

Bone marrow findings consistent with MDS or AML.

The participant is permanently discontinued from both carboplatin and gemcitabine 
during induction due to toxicity.
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
The participant is permanently discontinued from pembrolizumab during induction due to 
toxicity.

The participant misses more than 6 consecutive weeks of study interventions due to 
toxicity or any other cause before Cycle 1 Day 1 of post-induction. 
Participants should discontinue specific study interventions when any of the following 
occurs:

Unacceptable AEs related to the specific study intervention.

Pembrolizumab must be discontinued for any study intervention-related toxicity specified 
as a reason for permanent discontinuation as defined in the guidelines for dose 
modification due to AEs in Section 6.6.2.

The participant interrupts olaparib for more than 28 consecutive days without Sponsor 
consultation with documented SCF.
Note: Participants may remain on study intervention other than olaparib if appropriate 
(ie, pembrolizumab).

The participant interrupts pembrolizumab administration for more than 12 consecutive 
weeks for an AE/toxicity or for more than 3 weeks for administrative reasons without 
Sponsor consultation with documented SCF.
Note: Participants may remain on study intervention other than pembrolizumab if 
appropriate (ie, olaparib, carboplatin, gemcitabine).

The participant interrupts chemotherapy (carboplatin or gemcitabine) for more than 
6 consecutive weeks without Sponsor consultation with documented SCF.
Note: Participants may remain on study intervention other than carboplatin 
(ie, pembrolizumab or gemcitabine) or other than gemcitabine (ie, pembrolizumab or
carboplatin).

Completion of 35 administrations (approximately 2 years) of pembrolizumab, inclusive 
of induction and post-induction administrations. Participants may stay on study 
intervention other than pembrolizumab if appropriate (ie, olaparib, carboplatin, 
gemcitabine).
Participants may be eligible for an additional 17 administrations (approximately 1 year) 
as outlined in Section 8.12.6. As of Amendment 03, Second Course Retreatment is no 
longer an option for participants.
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.
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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 8.1.9. Participants who wish to withdraw from treatment and/or imaging 
may retain consent specifically for the non-invasive survival follow-up portion of the study. 
All participants are encouraged to be followed for survival (vital) status until death or the 
closure of the study, if they consent to do so. The procedures to be performed should a 
participant repeatedly 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 or trained staff. Delegation of study site personnel 
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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.

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 informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this 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 documented informed consent is in place. Refer to Appendix 7 for country-
specific requirements.
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.
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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 Institutional Review Board/Independent Ethics Committee’s 
(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.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
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.
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 
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
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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
Medical History
Demographic information 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.
Any autoimmune disorders should be recorded regardless of the onset date. 
Details regarding the disease under treatment in this study will be recorded separately and not 
listed as medical history.
If a medical condition is diagnosed at the time of Screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention during 
screening.
8.1.4.1
Breast Cancer History
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s TNBC, including investigator-determined tumor size per RECIST 1.1.
8.1.4.2
Prior Treatments for Breast Cancer
The investigator or qualified designee will review all prior treatment for the participant’s 
breast cancer diagnosis, including neoadjuvant/adjuvant treatments, other systemic 
treatments, radiation, and surgeries.
8.1.4.3
Childbearing Potential
A participant’s childbearing potential must be assessed, and the appropriate types and use of 
contraception should be discussed, as detailed in Appendix 5.
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 30 days before the first dose of induction study medication.
Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will review and record at each study visit all 
concomitant medication used during the study, including medications taken throughout 
induction, pre-randomization, and post-induction, and at treatment discontinuation and the 
30-day safety follow-up.
All treatments administered for AEs, reportable SAEs, and events of clinical interest (ECI)s 
(Section 8.4) should be recorded.
Washout requirements for CYP3A4 inhibitors/inducers taken during induction should be 
completed before the first dose of post-induction treatment (Section 5.2).
8.1.5.3
Subsequent Anticancer Therapy
Details of subsequent therapies for cancer and/or details of surgery for the treatment of the 
cancer, after discontinuation of treatment, will be collected during disease status and survival 
follow-up (Sections 8.12.4.2 and 8.12.4.3). Reasons for starting subsequent anticancer 
therapies, including access to other PD-1/PD-L1 inhibitors, PARP inhibitors, or 
investigational drugs will be collected.
Note: The mandatory Safety Follow-up visit should be conducted approximately 30 days 
after the last dose of study treatment or before the first dose of any new anticancer 
therapy, whichever comes first. Once a new anticancer therapy has been initiated, the 
participant will move into survival follow-up.
8.1.6
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 first study intervention. 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/rescreening visit 
requirements are provided in Section 8.12.1. “Re-screening” in this protocol refers to a 
participant who could not complete screening tests within the specified 28-day period. 
8.1.7
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.
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A single participant cannot be assigned more than 1 treatment/randomization number.
Only those participants who have completed induction and meet the eligibility requirements 
for post-induction, as detailed in Section 5, will be randomly assigned to either Arm 1 or 
Arm 2 of treatment, as shown in the study schema in Section 1.2.
The randomization number will be assigned during pre-randomization after the participant’s 
eligibility to enter post-induction has been determined. Administration of Cycle 1, Day 1 of 
post-induction study treatment may occur on the same day as randomization or no more than 
3 days after randomization.
8.1.8
Study Intervention Administration
Study treatment will be administered in 21-day cycles. Pembrolizumab will be administered 
by the investigator and/or study staff according to the specifications in the Pharmacy Manual. 
Carboplatin and gemcitabine will be administered per the approved product labels and
institutional guidelines. Participants will self-administer olaparib according to instructions 
provided by the investigator and/or study staff.
8.1.8.1
Timing of Dose Administration
On Day 1 and Day 8 of each 21-day cycle, study treatment will be administered by qualified 
study staff after all procedures and assessments have been completed. Study treatment can be 
administered within ±3 days of the targeted Day 1 or Day 8 of each cycle. Treatment doses of 
olaparib, carboplatin, or gemcitabine may be reduced, as detailed in Section 6.6. Dose 
reductions of pembrolizumab are not allowed.
8.1.8.1.1
Induction
Participants will receive pembrolizumab + gemcitabine + carboplatin for six, 21-day cycles 
as follows:
Day 1
Pembrolizumab 200 mg + Gemcitabine 1000 mg/m2 + Carboplatin AUC 2
Day 8
Gemcitabine 1000 mg/m2 + Carboplatin AUC 2
Depending on which individual components of the regimen are being administered during 
any given cycle, study treatment should be administered during induction in the following 
order:
1) Pembrolizumab 
2) Gemcitabine
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3) Carboplatin
Note: participants should not be dosed after Week 18 (-7 days) scan (see Section 8.2.2.2.1) 
during induction.
8.1.8.1.1.1
Pembrolizumab
Pembrolizumab will be administered during induction as a 30-minute IV infusion on Day 1 
of each 21-day cycle prior to gemcitabine and carboplatin. Sites should make every effort to 
target infusion timing to be as close to 30 minutes as possible. However, given the variability 
of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted 
(ie, infusion time is 30 minutes: -5 minutes/+10 minutes).
Dose modifications allowed for pembrolizumab are provided in Section 6.6.2.
8.1.8.1.1.2
Gemcitabine
Gemcitabine will be administered during induction as an IV infusion over 30 minutes on 
Day 1 and Day 8 of each 21-day cycle after pembrolizumab and prior to carboplatin. 
Dose modifications allowed for gemcitabine are provided in Section 6.6.4.
8.1.8.1.1.3
Carboplatin
Carboplatin will be administered during induction as an IV infusion given over no less than 
15 minutes on Day 1 and Day 8 of each 21-day cycle after gemcitabine. The dose of 
carboplatin should be calculated using the Calvert formula as shown below or per country or 
local/institutional guidelines:
Calvert Formula:
Total Dose (mg) = target AUC × (GFR + 25)
Dose modifications allowed for carboplatin are provided in Section 6.6.4.
Participants must receive up to 6 cycles but not less than 4 cycles of induction treatment and 
meet the eligibility requirements as described in Section 5 to be eligible for randomization 
into post-induction.
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8.1.8.1.2
Post-induction
Participants who meet the eligibility requirements for post-induction will be randomized on a 
1:1 basis to 1 of 2 treatment arms to receive continued pembrolizumab with either olaparib as 
a continuous daily dose or continued carboplatin and gemcitabine. The first dose of post-
induction study treatment should be administered within 3 days of randomization. All doses 
of post-induction study treatment should be administered in 21-day cycles as follows:
Arm 1
Day 1
Olaparib 300 mg BID orally + Pembrolizumab 200 mg 
Days 2 though 21
Olaparib 300 mg BID orally daily
Note: Participants who are randomized to Arm 1 (olaparib + pembrolizumab) of 
post-induction will not need to visit the study site at Day 8 of each cycle.
Arm 2
Day 1
Pembrolizumab 200 mg + Gemcitabine 1000 mg/m2 + Carboplatin AUC 2
Day 8
Gemcitabine 1000 mg/m2 + Carboplatin AUC 2
Depending on which individual components of the regimen are being administered during 
any given cycle, study treatment should be administered in the following order:
Arm 1
1) Olaparib
2) Pembrolizumab 
Arm 2
1) Pembrolizumab 
2) Gemcitabine
3) Carboplatin
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8.1.8.1.2.1
Olaparib
Participants in Arm 1 will self-administer, under observation by qualified study site staff, the 
planned dose of olaparib on Day 1 of each 21-day cycle prior to administration of 
pembrolizumab. The subsequent daily doses of olaparib will be self-administered on the 
remaining days of each respective cycle. When Day 1 visits cannot be performed in the 
morning, participants should take their morning dose of olaparib at home prior to the clinic 
visit.
Participants should be given clear instructions on how and when to take their study treatment. 
Olaparib tablets should be taken with one glass of water twice a day at the same time each 
day, approximately 12 hours 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 the 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, 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 greater 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.
The 300-mg dose of olaparib should be made up of 2 × 150 mg tablets. 100 mg tablets are 
provided for dose reduction. Dose modifications allowed for olaparib are provided in 
Section 6.6.1.
8.1.8.1.2.2
Pembrolizumab
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle after olaparib is administered to participants in Arm 1 and prior to gemcitabine and 
carboplatin to participants in Arm 2. Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible. However, given the variability of infusion pumps 
from site to site, a window of -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes: -5 minutes/+10 minutes).
Dose modifications allowed for pembrolizumab are provided in Section 6.6.2.
8.1.8.1.2.3
Gemcitabine
Gemcitabine will be administered as an IV infusion over 30 minutes on Day 1 and Day 8 of 
each 21-day cycle after pembrolizumab and prior to carboplatin in participants in Arm 2. 
Dose modifications allowed for gemcitabine are provided in Section 6.6.4.
8.1.8.1.2.4
Carboplatin
Carboplatin will be administered as an IV infusion given over no less than 15 minutes on 
Day 1 and Day 8 of each 21-day cycle after gemcitabine in participants. The dose of 
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carboplatin should be calculated using the Calvert formula as shown below or per country or 
local/institutional guidelines:
Calvert Formula:
Total Dose (mg) = target AUC × (GFR + 25)
Dose modifications allowed for carboplatin are provided in Section 6.6.4.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the post-induction 
treatment period should be encouraged to continue to be followed for all remaining study 
visits . Participants who discontinue study intervention prior to completion of induction 
should be followed for safety. Additional details regarding procedures to be followed after 
discontinuation from study treatment are outlined in Section 1.3 and in Section 8.12.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit 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.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal 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. 
8.1.10
Blinding of Study Intervention
This is an open-label study; therefore, the Sponsor, investigator, study site staff, and 
participant will know the study interventions administered.
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8.1.11
Blinding of Tumor Marker Status
Participant-level tumor PD-L1 results and BRCA biomarker status will be blinded in the 
database to the Sponsor (including clinical, statistical, statistical programming, and data 
management personnel), investigator, study site staff, and the participant throughout the 
study.
Access to the PD-L1 results and BRCA participant-level biomarker results will be limited to 
a designated team at the Sponsor (as further detailed in Section 9.2) who will be responsible 
for data review to ensure validity of results but who will have no other responsibilities 
associated with the study.
If requested by the investigator and after consultation with the Sponsor with documented 
SCF, unblinded BRCA participant-level biomarker results will be provided if a participant is 
not eligible for randomization to post-induction therapy or following discontinuation from 
post-induction treatment.
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 is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
Tumor Tissue Collection
Participants must sign the main study ICF prior to submitting existing tissue samples and/or 
undergoing a new biopsy.
During screening, participants are required to provide recently or newly obtained tumor 
tissue from an excisional or core biopsy (fine needle aspiration is not adequate) of a locally 
recurrent inoperable or metastatic tumor lesion. The tumor tissue will be used for central 
determination of TNBC, PD-L1, and BRCA status. Archival tissue samples (more than 
3 years old) will be allowed after consultation with the Sponsor with documented SCF. 
Tumor tissue samples must not be obtained from bone sites. Brain tissue is acceptable for 
TNBC and PD-L1, but not for BRCA testing.
The results of central testing to assess BRCA status will yield information about other genes 
and will support exploratory translational science objectives.
Note: Newly obtained tissue may be obtained at any time prior to the administration of 
systemic cytotoxic treatment for the treatment of metastatic TNBC tumors. Formalin-
fixed paraffin-embedded (FFPE) tumor blocks are preferred to slides. Newly obtained 
biopsies are preferred to archived tissue. If submitting unstained cut slides, newly cut 
slides should be submitted to the testing laboratory within 14 days from the date the 
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slides are cut (details pertaining to tumor tissue submission can be found in the 
Laboratory Manual). More than one tissue sample may be submitted after Sponsor 
communication, as needed.
An optional tumor biopsy sample may be collected at the end of treatment (ie, either 
induction or post-induction) in participants who provide optional biopsy consent (this 
consent may be obtained at any time during the study). 
8.2
Efficacy Assessments
8.2.1
Tumor Markers
Tumor markers for confirmation of TNBC, and determination of PD-L1 and BRCA status 
will be performed by a central vendor using commercially validated assays on tumor tissue 
collected prior to study enrollment (Section 8.1.13).

ER, PGR, and HER2 to confirm TNBC will be determined according to the most 
recent American Society of Clinical Oncologists (ASCO)/College of American 
Pathologists (CAP) guidelines [Hammond, M. E., et al 2010][Wolff, A. C., et al 
2018].

PD-L1 testing will confirm PD-L1 positive tumors as defined by CPS ≥1 and CPS 
≥10.

Myriad Genetics Inc.’s myChoice® CDx Plus assay (BRCA1/BRCA2) testing will 
confirm BRCAm and BRCAwt status for stratification before randomization. 

The myChoice® CDx Plus assay will simultaneously interrogate other genomic 
alterations (such as HRR, HRD, TMB, MSI), which will be analyzed and reported 
retrospectively (HRR testing will confirm HRD status) for exploratory purposes.
Tumor biomarkers cancer antigen (CA) 15-3, carcinoembryonic antigen (CEA), and 
CA 27.29 will be determined by the local laboratory, or central vendor if locally not available
(see Laboratory Manual) using commercially validated assays on blood samples obtained 
during screening and at each scheduled tumor scan (or corresponding study visit) during 
induction, post-induction, and disease status follow-up.
8.2.2
Tumor Scans and Assessment of Disease
As of Amendment 03: 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 study intervention (in post-induction or 
Second Course Retreatment phase) and deriving clinical benefit who are continuing on study 
treatment until criteria for discontinuation are met, local tumor imaging should continue per 
SOC schedule.
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Throughout this section, the term “scan” refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as computed tomography [CT]
or magnetic resonance imaging [MRI]), medical photography, or other methods as specified 
in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. For each participant, the same scan technique and consistent use of 
contrast should be used throughout the study to optimize the reproducibility of the
assessment of existing and new tumor burden and improve the accuracy of the response 
assessment based on scans. For scans of the chest, abdomen, and pelvis, CT with IV contrast 
is strongly preferred. For scans of the abdomen and pelvis, contrast-enhanced MRI may be 
used when CT with iodinated contrast is contraindicated and/or when mandated by local 
practice.
Brain scans (MRI is preferred) are required at screening and during the study (at the same 
schedule as other scans for evaluation of disease status) for participants with known brain 
metastases and those with worsening and/or new neurological symptoms. Brain imaging CT 
scans will be acceptable if MRI is medically contraindicated.
At screening, if a participant has a history of bone metastases and/or has new bone pain or 
other symptoms/signs suggestive of bone metastases, a bone scan is required, and if the bone 
scan is negative, a plain X-ray is also required. During the study, a bone scan (and plain 
X-ray, if participant has signs/symptoms of bone metastases and bone scan is negative) will 
be performed if clinically indicated for evaluation of known, worsening and/or new bone 
pain or other symptoms/signs suggestive of bone metastases OR if the site believes a 
participant has attained a CR. Any supplemental scans done to support a positive or negative 
bone scan should be submitted for BICR.
Guidance and preference for imaging modalities as well as the process for scan collection 
and transmission for BICR can be found in the Site Imaging Manual (SIM).
Measurable disease for participant eligibility will be determined based on RECIST 1.1 
(Section 8.2.2.5), as assessed by site/local radiology review. Although RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol follows a 
maximum of 10 target lesions in total and 5 per organ. While on study, scheduled scans
should be submitted for BICR. While on study, any unscheduled scans obtained for 
assessment of disease progression or other reasons, but capturing radiologic progression or 
used in response assessments, should also be submitted for BICR. 
8.2.2.1
Tumor Scans During Screening
8.2.2.1.1
Scans of Target Lesions
Baseline tumor scans must be performed during the 28-day screening window to confirm 
measurable disease based on RECIST 1.1, as assessed by site/local radiology review. 
Baseline tumor scans should be submitted for retrospective BICR.
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Scans performed as part of routine clinical management are acceptable for use as screening 
tumor scans, if they are of diagnostic quality, were performed within 28 days prior to Cycle 1 
Day 1 of induction, and were submitted for retrospective BICR.
8.2.2.1.2
Scans of Brain Metastases
Participants with previously treated brain metastasis(es) may be eligible for study 
participation provided metastatic disease to the brain is radiographically stable, ie, without 
site/investigator-assessed radiologic evidence of progression for at least 4 weeks prior to the 
screening brain scan. A brain scan must be obtained during screening (ie, within 28 days of 
Cycle 1, Day 1 of induction) and must be >4 weeks after the previous post-treatment brain 
scan. Any neurologic symptoms must have returned to baseline and steroids must not have 
been used for management of symptoms related to brain metastases for at least 14 days prior 
to the first dose of induction study intervention. Participants with carcinomatous meningitis 
are excluded regardless of clinical stability.
8.2.2.2
Tumor Scans During Induction
8.2.2.2.1
Timing of Tumor Scans
Tumor scans, including brain scans if required, conducted during induction should be 
performed every 6 weeks; ie, at Week 6 (42+7 days), Week 12 (84±7 days), and 
Week 18 (126-7 days). Timing of on-study tumor scans is relative to Cycle 1, Day 1 during
induction. Scan timing should follow calendar days from Cycle 1, Day 1 and should not be 
adjusted for any dose modifications.
8.2.2.2.2
Response Evaluation
Participants with tumor responses during induction of CR, PR, or SD at Week 18 (-7 days), 
according to RECIST 1.1 as determined by expedited BICR, are eligible regarding tumor 
response for randomization to post-induction. The site and Sponsor will be notified of the 
CR, PR, or SD response via e-mail, and randomization into 1 of the 2 arms of study treatment 
will be performed no more than 3 days prior to Cycle 1, Day 1 of post-induction.
The last induction scan at Week 18 (-7 days) will also be the baseline for assessment of 
post-induction tumor responses. A new assessment for any target or non-target lesions should 
be made using these images. Presence of measurable disease per RECIST 1.1 is not required
at post-induction baseline.
8.2.2.2.3
Determination of Radiographic Progression
Participants with radiographically documented disease progression as determined by BICR at 
any time point during induction will be discontinued from study intervention 
(Section 8.2.2.4).
Tumor response assessments by iRECIST criteria will not be used during induction. If PD 
seen by the site during induction is not verified by BICR, disease assessments should still be 
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performed by the site/investigator using RECIST 1.1 if the participant is stable and continues 
treatment at treating physician’s discretion.
8.2.2.3
Tumor Scans During Post-induction
8.2.2.3.1
Timing of Tumor Scans
After eligible participants are randomly assigned to and begin post-induction study 
interventions, subsequent tumor scans will be performed at Week 6 (42+7 days), and then
every 6 weeks (±7 days) for the first year. In the second year of post-induction, scans move 
to every 12 weeks (±7 days). Timing of tumor scans is relative to randomization date of 
post-induction. Scan timing should follow calendar days from the randomization date and 
should not be adjusted for any dose modifications.
8.2.2.3.2
Response Evaluation
Study treatment may be continued into post-induction for participants with centrally verified
stable disease or objective response (CR or PR) according to RECIST 1.1 during induction.
Note: During the post-induction treatment, response does not need to be verified in an 
expedited manner by BICR, but will be assessed locally. Only disease progression, as 
assessed by the site/local radiology review, is verified in an expedited manner by BICR 
during post-induction.
8.2.2.3.3
Determination of Radiographic Progression
As of Amendment 03: Central tumor response assessments will be discontinued. 
Participants with radiographically documented disease progression during post-induction as 
assessed by investigator/site/local radiology review according to RECIST 1.1 will be 
discontinued from study intervention. The section below is retained for reference.
Those participants with radiographically documented disease progression during 
post-induction, as assessed by site/local radiology review according to RECIST 1.1, and 
verified by expedited BICR, will be discontinued from study intervention (Section 8.2.2.4).
If the investigator considers the participant has disease progression per RECIST 1.1 criteria, 
but elects to implement iRECIST, study intervention may continue in clinically stable 
participants, and the investigator will assess for confirmation of progression by iRECIST at 
subsequent time points (Section 8.2.2.6 and Figure 3). Scans should continue to be submitted 
to the iCRO for potential retrospective review. If the investigator plans to continue study 
intervention beyond BICR-verified disease progression, Sponsor communication with 
documented SCF and an informed consent addendum are required.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 
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
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Participants being assessed under iRECIST during post-induction who have confirmed 
progression or unconfirmed progression with clinical instability will discontinue study 
interventions as described in Section 8.2.2.4.
8.2.2.4
Discontinuation and Follow-up Tumor Scans
In participants who discontinue all study interventions after verification of disease 
progression per expedited BICR during induction or post-induction, no further tumor scans
are required, and the participant will enter safety follow-up as described in Section 8.12.4.1 
and then survival follow-up as described in Section 8.12.4.3. It is preferred that disease 
progression is verified by BICR before discontinuation of study intervention.
In participants who discontinue all study interventions during post-induction for reasons 
other than radiographic disease progression, the participants will enter safety follow-up 
(Section 8.12.4.1), and every effort should be made to continue monitoring of disease status 
(Section 8.12.4.2). Scans should be performed at the same schedule as before treatment 
discontinuation depending on time elapsed since the start of study treatment and be submitted 
for BICR until (1) the start of new anticancer therapy, (2) disease progression as verified by 
BICR based on RECIST 1.1, (3) pregnancy, (4) death, (5) complete documented withdrawal 
of consent to study participation, or (6) the end of the study, whichever occurs first.
Participants who are clinically stable and treated past radiographic progression may continue 
to be assessed until progression is confirmed according to the rules of iRECIST, when 
clinically appropriate.
8.2.2.5
RECIST 1.1 Assessment of Disease During Induction and Post-induction
Participant eligibility to the induction phase will be assessed by site/local radiology review
based on RECIST 1.1. Participant eligibility to the post-induction phase and assessment of 
efficacy measures (other than OS), as described in the primary and secondary study 
objectives, will be performed by BICR based on RECIST 1.1. Although RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol allows a 
maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a 
broader sampling of tumor burden.
During the induction phase, the site and Sponsor will be notified by the iCRO of first 
radiologic evidence of disease progression as determined by expedited BICR based on 
RECIST 1.1.
During the post-induction phase, upon site/local radiology-assessed disease progression, 
the indicative scans are to be submitted immediately to the iCRO for BICR verification of 
progression. After submission of scan(s), the iCRO will email the assessment to the site and 
Sponsor.
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If, during post-induction, site/local radiology-assessed disease progression is not verified
by BICR, the process continues as follows:
•
If participant is clinically stable, continue study intervention per protocol
-
Continue scans per protocol schedule 
-
Send scans to iCRO
-
Continue local assessment by iRECIST
-
Do not change investigator assessment of progression
-
If subsequent scan(s) indicate progression, request verification from iCRO
•
If the participant is not clinically stable, best medical practice is to be applied. 
Communication with the Sponsor with documented SCF are strongly recommended to 
document clinical status instability.
Before stopping study intervention or imaging or starting new anticancer therapy in a 
participant who is clinically stable, communication with the Sponsor with documented 
SCF is required.
If, during post-induction, site/local radiology-assessed disease progression is verified by 
BICR, the process continues as follows:
•
Investigator judgement will determine action.
•
If the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor with documented SCF and an informed consent addendum are
required.
•
Obtain scans locally per original protocol schedule and continue local assessment by 
iRECIST
•
Continue to send scans to iCRO for potential retrospective review until one of the 
criteria for discontinuing imaging listed in Section 8.2.2.4 are met
Figure 2 illustrates the study intervention decision process involving verification of disease 
progression for participants.
•
For the purpose of this decision process, lack of clinical stability is defined as:
-
Unacceptable toxicity
-
Clinical signs or symptoms indicating clinically significant disease progression
-
Decline in performance status
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-
Rapid disease progression or threat to vital organs or critical anatomical sites 
(eg, CNS metastasis, respiratory failure due to tumor compression, spinal cord 
compression) requiring urgent alternative medical intervention
8.2.2.6
iRECIST Assessment of Disease During Post-induction
As of Amendment 03: iRECIST assessment of disease is no longer applicable for 
participants who have an initial PD evaluated by RECIST 1:1. Participants who are 
currently being assessed by iRECIST may continue to be assessed per iRECIST until iCPD is 
determined by investigator/site/local radiology review. The section below is retained for 
reference.
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator during 
post-induction to assess tumor response and progression and to make treatment decisions
[Seymour, L., et al 2017]. When clinically stable, participants may continue study 
intervention beyond RECIST 1.1 progression with continued assessment of response
according to the rules outlined in Appendix 9. iRECIST reflects that some participants can 
have a transient tumor flare after the start of immunotherapy then experience subsequent 
disease response. These data will be captured in the clinical database.
•
If participant is clinically stable (refer to Section 8.2.2.5), continue study intervention per 
protocol 
-
Perform scans 4 to 8 weeks after RECIST 1.1 progression
-
Continue investigator assessment per iRECIST
-
Continue to send scans to iCRO for potential retrospective review
•
If the participant is not clinically stable, best medical practice is to be applied. 
Any participant being assessed under iRECIST who is clinically unstable should be 
discontinued from study treatment and is not required to have repeat tumor scans for 
confirmation of progression by iRECIST.
8.2.2.7
Tumor Scan Flow for Determination of Disease Progression
Figure 2 and Figure 3 illustrate the tumor scan flow algorithm for RECIST 1.1 and iRECIST, 
respectively, for determination and verification of disease progression during post-induction 
in clinically stable participants. 
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Figure 2
RECIST 1.1 Assessment During Post-induction for Clinically Stable Participants 
After First Radiologic Evidence of Disease Progression as Assessed by the Investigator 
Note: Centrally verified refers to BICR.
Note: Documented Sponsor Consultation Form is required as part of Sponsor 
communication.
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Figure 3
iRECIST Assessment During Post-induction for Clinically Stable Participants 
8.2.3
Patient-Reported Outcomes
As of Amendment 03: PROs and Quality of Life assessments will be discontinued. The 
subsections below are retained for reference.
The PROs questionnaires performed is this study are the EORTC QLQ-C30, the breast 
cancer module EORTC QLQ-BR23, and the EQ-5D-5L™, and will be administered by 
trained study site personnel and completed electronically by the participants themselves.
PROs should be completed within 3 days prior to visit dose administration. It is strongly 
recommended that PROs are administered prior to AE evaluations and any discussions of 
disease status with the participant. The PROs are completed in the following order: EORTC 
QLQ-C30, then the EORTC QLQ-BR23, and then last the EQ-5D-5L at the time points 
specified in the SoAs (Section 1.3) and as briefly summarized in Section 8.2.3.1 and 
Section 8.2.3.2.
Site staff must not read, administer, or complete the PRO questionnaires on behalf of the 
participant. If the participant is unable to read the questionnaire (eg, is blind or illiterate), that 
participant may still participate in the study, but is exempt from completing PRO 
questionnaires. Participants exempt in this regard should be flagged appropriately by the site 
staff.
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8.2.3.1
Timing During Induction
The PROs are assessed during induction prior to AE evaluations, the administration of study 
treatments, and any discussions of disease status with the participant as follows:

On Day 1 of Cycles 1, 4, 5, and 6

At the Treatment Discontinuation Visit a

At the 30-day Safety Follow-up Visit a
a If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, 
PROs do not need to be repeated at the time of the mandatory Safety Follow-up Visit.
8.2.3.2
Timing During Post-induction
The PROs are assessed during post-induction prior to AE evaluations, the administration of 
study treatments, and any discussions of disease status with the participant as follows:

On Day 1 of each of the first 8 cycles 

After the first 8 cycles,

During Year 1 of post-induction, every second cycle (every 6 weeks) until end of
treatment, disease progression as determined by BICR, or death, whichever occurs 
first (Cycles 10, 12, 14, 16)

Starting in Year 2 of post-induction, every fourth cycle (every 12 weeks) until end of
treatment, disease progression as determined by BICR, or death, whichever occurs 
first (Cycles 18, 22, 26, 30, etc)

At the Treatment Discontinuation Visit a

At 30-day Safety Follow-up Visit a
a If the Treatment Discontinuation Visit occurs 30 days from the last dose of study treatment, 
PROs do not need to be repeated at the time of the mandatory Safety Follow-up Visit.
8.2.4
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status (Appendix 8) at 
screening and at pre-randomization; within 7 days prior to the administration of Cycle 1, 
Day 1 study treatment of induction and post-induction; prior to administration of study 
treatment on Day 1 of each subsequent treatment cycle during induction and post-induction;
and at treatment discontinuation and the safety follow-up, as specified in Section 1.3.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided throughout Section 8.3. The total amount of blood/tissue to be drawn/collected over 
the course of the study (from prestudy to poststudy 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 that includes a neurologic examination will be conducted 
during screening, pre-randomization, and at treatment discontinuation by an investigator or a 
medically qualified designee (consistent with local requirements), as per institutional 
standards. 
A brief directed physical examination that includes a neurologic examination will be 
conducted before study treatment administration at all on-treatment study visits by an 
investigator or a medically qualified designee (consistent with local requirements) per 
institutional standards.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be performed by the investigator or a medically qualified designee during 
screening and pre-randomization, at each study visit prior to any blood collection and the 
administration of each dose of study treatment, at treatment discontinuation, and at the safety 
follow-up.

Vital signs will include temperature, systolic and diastolic blood pressures, pulse, and 
respiratory rate. Vital signs should be measured within 3 days before each dosing day.

Height will be measured during screening only, and weight will be measured and 
recorded at screening and at all subsequent study visits through the safety follow-up.
Weight should be measured within 3 days before each dosing day.
8.3.3
Electrocardiograms
A single 12-lead ECG will be obtained using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTc intervals and will be reviewed by an 
investigator or a medically qualified designee (consistent with local requirements) during 
screening (with clinically significant abnormal findings recorded as medical history), and at 
pre-randomization and treatment discontinuation. Additional ECG evaluations may be 
performed as necessary.
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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 SoAs in Section 1.3.

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.
8.4
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 events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
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The investigator remains 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.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
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 causes 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 90 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.
For Pharmacovigilance purposes and characterization, any SAE of MDS/AML or new 
primary malignancy occurring after the 30 day follow up period should be reported to the 
Sponsor regardless of investigator’s assessment of causality or knowledge of the treatment 
arm.  Investigators will be asked during the regular follow up for OS if the participant has 
developed MDS/AML or a new primary malignancy and prompted to report any such cases.
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Section 5.1, or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy must be reported by the 
investigator.
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.
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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 11.
Table 11
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:
- participant has been 
exposed to any protocol-
specified intervention 
(eg, procedure, washout 
or run-in treatment 
including placebo run-in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable event.
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), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
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The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, 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.
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: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. 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).
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3. 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 the investigator’s assessment of causality.
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for olaparib, and any dose approximately ≥20% above the prescribed dose for 
carboplatin and gemcitabine as specified in this protocol or per local/country guidelines and 
should be reported as such. Olaparib, carboplatin, and gemcitabine must be used only in 
accordance with the dosing recommendations in this protocol. For pembrolizumab, any dose 
of 1000 mg or greater should be reported as an overdose. No specific information is available 
on the treatment of overdose of olaparib, carboplatin, gemcitabine, or pembrolizumab. In the 
event of overdose, the specific study intervention should be withheld, and the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
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 DNA for future research

Leftover tumor tissue

Leftover plasma or derivative for circulating tumor DNA (ctDNA)
8.9
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, this sample will be 
collected for the purpose of future biomedical research.
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Sample collection, storage, and shipment instruction for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.10
Biomarkers
As of Amendment 03: Biomarker sample collections will be discontinued. Biomarker 
samples already collected before implementation of Amendment 03 will be analyzed. 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:
All specimens collected on a dosing day should be drawn pre-dose, unless the visit cannot be 
performed in the morning and the participant has taken their morning dose of olaparib at 
home before the visit.

During screening
o
Tumor tissue

During induction pre-dose on Cycle 1, Day 1, Cycle 3, Day 1
o
Blood for genetic analysis
o
Blood for ctDNA analysis

During post-induction pre-dose on Cycle 1, Day 1; Cycle 2, Day 1; and Cycle 5, Day 1;
and at treatment discontinuation
o
Blood for ctDNA analysis
After Cycle 5, Day 1, additional blood samples for ctDNA analysis will be collected every 
6 weeks during Year 1 of post-induction, and every 12 weeks from Year 2 until the end of 
Year 5, or until discontinuation of study treatment, whichever is earlier. ctDNA collections 
post-induction should be aligned with clinic visit closest to tumor scan visits. If a clinic visit 
is not feasible, blood for ctDNA collection will not be collected.
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Laboratory Manual.
8.11
Medical Resource Utilization and Health Economics
As of Amendment 03: Medical Resource Utilization and Health Economics data
collection will be discontinued. The section below is retained for reference.
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation/randomization through 90 days following cessation of study 
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intervention, or 30 days following cessation of study intervention if the participant initiates 
new anticancer therapy, whichever is earlier. ER visits that are not considered SAEs should 
be reported through 30 days following cessation of study intervention.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Approximately 28 days before administration of study intervention on Cycle 1, Day 1 of 
induction, potential participants will be evaluated to determine that they fulfill the entry 
requirements as described in Section 5. Documented informed consent for the study must be 
obtained before any screening procedures (Section 8.1.1). Results of tests that were 
performed as part of routine clinical management before the participant provided 
documented informed consent are acceptable in lieu of a screening test if performed within 
the specified time frame. Consent for FBR is optional and can be provided before or after 
Cycle 1, Day 1.
Screening procedures as detailed in the SoA in Section 1.3.1 are to be completed within 
28 days of the administration of the first dose of induction study treatment, except for the 
following:

Laboratory tests are to be performed within 10 days before the start of induction study 
treatment.

ECOG performance status is to be performed within 7 days before the start of induction 
study treatment.

For WOCBP, a urine or serum pregnancy test will be performed within 24 hours before
the participant receives the first dose of study treatment of induction. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
Participants who initially did not meet the inclusion/exclusion criteria may repeat screening 
procedures after Sponsor communication, if needed. “Re-screening” in this protocol refers to 
a participants who could not complete screening tests within the specified 28-day period. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the corresponding 
inclusion criterion is met.
8.12.2
Treatment Visits
Timing of Study Assessments and Procedures
The timing of the study assessments and procedures for this study are presented in the 
Schedule of Activities (SoAs) in Section 1.3 and throughout Section 8. Starting with Cycle 7 
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of induction and post-induction, the pattern of study treatment administration, assessments, 
and procedures performed at Cycle 6 will be repeated unless otherwise stated.
8.12.2.1
Induction
Assessments/procedures should be performed during induction prior to administration of 
study intervention on Day 1 of each cycle unless otherwise specified in the SoA in 
Section 1.3.1.
Visit timing requirements during induction are as follows:

Treatment cycles are 21 days (starting with Cycle 1, Day 1 of induction).  

The window for each visit is ±3 days unless otherwise specified. 
Study interventions administered during induction are detailed in Section 8.1.8.
The full list of all visit assessments/procedures conducted during induction are provided in 
the SoA in Section 1.3.1. Specific procedures related to the efficacy assessments are detailed 
in Section 8.2 and those related to the safety assessments are detailed in Section 8.3.
8.12.2.2
Pre-randomization
During the approximately 14-day period after the Cycle 6, Day 8 dose of induction study 
intervention, potential participants will be evaluated to determine that they fulfill the 
post-induction eligibility requirements as described in Section 5. Note: participants are not 
eligible to be treated in post-induction if they miss more than 6 consecutive weeks of study 
interventions due to toxicity or any other cause before Cycle 1 Day 1 of post-induction
(Section 7.1). The minimum permitted interval between the last dose of pembrolizumab in 
induction and the first dose of pembrolizumab in post-induction is 21 days.
Pre-randomization procedures as detailed in the SoA in Section 1.3.2 are to be completed 
within this 14-day period, except for the following:

For WOCBP, a urine or serum pregnancy test will be performed within 24 hours before 
the participant receives the first dose of study treatment of induction. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.  

ECOG performance status should be performed within 7 days of administration of the 
Cycle 1, Day 1 dose of study intervention.

Participants with toxicities related to induction therapy may have up to 3 weeks for these 
events to recover to Grade 1 or less, or to achieve a Hb level of 9.0 g/dL.
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8.12.2.3
Post-induction
Assessments/procedures should be performed during post-induction before administration of 
study intervention on Day 1 of each cycle unless otherwise specified in the SoA in 
Section 1.3.2.
Note: Participants who are randomized to Arm 1 (olaparib + pembrolizumab) of 
post-induction will not need to visit the study site at Day 8 of each cycle.
Visit timing requirements during post-induction are as follows:

Administration of Cycle 1, Day 1 post-induction study treatment must occur within 3 
days after randomization.

Treatment cycles are 21 days (starting with Cycle 1, Day 1 of post-induction).  

The window for each visit is ±3 days unless otherwise noted.

Laboratory samples can be collected up to 72 hours prior to scheduled administration of 
study treatment and do not need repeated if obtained within 72 hours of Cycle 1, Day 1.
If both carboplatin and gemcitabine are permanently discontinued during post-induction 
(Section 7.1), the participant does not need to come to the clinic on Day 8 and will follow the 
treatment and procedure schedule for pembrolizumab.
Study interventions administered during post-induction are detailed in Section 8.1.8.
The full list of all visit assessments/procedures conducted during post-induction are provided 
in the SoA in Section 1.3.2. Specific procedures related to the efficacy assessments are 
detailed in Section 8.2 and to the safety assessments are detailed in Section 8.3.
8.12.3
Treatment Discontinuation
The End of Treatment Visit should occur at the time that study treatment is discontinued as 
detailed in Section 7.1. If the End of Treatment Visit occurs ≥30 days from last dose of study 
treatment, a separate Safety Follow-up Visit (Section 8.12.4.1) is not required.
For the full list of all visit assessments/procedures conducted at treatment discontinuation, 
please see the SoA in Section 1.3.3. Specific procedures related to the efficacy assessments 
are detailed in Section 8.2 and to the safety assessments are detailed in Section 8.3.
8.12.4
Post-treatment Follow-up
8.12.4.1
Safety Follow-up
After all study interventions are permanently discontinued (Section 7.1) in either induction or 
post-induction, the mandatory Safety Follow-up Visit should be conducted approximately 
30 days after the last dose of study treatment or before the initiation of a new anticancer 
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therapy, whichever comes first. All AEs, SAEs, and other reportable events will be followed 
to resolution as described in Section 8.4.3.
The Safety Follow-up Visit is the last required visit for participants who discontinue all study 
interventions for any reason during induction. 
8.12.4.2
Disease Status Follow-up
As of Amendment 03: Disease Status Follow-up Visits will be discontinued. The section 
below is retained for reference.
Participants who complete the protocol-required cycles of study intervention or who 
discontinue all study interventions for a reason other than disease progression during 
post-induction will move into disease status follow-up and should be assessed according to 
the already followed tumor scan schedule (Section 8.2.2.2 and Section 8.2.2.3). Every effort 
should be made to collect information regarding disease status until the start of new 
anticancer therapy, centrally verified disease progression, pregnancy, death, or the end of 
study. Information regarding new treatment for the disease under study will be collected if 
applicable.
Participants who complete all disease status assessments and/or will not have further disease 
status assessments must enter the Survival Follow-up Phase.
8.12.4.3
Survival Follow-up Contacts
As of Amendment 03: Survival Follow-up visits will be discontinued. Those participants 
remaining on study treatment at the time of Amendment 03 should continue to be 
monitored in the study through the AE reporting period (Section 8.4). The section below 
is retained for reference.
Participants will move into survival follow-up after centrally verified disease progression 
during post-induction or after starting a new anticancer therapy, whichever occurs first. 
During survival follow-up participants should be contacted by telephone approximately every 
12 weeks to assess for subsequent anticancer therapy, disease status, and survival (vital) 
status until death, complete documented withdrawal of consent from the study, or the end of 
the study, whichever occurs first.
Investigators will ask during the regular survival follow up if the participant has developed 
MDS/AML or a new primary malignancy and prompted to report any such cases.
Note: Survival (vital) status may be requested by the Sponsor at any time during the study.
The first survival follow-up assessment should be scheduled as described below: 

For participants who discontinue treatment intervention and who will not enter the 
disease status follow-up phase, the first survival follow-up assessment will be scheduled 
12 weeks after the discontinuation visit and/or Safety Follow-up visit (whichever is last).  
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
For participants who completed assessments in the disease status follow-up phase, the 
first survival follow-up assessment will be scheduled 12 weeks after the last disease 
status follow-up visit has been performed.
8.12.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before, but not limited to, an internal DMC 
review, interim and/or FA. 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 vital status.
8.12.6
Second Course Retreatment
Note: As of Amendment 03, the study will be discontinued based on the recommendation of 
the internal DMC, and Second Course Retreatment is no longer an option for participants. 
The section below is retained for reference.
Participants who are already receiving Second Course Retreatment and deriving clinical 
benefit may continue Second Course Retreatment, and local tumor imaging assessments 
should continue per SOC schedule, until radiographic disease progression per RECIST 1.1 as 
determined by investigator/site/local radiology review. No treatment beyond progression will 
be authorized.
8.12.6.1
Conditions of Second Course Retreatment 
Participants who stop pembrolizumab during post-induction with SD or better may be 
eligible for up to 17 additional administrations of pembrolizumab if they progress after 
stopping pembrolizumab and only after consultation with the Sponsor with documented SCF, 
followed by reconsent to main study ICF. Retreatment with pembrolizumab is termed Second 
Course Retreatment and is available only if the study remains open, and the participant meets 
the following conditions:
Either

Stopped post-induction treatment with pembrolizumab after attaining a confirmed CR 
based on RECIST 1.1 by site/local radiology assessment, and

Was treated with at least 8 cycles of pembrolizumab (inclusive of induction and post-
induction) before discontinuing study treatment, and

Received at least 2 cycles of post-induction pembrolizumab beyond the date when the 
initial CR was declared,
OR
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
Had SD, PR, or CR and stopped post-induction pembrolizumab treatment after 
35 administrations for reasons other than disease progression or intolerability,
AND

Experienced an investigator-determined and BICR-verified PD by RECIST 1.1 after 
stopping post-induction treatment with pembrolizumab, and

No new anticancer therapy was administered since the last dose of post-induction 
pembrolizumab, and

The participant meets the safety parameters listed in the post-induction 
inclusion/exclusion criteria, and

The study is ongoing.
An objective response or disease progression that occurs for a participant during Second 
Course Retreatment will not be counted as an event in the primary efficacy analyses in this 
study.
8.12.6.2
Treatment Requirements for Second Course Retreatment
Participants may resume pembrolizumab in combination with the same randomly assigned 
treatments received during post-induction, either olaparib (Arm 1) or gemcitabine and/or 
carboplatin (Arm 2), at the discretion of the investigator and after documented consultation 
with the Sponsor, with documented SCF. The use of study treatments in combination with 
pembrolizumab that are different from those received during post-induction are not 
permitted. 

If either carboplatin or gemcitabine (Arm 2) were discontinued during post-induction due 
to toxicity and the participant experiences BICR-verified PD on the continued single-
agent chemotherapy, the participant may be eligible to continue the single-agent 
chemotherapy in combination with Second Course Retreatment with pembrolizumab 
after consultation with the Sponsor, with documented SCF.

If olaparib (Arm 1) or both carboplatin and gemcitabine (Arm 2) were discontinued 
during post-induction due to toxicity, and the participant achieved or sustained an SD or 
better after completing 35 administrations of pembrolizumab monotherapy, and the 
participant then experiences BICR-verified PD, the participant may be eligible for 
Second Course Retreatment with pembrolizumab as monotherapy after consultation with 
the Sponsor, with documented SCF.
8.12.6.3
Visit Requirements of Second Course Retreatment
Treatments, assessments, and procedures during Second Course Retreatment will be 
performed as specified in the SoAs in Section 1.3.4 for participants who are eligible to 
resume pembrolizumab in combination with olaparib (Arm 1) or pembrolizumab in 
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combination with gemcitabine and/or carboplatin (Arm 2); or for participants who are 
eligible to resume pembrolizumab monotherapy.
Study cycles will reset to Cycle 1 with the first dose of Second Course Retreatment. 
Treatment cycles are 3 weeks (starting with the first pembrolizumab retreatment) and visit 
windows are ±3 days unless otherwise noted. Starting with Cycle 7, the pattern of study 
treatment administration, assessments, and procedures performed at Cycle 6 will be repeated 
unless otherwise stated. 
8.12.6.4
Study Treatments During Second Course Retreatment
Participants who start retreatment should resume pembrolizumab at 200 mg IV Q3W. 
Participants who continue with olaparib (Arm 1), or gemcitabine and/or carboplatin (Arm 2) 
should receive the same dose level given at the last dose of post-induction and should follow 
the dose schedule as detailed in Section 8.1.8.1.2.
8.12.6.5
Concomitant Medications During Second Course Retreatment
Enter new medications started during Second Course Retreatment through the safety 
follow-up. Record all medications taken for AEs as defined in Section 8.4.
8.12.6.6
Laboratory Tests During Second Course Retreatment
Laboratory tests for determining eligibility for retreatment are to be performed within 
10 days prior to the first retreatment dose. See Section 8.3.4 for details regarding laboratory 
tests.
For WOCBP, a urine or serum pregnancy test should be performed within 24 hours prior to 
receiving the first retreatment dose. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. While the participant is on study, 
pregnancy testing should be conducted monthly and as per local regulations where applicable
(see Section 10.5.3).
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time 
point. T3 (or Free T3), Free T4, or TSH can be assayed based on local standards and should 
be repeated every 2 cycles after Cycle 5.
Coagulation factors should be monitored closely throughout the Second Course Retreatment 
for any participant receiving anticoagulant therapy (see Section 10.2).
Clinically significant abnormal laboratory test results that are drug-related AEs should be 
followed until return to within the normal range or baseline. Laboratory tests do not need to 
be repeated after the end of retreatment if values are within normal range.
Laboratory safety measurements will be graded per NCI CTCAE v5.0.
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8.12.6.7
Vital Signs During Second Course Retreatment
Vital signs will include temperature, pulse, respiratory rate, weight, and blood pressure as 
detailed in Section 8.3.2. Height will not be measured in the Second Course Retreatment. 
Vital signs should be measured within 3 days before each dosing day.
8.12.6.8
Adverse Events During Second Course Retreatment
Adverse events will be assessed and recorded during Second Course Retreatment as detailed
in Section 8.4.
8.12.6.9
Tumor Scans During Second Course Retreatment
As of Amendment 03: Central tumor response assessments will be discontinued. For 
participants who are already receiving Second Course Retreatment and deriving clinical 
benefit who are continuing on study treatment until criteria for discontinuation are met, local 
tumor imaging should continue per SOC schedule. Participants with radiographically 
documented disease progression during Second Course Retreatment as assessed by 
investigator/site/local radiology review according to RECIST 1.1 will be discontinued from 
study intervention. Participants who are currently being assessed by iRECIST during Second 
Course Retreatment may continue to be assessed per iRECIST until iCPD is determined by 
investigator/site/local radiology review. Treatment beyond RECIST 1.1 progression or iCPD 
will no longer be authorized after implementation of Amendment 03. The section below is 
retained for reference.
Tumor scans must be or must have been performed within 28 days prior to Cycle 1, Day 1 of 
Second Course Retreatment. Local readings (investigator assessment with site radiology 
readings) will be used to determine eligibility. Scans should not be submitted for BICR.
Tumor scans during Second Course Retreatment should begin 9 weeks (±7 days) after 
Cycle 1, Day 1 of Second Course Retreatment and should be assessed using RECIST 1.1 
criteria. Subsequent tumor scans should be performed every 9 weeks (±7 days), or more 
frequently if clinically indicated.
Per iRECIST (Section 8.2.2.6), if tumor scans show initial PD, tumor assessment should be 
repeated ≥4 weeks later in order to confirm PD with the option of continuing retreatment 
while awaiting radiologic confirmation of progression. Participants who obtain a 
confirmation scan do not need to undergo scheduled tumor scans if it is <4 weeks later and 
may wait until the next scheduled tumor scan time point if clinically stable.
Tumor scans should continue to be performed until disease progression, the start of new 
anticancer therapy, pregnancy, withdrawal of consent, or death, whichever occurs first. 
Disease progression may be confirmed at least 4 weeks after the first tumor scan indicating 
PD in clinically stable participants. Should the investigator wish to continue a clinically 
stable participant after investigator assessed progression, communication with the Sponsor, 
with documented SCF approving continued treatment, is required. In such cases the treatment 
administered must remain unchanged.
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In participants who discontinue retreatment, tumor scans should be performed at the time of 
retreatment discontinuation (±4-week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. In participants who discontinue retreatment due to confirmed disease 
progression, this is the final required tumor scan.
In participants who discontinue retreatment without further documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic scans 
every 9 weeks (±7 days) until (1) the start of new anticancer therapy, (2) disease progression, 
(3) pregnancy, (4) death, or (5) the end of the study, whichever occurs first.
8.12.6.10
Discontinuation During Second Course Retreatment
Discontinuation of study retreatments should follow the criteria detailed in Section 7.1, and 
the participant will enter end of treatment and follow-up as detailed in Section 1.3.3. 
Participants must discontinue pembrolizumab after 17 administrations. Tumor scan
requirements for these participants are described in Section 8.12.6.9.
9
STATISTICAL ANALYSIS PLAN
Note: As of Amendment 03, the Statistical Analysis Plan is amended as follows.
Based on the data from a prespecified interim safety and efficacy analysis for 
KEYLYNK-009 (data cutoff 15-DEC-2022), the internal DMC recommended discontinuing 
the study because the combination of pembrolizumab plus olaparib did not show an 
improvement in PFS compared with the combination of chemotherapy plus pembrolizumab. 
Based upon these data and the recommendation of the internal DMC, the prespecified final 
analysis of the study described in the SAP will not be performed. Selected safety analyses 
will be performed at the end of the study.
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to these hypotheses, then the protocol will be amended (consistent 
with International Conference on Harmonization [ICH] Guideline E9). Changes to the 
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 a supplemental Statistical 
Analysis Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the study. Post-
hoc exploratory analyses will be clearly identified in the CSR. The PRO analysis plan will be 
included in the sSAP. A separate biomarker analysis plan may be provided as appropriate in 
the sSAP.
In this section, the number of participants refers to the number of randomized participants in 
post-induction.
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9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12. As of Amendment 03, the prespecified final 
analysis of the study described in the SAP will not be performed. The SAP summary has 
been updated accordingly.
Study Design Overview
An Open-label, Randomized, Phase 2 Study of Olaparib Plus Pembrolizumab 
Versus Chemotherapy Plus Pembrolizumab in Participants With Locally 
Recurrent Inoperable or Metastatic Triple Negative Breast Cancer (TNBC) After 
Induction of Clinical Benefit With First-line Chemotherapy Plus Pembrolizumab
Treatment Assignment
Approximately 260 participants will be expected to be randomized 
post-induction in a 1:1 ratio between two treatment groups: (1) olaparib + 
pembrolizumab arm and (2) chemotherapy + pembrolizumab arm. 
Stratification factors are as follows:

Response to the induction therapy (CR or PR versus SD) at Week 18 
(-7 days) as assessed by BICR

PD-L1 positive (CPS ≥1) versus PD-L1 negative (CPS <1)

BRCAm versus BRCAwt
This is an open-label study.
As of Amendment 03, all ongoing participants may have the option to continue 
receiving study treatment, until criteria for discontinuation are met, if they are 
deriving clinical benefit.
Analysis Populations
Efficacy: Intention-to-Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

Progression-free survival (PFS) 

Overall survival (OS)
Secondary Endpoints

AEs and discontinuations due to AEs 

PRO assessment 
Statistical Methods for
Key Efficacy Analyses
The primary hypotheses comparing olaparib + pembrolizumab to chemotherapy 
+ pembrolizumab with respect to PFS and OS will be evaluated using a stratified 
log-rank test. The hazard ratio will be estimated using a stratified Cox regression 
model. 
Statistical Methods for
Key Safety Analyses
The safety analysis 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% 
confidence intervals (CIs) provided for between-arm comparisons; only point 
estimates by treatment arm are 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.
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Interim Analyses
As of Amendment 03, the prespecified final analysis of the study described in the 
SAP will not be performed.
Multiplicity
As of Amendment 03, no final analysis of the study will be performed.
Sample Size and Power
As of Amendment 03, no final analysis of the study will be performed.
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.
Although the trial is an open-label study, analyses or summaries generated by randomized 
treatment assignment, actual treatment received, PD-L1 biomarker results and BRCA status
will be limited and documented. The investigator, study team at the Sponsor consisting of 
clinical, statistical, statistical programming and data management personnel, study site staff, 
and the participant will be blinded to subject-level PD-L1 biomarker results and BRCA 
CCI
CCI
CCI
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status. A summary of PD-L1 and BRCA biomarker prevalence may be provided to the study 
team at the Sponsor by the unblinded designated Sponsor statistician. Further documentation 
will be provided in the sSAP. In addition, independent radiologist(s) will perform the central 
tumor scan review without knowledge of treatment assignments.
Planned IAs are described in Section 9.7. The treatment-level results of the IAs will not be 
shared with the investigator prior to completion of the study.
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:
Progression-free survival (PFS) – PFS is defined as the time from randomization to the first 
documented disease progression or death due to any cause, whichever occurs first, based on 
RECIST 1.1 by BICR.
Overall Survival (OS) - OS is defined as the time from randomization to death due to any 
cause.
Exploratory:
Objective Response Rate (ORR): – ORR is defined as the proportion of participants in the 
analysis population who have a best overall response of either confirmed CR or PR after the 
randomization, based on RECIST 1.1 as assessed by BICR.
Duration of Response (DOR): – For participants who demonstrate confirmed CR or PR, 
DOR is defined as the time from first documented evidence of CR or PR (that is 
subsequently confirmed) after the date of randomization until the first documented date of 
disease progression or death due to any cause, whichever occurs first, based on RECIST 1.1
by BICR.
Disease Control Rate (DCR): – DCR is defined as the percentage of participants who have 
achieved CR or PR after the randomization or have demonstrated SD for at least 24 weeks 
after the randomization, based on RECIST 1.1 by BICR.
PFS after next line treatment (PFS2): – PFS2 is defined as the time from randomization to 
subsequent disease progression after initiation of new anticancer therapy as assessed by 
investigator according to the local standard of clinical practice, or death due to any cause, 
whichever occurs first. 
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Time to First Subsequent Treatment (TFST): – TFST is defined as the time from the date 
of randomization until initiation of first subsequent anticancer therapy or death due to any 
cause, whichever occurs first. 
Time to Second Subsequent Treatment (TSST): – TSST is defined as the time from the 
date of randomization until initiation of second subsequent anticancer therapy or death due to 
any cause, whichever occurs first.
Time until Discontinuation of study treatment or Death (TDT): – TDT is defined as the 
time from the date of randomization to discontinuation of study treatment or death due to any 
cause, whichever occurs first.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2, including, but not limited to, the 
incidence of, causality of, and outcome of AEs/SAEs; and changes in vital sign 
measurements and laboratory values. 
9.4.3
PRO Endpoints
The following secondary PRO endpoints will be evaluated as described in Section 4.2.1.3:

Global Health Status/QoL scale (EORTC QLQ-C30 Items 29 and 30)

Physical functioning (EORTC QLQ-C30 Items 1-5)

Emotional functioning (EORTC QLQ-C30 Items 21-24)

Systemic therapy side effects (EORTC QLQ-BR23 Items 1-4, 6, 7, and 8)

Visual analogue scale (VAS) based the EuroQoL 5-dimension, 5-level questionnaire 
(EQ-5D-5L)

Time to Deterioration (TTD), the time from baseline to the first onset of a 
confirmed*≥10-point deterioration from baseline in PRO scores for the following 
domains:
- EORTC QLQ-C30 global health status/HRQoL (Items 29 and 30),
- EORTC QLQ-C30 physical functioning (Items 1-5),
- EORTC QLQ-C30 emotional functioning (Items 21-24), and
- EORTC QLQ-BR23 systemic therapy side effects (Items 1-4, 6, 7, and 8)
*confirmed by a ≥10-point deterioration after baseline in the subsequent PRO score
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9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The intention-to-treat (ITT) population will serve as the population for primary efficacy 
analysis. All randomized participants will be included in this population. Participants will be 
included in the treatment arm to which they are randomized. 
The analysis population for ORR consists of all randomized participants with measurable 
disease at the baseline for the post-induction.
9.5.2
Safety Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population. For most participants this will be the treatment group to which 
they are randomized. Participants who take incorrect study treatment for the entire treatment 
period will be included in the treatment group corresponding to the study treatment actually 
received. Any participant who receives the incorrect study treatment for one cycle, but 
receives the correct treatment for all other cycles, will be analyzed according to the correct 
treatment group and a narrative will be provided for any events that occur during the cycle 
for which the participant is incorrectly dosed.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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 full analysis set (FAS) population, defined as 
randomized participants who have at least one PRO assessment available and have received 
at least one dose of study treatment.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the induction phase or exploratory objectives will be described 
in the sSAP.
9.6.1
Statistical Methods for Efficacy Analyses
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. The efficacy analyses for ORR, DOR, DCR, and PFS will include responses and 
documented progression events that occur prior to Second Course treatment. If there are a 
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small number of responses/events in one or more strata, for the purpose of analysis strata will 
be combined to ensure sufficient number of responses/events in each stratum. Details 
regarding the combining of strata will be specified in the sSAP prior to database lock based 
on a blinded review of response counts by stratum.
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. 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 both the stratified log-rank test and the 
stratified Cox model.
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 and the 
date of death. Participants who do not experience a PFS event will be censored at the last 
disease assessment. Sensitivity analyses will be performed for 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, one
primary and two 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 one
missed disease assessment, the data are censored at the last disease assessment prior to the 
missed visits. Also, 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 intention-to-treat 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 initiation of new anticancer treatment or discontinuation of treatment due to 
reasons other than CR 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 12.
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Table 12
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 
complete response; 
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: 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 contact. Analysis using the Restricted Mean Survival Time method may be 
conducted for OS to account for the possible nonproportional hazards effect and to estimate 
the absolute benefit of experimental treatment.
Additional supportive unstratified analyses may also be provided. Further details of
sensitivity analyses will be described in the sSAP as needed.
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9.6.1.3
Analysis Strategy for Key Efficacy Endpoints 
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 13. 
Table 13
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary Hypothesis 1
PFS as assessed by 
BICR according to 
RECIST 1.1 in the 
overall population
Test: Stratified log-rank test
Estimation: Stratified Cox
model with Efron’s tie
handling method
ITT
Primary censoring rule
• Sensitivity analysis 1
• Sensitivity analysis 2
(More details are in Table 12)
Primary Hypothesis 2 
OS in the overall 
population 
Test: stratified log-rank test
Estimation: stratified Cox model 
with Efron’s tie handling 
method
ITT
Censored at last known alive 
date
Secondary Estimation
PFS as assessed by 
BICR according to 
RECIST 1.1 in 
participants with 
BRCAm tumors or with 
PD-L1 positive tumors 
(CPS ≥10)
Estimation: Stratified Cox
model with Efron’s tie
handling method
ITT
Primary censoring rule
• Sensitivity analysis 1
• Sensitivity analysis 2
(More details are in Table 12)
OS in participants with 
BRCAm tumors or with 
PD-L1 positive tumors 
(CPS ≥10)
Estimation: Stratified Cox
model with Efron’s tie
handling method
ITT
Censored at last known alive 
date
Abbreviations: BRCAm = breast cancer susceptibility gene mutation; BICR = blinded independent central review; 
ITT = intent-to-treat; OS = overall survival; PFS = progression-free survival; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumors Version 1.1.
† Statistical models are described in further detail in the text. For stratified analyses, the stratification factors used for 
randomization will be used as stratification factors for analysis.
9.6.2
Statistical Methods for Safety Analyses
The primary safety analyses will include only events that occur prior to Second Course 
Treatment.
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including adverse experiences (AEs), laboratory tests, and vital signs after randomization.
The safety analysis will follow a tiered approach (Table 14). The tiers differ with respect to 
the analyses that will be performed. Adverse events (specific terms as well as system organ 
class terms) are either pre-specified as Tier-1 endpoints, or will be classified as belong to 
“Tier 2” or “Tier 3”, based on the number of events observed.
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Tier 1 Events
Safety parameters or adverse events of special interest that are identified a priori constitute 
Tier 1 safety endpoints that will be participant to inferential testing for statistical 
significance.
AEs of special interest that are immune-mediated or potentially immune-mediated are well
documented and will be evaluated separately; however, these events have been characterized
consistently throughout the pembrolizumab clinical development program and determination
of statistical significance is not expected to add value to the safety evaluation. Finally, there 
are no known AEs associated with participants with breast cancer for which determination of 
a p-value is expected to impact the safety assessment. Therefore, there are no Tier 1 events 
for this protocol.
Tier 2 Events
Tier 2 parameters 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, an
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other AEs and predefined limits of change 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 endpoints that are not Tier 1 or 2 events are considered Tier 3 events. The broad AE 
categories consisting of the proportion of participants with any AE, a drug-related AE, a 
serious AE, an AE which is both drug-related and serious, a Grade 3 to 5 AE, a drug-related 
Grade 3 to 5 AE, and discontinuation due to an AE will be considered Tier 3 endpoints. Only 
point estimates by treatment group are provided for Tier 3 safety parameters.
Continuous Safety Measures
Continuous measures such as changes from baseline in laboratory and vital signs parameters, 
summary statistics for baseline, on-treatment, and change from baseline values will be 
provided by treatment group in table format.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
AEs (incidence ≥10% of participants in one of the 
treatment groups)
X
X
Serious AEs (incidence ≥5% of participants in one of 
the treatment groups)
X
X
Grade 3 to 5 AEs (incidence ≥5% of participants in 
one of the treatment groups)
X
X
Tier 3
Any AE
X
Any serious AE 
X
Any Grade 3 to 5 AE
X
Any drug-related AE
X
Any serious and drug-related AE
X
Any Grade 3 to 5 and drug-related AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs (incidence <10% of participants in 
all of the treatment groups)
X
Change from baseline results (laboratory, vital signs) 
X
Abbreviations: AE = adverse event; CI = confidence interval; SOC = system organ class X = results will be 
provided.
Methods for safety analyses related to the induction phase will be described in the sSAP.
9.6.3
Statistical Methods for Patient-reported Outcomes (PRO) Analyses
Participants in the induction and post induction periods will be analyzed separately. The 
analysis methods regarding between treatment comparisons will only be applied to the post-
induction period.
To assess the treatment effect on the PROs, for each continuous PRO endpoint, a constrained 
longitudinal data analysis (cLDA) model will be used as the primary analysis method, with 
the PRO score as the response variable, and treatment, time, treatment by timepoint 
interaction, and stratification factors (used for randomization and defined in Section 6.3.2) as 
covariates. 
The treatment effect on PRO score change from baseline will be evaluated at the primary
analysis time point, where the baseline PRO assessment is defined as the last PRO 
assessment that occurs prior to the first dose of post-induction. The between-group 
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comparison will be performed and the differences in the least-squares mean change from 
baseline at the primary analysis time point will be reported, together with 95% CI and 
nominal p-value. In addition, model-based least-squares mean score with corresponding 95% 
CI will be provided by treatment group at primary analysis time point. 
TTD is defined as the time from baseline to the first onset of a ≥10 point deterioration from 
baseline in PRO score with confirmation at the subsequent visit of a ≥10 point deterioration 
from baseline. The Kaplan-Meier method will be used to estimate the TTD survival curves 
for global health status/QoL (QLQ-C30 Items 29 and 30), physical functioning (QLQ-C30 
Items 1-5), emotional functioning (Items 21-24), and BR23 systemic therapy side effects 
(Items 1-4, 6, 7, and 8), separately, in each treatment arm. Stratified Cox proportional 
hazards models with Efron’s method of tie handling will be used to assess the magnitude of 
the treatment difference for pembrolizumab plus olaparib compared to pembrolizumab plus 
carboplatin and gemcitabine. Stratification factors used for randomization will be used in the 
stratified Cox proportional hazards models. The HR, 95% CI, and nominal p-value will be 
reported.
Details of additional PRO analyses and methods related to the induction phase will be 
included in the sSAP.
9.6.4
Summaries of Baseline Characteristics and Demographic 
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
screened and randomized and the primary reasons for screening failure and discontinuation
will be displayed. Demographic variables baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
Note: As of Amendment 03, the prespecified final analysis of the study described in the SAP 
will not be performed. The information related to FA is retained for reference.
The internal DMC will serve as the primary reviewer of the results of the interim analysis 
(analyses) of the study and will make recommendations for discontinuation of the study or 
protocol modifications. The limited Sponsor personnel will be unblinded to results at the 
treatment level. The extent to which individuals are unblinded IAs will be documented. 
Additional logistical details will be provided in the internal DMC Charter.
Treatment-level results from the interim analysis will be provided by the unblinded 
statistician to the internal DMC. 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 IAs.
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9.7.1
Efficacy Interim Analyses
CCI
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9.7.2
Safety Interim Analyses
The internal DMC will be responsible for periodic interim safety reviews, as specified in the 
DMC charter. Interim safety analysis will also be performed at the time of interim efficacy 
analysis. 
9.8
Multiplicity
9.8.1
Progression-free Survival 
CCI
CCI
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9.8.2
Overall Survival 
9.9
Sample Size and Power Calculations
CCI
CCI
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of each subgroup. The 
following are examples of classification variables:

Age category (<65 years vs ≥65 years)
CCI
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
Race: white versus nonwhite

Geographic region (Europe /North America vs Asia vs Rest of World) 

Ethnic origin (Hispanic vs Non-Hispanic)

ECOG status (0 vs 1)

Visceral disease (yes vs no)

PD-L1 status (CPS ≥1 vs CPS <1; CPS ≥10 vs CPS <10)

Response at randomization assessed by BICR (CR/PR vs SD)

Genomic tumor status (BRCAmutant vs BRCA wild type)
Note: Not-determined BRCA status due to the test failure will be put under the category 
of BRCA wild type.

HRD status (HRD≥33 vs HRD<33)

BRCA by HRD status (BRCAmutant and HRD≥33 vs BRCAmutant and HRD<33 vs 
BRCA wild type and HRD≥33 vs BRCA wild type and HRD<33)

Menopausal status (for females only; pre- vs postmenopausal)
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate. Summary statistics will be provided on 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
As of Amendment 03, the Steering Committee and internal Data Monitoring Committee are 
no longer applicable.
10.1.4.1
Steering Committee
This study will be conducted in consultation with a Steering Committee. The Steering 
Committee may be comprised of some or all of the following members:

Sponsor personnel,

Investigators participating in the study, and

Consulting therapeutic-area experts and clinical trialists.
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The Steering Committee will provide guidance on the operational aspects of the study and 
evaluate recommendations from the Data Monitoring Committee (DMC).
Specific details regarding responsibilities and governance of the Steering Committee will be 
described in a separate charter.
10.1.4.2
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate internal DMC will 
monitor the interim data from this study. The internal DMC is comprised of members of 
Sponsor Senior Management, none of whom are directly associated with the conduct of this 
study. The internal DMC will monitor the study progress for evidence of any adverse effects 
of study intervention. The internal DMC will also make recommendations to the Sponsor 
study team regarding steps to ensure both participant safety and the continued ethical 
integrity of the study. Specific details are described in the internal DMC charter.
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 
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Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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.
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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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 participants’ 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.
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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 18 will be performed by the local laboratory.

Following Cycle 1, Day 1 of induction and post-induction study intervention, 
collection of samples for pre-dose laboratory assessments may be performed up to 
3 days (72 hours) prior to dosing in subsequent cycles.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5.1 and Section 5.2 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the Investigator or required by local regulations.
Table 18
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
(reticulocytes/erythrocytes% 
or absolute reticulocytes)
WBC count with Differential 1
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea Nitrogen 
(BUN) 2
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
Carbon dioxide 
(CO2 or 
bicarbonate) 3
Chloride
Phosphorous
Creatinine or 
creatinine clearance 4
Sodium
Alanine Aminotransferase 
(ALT)/ 
Serum Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose
(nonfasting)
Calcium
Alkaline phosphatase
Magnesium
Thyroid-stimulating 
hormone (TSH) 5
Triiodothyronine 
(T3) 5
Free thyroxine 5
Lactate 
dehydrogenase 
(LDH)
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 
Screening 
Tests
Serum or urine β-human chorionic gonadotropin (β-hCG) pregnancy test (as needed for 
WOCBP). Refer to Appendix 5 for additional testing requirements.
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing potential 
only)
Serum Vitamin D
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) as required by local health authority or institutional regulations. Refer to Appendix 
7 for country-specific information.

Coagulation factors (PT or INR, and aPTT/PTT) is required during screening to establish 
eligibility. Additional testing to be conducted as clinically indicated for participants 
taking anticoagulation therapy.

Blood collection for CA 15-3, CEA, CA 27.29 is required before Cycle 1 Day 1, but 
results are not required before dosing.
Other Tests

Bone marrow or blood cytogenetic analysis for prolonged hematological toxicities 
(Section 6.6.1.2). This should include an aspirate for cellular morphology, cytogenetic 
analysis and flow cytometry, and a core biopsy for bone marrow cellularity.

CA 15-3, CEA, CA 27.29 according to the tumor scan schedule
Abbreviations:  aPTT = activated partial thromboplastin time; CA = cancer antigen; CEA = carcino-embryonic antigen; 
HIV = human immunodeficiency virus; INR = international normalized ratio; MCH = mean corpuscular hemoglobin; 
MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; 
WBC = white blood cell
NOTES:
1.
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
2.
BUN is preferred; if not available, urea may be tested. 
3.
Performed only if considered the local standard of care. 
4.
GFR (measured or calculated) or creatinine clearance can be used in place of creatinine.
5.
Free T3 is acceptable where T3 cannot be determined. There may be instances when sites are unable to obtain the
thyroid function testing results prior to scheduled dosing. After Cycle 1, review of thyroid function test results after 
dosing is acceptable.
The Investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
The following laboratory results will be performed by the central laboratory:
•
TNBC tumor markers (estrogen receptor [ER] and progesterone receptor [PGR] and 
human epidermal growth factor receptor-2 [HER2])
The following blinded laboratory results will be performed by the central laboratory:
•
Breast cancer gene (BRCA)
•
Programmed cell death-ligand 1 (PD-L1)
The BRCA status and PD-L1 results will be blinded to the investigator, participants, study 
site staff, and the Sponsor. These results will not be unblinded until the study is unblinded.
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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 non-therapeutic 
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, 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 a reportable event. Refer to Section 8.4.6 for additional details.
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.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
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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 judgement 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.
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
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(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.
-
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 activities of daily living (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)?
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-
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?
◦
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.
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
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:
◦
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.
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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.
-
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).
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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
Female Participants
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

Intrauterine hormone-releasing system (IUS)c,d

Intrauterine device (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 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 Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive implants are limited to those which inhibit ovulation.
c Male condoms must be used in addition to the hormonal contraception.
d IUS is a progestin releasing IUD.
Note: 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 should not be used together (due to risk of failure with friction).
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Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 5.1:

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.
o
The following are not acceptable methods of contraception:

Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and 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.
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. This test should be repeated a maximum of 
24 hours before the first dose.
Following initiation of treatment, additional pregnancy testing will be performed at monthly
intervals during the treatment period in WOCBP, at treatment discontinuation, at the 30-day 
safety follow-up, and as required locally.
Pregnancy testing (urine or serum as required by local regulations) should continue to be 
conducted for the time required to eliminate systemic exposure after the last dose of each 
study intervention(s) as noted in Section 5.1. The length of time required to continue 
pregnancy testing for each study intervention is as follows:
◦
Olaparib: 180 days
◦
Pembrolizumab: 120 days
◦
Chemotherapy: 180 days
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
Refer to Appendix 7 for country-specific requirements.
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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 8.8 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 principal 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
5.1 Inclusion Criteria
Inclusion Criterion No. 9: Male participants are required to continue using contraception for 
4 months after chemotherapy discontinuation.
Inclusion Criterion No. 10: WOCBP are required to continue using contraception for 
7 months after chemotherapy discontinuation.
1.3.3 End-of-Treatment and Follow-up After Treatment Discontinuation; 
10.5.3 Pregnancy Testing
The length of time to require to continue pregnancy testing for each study intervention is 
180 days following the last dose of olaparib, 120 days following the last dose of 
pembrolizumab, and 210 days following the last dose of chemotherapy.
10.7.2
Germany
Sections 1.3 Schedule of Activities and 10.5 Appendix 5 Contraceptive Guidelines 
Pregnancy testing: Monthly urine pregnancy testing is required during study treatment as 
well as at the end of treatment/discontinuation visit.
Sections 1.1, 4.4, 5.1, 7.1, 7.2, 8.1.1, 8.1.1.1, 8.1.1.2, and 8.4
Legally Acceptable Representative: Persons of legal age, who are incapable of 
comprehending the nature, significance and implications of the clinical trial and of 
determining their will, are excluded from the trial at German sites; therefore, all references to 
a participant’s “legally acceptable representative” in the protocol are not applicable for 
participants in Germany.
Section 5.2 Exclusion Criteria
Exclusion Criterion 10: HIV testing is required at screening for participants.
Exclusion Criterion 11: hepatitis B and C testing is required at screening for participants.
Section 6.5.2 Prohibited Concomitant Medications
Live vaccines must not be administered for 90 days after the last dose of study intervention.
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10.7.3
Japan
Section 6.1 Study Intervention(s) Administered
Table 2 Study Interventions 
Carboplatin and Gemcitabine used in this study are categorized as “product(s) used in the
clinical trial other than test product(s)” in Japan local regulation.
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10.8
Appendix 8: Eastern Cooperative Oncology Group Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature; eg, light house work, office 
work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% 
of waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed 
or chair
5
Dead
Source: Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
http://ecog-acrin.org/resources/ecog-performance-status 
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10.9
Appendix 9: Description of the iRECIST Process for Assessment of Disease 
Progression During Post-induction
As of Amendment 03: iRECIST assessment of disease is no longer applicable for 
participants who have an initial PD evaluated by RECIST 1:1. Participants who are 
currently being assessed by iRECIST may continue to be assessed per iRECIST until iCPD is 
determined by the investigator/site/local radiology review. The appendix below is retained 
for reference.
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression during post-induction, and to guide decisions about changes in 
management.
Assessment During Post-induction Prior to RECIST 1.1 Progression
Until radiographic disease progression during post-induction based on RECIST 1.1 is 
verified by BICR in clinically stable participants, there is no distinct iRECIST assessment
(see Figure 2).
Assessment and Decision During Post-induction at RECIST 1.1 Progression
For participants who show radiological PD during post-induction, based on RECIST 1.1 as 
verified by BICR, the investigator will decide whether to use iRECIST for participant 
management (see Figure 3). If the investigator elects to use iRECIST, the clinically stable 
participant may continue study treatment until repeat scan is obtained 4 to 8 weeks later. 
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at
BICR-determined first radiologic evidence of PD and is not required to have repeat tumor 
scans for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Scans should continue to be sent into the 
imaging contract research organization (iCRO) for potential retrospective BICR.
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Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed PD) and iCPD 
(confirmed PD). For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of 
which factors caused the progression.
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculate and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Scan
On the confirmatory scan, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
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o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional scans for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
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Management Following the Confirmatory Scan
If repeat scans do not confirm disease progression, and the participant continues to be 
clinically stable, study treatment is to continue. The regular scan schedule is to be followed. 
If disease progression is confirmed, participants may be discontinued from study treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) and clinically 
meaningful benefit, study treatment may be continued following communication with the 
Sponsor, with documented SCF. If study treatment is continued, tumor scans are to be 
performed following the intervals as outlined in Section 1.3 and submitted to the iCRO for 
potential retrospective review.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Scan above) is repeated. Progression 
must be confirmed before iCPD can occur.
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The decision process on the subsequent iUPD is identical to the iUPD confirmation process 
for the initial disease progression, with one exception, which can occur if new lesions had 
occurred at a prior instance of iUPD, had not resolved, then worsened (increase in size or 
number) leading to the second iUPD. If new lesion worsening has not resolved at the 
confirmatory scan, then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a 
decrease in the new lesion burden allows resolution to iSD or iPR, or until new or worsening 
cause of progression indicates iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
1L
first-line
ADL
activities of daily living
AE
adverse event 
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
APaT
all participants as treated
aPTT
activated partial thromboplastin time
AR
androgen receptor
ASCO
American Society of Clinical Oncologists
AST
aspartate aminotransferase
ATM
ataxia-telangiectasia mutated
AUC
area under the concentration-time curve
AxMP
auxiliary medicinal product
BCG
bacillus Calmette–Guérin
BER
base excision repair
β-hCG
β-human chorionic gonadotropin
BICR
blinded independent central review
BID
twice daily
BRCA1
breast cancer susceptibility gene 1
BRCA1/2
breast cancer susceptibility gene 1/2
BRCAm
breast cancer susceptibility gene mutation
BRCAwt
breast cancer susceptibility gene wildtype
BUN
blood urea nitrogen
CA 15-3
cancer antigen 15-3
CA 27.29
cancer antigen 27.29
CAP
College of American Pathologists
CBC
complete blood count
CD3 
cluster of differentiation 3
CD8
cluster of differentiation 8
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CEA
carcinoembryonic antigen
cfDNA
cell-free deoxyribonucleic acid
cfRNA
cell-free ribonucleic acid
CFR
Code of Federal Regulations
CI
confidence interval
cLDA
constrained longitudinal data analysis
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease caused by severe acute respiratory syndrome coronavirus 2
CPS
combined positive score
CR
complete response
CrCl
creatinine clearance
CRF
case report form 
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group
08BLRN

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Abbreviation
Expanded Term
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTR
Clinical Trials Regulation
CYP3A4
cytochrome P450 (3A4) 
DCR
disease control rate
DILI
drug-induced liver injury
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
DRFS
distant recurrence-free survival
DSB
double strand breaks
dUCBT
double umbilical cord transplantation
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
EEA
European Economic Area
EMA
European Medicines Agency
ELISA
enzyme-linked immunoassay
EORTC QLQ
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire
EORTC QLQ-BR23
European Organisation for Research and Treatment of Cancer Breast Cancer–
Specific Quality of Life Questionnaire
EORTC QLQ-C30
European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30
ePRO
electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life 5-dimension, 5-level Questionnaire
ER
estrogen receptor
ESMO
European Society for Medical Oncology
EU
European Union
EU CTR
European Union Clinical Trials Regulation
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FA
final analysis
FAS
full analysis set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed paraffin-embedded
FPR
first participant randomized
FSH
follicle stimulating hormone 
FSR
First site ready
gBRCAm
germline breast cancer gene mutation
gBRCAwt
germline breast cancer gene wildtype
GCP
Good Clinical Practice 
G-CSF
granulocyte colony stimulating factor
GFR
glomerular filtration rate
GI
gastrointestinal
GM-CSF
granulocyte macrophage colony stimulating factor
GMP
Good Manufacturing Practice
GSK3
glycogen synthase kinase-3 beta
H1, 2, 3
hypothesis 1, 2, 3
Hb
hemoglobin
08BLRN

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Abbreviation
Expanded Term
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDPE
high-density polyethylene
HER2
human epidermal growth factor receptor-2
HIV
human immunodeficiency virus
HR
homologous recombination or hazard ratio
HR+
hormone receptor-positive
HRD
homologous recombination repair deficiency
HRQoL
health-related quality-of-life
HRR
homologous recombination repair
HRT
hormone replacement therapy
IA1, 2, 3, 4
interim analysis 1, 2, 3, 4
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCPD
iRECIST confirmed progressive disease 
iCR
iRECIST confirmed complete response
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
IFN
interferon-gamma
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV-type
Ig-variable–type
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
iPR
iRECIST partial response
irAE/s
immune-related adverse event/s
IRB
Institutional Review Board 
iRECIST
Modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
iSD
iRECIST confirmed stable disease
ITT
intention-to-treat
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous/ly
IVD
in vitro diagnostic
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
LOH
loss of heterozygosity
mAb
monoclonal antibody
MATE
multidrug and toxic compound extrusion
MCH
mean corpuscular hemoglobin
mCRPC
metastatic castration-resistant prostate cancer
MCV
mean corpuscular volume
MDS
myelodysplastic syndrome
MHC
major histocompatibility complex
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22-MAY-2023
Abbreviation
Expanded Term
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSI
microsatellite instability
mTNBC
metastatic triple negative breast cancer
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NHEJ
non-homologous end-joining
NI
non-inferiority
NIMP
non-investigational medicinal product
NSAE
nonserious adverse event
NSAID/s
nonsteroidal anti-inflammatory drug/s
NSCLC
non-small cell lung cancer
OATP
organic-anion-transporting polypeptide
OCT
organic cation transporter
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PARP
polyadenosine 5diphosphoribose (polyADP ribose) polymerization
PARPi
polyadenosine 5diphosphoribose (polyADP ribose) polymerization inhibitor
PD
progressive disease
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PFS
progression-free survival
PFS2
progression-free survival after next-line treatment
PGR
progesterone receptor
PK
pharmacokinetic(s)
PKCθ
protein kinase C-theta
PO
by mouth
PR
partial response
pRBC
packed red blood cell
PRO
patient-reported outcomes
PSA
prostate-specific antigen
PT
prothrombin time
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once daily
QoL
quality of life
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SCF
Sponsor Consultation Form
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
SoA
schedule of activities
SOC
standard of care
sSAP
supplemental statistical analysis plan
SSBs
single strand breaks
SUSAR
suspected unexpected serious adverse reaction
08BLRN

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22-MAY-2023
Abbreviation
Expanded Term
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
T4
thyroxine
TCR
T-cell receptor
TDT
time until discontinuation of study treatment or death
TFST
time to first subsequent treatment
TIL
tumor-infiltrating lymphocyte
TMDD
target-mediated drug disposition
TNBC
triple negative breast cancer
TNFR
tumor necrosis factor receptor
TSH
thyroid stimulating hormone
TSST
time to second subsequent treatment
TTD
time to deterioration
ULN
upper limit of normal
US 
United States
UTI
urinary tract infection
VAS
visual analogue scale
VEGF
vascular endothelial growth factor 
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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11
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