A Phase 1, Open-Label, Multicenter Study to Assess the Safety and Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination With Pembrolizumab in Participants With KRAS Mutant Advanced or Metastatic Non-Small Cell Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma
Phase: PHASE1
Conditions: Neoplasms, Carcinoma, Non-Small-Cell Lung, Pancreatic Neoplasms, Colorectal Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 1, Open-Label, Multicenter Study to Assess 
the Safety and Tolerability of mRNA-5671/V941 as a 
Monotherapy and in Combination with Pembrolizumab 
in Participants with KRAS Mutant Advanced or 
Metastatic Non-Small Cell Lung Cancer, Colorectal 
Cancer or Pancreatic Adenocarcinoma
NCT03948763
24 March 2022

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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 CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1, Open-Label, Multicenter Study to Assess the Safety and 
Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination with 
Pembrolizumab in Participants with KRAS Mutant Advanced or Metastatic Non-Small Cell 
Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma
Protocol Number: 001-08
Compound Number: V941
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
17861
Approval Date: 24 March 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 8
24-MAR-2022
To transition ongoing study participants, who are on active treatment with 
pembrolizumab in the post-treatment follow-up phase, into a 
pembrolizumab extension study before the close out of this study.
Amendment 7
24-JUN-2021
To update the dose modification and toxicity management guidelines for 
irAEs.
Amendment 6
23-JAN-2020
Defined the KRAS and HLA testing criteria, reduced the number of PBMC 
assessments, and modified the sample size.
Amendment 5
24-JUL-2019
Added leukaphereses in Part 2; clarified KRAS testing approach, buccal 
swab sampling, tumor biopsies, and additional consent after progression.
Amendment 4
22-MAR-2019
Updated protocol for the new formulation (removed STING) and the 
corresponding dose level changes
Amendment 3
27-APR-2018
Changes to the timing of pre-screening and screening procedures and other 
administrative changes.
Amendment 2
19-MAR-2018
Generated by Merck
Amendment 1
23-JAN-2018
Generated by Moderna; addressed regulatory authority feedback.
Original Protocol
08-DEC-2017
Original protocol; Moderna.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 001-08
Overall Rationale for the Amendments:
To transition ongoing study participants, who are on active treatment with pembrolizumab in the post-treatment follow-up phase, into 
a pembrolizumab extension study before the close out of this study.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis
1.2 Schema
4.1 Overall Design
4.4 Beginning and End of Study 
Definition
6.3.1 Intervention Assignment
6.7 Intervention After the End of 
the Study
7.2 Participant Withdrawal From 
the Study
8.11.4 End of 
Treatment/Discontinuation Visit
8.11.5.3 Survival Follow-up 
Visits
Added language to give participants in the 
post-treatment phase an option to 
discontinue this study and transition into a 
pembrolizumab extension study. Provided 
details regarding randomization number 
(Section 6.3.1)
To allow for the participants to rollover into a 
pembrolizumab extension study before the close out 
of this study. Also, to clarify that participants in 
survival follow-up phase will not be rolled-over.
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA)
Clarification to period of treatment end
To identify possibility of discontinuation and 
activities associated with discontinuation.
1.1 Synopsis
6.1 Study Intervention(s) 
Administered
Updated the “Use” column in Intervention 
Groups table and Study Interventions table 
with “Test Product” or Comparator” for all 
the Arms.
Updated the “Arm Type” column in Study 
Interventions table with “Experimental” or 
“Active Comparator” for all the Arms, and 
also added a footnote pertaining to IMP 
and NIMP/AxMP.
To align with the European Union Clinical Trial 
Regulation requirements.
1.1 Synopsis
5.1 Inclusion Criteria
8.1.1 Informed Consent
8.1.1.1 General Informed 
Consent
8.4.1 Time Period and Frequency 
for Collecting AE, SAE, and 
Other Reportable Safety Event 
Information
10.1.7 Data Quality Assurance
Updated the ‘signed informed consent’ to 
‘documented informed consent’
Legal language update to address new study needs 
as a result of COVID-19.
4.2.1.6 Planned Exploratory 
Biomarker Research
Added an “or” to the text “tumor and/or
blood RNA Analyses.”
To ensure exploratory biomarker section allows 
flexibility.
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Section # and Name
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria
6.5.2 Prohibited Concomitant 
Medications
Edited to include reference to COVID-19.
Provide additional information regarding COVID-19 
and other vaccines.
8.1.9.1 Withdrawal From Future 
Biomedical Research
10.6 Appendix 6: Collection and 
Management of Specimens for 
Future Biomedical Research 
Sponsor mailbox address corrected to 
clinical.specimen.management@MSD.com
and minor updates made to the text
Correction to the Sponsor mailbox address per the 
latest company norms and text changes made for 
clarity and better readability
10.6 Appendix 6: Collection and 
Management of Specimens for 
Future Biomedical Research
Added superscripted footnotes 3 and 4 
corresponding to existing “13. References” 
at the end of the appendix.
Appendix 6 contains references (at the bottom of the 
appendix, “13. References” numbered 1-4). These 
references have corresponding footnotes in the 
text/headings.
8.3.5 Pregnancy Test
Renumbered (previously Section 8.3.4.2)
Created new section heading.
8.4.1 Time Period and Frequency 
for Collecting AE, SAE, and 
Other Reportable Safety Event 
Information
Provided an exception for positive 
pregnancy test at screening.
Clarification of reportable pregnancy.
Document History
Updated document column
To align with protocol formatting standards.
Global
Minor administrative and formatting 
changes were made.
For clarity and better readability.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 
alone) in Part 1.............................................................................................22
1.3.2
Schedule of Activities for Combination Therapy Arm B (mRNA-
5671/V941 + pembrolizumab) in Part 1 and Part 2.....................................26
1.3.3
Schedule of Activities for Crossover Participants .......................................31
2
INTRODUCTION..........................................................................................................34
2.1
Study Rationale....................................................................................................34
2.2
Background ..........................................................................................................37
2.2.1
mRNA-5671/V941 Pharmaceutical and Therapeutic Background..............37
2.2.1.1
In Vivo Pharmacology .......................................................................37
2.2.1.2
Toxicology.........................................................................................37
2.2.2
Pembrolizumab Pharmaceutical and Therapeutic Background ...................40
2.2.3
Ongoing Clinical..........................................................................................41
2.2.3.1
mRNA-5671/V941 Clinical Studies ..................................................41
2.2.3.2
Pembrolizumab (MK-3475) Clinical Studies ....................................41
2.3
Benefit/Risk Assessment......................................................................................41
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................42
4
STUDY DESIGN............................................................................................................44
4.1
Overall Design......................................................................................................44
4.2
Scientific Rationale for Study Design.................................................................47
4.2.1
Rationale for Endpoints ...............................................................................47
4.2.1.1
Efficacy Endpoints.............................................................................47
4.2.1.1.1
Response Rate Assessed by RECIST version 1.1....................47
4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics 
(iRECIST)................................................................................47
4.2.1.2
Safety Endpoints................................................................................48
4.2.1.3
Pharmacokinetic Endpoints ...............................................................48
4.2.1.4
Pharmacodynamic Endpoints.............................................................49
4.2.1.4.1
Immunogenicity .......................................................................49
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4.2.1.5
Antidrug Antibodies (ADA) ..............................................................49
4.2.1.6
Planned Exploratory Biomarker Research.........................................49
4.2.1.6.1
Planned Genetic Analysis ........................................................51
4.2.1.7
Future Biomedical Research..............................................................51
4.3
Justification for Dose...........................................................................................52
4.3.1
Rationale for Pembrolizumab Dose.............................................................52
4.3.2
Rationale for Starting and Maximum Dose of mRNA-5671/V941.............53
4.3.3
Rationale for Dose Interval and De-escalation Increments .........................54
4.3.4
Dose Finding Using a Modified Toxicity Probability Interval Design........55
4.4
Beginning and End of Study Definition .............................................................57
4.4.1
Clinical Criteria for Early Study Termination .............................................57
5
STUDY POPULATION ................................................................................................57
5.1
Inclusion Criteria.................................................................................................58
5.2
Exclusion Criteria................................................................................................61
5.3
Lifestyle Considerations......................................................................................63
5.3.1
Meals and Dietary Restrictions....................................................................63
5.3.2
Contraception...............................................................................................63
5.3.3
Pregnancy.....................................................................................................64
5.3.4
Use in Nursing Women................................................................................64
5.4
Screen Failures.....................................................................................................64
5.5
Participant Replacement Strategy......................................................................64
6
STUDY INTERVENTION............................................................................................65
6.1
Study Intervention(s) Administered...................................................................66
6.1.1
mRNA-5671/V941 Administration .............................................................67
6.1.2
Pembrolizumab Administration...................................................................67
6.2
Preparation/Handling/Storage/Accountability .................................................67
6.2.1
Dose Preparation..........................................................................................67
6.2.2
Handling, Storage, and Accountability........................................................67
6.3
Measures to Minimize Bias: Randomization and Blinding..............................68
6.3.1
Intervention Assignment..............................................................................68
6.3.2
Stratification.................................................................................................69
6.3.3
Blinding........................................................................................................69
6.4
Study Intervention Compliance..........................................................................69
6.5
Concomitant Therapy..........................................................................................69
6.5.1
Acceptable Concomitant Medications .........................................................70
6.5.2
Prohibited Concomitant Medications ..........................................................70
6.5.3
Rescue Medications and Supportive Care ...................................................71
6.5.3.1
mRNA-5671/V941 Supportive Care Guidelines ...............................71
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6.5.3.2
Pembrolizumab Supportive Care Guidelines.....................................73
6.6
Dose Modification (Escalation/Titration/Other)...............................................73
6.6.1
Dose Administration/Escalation ..................................................................73
6.6.1.1
Dose Administration (Preparation)....................................................73
6.6.2
Definition of Dose-limiting Toxicity...........................................................73
6.6.3
Dose Modification of mRNA-5671/V941 ...................................................75
6.6.4
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................75
6.7
Intervention After the End of the Study............................................................81
6.8
Clinical Supplies Disclosure................................................................................81
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................82
7.1
Discontinuation of Study Intervention...............................................................82
7.2
Participant Withdrawal From the Study...........................................................83
7.3
Lost to Follow-up .................................................................................................83
8
STUDY ASSESSMENTS AND PROCEDURES........................................................83
8.1
Administrative and General Procedures ...........................................................84
8.1.1
Informed Consent.........................................................................................84
8.1.1.1
General Informed Consent.................................................................84
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................85
8.1.2
Inclusion/Exclusion Criteria ........................................................................85
8.1.3
Participant Identification Card.....................................................................85
8.1.4
Medical History ...........................................................................................86
8.1.5
Prior and Concomitant Medications Review...............................................86
8.1.5.1
Prior Medications...............................................................................86
8.1.5.2
Concomitant Medications..................................................................86
8.1.6
Assignment of Screening Number...............................................................86
8.1.7
Assignment of Treatment/Randomization Number.....................................86
8.1.8
Study Intervention Administration ..............................................................87
8.1.8.1
Timing of Dose Administration.........................................................87
8.1.9
Discontinuation and Withdrawal .................................................................87
8.1.9.1
Withdrawal From Future Biomedical Research ................................87
8.1.10
Participant Blinding/Unblinding..................................................................88
8.1.11
Calibration of Equipment.............................................................................88
8.2
Efficacy Assessments ...........................................................................................88
8.2.1
Tumor Imaging and Assessment of Disease................................................88
8.2.1.1
Initial Tumor Imaging........................................................................88
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8.2.1.2
Tumor Imaging During the Study......................................................89
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................89
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................89
8.2.1.5
iRECIST Assessment of Disease.......................................................90
8.2.2
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........91
8.3
Safety Assessments...............................................................................................92
8.3.1
Physical Examinations.................................................................................92
8.3.1.1
Full Physical Examination.................................................................92
8.3.1.2
Directed Physical Examination..........................................................92
8.3.2
Vital Signs....................................................................................................92
8.3.3
Electrocardiograms ......................................................................................92
8.3.4
Clinical Safety Laboratory Assessments .....................................................93
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................93
8.3.5
Pregnancy Test.............................................................................................94
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................94
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................94
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......96
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...97
8.4.4
Regulatory Reporting Requirements for SAE .............................................97
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................97
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................98
8.4.7
Events of Clinical Interest (ECIs)................................................................98
8.5
Treatment of Overdose........................................................................................98
8.6
Pharmacokinetics.................................................................................................99
8.6.1
Blood Collection for PK, ADA, and Biomarkers ........................................99
8.6.1.1
Blood Collection for PK ....................................................................99
8.6.1.2
Blood Collection for Antidrug Antibodies ........................................99
8.6.1.3
Blood Collection for Biomarkers.......................................................99
8.7
Pharmacodynamics............................................................................................100
8.8
Future Biomedical Research Sample Collection.............................................100
8.9
Planned Genetic Analysis Sample Collection..................................................100
8.10
Biomarkers .........................................................................................................100
8.10.1
Pre-screening Biomarker Samples.............................................................100
8.10.1.1
Tumor KRAS Mutation Testing ......................................................100
8.10.1.2
Human Leukocyte Antigen Typing .................................................101
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8.10.2
Archival Tumor Sample.............................................................................101
8.10.3
Blood Samples ...........................................................................................101
8.10.4
Immunogenicity Assessment .....................................................................101
8.10.4.1
PBMC Collection.............................................................................101
8.10.4.2
Leukapheresis ..................................................................................101
8.10.5
Exploratory Analyses.................................................................................102
8.11
Visit Requirements.............................................................................................102
8.11.1
Pre-screening (Part 2 only) ........................................................................102
8.11.2
Screening....................................................................................................103
8.11.3
Treatment Period/Vaccination Visit ..........................................................103
8.11.4
End of Treatment/Discontinuation Visit....................................................103
8.11.5
Post-treatment Visit ...................................................................................104
8.11.5.1
Safety Follow-up Visit.....................................................................104
8.11.5.2
Imaging Follow-up Visit(s) .............................................................104
8.11.5.3
Survival Follow-up Visits................................................................104
8.11.6
Survival Status ...........................................................................................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................105
9.1
Statistical Analysis Plan Summary...................................................................105
9.2
Responsibility for Analyses/In-house Blinding ...............................................106
9.3
Hypotheses/Estimation ......................................................................................106
9.4
Analysis Endpoints.............................................................................................106
9.4.1
Efficacy/Immunogenicity Endpoints .........................................................106
9.4.2
Safety Endpoints........................................................................................107
9.5
Analysis Populations..........................................................................................107
9.5.1
Safety Analysis Populations ......................................................................107
9.5.2
Pharmacokinetic/Immunogenicity Analysis Populations ..........................107
9.5.3
Efficacy Analysis Populations...................................................................108
9.6
Statistical Methods.............................................................................................108
9.6.1
Statistical Methods for Safety Analysis.....................................................108
9.6.2
Statistical Methods for Efficacy Analysis..................................................108
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................108
9.6.3.1
Demographic and Baseline Characteristics .....................................108
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........109
9.7
Interim Analyses ................................................................................................109
9.8
Multiplicity .........................................................................................................109
9.9
Sample Size and Power Calculations ...............................................................109
9.10
Subgroup Analyses.............................................................................................109
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9.11
Compliance (Medication Adherence)...............................................................109
9.12
Extent of Exposure.............................................................................................110
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................111
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......111
10.1.1
Code of Conduct for Clinical Trials...........................................................111
10.1.2
Financial Disclosure...................................................................................113
10.1.3
Data Protection...........................................................................................113
10.1.3.1
Confidentiality of Data ....................................................................114
10.1.3.2
Confidentiality of Participant Records.............................................114
10.1.3.3
Confidentiality of IRB/IEC Information..........................................114
10.1.4
Publication Policy......................................................................................114
10.1.5
Compliance with Study Registration and Results Posting Requirements .115
10.1.6
Compliance with Law, Audit, and Debarmen ...........................................115
10.1.7
Data Quality Assurance .............................................................................116
10.1.8
Source Documents .....................................................................................116
10.1.9
Study and Site Closure...............................................................................117
10.2
Appendix 2: Clinical Laboratory Tests............................................................118
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................119
10.3.1
Definition of AE ........................................................................................119
10.3.2
Definition of SAE ......................................................................................120
10.3.3
Additional Events Reported in the Same Manner as SAE.........................121
10.3.4
Recording AE and SAE .............................................................................121
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................125
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................127
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................128
10.5.1
Definitions..................................................................................................128
10.5.2
Contraception Requirements......................................................................129
10.5.3
Pregnancy Testing......................................................................................130
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................131
10.7
Appendix 7: Country-specific Requirements..................................................136
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................137
10.9
Appendix 9: Abbreviations ...............................................................................141
11
REFERENCES.............................................................................................................145
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LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design......................................................56
Table 2
Adequate Organ Function Laboratory Values .........................................60
Table 3
Study Interventions..................................................................................66
Table 4
Cytokine Release Syndrome Treatment Guidelines ................................72
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .......................................................76
Table 6
Guidelines for Pembrolizumab Infusion Reaction Dose Modification 
and Treatment ..........................................................................................80
Table 7
Imaging and Treatment Requirements After First Radiologic Evidence 
of Progressive Disease.............................................................................91
Table 8
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................96
Table 9
Protocol-required Safety Laboratory Assessments..................................118
Table 10
Highly Effective Contraception Methods................................................130
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LIST OF FIGURES
Figure 1
Study Design (Dose De-escalation and Expansion) ................................20
Figure 2
Study Design (Treatment Course) ...........................................................21
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1, Open-Label, Multicenter Study to Assess the Safety and 
Tolerability of mRNA-5671/V941 as a Monotherapy and in Combination with 
Pembrolizumab in Participants with KRAS Mutant Advanced or Metastatic Non-Small Cell 
Lung Cancer, Colorectal Cancer or Pancreatic Adenocarcinoma
Short Title: A Phase 1 Study of mRNA-5671/V941 as Monotherapy and in Combination 
with Pembrolizumab
Hypotheses, Objectives, and Endpoints:
There will be no hypothesis testing in this study.
The objectives and endpoints apply to the study population of male and female participants at 
least 18 years of age with advanced/metastatic solid tumors who have received, or been 
intolerant to, or been ineligible for, all treatments known to confer clinical benefit.
Primary Objectives
Primary Endpoints
- To determine the safety and tolerability of 
mRNA-5671/V941 as monotherapy and in 
combination with pembrolizumab infusion 
and to establish a preliminary recommended 
Phase 2 dose of mRNA-5671/V941 in 
combination with pembrolizumab infusion
- Dose-limiting toxicity (DLT)
- Adverse event (AE) 
- Discontinuing study treatment due to an AE
Secondary Objectives
Secondary Endpoints
- To evaluate objective response rate (ORR) 
as assessed by the investigator based on 
RECIST 1.1 and iRECIST following 
administration of mRNA-5671/V941 as a 
monotherapy and in combination with 
pembrolizumab
- Objective response is a confirmed complete 
response (CR) or partial response (PR)
- To evaluate the immunogenicity of mRNA-
5671/V941 as a monotherapy and in 
combination with pembrolizumab
- Presence of and changes in the quantity of 
mutant KRAS specific T cells in the blood
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Dose Escalation: The treatment of KRAS 4MUT+ 
(G12D, G12V, G13D, or G12C) solid tumors
Cohort Expansion: The treatment of patients with HLA 
types HLA-A11:01 and/or HLA-C08:02 (and/or
potentially other additional HLA types to be specified in 
the Procedures Manual) and mutated KRAS (G12D, 
G12V, G13D or G12C) advanced or metastatic NSCLC, 
non-MSI-H CRC, or pancreatic adenocarcinoma.
Population
Participants with advanced/metastatic solid tumors.
Note: Sponsor changed the terminology referring to 
individuals who take part in clinical trials to “Participant” 
from the previously used term “Subject.” For the purpose 
of any trial-related documents using the previous 
terminology, the term “Participant” is equivalent to 
“Subject.”
Study Type
Interventional
Intervention Model
Dose Escalation
This is a multi-site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 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.
Number of Participants:
Approximately 100 participants will be allocated.
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Intervention Groups and Duration:
Intervention 
Groups 
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm A: 
mRNA-
5671/V941 
monotherapy
mRNA-
5671/V941
DL 1: 1.0 
mg
DL -1: 0.40 
mg
DL -2: 0.20 
mg
DL -3: 0.10 
mg
Q3W
IM
9 cycles
Test 
product
Arm B:
mRNA-
5671/V941 + 
pembrolizumab
mRNA-
5671/V941
DL 1: 1.0 
mg
DL -1: 0.40 
mg
DL -2: 0.20 
mg
DL -3: 0.10 
mg
Q3W
IM
9 cycles
Test 
product
Pembrolizumab
200 mg
Q3W
IV
35 cycles
Comparator
DL=dose level; DL -1=first dose reduction; DL -2=second dose reduction; DL -3=third dose 
reduction; Q3W=every 3 weeks; IM=intramuscularly; IV=intravenously.
Participants may receive up to 9 doses total of mRNA-5671/V941 in either the monotherapy or 
combination arm. Dose Levels DL -1, DL -2, and DL -3 will only be enrolled in the event that 
DLTs are observed in the starting dose (1.0 mg), per the mTPI design.
Total 
Number 
Depending on the observation of DLTs during Part A, the study will consist 
of ≤9 total intervention groups (up to 8 in Part A and 1 for Part B).
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Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form (ICF) through the final protocol-specified 
contact.
After a pre-screening phase of up to 21 days (Part 2) and a screening phase 
of up to 28 days, each participant will be assigned to receive study 
intervention until disease progression is radiographically documented and, 
when clinically appropriate, confirmed by the site per modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics 
(iRECIST), unacceptable adverse event(s) (AEs), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the participant, noncompliance with study intervention or 
procedure requirements or administrative reasons requiring cessation of 
treatment, or until the participant has received 35 administrations of 
pembrolizumab (approximately 2 years).
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4. Participants on treatment with pembrolizumab 
monotherapy in the post-treatment phase are discontinued and may be 
enrolled in to a pembrolizumab extension study.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, 
and confirmed by the site per iRECIST, initiating a non-study cancer 
treatment, withdrawing consent, or becoming lost to follow-up. All 
participants will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
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A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The dose finding and expansion study design is depicted in Figure 1.
Figure 1
Study Design (Dose De-escalation and Expansion)
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The treatment course for the study is depicted in Figure 2.
Figure 2
Study Design (Treatment Course)
Participants on active treatment with pembrolizumab monotherapy in the post-treatment phase are discontinued 
and may be enrolled in to a pembrolizumab extension study. Participants in survival follow-up phase will not be 
rolled-over.
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 alone) in Part 1
Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 alone) in Part 1
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of 
Cycle:
1
2
1
1
8
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window 
(Days):
-28 to -1
+3
±3
±3
<14
+14
±7
±7
Administrative Procedures 
Informed Consent 
X
Informed Consent for 
Future Biomedical 
Research
X
Optional
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographic and 
Medical History 
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X*
X
X
*only applicable if participant has a required 
visit for collection of 
Pharmacokinetics/Pharmacodynamics/
Biomarkers sample(s)
Treatment Allocation  
X
Anti-cancer therapy 
information 
collection
X
X
X
Study Medication Administration
mRNA-5671/V941 
IM Administration
X
X
X
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Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 alone) in Part 1
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of 
Cycle:
1
2
1
1
8
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window 
(Days):
-28 to -1
+3
±3
±3
<14
+14
±7
±7
Efficacy Procedures
Tumor Imaging and 
Response Assessment
X
X
X
X
Imaging will be obtained via CT, PET/CT, or 
MRI. Medical Photography for cutaneous 
lesions (if applicable) should be obtained on 
the same schedule as imaging. On study 
imaging should be performed every 9 weeks 
(± 7 days) and EOT imaging should be 
performed at time of treatment discontinuation 
(± 4 weeks).
Survival Status
X
After investigator determined PD or start of 
new anticancer treatment. In addition, upon 
Sponsor request, participants may be contacted 
for survival status at any time during the 
course of the study.
Safety Procedures
Full Physical 
Examination
X
X
X
It is not necessary to repeat C1D1 testing if the 
Screening testing was performed within 3 days 
prior to C1D1. 
Height
X
Weight
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X*
X
*only applicable if participant has a required 
visit for collection of Pharmacokinetics/
Pharmacodynamics/Biomarkers sample(s)
Vital Signs 
X
X
X
X
X
X*
X
X
VS: heart rate, respiratory rate, blood pressure, 
temperature
*only applicable if participant has a required 
visit for collection of Pharmacokinetics/
Pharmacodynamics/ Biomarkers sample(s)
12-lead 
Electrocardiograph 
(ECG)
X
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Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 alone) in Part 1
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of 
Cycle:
1
2
1
1
8
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window 
(Days):
-28 to -1
+3
±3
±3
<14
+14
±7
±7
Eastern Cooperative 
Oncology Group 
(ECOG) Performance 
Status
X
X
X
X
X
X
It is not necessary to repeat C1D1 testing if the 
Screening testing was performed within 3 days 
prior to C1D1.
Adverse Events 
Reporting
X
X
X
X
X
X*
X
AEs will be followed until the 30-day follow 
up visit and SAEs will be followed for 120 
days after last dose of study medication. 
*only applicable if participant has a required 
visit for collection of Pharmacokinetics/
Pharmacodynamics/ Biomarkers sample(s)
Clinical Laboratory Assessments
Serum
(hCG; women of 
child-bearing 
potential [WOCBP] 
only) or Urine 
Pregnancy Test 
(WOCBP only)
X
X
Screening and within 72 hours prior to the first 
dose of study treatment. Additional 
urine/serum pregnancy tests may be performed 
if clinically warranted, or as defined by local 
regulations. If a urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test 
is required and should be negative.  
Human 
immunodeficiency 
virus (HIV), hepatitis 
B and C screen (per 
site SOP)
X
Assessment should be based on history unless 
testing is required by local regulation.
Urinalysis
X
X
Hematology
X
X
X
X
X
X
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
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Schedule of Activities for Monotherapy Arm A (mRNA-5671/V941 alone) in Part 1
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of 
Cycle:
1
2
1
1
8
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window 
(Days):
-28 to -1
+3
±3
±3
<14
+14
±7
±7
Prothrombin 
(PT)/International 
Normalized Ratio 
(INR) and Activated 
Partial 
Thromboplastin Time 
(aPTT)
X
X
X
X
Additional testing may be performed for 
participants who are on warfarin-based 
anticoagulants at the discretion of the 
Investigator.
Pharmacokinetics/Pharmacodynamics/Biomarkers (Please refer to Procedures Manual)
Blood for Genetic 
Analyses
X
Collect predose C1D1
Blood for RNA 
Analyses
X
X
Collect predose on C1D1 and predose on 
C2D1.
Peripheral Blood 
Mononuclear Cells 
(PBMC) for 
Immunogenicity
Assessment
X
X
X
Collect predose on Day 1 of C1, and on both 
Day 8 of C4 and on Day 1 of C6.
Plasma for ctDNA
X
X
X
Collect plasma samples predose on Day 1 of 
C1, C4, and C9, and at EOT. 
Blood for T-Cell 
receptor (TCR) 
repertoire (DNA)
X
X
Collect predose on Day 1 of C1 predose on 
Day 8 of C4.
Tumor Tissue Collection 
Archival Tumor 
Sample 
X
Please refer to Procedures Manual.
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1.3.2
Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Trial Period:
Screening Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Pre-
screening*
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-
up
Survival 
Follow-up
* Pre-screening is only applicable 
for Part 2 and does not apply to Part 
1
Treatment Day of 
Cycle:
1
2
1
1
8
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-49 to -28
-28 to -1
+3
±3
±3
± 3
<14
+14
±7
±7
Administrative Procedures
Informed Consent 
X*
X
*Must be obtained before any HLA 
or other testing in Pre-screening is 
performed (Part 2) 
Informed Consent for 
Future Biomedical 
Research
X
Optional
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographic and 
Medical History 
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X*
X
X
X
*only applicable if participant has a 
required visit for collection of 
Pharmacokinetics/
Pharmacodynamics/ Biomarkers 
sample(s)
Treatment Allocation  
X
Anti-cancer therapy 
Information collection
X
X
X
Study Medication Administration
mRNA-5671/V941 IM 
Administration
X
X
X
Pembrolizumab 
infusion (IV) 
X
X
X
X
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Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Trial Period:
Screening Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Pre-
screening*
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-
up
Survival 
Follow-up
* Pre-screening is only applicable 
for Part 2 and does not apply to Part 
1
Treatment Day of 
Cycle:
1
2
1
1
8
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-49 to -28
-28 to -1
+3
±3
±3
± 3
<14
+14
±7
±7
Efficacy Procedures
Tumor Imaging and 
Response Assessment
X
X
X
X
X
Imaging will be obtained via CT, 
PET/CT, or MRI. Medical 
Photography for cutaneous lesions 
(if applicable) should be obtained on 
the same schedule as imaging. On 
study imaging should be performed 
every 9 weeks (± 7 days) and EOT 
imaging should be performed at 
time of treatment discontinuation (± 
4 weeks).
Survival Status
X
After investigator determined PD or 
start of new anticancer treatment. In 
addition, upon Sponsor request, 
participants may be contacted for 
survival status at any time during 
the course of the study.
Safety Procedures
Full Physical 
Examination
X
X
X
It is not necessary to repeat C1D1 
testing if the Screening testing was 
performed within 3 days prior to 
C1D1. 
Height
X
Weight
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X*
X
X
*only applicable if participant has a 
required visit for collection of 
Pharmacokinetics/
Pharmacodynamics/
Biomarkers sample(s)
Vital Signs 
X
X
X
X
X
X*
X
X
X
VS: heart rate, respiratory rate, 
blood pressure, temperature
*only applicable if participant has a 
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Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Trial Period:
Screening Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Pre-
screening*
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-
up
Survival 
Follow-up
* Pre-screening is only applicable 
for Part 2 and does not apply to Part 
1
Treatment Day of 
Cycle:
1
2
1
1
8
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-49 to -28
-28 to -1
+3
±3
±3
± 3
<14
+14
±7
±7
required visit for collection of 
Pharmacokinetics/Pharmacodynami
cs/Biomarkers sample(s)
12-lead ECG
X
ECOG Performance 
Status
X
X
X
X
X
X
X
It is not necessary to repeat C1D1 
testing if the Screening testing was 
performed within 3 days prior to 
C1D1.
Adverse Events 
Reporting
X
X
X
X
X
X*
X
X
X
AEs will be followed until the 30-
day follow up visit and SAEs will be 
followed for 120 days after last dose 
of study medication. 
*only applicable if participant has a 
required visit for collection of 
PK/Pharmacodynamics/Biomarkers 
sample(s)
Clinical Laboratory Assessments 
Review of prior local 
tumor KRAS
mutational testing 
results
X
If not already tested as per routine 
standard of care, tumor KRAS
mutational testing may be 
performed, but only with Sponsor 
approval. Please refer to Procedures 
Manual.
HLA testing
(Part 2 only)
X
In Part 1, no sample is collected.  In 
Part 2, the required HLA type must 
be confirmed in Pre-screening. If 
routine standard of care KRAS
testing has not been performed prior 
to Pre-screening, Sponsor approval 
is needed for HLA testing and 
KRAS mutation testing in Pre-
screening.  Please refer to 
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Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Trial Period:
Screening Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Pre-
screening*
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-
up
Survival 
Follow-up
* Pre-screening is only applicable 
for Part 2 and does not apply to Part 
1
Treatment Day of 
Cycle:
1
2
1
1
8
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-49 to -28
-28 to -1
+3
±3
±3
± 3
<14
+14
±7
±7
Procedures Manual.
Serum
(hCG; WOCBP only) 
or Urine Pregnancy 
Test (WOCBP only)
X
X
Screening and within 72 hours prior 
to the first dose of study treatment. 
Additional urine/serum pregnancy 
tests may be performed if clinically 
warranted, or as defined by local 
regulations. If a urine pregnancy test 
cannot be confirmed as negative, a 
serum pregnancy test is required and 
should be negative.  
HIV, hepatitis B and C 
screen (per site SOP)
X
Assessment should be based on 
history unless testing is required by 
local regulation.
Urinalysis
X
X
Hematology
X
X
X
X
X
X
X
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
Additional testing may be 
performed for participants who are 
on warfarin-based anticoagulants at 
the discretion of the Investigators.
Thyroid Function (T3, 
or FT3, FT4, and TSH)
X
X
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 
7, etc.), 
Pharmacokinetics/Pharmacodynamics/Biomarkers (Please refer to Procedures Manual)
Blood for Genetic 
Analyses
X
Collect predose on C1D1
Blood for RNA 
Analysis
X
X
Collect predose on C1D1
and predose on C2D1.  
Serum for 
Pembrolizumab
Pharmacokinetics
X
X
X
X
X
Collect predose at Cycles 1, 2, 4, 8 
and every 4 cycles thereafter. May 
be collected ≤24 hours prior to 
dosing. 
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Schedule of Activities for Combination Therapy Arm B (mRNA-5671/V941 + pembrolizumab) in Part 1 and Part 2
Trial Period:
Screening Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment Cycle/Title:
Pre-
screening*
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-
up
Survival 
Follow-up
* Pre-screening is only applicable 
for Part 2 and does not apply to Part 
1
Treatment Day of 
Cycle:
1
2
1
1
8
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-49 to -28
-28 to -1
+3
±3
±3
± 3
<14
+14
±7
±7
Collect postdose at Cycles 1 & 2: 
Sample drawn within 30 minutes 
after end of pembrolizumab 
infusion.
Serum for Anti-
pembrolizumab 
Antibodies 
X
X
X
X
X
Collect predose at cycles 1, 2, 4, 8 
and every 4 cycles thereafter. May 
be collected ≤24 hours prior to 
dosing. 
PBMC for 
Immunogenicity
Assessment
X
X
X
Collect predose on Day 1 of C1
(unless a screening leukapheresis is
collected); and on both Day 8 of C4
and on Day 1 of C6 (unless a 
leukapheresis is collected on Day 8 
of C4).
Leukapheresis
X
X
Leukaphereses during Screening and 
on Day 8 of C4 are optional and 
may only be performed if the 
leukapheresis pack can be processed 
appropriately. Refer to Procedures 
Manual for collection instructions.
Plasma for ctDNA
X
X
X
X
Collect plasma samples predose on 
Day 1 of C1, C4, C9, and C12, and 
at EOT. 
Blood for T-Cell 
receptor (TCR) 
repertoire (DNA)
X
X
Collect predose on Day 1 of C1 and 
predose on Day 8 of C4.
Tumor Tissue Collection
Archival Tumor 
Sample 
X
Please refer to Procedures Manual.
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1.3.3
Schedule of Activities for Crossover Participants
Schedule of Activities for Crossover Participants
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of
Cycle:
1
1
1
8
1
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
<14
+14
±7
±7
Administrative Procedures
Informed Consent 
X
Review ICFs at crossover Screening visit.
Informed Consent 
for Future 
Biomedical 
Research
X
Optional
Inclusion/Exclusion 
Criteria
X
Prior/Concomitant 
Medication Review
X
X
X
X
X*
X
X
X
*only applicable if participant has a required visit for 
collection of 
Pharmacokinetics/Pharmacodynamics/Biomarkers 
sample(s)
Anti-cancer therapy 
Information 
collection
X
X
X
Study Medication Administration
mRNA-5671/V941 
IM Administration
X
X
X
Participants who had PD prior to completion of 9 doses 
of mRNA-5671/V941 in Arm A will receive their 
remaining doses of mRNA-5671/V941 in crossover 
(total of 9 doses).
Pembrolizumab 
infusion (IV) 
X
X
X
X
Participants who completed 9 doses of mRNA-
5671/V941 will receive pembrolizumab monotherapy 
up to total 35 cycles. 
Efficacy Procedures
Tumor Imaging and 
Response 
Assessment
X
X
X
X
X
Imaging will be obtained via CT, PET/CT, or MRI. 
Medical Photography for cutaneous lesions (if 
applicable) should be obtained on the same schedule as 
imaging. On study imaging should be performed every 
9 weeks (±7 days) and EOT imaging should be 
performed at time of treatment discontinuation (±4 
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Schedule of Activities for Crossover Participants
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of
Cycle:
1
1
1
8
1
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
<14
+14
±7
±7
weeks). Screening imaging will not need to be 
performed if previous imaging was performed within 4 
weeks. 
Survival Status
X
After investigator determined PD or start of new 
anticancer treatment. In addition, upon Sponsor 
request, participants may be contacted for survival 
status at any time during the course of the study.
Safety Procedures
Full Physical 
Examination
X
X
X
It is not necessary to repeat C1D1 testing if the
Screening testing was performed within 3 days prior to 
C1D1. 
Weight
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X*
X
X
*only applicable if participant has a required visit for 
collection of Pharmacokinetics/Pharmacodynamics/
Biomarkers sample(s)
Vital Signs 
X
X
X
X
X*
X
X
X
VS: heart rate, respiratory rate, blood pressure, 
temperature
*only applicable if participant has a required visit for 
collection of Pharmacokinetics/Pharmacodynamics/
Biomarkers sample(s)
12-lead ECG
X
ECOG Performance 
Status
X
X
X
X
X
X
X
Adverse Events 
Reporting
X
X
X
X
X*
X
X
X
AEs will be followed until the 30-day follow up visit 
and SAEs will be followed for both 30 day and 120 
days after last dose of study medication.
*only applicable if participant has a required visit for 
collection of Pharmacokinetics/Pharmacodynamics/
Biomarkers sample(s)
Clinical Laboratory Assessments
Serum
(hCG; WOCBP 
only) or Urine 
X
X
Screening and within 72 hours prior to the first dose of 
study treatment.  Additional urine/serum pregnancy 
tests may be performed if clinically warranted, or as 
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Schedule of Activities for Crossover Participants
Trial Period:
Screening 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
1
2
3-9
10 to 35
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day of
Cycle:
1
1
1
8
1
At time of 
treatment 
discontinuation
30 days post 
last dose of 
study 
treatment
Every 9 
weeks
Every 12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
<14
+14
±7
±7
Pregnancy Test 
(WOCBP only)
defined by local regulations. If a urine pregnancy test 
cannot be confirmed as negative, a serum pregnancy 
test is required and should be negative.  
Urinalysis
X
X
Hematology
X
X
X
X
X
X
X
PT/INR and aPTT
X
X
X
X
Additional testing may be done to participants who are 
on warfarin-based anticoagulants at the discretion of 
the Investigators.
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
X
Thyroid Function 
(T3, or FT3, FT4, 
and TSH)
X
X
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, etc.)
Pharmacokinetics/Pharmacodynamics/Biomarkers (Please refer to Procedures Manual)
Serum for 
Pembrolizumab
Pharmacokinetics
X
X
X
X
X
Collect predose at Cycles 1, 2, 4, 8 and every 4 cycles 
thereafter. May be collected ≤24 hours prior to dosing. 
Collect postdose at Cycles 1 & 2: Sample drawn within 
30 min. after end of pembrolizumab infusion.
Serum for Anti-
pembrolizumab
Antibodies 
X
X
X
X
X
Collect predose at Cycles 1, 2, 4, 8 and every 4 cycles 
thereafter. May be collected ≤24 hours prior to dosing.
PBMC for 
Immunogenicity
Assessment
X
X
X
Collect predose on Day 1 of C1 and on both Day 8 of 
C4 and on Day 1 of C6.
Plasma for ctDNA
X
X
X
X
Collect predose on Day 1 for C1, C4, C9, and C12, and 
at EOT.
Blood for T-Cell 
receptor (TCR) 
repertoire (DNA)
X
X
Collect predose on Day 1 of C1 and per-dose on Day 8 
of C4.
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2
INTRODUCTION
mRNA-5671/V941 contains an mRNA Drug Substance that encodes 4 antigens containing 
KRAS mutations (G12D, G12V, G13D, G12C). mRNA-5671/V941 is under study for the 
treatment of solid tumors as monotherapy and as combination therapy with pembrolizumab. 
This is a first-in-human, dose-escalation, and dose-finding study to assess the safety and 
tolerability of mRNA-5671/V941, both as monotherapy and as combination therapy with 
pembrolizumab. Refer to the mRNA-5671/V941 IB for further information.
2.1
Study Rationale
Recent breakthroughs in cancer immunotherapy (eg, checkpoint inhibitors and chimeric 
antigen receptor T-cell therapies) have demonstrated that long-lasting, curative-intent 
antitumor activity can be achieved in patients with metastatic epithelial cancers by activating 
specific antitumor T cells. The steps required for proliferation, migration, and activation of 
T cells in a successful antitumor response have been described as the “Cancer Immunity 
Cycle” [Chen, D. S. 2013]. Furthermore, it has become apparent that when an effective T-
cell response occurs, the antitumor T cells recognize peptide fragments presented by major 
histocompatibility complex (MHC) that harbor cancer-specific somatic mutations. In the vast 
majority of cases, these mutations appear to be randomly occurring passenger mutations that 
are present only in that individual patient’s cancer, as opposed to oncogenic driver mutations. 
However, finding oncogenic driver mutations that encode targetable T-cell epitopes has 
considerable therapeutic implications: (a) driver mutations are subject to positive selection, 
as they confer survival advantages for the tumor, and (b) such epitopes would be shared 
between patients, enabling a more straightforward approach to developing therapeutic 
interventions. 
The most frequently mutated oncogene in cancer is KRAS, which is mutated in 
approximately 30% of epithelial cancers, primarily lung cancers, colorectal cancers (CRC) 
and pancreatic cancers [Pylayeva-Gupta, Y., et al 2011]. The 4 most prevalent KRAS mutant 
antigens in these 3 malignancies are G12D, G12V, G13D, and G12C, which constitute 80% 
to 90% of the KRAS mutations [Prior, I. A., et al 2012] [Cox, A. D., et al 2014]. KRAS has 
multiple downstream signaling pathways, and although drugs have been developed to target 
individual pathway components, direct inhibition of KRAS could be more efficacious. 
Unfortunately, direct inhibition of KRAS has proven clinically challenging; despite 
significant efforts, no successful KRAS targeted cancer therapy has been developed yet
[Kempf, E., et al 2016]. 
KRAS mutations occur in approximately 40% of CRCs. The presence of a KRAS mutation 
in CRC confers a worse prognosis for patients [Lee, D. W., et al 2015]. KRAS mutations also 
mediate primary resistance to anti-epidermal growth factor receptor (EGFR) monoclonal 
antibodies, such that treatment with these monoclonal antibodies is not indicated in this 
population. Chemotherapy remains the first line of treatment for metastatic CRC patients. 
Various oxaliplatin and irinotecan-based regimens have been shown to prolong survival, but 
none are administered with curative intent. Anti–programmed cell death protein 1 (PD-1) 
therapies alone are not effective in metastatic CRC except in rare cases of mismatch repair 
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deficient/microsatellite instability-high (MSI-H) tumors [Boland, C. R. 2010] [Le, D. T., et al 
2015] [Lee, D. W., et al 2015], [Ashktorab, H., et al 2016]. Many single agent and 
combination trials with various immunotherapy agents are being investigated to overcome 
these limitations.
Pancreatic adenocarcinoma is one of the deadliest cancers, with 5-year overall survival of 
less than 5%. While some improvements have been made in both the adjuvant and neo-
adjuvant setting over the past 10 years, success has been measured only in months. The only 
curative option remains surgery; however, less than 20% of patients are eligible to undergo 
surgery at the time of diagnosis, and the rate of relapse is high in those that have undergone 
surgical resection [Zeitouni, D., et al 2016]. In approximately 98% of cases of pancreatic 
adenocarcinomas, mutated KRAS is one of the oncogenic drivers; approximately 90% of 
those KRAS mutations involve 1 of 4 target alleles: G12C, G12V, G12D, and G13D [Prior, I. 
A., et al 2012] [Cox, A. D., et al 2014]. Many attempts have been made to target KRAS and 
the RAS-MEK-ERK pathway in pancreatic cancer, but there has not been much success 
[Jamieson, D., et al 2016] [Ning, C., et al 2017]. Advances in immunotherapy for pancreatic 
cancer have also been impeded by challenges that include the dense stromal nature of the 
tissue, the inability of effector cells to penetrate the tumor microenvironment, and substantial 
local immune suppression.
While previous efforts have been made to generate a therapeutic cancer vaccine that targets
mutant KRAS, based on observations that mutated KRAS peptides can be recognized in the 
context of HLA-A2 (the most prevalent MHC class I molecules in Caucasians), these have 
not been effective to date. Our interest in generating a therapeutic vaccine to target mutant 
KRAS resulted from a recent manuscript that describes KRAS-mutant specific T cells 
mediating significant antitumor efficacy [Tran, E., et al 2016] in the context of HLA-C08:02 
and preclinical data that demonstrated that HLA-A11:01 can present KRAS G12D peptides 
[Wang, Q. J., et al 2016].
The Sponsor is developing a new mRNA-based therapeutic vaccine technology that allows 
for induced production of a broad array of secreted, membrane-bound, and intracellular 
proteins both in cell culture and in many animal models and humans. Vaccination with 
antigen-encoding mRNA is an attractive technology platform for the delivery of mutant 
KRAS antigens because the therapeutic vaccine can deliver multiple mutations in a single 
vaccination. These mutations are endogenously translated and enter into the natural cellular 
antigen processing and presentation pathway. Moreover, this mRNA-based therapeutic 
vaccine technology, which is delivered IM, overcomes the challenges commonly associated 
with DNA-based therapeutic vaccines, such as risk of genome integration or the high doses 
and devices needed for administration (eg, electroporation). mRNA-5671/V941 is a 
therapeutic KRAS vaccine developed to elicit an antitumor T-cell response in patients’
KRAS mutated cancers, in particular non-small cell lung cancer (NSCLC), non-MSI-H CRC 
and pancreatic cancer. This therapeutic vaccine is a concatemer that consists of the 4 most 
prevalent KRAS mutant antigens (G12D, G12V, G13D, and G12C) in these cancers; these 4 
point mutations address 80% to 90% of the KRAS mutations present in these 3 malignancies 
[Prior, I. A., et al 2012] [Cox, A. D., et al 2014]. 
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Recent breakthroughs in cancer immunotherapy (eg, checkpoint inhibitors and chimeric 
antigen receptor-T-cell therapies) have demonstrated that powerful antitumor responses can 
be achieved by activating large numbers of T cells in a variety of cancer settings. In 
particular, immune checkpoint blockade is a broadly applicable therapeutic approach, and 
treatment with agents targeting this mechanism has led to remarkable clinical benefit for 
patients with metastatic melanoma, NSCLC, bladder cancer, renal cancer, and head and neck 
squamous cell carcinoma (HNSCC). Multiple checkpoint inhibitor biologic agents (eg, 
pembrolizumab) are currently approved for human use in these cancer types, including 
agents that target cytotoxic T lymphocyte–associated antigen 4 (CTLA-4); PD-1; and its 
ligand, programmed death ligand 1 (PD-L1). Pembrolizumab (Keytruda™) is a potent 
humanized immunoglobulin G4 monoclonal antibody 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 a high affinity and potent 
receptor blocking activity for PD-1. Inhibitory receptors and their ligands play 
complementary roles in down-regulating adaptive immunity; pembrolizumab overcomes 
T-cell exhaustion in peripheral tissues [Sharma, P. 2015]. Although it is clear that single 
agent checkpoint inhibitor therapy can provide significant benefit for certain patients, many 
patients have incomplete or no response to this therapy. Thus, an unmet need remains for 
new treatment options, especially ones that can be used in combination with first generation 
breakthrough immunotherapies. 
mRNA-5671/V941 is a novel therapeutic vaccine that is hypothesized to enhance the 
antitumor immune activity of the PD-1-blocking antibody pembrolizumab. Therefore, 
mRNA-5671/V941 may have the potential to provide benefit in terms of increased efficacy 
in patients with a variety of advanced solid malignancies with unmet need. 
While emerging data support the use of PD-1 inhibitors such as pembrolizumab in tumors in 
which PD-L1 expression can be demonstrated, there remains a strong rationale for the 
potential utility of combinations that include PD-1 inhibitors, even in putatively PD-L1 
“negative” tumors [Topalian, S. L., et al 2016]. Mechanistically, there is an adaptive 
component to PD-L1 expression by tumors, ie, tumors may initially appear PD-L1 negative 
but upregulate PD-L1 expression in response to IFNγ secretion by infiltrating tumor 
lymphocytes [Taube, J. M., et al 2012]. Finally, recent preclinical data explicitly demonstrate 
the ability of a therapeutic cancer vaccine to induce PD-L1 expression in PD-L1–low tumors, 
leading to intratumor infiltration of CD8+ T cells when given in combination with a PD-1 
inhibitor [Soares, K. C., et al 2015]. Thus, there is a scientific rationale for the combination 
of a therapeutic vaccine with pembrolizumab in patients whose tumors do not express 
PD-L1.
For patients with advanced disease and no available standard therapies, treatment with 
mRNA-5671/V941 and pembrolizumab is considered acceptable, as mRNA-5671/V941 may 
enhance the pembrolizumab response beyond that seen in prior studies. Many patients in the 
refractory setting currently receive investigational immunotherapy targeting the PD-1/PD-L1 
axis, such as pembrolizumab, regardless of PD-L1 status.
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2.2
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on mRNA-
5671/V941, and the IB/approved labeling for detailed background information on 
pembrolizumab. This is a first-in-human (FIH) study.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (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 intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications. For more details on specific indications refer to the 
pembrolizumab Investigator’s Brochure.
2.2.1
mRNA-5671/V941 Pharmaceutical and Therapeutic Background
2.2.1.1
In Vivo Pharmacology
mRNA-5671/V941 contains an mRNA Drug Substance that encodes 4 antigens containing 
KRAS mutations (G12D, G12V, G13D, G12C), formulated in an SM-102 lipid nanoparticle
(LNP).
Recent data from the Yang laboratory at the National Cancer Institute demonstrated that 
coimmunization with 10–amino acid peptides spanning the G12D and G12V mutations of 
KRAS and a class II helper peptide derived from hepatitis B virus core 128–140 could 
invoke T-cell responses specific for the respective mutations in mice transgenic for the 
human HLA-A11:01 class I allele [Wang, Q. J., et al 2016]. Data that showed the superior 
immunogenicity of KRAS G12D using a therapeutic mRNA vaccine encoding KRAS G12D 
relative to peptide vaccination was obtained in collaboration with the Yang lab. Furthermore, 
cluster of differentiation 8 (CD8) T cells specific to KRAS G12D and G12V were detected 
when HLA-A11:01 knock-in mice were immunized with mRNA-5671/V941. 
2.2.1.2
Toxicology
To support the proposed V941-001 Phase 1 clinical study, the safety and tolerability of 
mRNA-5671/V941 was evaluated in a Good Laboratory Practices (GLP)-compliant 1-month 
toxicity study, in Sprague Dawley rats at 0.01, 0.03, and 0.10 mg per dose via intramuscular 
(IM) injection administered weekly for a total of 5-doses, followed by a 2-week treatment-
free period. The mRNA was formulated in a LNP consisting of 4 lipids (SM-102, PEG2000-
DMG, DSPC, and cholesterol). Doses of 0.01, 0.03 and 0.10 mg per dose tested in the rat 
toxicology study approximate to human equivalent doses (HED) of 0.34, 1.03 and 3.40 mg, 
respectively (based on group mean body weight of 0.328 kg in rats, and using an average 
human body weight of 70 kg), and thus approximate to margins of 0.34-, 1.03-, and 3.40-fold 
over the human starting dose of 1.0 mg. The Sponsor has determined the no-observed 
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adverse effect level (NOAEL) to be 0.03 mg/week based on low severity and incidence of the 
clinical and microscopic findings at this dose in rats, as summarized below. The related 
mRNA-4157/V940 therapeutic vaccine, a personalized therapeutic cancer vaccine developed 
using the same mRNA technology platform, has also been evaluated in Phase 1 clinical trials 
and is formulated in a LNP consisting of the same 4 lipids (SM-102, PEG2000-DMG, DSPC 
and cholesterol) and has been well-tolerated in patients up to 1 mg intramuscularly (Section
4.3.2). Therefore, the proposed starting dose for the V941-001 clinical study of 1.0 mg is 
expected to be similarly tolerated as mRNA-4157/V940. The Sponsor intends the clinical 
starting dose to achieve some level of pharmacological activity; therefore, the use of a 
NOAEL from the GLP rat toxicity study allows interpretation of the anticipated risk of 
toxicity from the mRNA and lipid formulation at this dose. The NOAEL of 0.03 mg achieved 
in rat GLP study converted to an HED represents a 1.03-fold safety margin compared to the 
proposed starting dose of 1.0 mg. The findings in the rat GLP study are further summarized 
below.
The results of this GLP-compliant, repeat-dose toxicity study of mRNA-5671/V941 in rats 
indicated that mRNA-5671/V941 administered weekly by IM injection at 0.01, 0.03, and 
0.10 mg per dose for a total of 5 doses was well tolerated at all dose levels (no mRNA-
5671/V941 related mortality observed). Weekly administration of mRNA-5671/V941 to 
Sprague Dawley rats (both male and female) was associated with a dose-dependent slight to 
mild decreases in body weight gain which correlated with slightly reduced food 
consumption. Dose-dependent changes consistent with an inflammatory response were noted 
in clinical observations at the injection site (described as injection site being swollen and firm 
to touch with associated erythema), clinical pathology parameters (eg, increased white blood 
cells (WBC) parameters driven predominantly by neutrophils as well as mild increases in 
fibrinogen, globulin). Additional findings suggestive of inflammation at the high-dose (0.10 
mg/dose) consisted of minimal to mild increases in body temperature and serum cytokines 
(eg, MCP-1, interferon γ-induced protein 10, IL-6, and macrophage inflammatory protein 
1α). Dose-related target organ effects were also generally consistent with local and systemic 
inflammation and occurred at the injection site, bone marrow, the inguinal and/or popliteal 
lymph nodes, the connective tissue surrounding the sciatic nerve, the spleen, and the liver of 
rats. At the end of a 2-week treatment-free period, all findings were fully recovered with the 
exception of findings associated with local and systemic inflammation at the injection site, 
popliteal/inguinal lymph node, the connective tissue surrounding the sciatic nerve, bone 
marrow and the liver which were considered to be partially recovered and were 
characteristically minimal to mild in severity and showed evidence of continued resolution. 
This rat GLP study involved a more dose-dense regimen (weekly) compared to the proposed 
human dosing frequency of every 3 weeks which is intended to align with the 
pembrolizumab dosing schedule; importantly, a more aggressive regimen than the intended 
clinical dosing frequency was selected for the toxicology studies to thoroughly characterize 
drug product toxicity. The mRNA-5671/V941 therapeutic vaccine to be administered in the 
Phase 1 study consists of only an mRNA-encoding KRAS antigen formulated in a LNP. The 
LNP formulation constituents utilized in the GLP rat study were generally similar to the 
composition of the LNP formulation intended for use in the Phase 1 study. KRAS is a 
mutated human epitope highly dependent on human HLA in order to elicit a specific immune 
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response; therefore, the sequence tested in the rat GLP toxicology study represented a 
human-based sequence of mRNA-encoding KRAS that will be used in the clinical study, and 
was manufactured in a similar manner to how mRNA-5671/V941 will be manufactured in 
this clinical study. Of note, the version of mRNA-5671/V941evaluated in the rat GLP study 
included an mRNA-encoding KRAS antigen as well as an mRNA component encoding a 
constitutively active STING since the Sponsor initially intended to evaluate the immunogenic 
potential of both these components together. However, the present Phase 1 clinical study will 
only evaluate the immunogenic potential of mRNA-encoding KRAS (without an 
mRNA-encoding STING). 
The Sponsor also characterized toxicology endpoints in a nonterminal exploratory monkey 
study by administering an mRNA-encoding model antigen expected to be immunogenic to 
monkeys (HPV16 E6/E7 mRNA) by IM injection on Day 1 and 15 at 100 µg/dose. Further, 
since the Sponsor previously intended to evaluate a drug product with mRNA-encoding 
constitutively active STING antigen, the monkey study assessed potential for any differential 
effects attributed to an mRNA-encoding constitutively active STING antigen individually or 
combined with HPV16 E6/E7 mRNA. Reversibility of findings was assessed during a 2-
week treatment-free period. The results indicated that a mRNA-based therapeutic vaccine
containing STING mRNA alone or in combination with an mRNA-encoding antigen (HPV16 
E6/E7) was well tolerated at 100 µg/dose and there were no test article-related mortalities, 
clinical observations, no local reactions at the site of administration or changes in body 
weight or food consumption during the study or changes in serum chemistry. Changes in 
hematology, coagulation, d-dimer, c-reactive protein, complement and cytokine were 
consistent with an inflammatory response. These changes were generally absent after a 2-
week treatment-free period, suggesting a reversibility of the effect. Hematology, coagulation, 
d-dimer, c-reactive protein, Bb fragment, C3a and C5B9, cytokine data sets indicate no 
significant differences between an mRNA therapeutic vaccine with or without STING 
mRNA. Based on available nonclinical data, removal of STING mRNA from the drug 
product is likely to be subtractive and result in an equivalent or decreased toxicology profile 
for an mRNA-encoding KRAS only therapeutic vaccine compared to an mRNA-encoding 
KRAS and STING.
The novel lipid component of the LNP formulation, SM-102 was not genotoxic when tested 
in a bacterial reverse mutation (Ames) test or an in vitro micronucleus test. Results of an in 
vivo micronucleus study performed in the Sprague Dawley rat completed with a similar 
mRNA-based vaccine (mRNA-1706 encoding the Zika virus prME polypeptide), that was 
formulated with the same LNPs as mRNA-5671/V941 are considered weakly positive at 
doses in excess of 2 mg/kg via the intravenous (IV) route of administration. These 
observations are unlikely to indicate a risk to humans after IM administration due to minimal 
systemic exposure. 
Overall, the nonclinical toxicity of mRNA-5671/V941 formulated in a LNP consisting of 4
lipids (SM-102, PEG2000-DMG, DSPC, and cholesterol) was considered adequately 
assessed in a GLP-compliant, repeat-dose toxicity study with weekly administration by IM 
injection at 0.01, 0.03, and 0.10 mg per dose for a total of 5 doses followed by a 2-week 
treatment-free period. The nonclinical toxicity of the lipid nanoparticle (LNP), the mRNA 
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chemistry and any differential effects with or without STING mRNA were assessed in 
nonclinical models. Any immunological effects of KRAS antigen expression are likely to be 
participant-specific and are more adequately assessed clinically. Based on available 
nonclinical data, removal of STING mRNA from the drug product is likely to be subtractive 
and result in an equivalent or decreased toxicology profile for an mRNA-encoding KRAS 
therapeutic vaccine only compared to an mRNA-encoding KRAS and STING. Therefore, the 
NOAEL of 0.03 mg achieved in rat GLP study converted to an HED represents a 1.03-fold 
safety margin compared to the proposed starting dose of 1.0 mg.
2.2.2
Pembrolizumab Pharmaceutical and Therapeutic Background
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 CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T cells (Tregs) 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 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 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 advanced solid tumors.
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2.2.3
Ongoing Clinical
2.2.3.1
mRNA-5671/V941 Clinical Studies
This is the first clinical trial with mRNA-5671/V941.
2.2.3.2
Pembrolizumab (MK-3475) Clinical Studies
Ongoing clinical studies with pembrolizumab are being conducted in multiple solid tumors. 
In addition, multiple combinations with pembrolizumab are also being investigated. Refer to 
pembrolizumab IB for study details.
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.
mRNA-5671/V941 is a novel therapeutic vaccine that is hypothesized to enhance the 
antitumor immune activity of the PD-1-blocking antibody pembrolizumab. Therefore, 
mRNA-5671/V941 may potentially provide benefits in terms of increased efficacy in 
participants with a variety of advanced KRAS mutant solid malignancies with unmet need.
mRNA-5671/V941 encodes for the 4 KRAS mutations (G12D/G12V/G13D/G12C), which 
are not seen in normal healthy human cells. This approach allows the T cells to be trained 
and then target the mutated cancer cells, which enables cell killing. The fact that these 
mutations are not found in normal cells potentially reduces the risk of an autoimmune 
reaction against healthy tissue.
Risk to participants who receive mRNA-5671/V941 is expected to be low and to primarily 
involve mild to moderate ISRs (eg, swelling and erythema), which have been observed in 
animal studies and are generally observed and expected for other IM administered 
therapeutic vaccines. These local reactions may consist of transient and dose-dependent pain, 
swelling, and erythema. Possible mild to moderate systemic reactions, which are also 
transient, may include fever, fatigue, chills, headache, myalgia, and arthralgia. In addition, 
other adverse events (AEs) that have been generally associated with approved IM 
administered therapeutic vaccines have included mild hematological and clinical chemistry 
abnormalities that are usually reversible. 
Participants who receive mRNA-5671/V941 could experience signs and symptoms consistent 
with a complement activation-related pseudoallergy (CARPA) response, which has been 
observed with the administration of approved liposomal products, contrast agents, pegylated 
proteins, and antibodies [Szebeni, J. 2014], as well as small interfering RNA products 
formulated in LNPs [Coelho, T., et al 2013] [Fitzgerald, K. 2014]. The signs and symptoms 
of CARPA resemble those of an acute hypersensitivity reaction. However, complement 
activation is far less likely to be associated with clinical signs for LNP products such as 
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mRNA-5671/V941, which are administered IM at a much lower dose, on a mg/kg basis, than 
other clinical entities that cause CARPA in humans and nonclinical species. 
Pembrolizumab is approved for use in multiple cancer types, and is under investigation in 
several phases of clinical development for many more. Despite much progress in the field of 
immune-oncology therapeutics, an unmet medical need exists, as not all participants respond 
to pembrolizumab monotherapy, most responses are not complete, and it is only approved for 
use in limited tumor types. Combining pembrolizumab with mRNA-5671/V941 may allow 
more participants to derive greater clinical benefit than with pembrolizumab monotherapy. 
This study intends to assess the safety, tolerability, and immunogenicity of mRNA-
5671/V941 as a monotherapy and in combination with pembrolizumab in participants with 
advanced or metastatic KRAS+ solid tumors, and to determine the recommended phase 2 
dose (RP2D) of mRNA-5671/V941 to be used in combination with pembrolizumab. 
The anticipated toxicities of mRNA-5671/V941 (primarily ISRs) are not expected to overlap 
or synergize with the known and well-characterized safety profile of pembrolizumab. 
However, all safety findings will be closely monitored and reviewed by the Sponsor.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
There will be no hypothesis testing in this study.
The objectives and endpoints apply to the study population of male and female participants at 
least 18 years of age with advanced/metastatic solid tumors who have received, or been 
intolerant to, or been ineligible for, all treatments known to confer clinical benefit.
Objectives
Endpoints
Primary
•
To determine the safety and tolerability 
of mRNA-5671/V941 as monotherapy 
and in combination with pembrolizumab 
infusion and to establish a preliminary 
recommended Phase 2 dose of mRNA-
5671/V941 in combination with 
pembrolizumab infusion
•
Dose-limiting toxicity (DLT)
•
Adverse event (AE)
•
Discontinuing study treatment due to an 
AE
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Objectives
Endpoints
Secondary
•
To evaluate objective response rate 
(ORR) as assessed by the investigator 
based on RECIST 1.1 and iRECIST 
following administration of mRNA-
5671/V941 as a monotherapy and in 
combination with pembrolizumab
•
Objective response is a confirmed 
complete response (CR) or partial 
response (PR)
•
To evaluate the immunogenicity of 
mRNA-5671/V941 as a monotherapy 
and in combination with pembrolizumab
•
Presence of and changes in the quantity 
of mutant KRAS specific T cells in the 
blood
Tertiary/Exploratory
•
To evaluate progression-free survival 
(PFS) as assessed by investigator based 
on RECIST 1.1 and iRECIST and 
overall survival (OS) following 
administration of mRNA-5671/V941 as 
a monotherapy and in combination with 
pembrolizumab
•
PFS is time from the first dose of study 
medication to the first documented 
disease progression or death due to any 
cause, whichever occurs first
•
OS is the time from the first dose of 
study medication to death due to any 
cause
•
To evaluate changes in relevant 
immunogenic and pharmacodynamic 
biomarkers
•
Expression of immune markers
•
T-cell receptor (TCR) clonality and 
diversity in blood
•
To characterize changes in circulating 
levels of tumor cell DNA (ctDNA) in 
plasma
•
ctDNA plasma levels
•
To evaluate the PK of pembrolizumab
•
PK parameters including area under the 
curve (AUC), maximum concentration 
(Cmax), and minimum concentration 
(Cmin)
•
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 mRNA-
5671/V941
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor 
and blood RNA variation, proteomics 
and IHC, and other biomarkers
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4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, worldwide, open label, nonrandomized, Phase 1 study of 
mRNA-5671/V941, as monotherapy and in combination with pembrolizumab in participants 
with KRAS 4MUT+ (G12D, G12V, G13D or G12C) solid tumors in the dose finding and 
confirmation phase, and in combination with pembrolizumab in participants with HLA types 
HLA-A11:01 and/or HLA-C08:02 (and/or potentially other additional HLA types to be 
specified in the Procedures Manual) with advanced or metastatic KRAS 4MUT+ (G12D, 
G12V, G13D or G12C) NSCLC, non-MSI-H CRC, or pancreatic adenocarcinoma in the 
cohort expansion phase.
This study will evaluate the safety, tolerability, and preliminary efficacy of 
mRNA-5671/V941 as monotherapy (Arm A), and in combination with pembrolizumab (Arm 
B). There are 2 parts in this study, dose finding and confirmation (Part 1) and tumor cohort 
expansion (Part 2), which will include 3 cohorts.
In Pre-screening (Part 1 and Part 2), local tumor testing results will be reviewed to identify 
potential participants with any of the required 4 tumor KRAS mutations (G12D, G12V, 
G13D or G12C). For Part 2 only, potential participants will also be tested for the required 
HLA types HLA-A11:01 and/or HLA-C08:02 (and/or potentially other additional HLA types 
as specified in the Procedures Manual).
The selected participant population for Part 1 will then be screened and allocated to receive 
mRNA-5671/V941 as monotherapy (Arm A) or mRNA-5671/V941 in combination with 
pembrolizumab (Arm B) using an interactive voice response system/integrated web response 
system (IVRS/IWRS). mRNA-5671/V941 will be administered intramuscularly (IM) every 3 
weeks (Q3W) on Day 1 of a 21-day cycle. In Arm B, pembrolizumab will be administered 
intravenously (IV) Q3W on Day 1 of each cycle.
In Part 1 of the study, a modified Toxicity Probability Interval (mTPI) design [Ji, Y. 2013]
will be used to identify the recommended Phase 2 dose (RP2D) of mRNA-5671/V941 in 
Arm A (mRNA-5671/V941 as a single agent), and to identify and confirm the RP2D in Arm 
B (mRNA-5671/V941 in combination with pembrolizumab). The 1.0 mg dose level (DL 1) 
of mRNA-5671/V941 will be evaluated independently in each arm. DL -1, DL -2 & DL -3 
(0.40 mg, 0.20 mg, and 0.10 mg, respectively) may be used as alternative dose levels should 
the 1.0 mg dose level prove to be intolerable. Lower and/or higher doses of mRNA-
5671/V941 may be explored depending on the combined safety, pharmacokinetic (PK), and 
pharmacodynamic data available at each dose level. The dose of pembrolizumab in
Part 1/Arm B and in Part 2 will remain constant at 200 mg every 3 weeks.
Participants will be enrolled to receive mRNA-5671/V941 monotherapy (Arm A) at the 
1.0 mg dose level. Treatment allocation will be accomplished by nonrandom assignment. 
Enrollment in Arm B (mRNA-5671/V941 in combination with pembrolizumab at the 1.0 mg 
DL 1 will begin once the DLT observation period for Arm A has been completed and the 
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1.0 mg DL 1 dose has been deemed safe. If dose reductions to DL -1, DL -2, or DL -3 in 
Arm A are required, then Arm B enrollment at the reduced dose level in combination with 
pembrolizumab will only be initiated once that mRNA-5671/V941 dose has been deemed 
safe. The final number of participants enrolled in Part 1 will depend on the empirical safety 
observations (DLT), and what dose is ultimately identified as the RP2D using the mTPI 
design.
Dose finding and confirmation in Arm B will end after 14 participants have been treated at 
any of the selected doses (which may include the optional doses). The pool adjacent-violators 
algorithm [Ji, Y. 2013] will be used to estimate the DLT rates across doses in each treatment 
arm under the assumption of monotonicity between DLT rates and dose levels. The dose with 
an estimated DLT rate closest to 30% may be treated as a preliminary RP2D. The totality of 
the data will be considered before deciding on the dose(s) to carry forward to Part 2. The 
RP2D of mRNA-5671/V941 in the combination arm (Arm B) will not exceed, but may equal, 
the RP2D in the mRNA-5671/V941 monotherapy arm (Arm A).
In Part 2, participants with advanced solid tumors who have received various prior lines of 
therapy will be enrolled into each of the following 3 expansion cohorts for the following 
tumor types: 40 participants with advanced/metastatic NSCLC, 15 participants with non-
MSI-H CRC, and 15 participants with pancreatic adenocarcinoma. Participants must have 
tumor KRAS G12D, G12V, G13D, or G12C mutations, as determined by local testing, and
must also have confirmed HLA types HLA-A11:01 and/or HLA-C08:02 (and/or potentially 
other additional HLA types to be specified in the Procedures Manual). Part 2 will further 
evaluate safety and efficacy of mRNA-5671/V941 in combination with pembrolizumab at the 
mRNA-5671/V941 RP2D defined in Part 1 Arm B. 
The final RP2D for future studies will be confirmed using all available safety information 
(including early and late toxicities from Parts 1 and 2), as well as immunogenicity and 
pharmacodynamic data, and preliminary efficacy assessments.
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension study.
Participants in survival follow-up phase will not be rolled-over.
Preliminary efficacy will be evaluated using objective response rate (ORR) assessed by the 
investigator based on the Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) as a secondary objective. Progression-free survival (PFS) based on RECIST 
1.1 as assessed by the investigator and overall survival (OS) will be evaluated as exploratory 
objectives. ORR and PFS will be also assessed by modified Response Evaluation Criteria in 
Solid Tumors 1.1 for immune-based therapeutics (iRECIST).
Participants will be monitored carefully for the development of adverse events AEs, and for 
clinical and/or radiographic evidence of disease progression according to RECIST 1.1. 
However, iRECIST may be used by the investigator for treatment decisions. In participants 
who have initial evidence of radiological progressive disease by RECIST 1.1, it will be at the 
discretion of the investigator whether to continue a participant on study treatment until repeat 
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imaging is obtained. This clinical judgment decision should be based on the participant’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory 
data. Participants may continue to receive study treatment until tumor assessment is repeated 
4 to 8 weeks later in order to confirm progressive disease by iRECIST per site assessment.
Adverse events (AEs) will be evaluated by the investigator, according to criteria outlined in 
the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of mRNA-5671/V941 when administered 
as monotherapy or in combination with pembrolizumab as per the primary objective of this 
study.
There will be no intraparticipant dose escalation for participants enrolled in this study. The 
definition of DLTs and criteria for dose modification of mRNA-5671/V941 and 
pembrolizumab are outlined in Sections 6.6.1 to 6.6.4. Pembrolizumab will be administered 
at a fixed dose of 200 mg every 3 weeks.
Participants may receive study treatment with mRNA-5671/V941 (Arm A and Arm B) for up 
to 9 cycles and with pembrolizumab (Arm B) for up to 35 cycles (24 months). Participants 
will be treated until progressive disease, unacceptable toxicity, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw treatment, 
participant withdrawal of consent, pregnancy of the participant, noncompliance with trial 
treatment or procedure requirements, participant completes treatment, or administrative 
reasons requiring cessation of treatment, at which point they will be discontinued from the 
study.
Participants in Part 1 Arm A who develop progressive disease during therapeutic vaccination 
monotherapy or within 6 months after completing therapeutic vaccination monotherapy may 
be eligible to crossover and receive pembrolizumab, at the investigator’s discretion and after 
consultation with and approval by the Sponsor.
1. Participants who have not completed 9 doses of mRNA-5671/V941 as monotherapy 
at the time of progressive disease may be eligible to crossover and complete the 
remaining therapeutic vaccine doses as part of combination therapy with 
pembrolizumab. The first dose of combination treatment will not occur until after the 
21-day Cycle 1 of mRNA-5671/V941 monotherapy treatment is completed.
2. Participants who have completed 9 doses of mRNA-5671/V941 as monotherapy may 
be eligible to crossover and receive pembrolizumab as monotherapy if:
a.
They have radiologic evidence of progressive disease within 6 months after 
completing mRNA-5671/V941 monotherapy, AND
b. Have not started subsequent anti-neoplastic therapy.
Participants may continue receiving crossover treatment until disease progression, 
unacceptable toxicity, intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw treatment, participant withdrawal of consent, pregnancy 
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of the participant, noncompliance with trial treatment or procedure requirements, 
administrative reasons requiring cessation of treatment, or the completion of 35 cycles of 
pembrolizumab treatment. These participants’ safety and efficacy data will be analyzed 
separately than that of the participants enrolled in Arm B.
All participants will be followed for at least 30 days after their last dose of mRNA-
5671/V941 or pembrolizumab therapy for AE monitoring. Serious adverse events (SAE) will 
be collected for120 days after discontinuation of study treatment, 30 days if the participant 
initiates new anticancer therapy less than 30 days after study treatment discontinuation, or the 
day new anticancer therapy is initiated if between 30 days and 120 days after study treatment 
discontinuation. Participants with an ongoing AE of Grade >1 at the time of treatment 
discontinuation will be followed until resolution of the AE to Grade 0-1, until considered 
stable by the treating physician, or until beginning a new anticancer therapy, whichever 
occurs first.
Participants who discontinue treatment for reasons other than confirmed progressive disease 
will have post treatment follow-up for disease status (including imaging) until progressive
disease, initiating a new anticancer therapy, withdrawing consent for study participation, or 
becoming lost to follow up.
After confirmed progressive disease each participant will be contacted by telephone every 12 
weeks (84±7 days) for survival until withdrawal of consent to participate in the study, 
becoming lost to follow up, death, or end of the study, whichever occurs first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
4.2.1.1.1
Response Rate Assessed by RECIST version 1.1
RECIST 1.1 will be used to determine the objective response. Although traditional RECIST 
1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation Criteria in 
Solid Tumors 1.1 for immune-based therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab Section 8.2.1.5. Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
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immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions  as well as for exploratory efficacy 
analyses when specified.
4.2.1.2
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of mRNA-
5671/V941 as monotherapy and as combination therapy with pembrolizumab in participants 
with advanced/metastatic solid tumors. The primary safety analysis will be based on 
participants who experience toxicities as defined by CTCAE Version 4.0 criteria and DLTs 
further defined in Section 6.6.2. Safety will be assessed by quantifying the toxicities and 
grades of toxicities experienced by participants who have received mRNA-5671/V941 as 
monotherapy and in combination with pembrolizumab.
For adverse events, attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded. AEs that will be analyzed 
include, but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
4.2.1.3
Pharmacokinetic Endpoints
An exploratory objective of this study is to characterize the pharmacokinetic (PK) profile of 
pembrolizumab following administration as combination therapy with mRNA-5671/V941. 
The serum concentrations of pembrolizumab will serve as the primary readout for the PK, 
and these data will be used to derive PK parameters of pembrolizumab when administered in 
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combination. Furthermore, the results of these analyses will be used in conjunction with the 
pharmacodynamics, and safety and exploratory endpoint data to help assess future dosing 
strategies.
4.2.1.4
Pharmacodynamic Endpoints
4.2.1.4.1
Immunogenicity
A secondary objective of this study is to evaluate the immunogenicity of mRNA-5671/V941
when administered alone and in combination with pembrolizumab. This will be assessed by 
quantifying the presence of and changes in KRAS-specific T cells in peripheral blood. 
Exploratory immunogenicity endpoints may also include changes in immune markers as 
assessed by gene expression analyses and the clonality and diversity of TCRs in the blood.
4.2.1.5
Antidrug Antibodies (ADA)
Formation of antidrug antibodies (ADA) can potentially confound drug exposures at 
therapeutic doses and prime for subsequent infusion-related toxicity. Antidrug 
(pembrolizumab) antibody response at the beginning of each cycle will be determined to 
understand drug metabolism, exposure, and safety. The incidence of ADA and neutralizing 
ADA will be evaluated and summarized over time by dose. Correlations between the 
presence/absence of positivity for antidrug antibodies and PK and pharmacodynamic 
markers, activity, and safety of mRNA-5671/V941 and/or pembrolizumab will be explored.
4.2.1.6
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations 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.  Finally, microsatellite 
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instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
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 immuno-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 blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in tumor tissue 
and/or in blood may be performed to define gene signatures that correlate to clinical response 
to treatment with pembrolizumab or other immunotherapies. Pembrolizumab induces a 
response in tumors that likely reflects an inflamed/immune phenotype. 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 and 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 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 pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
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(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy 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.
4.2.1.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, severity, 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a sample will be collected for DNA analysis 
from consenting participants.
DNA samples will be used for research related to the study intervention(s), the disease under 
study, and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases, and study intervention(s). 
Genetic research may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data.
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
4.2.1.7
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
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4.3
Justification for Dose
4.3.1
Rationale for Pembrolizumab Dose
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically-
based PK [PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort 
B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied. Subsequently, flat dose-exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 200 mg Q3W 
as the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
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Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.2
Rationale for Starting and Maximum Dose of mRNA-5671/V941
The planned clinical starting dose for mRNA-5671/V941 is 1.0 mg. The selection of this 
starting dose is based on support by the safety and tolerability of the 1.0 mg dose of the 
similarly formulated mRNA-4157/V940 personalized therapeutic cancer vaccine that has 
been evaluated in clinical trials. Overall, based on HED, the NOAEL of 0.03 mg achieved in 
the rat GLP study converted to a human equivalent dose represents an approximate 1.03-fold 
safety margin compared to the proposed human starting dose of 1.0 mg. Therefore, the 1.0 
mg starting dose is supported by the nonclinical safety and tolerability demonstrated in the 
mRNA-5671/V941 GLP-compliant 1-month toxicity study as well as based on the clinical 
experience from the related mRNA-4157/V940 therapeutic vaccine developed using the same 
mRNA technology platform. mRNA-4157/V940 has been evaluated in Phase 1 clinical trials 
and is formulated in a LNP consisting of the same 4 lipids (SM-102, PEG2000-DMG, DSPC 
and cholesterol). It has been well-tolerated in patients up to 1.0 mg intramuscularly.
mRNA-4157/V940 is currently in Phase 1 development, both as monotherapy and in 
combination with pembrolizumab. Each patient’s mRNA-4157/V940 therapeutic vaccine
consists of a single mRNA that encodes up to 34 neoantigens designed specifically to each 
individual patient’s tumor mutanome and HLA type. The Phase 1 first in human study of 
mRNA-4157-P101 (NCT03313778) is currently ongoing. This study is an open-label, Phase 
1, multicenter dose-escalation, First-In-Human study of mRNA-4157/V940 monotherapy in 
participants with resected solid tumors (Part A) who are in the adjuvant setting (ie, status 
post-resection); mRNA-4157/V940 in combination with pembrolizumab in participants with 
unresectable (locally advanced or metastatic) solid tumors (Part B, C); and mRNA-
4157/V940 in combination with pembrolizumab in melanoma participants who are in the 
adjuvant setting (Part D).
As of 31-DEC-2019, mRNA-4157/V940 has been dosed to 75 patients in total, 15 patients as 
monotherapy and 60 patients in combination with pembrolizumab at multiple dose levels. Of 
those, 44 patients received mRNA-4157/V940 at a dose level of 1 mg in combination with 
pembrolizumab. There were no dose limiting toxicities reported at any dose levels, including 
the 1 mg dose. While the tumor antigens encoded by the mRNAs of mRNA-4157/V940
personalized therapeutic cancer vaccine do differ from those encoded by the mRNA of 
mRNA-5671/V941 (encoding mutated KRAS epitopes), mRNA-5671/V941 is expected to 
have a similar clinical tolerability profile to mRNA-4157/V940 as both therapeutic vaccines 
are intended for IM delivery to patients with advanced cancers and both consist of similar 
mRNA nucleotide chemistry formulated for delivery in a lipid nanoparticle (LNP) 
formulation with overall comparable ratios of constituents (including the cationic lipid SM-
102, PEG-DMG, etc.). Any dose limiting toxicities that might occur during the DLT 
observation period would be anticipated to be due to the LNP, independent of the identity of 
the encapsulated mRNA; as such, the available clinical experience with mRNA-4157 up to 
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1.0 mg supports the initiation of clinical dosing for evaluation of therapeutic benefit to 
advanced cancer patients with mRNA-5671/V941 at 1.0 mg. 
As described in the repeat-dose GLP toxicology studies in outbred Sprague Dawley rats, the 
no observed adverse effect level (NOAEL) is to be 0.03 mg based on low severity and 
incidence of the clinical and microscopic findings at this dose in rats. Therefore, the proposed 
human starting dose of 1.0 mg represents an approximate 1.03-fold safety margin. The 
Sponsor considers this a sufficient safety margin for the 1.0 mg starting dose in this clinical 
study, especially given that the 1.0 mg mRNA-4157/V940 dose has been well tolerated 
clinically. 
In summary, 44 patients have been dosed at the 1.0 mg dose level with mRNA-4157/V940, a 
therapeutic IM vaccine similar in formulation to mRNA-5671/V941 and expected to exhibit a 
safety profile similar to that of mRNA-5671/V941. This dose of mRNA-4157/V940 has been 
found to be safe in human cancer patients, supporting a starting dose for mRNA-5671/V941 
of 1.0 mg.
Nine cycles of mRNA-5671/V941 are planned in order to boost the intended tumor-killing 
T-cell population over an extended period of time by promoting optimal development of 
T effector memory cells [Knudsen, M. L., et al 2014]. The 21-day cycle allows for maximal 
contraction of the antigen-specific CD8+ T-cell response before boosting, which has been 
found to produce the best maintenance of CD8+ T cells with high recall capacity. From a 
safety perspective, the Sponsor assessed the toxicity of mRNA-5671/V941 in outbred 
Sprague Dawley® rats at 0.01, 0.03, and 0.10 mg per dose via IM injection administered 
weekly for a total of 5 doses, followed by a 14-day post-study recovery period. This 
preclinical weekly injection schedule is 3-fold more dose-dense over time than the clinical 
dosing schedule in this study and thus provides an additional margin to avoid potential 
cumulative toxicity. The Sponsor considers this Q3W 9 dose regimen appropriate for 
mRNA-5671/V941. 
4.3.3
Rationale for Dose Interval and De-escalation Increments
The human starting dose and dosing interval of mRNA-5671/V941 are based on an 
integration of nonclinical toxicological, pharmacological, and efficacy data, as well as on 
safety data from the similarly formulated mRNA-4157/V940 therapeutic vaccine, as 
described in Section 4.3.2. Dose de-escalation decisions will be made according to mTPI, 
based on 3 dosing outcomes, ie, underdosing, proper dosing, or overdosing. In the case of 
overdosing at 1.0 mg, mTPI will recommend de-escalating the dose level using model-based 
inference on the toxicity probability. If required, mTPI dose de-escalation will follow 
approximately half-log increments, rounded up to the next 0.10 mg (ie, 0.40 mg [DL -1], 
0.20 mg [DL -2], and 0.10 mg [DL -3] doses). The mTPI dose evaluation scheme is 
consistent with US Food and Drug Administration (FDA) guidance for early-phase clinical 
trials involving cellular and gene therapy products [U.S. Department of Health and Human 
Services 2015]. 
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In tumor cohorts of participants treated with a combination of mRNA-5671/V941 and 
pembrolizumab, the dose of mRNA-5671/V941 to be used in combination with 
pembrolizumab must have been deemed safe as monotherapy based on mTPI evaluation and 
will not exceed the maximum tolerated dose (MTD)/ maximum administered dose (MAD) 
for monotherapy. If an MTD/MAD for the monotherapy arm is established, the dose of 
mRNA-5671/V941 in combination with pembrolizumab may continue up to that dose.
4.3.4
Dose Finding Using a Modified Toxicity Probability Interval Design
Dose finding will follow the mTPI design [Ji Y, Li Y, Bekele BN 2007] with a target DLT 
rate of 30% (a different DLT rate may be considered in participants evaluable for DLT). 
Dose escalation and de-escalation decisions are based on the mTPI design and depend on the 
number of participants enrolled and number of DLTs observed at the current dose level. It is 
to be noted that participants in the dose finding phase will not be restricted by HLA type. 
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate, 3, 4, 5, or 6 participants may be enrolled within 7-14 days of the opening of a dose 
cohort. In Table 1, the columns indicate the numbers of participants treated at the current 
dose level, and the rows indicate the numbers of participants experiencing DLT. The entries 
of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, 
staying at the same dose, de-escalating the dose, and excluding the dose from the trial due to 
unacceptable toxicity, respectively. For example, if 0 out of 3 participants at a given dose 
level develop a DLT, then the dose can escalate to the next level. If 2 participants out of 3 
develop a DLT, the dose will be de-escalated to the next lower dose level. If 3 out of 3 
participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose 
should be de-escalated, and the current dose will not be explored further. If 1 out of 3 
participants at a given dose level develops a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
When adding participants to a dose level in response to a “stay” decision, the number of 
additional participants to be enrolled is capped to minimize the exposure to a dose that may 
be unacceptably toxic (denoted as DU in Table 1). Secondly, to determine how many more 
participants can be enrolled at the dose level, one can count steps in diagonal direction (down 
and to the right) from the current cell to the first cell marked DU. For example, if 1 of 3 
participants have experienced a DLT at a given dose level, no more than an additional 3 
participants should be enrolled at this dose level until additional DLT data are available. This 
is because this dose level would be considered unacceptably toxic if all 3 of the additional 
participants experience a DLT (ie, 4/6 participants with DLT in Table 1). The same 
principles will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that dose 
level.
A D or DU decision at the lowest dose level will stop the trial. An E decision at the highest 
dose level will result in staying at that level. During dose finding, it may be acceptable to 
deescalate to an intermediate dose that was not predefined and not previously-studied if 
evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new 
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participants may be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level.
After 14 participants have been enrolled at any of the tested doses (including intermediate 
doses), dose finding will stop if the mTPI table indicates “S” for staying at current dose. 
Otherwise, up to 14 new participants may be enrolled at a lower dose if “D” or “DU” is 
indicated, or at a higher dose if “E” is indicated.
The pool-adjacent-violators-algorithm [Ji, Y. 2013] will be used to estimate the DLT rates 
across doses. The dose with an estimated DLT rate closest to 30% will be treated as a 
preliminary MTD. However, the totality of the data will be considered before deciding on the 
dose(s) to carry forward to Part 2, and the escalation schedule may be adjusted based on 
pharmacodynamic, PK, and safety data emerging throughout the trial. The preliminary RP2D 
of mRNA-5671/V941 in the combination arm (Arm B) will not exceed, but may be equal to, 
the preliminary RP2D in the mRNA-5671/V941 monotherapy arm (Arm A).
Note that although 30% was the target toxicity rate used to generate the guidelines in
Table 1, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 30%.
Table 1
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of 
participants with at 
least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
D=de-escalate to the next lower dose; DU=the current dose is unacceptably toxic; E=escalate to the next higher dose; S=stay 
at the current dose.
Target toxicity rate = 30%
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [Ji Y, Li Y, Bekele BN 2007] [Ji, Y. 2013]
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension study. 
Participants in the survival follow-up phase will not be rolled-over.
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the following specified criteria:
1. Incidence or severity of adverse drug reactions in this or other studies suggest a 
potential health hazard to participants. 
2. In addition to DLT and dose de-escalation criteria defined in the dose finding phase 
of the study, if, in the expansion cohorts, toxicities observed meet the definition of a 
DLT and occur in >33% of the total number of enrolled participants, the study will 
pause, and an expedited ad hoc safety evaluation will be assessed by the Sponsor 
prior to further enrollment in the study.
3. Plans to modify or discontinue the development of the study drug.
4. Poor adherence to protocol and regulatory requirements.
5. Quality or quantity of data recording is inaccurate or incomplete.
Ample notification will be provided in the event of Sponsor decision to no longer supply 
mRNA-5671/V941 or pembrolizumab.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. All participants: Have a histologically confirmed advanced or metastatic KRAS 
4MUT+ (G12D, G12V, G13D or G12C) solid tumor identified by local laboratory 
testing, and who have received, or been intolerant to, or ineligible for all treatment known 
to confer clinical benefit.
Note: If local tumor KRAS mutation testing has not previously been performed as 
standard of care, such testing may be conducted on study in Pre-screening to 
determine eligibility, but only if discussed with and approved by the Sponsor.
Part 2 only: Have a histologically confirmed advanced or metastatic NSCLC, 
non-MSI-H CRC, or pancreatic adenocarcinoma, and confirmed HLA types 
HLA-A11:01 and/or HLA-C08:02 (and/or potentially other additional HLA types to be 
specified in the Procedures Manual).
NSCLC: Participants must have been tested for mutations affecting EGFR and/or 
anaplastic lymphoma kinase (ALK). Participants with ALK or EGFR-positive NSCLC 
must have had recurrent or progressive disease (PD) after treatment with the 
corresponding inhibitor and current standard of care, in any sequence.
Non-MSI-H CRC: Participant tumors must have been locally tested for MSI and have 
been found to be non-MSI-H.
Demographics
2. Participant is Male or Female.
3. Participant is at least 18 years of age, at the time of providing documented informed 
consent.
Male Participants
4. A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 120 days after the last dose of study
intervention and refrain from donating sperm during this period.
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Female Participants
5. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 120 days after the last dose of study intervention.
Informed Consent
6. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study without 
participating in future biomedical research. 
Additional Categories
7. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. For Part 1 only: 
Cutaneous lesions can be considered in addition to imaging, but measurable disease 
should be defined by radiologic assessment.
8. Have an evaluable archival tumor sample to submit for analysis. Formalin-fixed, paraffin 
embedded (FFPE) tissue blocks are preferred to slides.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 14 days from the date slides are cut. Details pertaining to tumor 
tissue submission can be found in the Procedures Manual.
9. Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected within 7 days prior to the start of study intervention.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; 
ULN=upper limit of normal.
1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2Creatinine clearance (CrCl) should be calculated per institutional standard.
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.
10. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
In order to be eligible to crossover from Arm A into Arm B in Part 1 of this trial, the 
participant must meet the following criteria:
11. Have radiographic disease progression as defined by RECIST v1.1 on Arm A 
mRNA-5671/V941 monotherapy and have Sponsor approval for crossover.
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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization or treatment allocation (see 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 72 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 participant to start receiving study 
medication. 
2. Has an active infection requiring therapy.
3. Has a history of interstitial lung disease.
4. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) 
except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. Use 
of nonsystemic steroids is permitted.
5. Has conditions, therapy, or laboratory abnormality that might confound the results of the 
study, interfere with the participant’s participation for the full duration of the study, make 
administration of the study drugs hazardous, or make it difficult to monitor adverse 
effects such that it is not in the best interest of the participant to participate, in the opinion 
of the treating investigator.
6. Has not fully recovered from any effects of major surgery or has evidence of detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study treatment administration. Surgery requiring regional/epidural anesthesia 
must be completed at least 72 hours before first study treatment administration and 
participants should be recovered.
Prior/Concomitant Therapy
7. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) prior to the first dose of study therapy, non-cytotoxic 
small molecule therapeutics within 5 half-lives (or 2 weeks, whichever is longer) prior to 
the first dose of study treatment, or has not recovered to CTCAE Grade 1 or better from 
any adverse events that were due to cancer therapeutics administered more than 4 weeks 
earlier (this includes participants with previous immunomodulatory therapy with residual 
immune-related adverse events). Participants receiving ongoing replacement hormone 
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therapy for endocrine immune-related adverse events will not be excluded from 
participation in this study.
8. Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. Refer to Section 6.5 for information 
on COVID-19 vaccines.
9. Has received hematopoietic colony-stimulating growth factors (eg, granulocyte-colony 
stimulating factor, erythropoietin, granulocyte-macrophage-colony stimulating factor, 
macrophage-colony stimulating factor) within 2 weeks prior to the first dose of study 
intervention.
10. Discontinued from therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (TCR; eg, 
CTLA-4, OX 40, and CD137) due to a Grade 3 or higher immune-related adverse event 
(irAE).
Prior/Concurrent Clinical Study Experience
11. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 28 days prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
12. 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.
13. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
14. 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 imaging (note 
that the repeat imaging 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 
intervention.
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15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
16. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
17. 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.
18. Has a known history of HIV.
Note: No testing for HIV is required unless mandated by local health authority.
19. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
Other Exclusions 
20. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
21. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Contraception
Pembrolizumab and/or mRNA-5671/V941 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 medication 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 medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study medication. 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.
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5.3.3
Pregnancy
If a participant inadvertently becomes pregnant while on treatment, the participant will be 
immediately discontinued from study intervention. The site will contact the participant at 
least monthly and document the participant’s status until the pregnancy has been completed 
or terminated. The outcome of the pregnancy will be reported to the Sponsor without delay 
and within 24 hours if the outcome is a serious adverse experience (eg, death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study Investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor. If 
a male participant impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy must be reported to the Sponsor and followed as 
described in Section 8.4.
5.3.4
Use in Nursing Women
It is unknown whether pembrolizumab is 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.
5.4
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.
5.5
Participant Replacement Strategy
In order to adequately evaluate the safety of the doses administered in this study, all 
participants enrolled must meet the criteria for evaluability for Cycle 1. Participants are 
considered nonevaluable and will be replaced if:
•
They are allocated but not treated.
•
They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related adverse events during Cycle 1 in the dose finding
phase of the study (Part 1).
•
They receive less than 100% of the total mRNA-5671/V941 or less than 90% of the 
total pembrolizumab infusion in Cycle 1 (eg, if the infusion had to be discontinued 
due to an infusion reaction) and did not experience a DLT.
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Participants who are not evaluable will be replaced unless accrual to the cohort has stopped.  
Nonevaluable participants will not be counted toward the total number of participants in the 
cohort for DLT evaluation.
If a participant experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the Sponsor and investigator. However, if the participant is deriving 
clinical benefit from the trial treatment, the participant may be allowed to continue after 
discussion between the Sponsor and the investigator.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
Table 3
Study Interventions
Arm Name
Arm Type
Intervention Name
Type
Dose 
Formulati
on
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm A –
mRNA-5671/
V941 mono-
therapy
Experimental
mRNA-5671/V941
Biological/V
accine
Ampule
1.0 mg/mL
DL 1: 1.00 mg 
DL -1: 0.40 mg
DL -2: 0.20 mg
DL -3: 0.10 mg
IM
Q3W for up to 9 
cycles
Test 
Product
IMP
Provided centrally by 
the Sponsor
Arm B and 
Cross-over 
mRNA-5671/
V941 + 
pembrolizumab
Experimental
mRNA-5671/V941
Biological/V
accine
Ampule
1.0 mg/mL
DL 1: 1.00 mg
DL -1: 0.40 mg
DL -2: 0.20 mg
DL -3: 0.10 mg
IM
Q3W for up to 9 
cycles
Test 
Product
IMP
Provided centrally by 
the Sponsor
Arm B and 
Cross-over 
mRNA-5671/
V941 + 
pembrolizumab
Active 
Comparator
Pembrolizumab
Biological/V
accine
Ampule
25 mg/mL
200 mg
IV Infusion
Q3W for up to 35 
cycles
Compar
ator
IMP
Provided centrally by 
the Sponsor
AxMP=auxiliary medicinal product; DL=dose level; IMP=investigational medicinal product; NIMP=non-investigational medicinal product; Q3W=every 3 weeks.
Participants may receive up to 9 total doses of mRNA-5671/V941 in either the monotherapy or combination arm. 
Dose Levels DL -1, DL -2, and DL -3 will only be enrolled in the event that DLTs are observed in the starting dose (1.0 mg), per the mTPI design.
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 European Economic Area (EEA). 
Country differences with respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
mRNA-5671/V941 Administration
For all participants, mRNA-5671/V941 will be administered by IM injection into the deltoid
or thigh muscle (deltoid preferred). The Pharmacy Manual contains specific instructions for 
the preparation and administration of mRNA-5671/V941.
6.1.2
Pembrolizumab Administration
For participants receiving mRNA-5671/V941 in combination with pembrolizumab, 
pembrolizumab will be administered at the study site as a 30-minute IV infusion of a 200 mg 
fixed dose on Day 1 of each 3-week (21-day) cycle 30 to 60 minutes following the 
administration of mRNA-5671/V941. Sites should make every effort to keep infusion 
duration as close to 30 minutes as possible. However, given the variability of infusion pumps 
from site to site, a window of 25 to 40 minutes is permitted for infusion duration. The 
Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion and administration of the infusion solution.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of mRNA-5671/V941 and pembrolizumab are 
provided in the Pharmacy Manual.
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
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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.
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
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). There are 2 treatment arms. 
Participants will be allocated to 1 of 2 treatment arms: mRNA-5671/V941 monotherapy 
(Arm A) or mRNA-5671/V941 in combination with pembrolizumab (Arm B) using an 
IVRS/IWRS in Part 1.
In Part 1 of the study, treatment will be allocated by nonrandom assignment. Enrollment into 
DL1 in Arm B will begin once all participants in DL1 Arm A complete the DLT evaluation 
(1 cycle) and DL1 of Arm A has been demonstrated to be safe and tolerable in this cohort.
If/when both treatment arms are open for enrollment, IVRS/IWRS will alternate participant 
assignment between Arm A and Arm B starting with Arm A. An observation period of at 
least 7 days will occur between treatment initiation for the first participant and second 
participant within each dose level. A new dose cohort at DL -1, -2, or -3 may open for 
enrollment without delay once the 21-day DLT observation period of the previous dose 
cohort is completed and a dose de-escalation decision is made. 
Participants on Arm A, who have radiological evidence of disease progression may be 
allowed to crossover to Arm B, at the investigator’s discretion and after consultation with 
and approval by the Sponsor. Cohort assignment of crossover participants will be determined 
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at time of crossover by the Sponsor based on safety evaluation of the combination therapy 
cohorts. Refer to Section 4.1 for more information regarding eligibility for crossover. 
When Part 2 is open for enrollment, IVRS/IWRS will assign participants to 1 of 3 cohorts by 
tumor type. 
In a situation where reallocation/rerandomization of participants is planned (eg, study 
extension periods), the reallocation/rerandomization will be based on a new 
allocation/randomization schedule; however, each participant will retain his/her original 
treatment/randomization number. Only the study intervention regimen associated with the 
reallocation/rerandomization period or phase may change.
6.3.2
Stratification
In Part 1 of the study, no stratification based on age, sex, or other characteristics will be used.
In Part 2 of the study, treatment allocation will be stratified according to the following 
factors:
1. Tumor type: Non-Small Cell Lung Cancer, Colorectal Cancer or Pancreatic 
Adenocarcinoma
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Administration of study medication(s) will be witnessed by the investigator and/or study 
staff. The total volume of study medication infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
Interruptions from the protocol-specified treatment plan for more than 12 weeks for nondrug-
related or administrative reasons require consultation between the investigator and the 
Sponsor and written documentation of the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
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6.5.1
Acceptable Concomitant Medications
Treatment by local surgery and/or radiation therapy of isolated or symptomatic progressing 
lesions in the setting of improving baseline disease may be permitted for palliative or 
potentially curative management following completion of Cycle 2. Subsequently, all 
interventions, including continuation of study intervention, should be discussed with the 
Sponsor Clinical Director or designee.
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this trial:
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab or mRNA-5671/V941
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion after the DLT observation period in order for 
the participant to be considered evaluable for DLT.
•
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 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.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
ECI that is suspected to have an immunologic etiology. The use of physiologic doses 
of corticosteroids may be approved after consultation with and approval by the 
Sponsor.
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•
Granulocyte-colony stimulating factors and erythropoietin should not be used 
prophylactically during the DLT evaluation period. Use of prophylactic colony 
stimulating factors may be considered thereafter following consultation with and 
approval by the Sponsor.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and events of clinical interest (ECIs) as defined in Section 8.4.
6.5.3
Rescue Medications and Supportive Care
6.5.3.1
mRNA-5671/V941 Supportive Care Guidelines
Participants should receive appropriate supportive care measures for adverse experiences 
potentially associated with mRNA-5671/V941 administration as deemed necessary by the 
treating investigator including, but not limited to, the item(s) outlined below.
Management of Cytokine Release Syndrome (CRS): Cytokine release syndrome is defined 
in CTCAE v4 as a disorder characterized by nausea, headache, tachycardia, hypotension, 
rash, and shortness of breath. CRS occurs when lymphocytes (B cells, T cells, and/or natural 
killer cells) and/or myeloid cells (macrophages, dendritic cells, and monocytes) become 
activated and release inflammatory cytokines [Lee, D. W., et al 2014]. In addition to the 
symptomatology defined under CTCAE, CRS may present with fever, chills, myalgias, and 
malaise [Lee, D. W., et al 2014]. Table 4 shows treatment guidelines for participants who 
experience CRS.
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Table 4
Cytokine Release Syndrome Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at
subsequent dosing
Grade 1
Mild reaction: Therapy interruption 
not indicated.  Intervention not 
indicated.
Increase monitoring of vital signs and 
oxygen saturation, as medically indicated, 
until the participant is deemed medically 
stable in the opinion of the Investigator
None
Grade 2
Therapy interruption indicated but 
responds promptly to symptomatic 
treatment (eg, NSAIDS, narcotics, 
IV fluids).  Prophylactic medications 
indicated for ≤24 hours
Increase monitoring of vital signs and 
oxygen saturation, as medically indicated, 
until the participant is deemed medically 
stable in the opinion of the Investigator
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Perform fever work-up to exclude infectious 
etiologies; treat neutropenia if present
Participant may be premedicated 1.5 
hours (± 30 minutes) prior to 
mRNA-5671/V941 administration 
with acetaminophen 500 to 1000 mg 
PO (or equivalent dose of 
antipyretic)
Grade 3
Prolonged (eg, not rapidly 
responsive to symptomatic 
medication); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates)
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Anti-IL6 (eg, tocilizumab)
Empiric antibiotics 
Participants with ≥Grade 3 CRS need to be 
monitored very closely, likely in an 
intensive care setting
For Grade 3 CRS, discuss with 
Sponsor prior to restart of mRNA-
5671/V941 treatment. 
Participant may be premedicated 1.5 
hours
(± 30 minutes) prior to mRNA-
5671/V941 administration with
acetaminophen 500 to 1000 mg PO
(or equivalent dose of antipyretic)
Grade 4
Life-threatening consequences; 
pressor or ventilatory support 
indicated
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Anti-IL6 (eg, tocilizumab)
Empiric antibiotics 
Participants with ≥Grade 3 CRS need to be 
monitored very closely, likely in an 
intensive care setting
Permanently discontinue mRNA-
5671/V941 in participants who 
develop Grade 4 CRS  
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6.5.3.2
Pembrolizumab Supportive Care Guidelines
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, Table 5. 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.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 5 in Section 
6.6 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Administration/Escalation
6.6.1.1
Dose Administration (Preparation)
Details on preparation and administration mRNA-5671/V941 and pembrolizumab are 
provided in the appropriate Pharmacy or Procedures Manual.
6.6.2
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI-CTCAE Version 4.0 based on the investigator 
assessment.
The DLT window of observation will be 21 days from the first dose of study treatment 
(Cycle 1). Participants will be monitored for DLTs during treatment with mRNA-5671/V941
as a monotherapy as well as in when mRNA-5671/V941 is administered in combination with 
pembrolizumab.
For dose-escalation decisions, an evaluable participant is defined as a participant who meets 
one of the following criteria:
•
Receives any amount of an mRNA-5671/V941 dose alone or in combination with a 
pembrolizumab dose and experiences a DLT during Cycle 1.
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•
Receives 100% of an mRNA-5671/V941 dose in Arm A, Cycle 1 or 100% of an 
mRNA-5671/V941 dose and/or ≥ 90 % of a pembrolizumab dose in Arm B, Cycle 1, 
is followed up for ≥ 21 days after the first dose of study treatment, and does not 
experience a DLT.
Participants who are not considered to be evaluable may be replaced (Section 5.5).
The occurrence of any of the following toxicities will be considered a DLT if judged by the 
investigator to be possibly related to administration of either mRNA-5671/V941
monotherapy or mRNA-5671/V941 in combination with pembrolizumab (ie, the toxicity is 
not attributable to the disease or disease-related processes under investigation or other 
causes):
1. Grade 4 nonhematologic toxicity (ie. Not a laboratory finding).
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:
3. Grade 4 thrombocytopenia of any duration
4. Grade 3 thrombocytopenia associated with clinically significant bleeding 
5. Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting that does not require anti-emetics or anti-diarrheals per standard of care; 
Grade 3 rash that does not require corticosteroids or anti-inflammatory agents per 
standard of care.
6. Any Grade 3 or Grade 4 nonhematologic laboratory value that meets one of the 
following criteria:
•
Clinically significant medical intervention is required to treat the participant.
•
The abnormality leads to hospitalization.
•
The abnormality persists for >1 week.
•
The abnormality results in a drug-induced liver injury.
The following are exceptions: clinically nonsignificant, treatable, or reversible 
laboratory abnormalities, such as those related to liver function and uric acid.
7. Febrile neutropenia Grade 3 or Grade 4:
•
Grade 3 is defined as absolute neutrophil count (ANC) < 1000/mm3 with a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) 
for more than 1 hour.
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•
Grade 4 is defined as ANC < 1000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour with 
life-threatening consequences and urgent intervention indicated.
8. Prolonged delay (> 2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
9. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1.
10. Grade 5 toxicity
11. Any other toxicity that is clinically significant and/or unacceptable and is judged to 
be a DLT by the investigator in collaboration with the Sponsor.
6.6.3
Dose Modification of mRNA-5671/V941
Individual participant dose modifications of mRNA-5671/V941 (dose increases or dose 
reductions) are not permitted in the study, unless the participant is crossing over to Arm B, 
which may result in a reduced dose of mRNA-5671/V941, if a lower dose is determined to be 
the safe dose in combination. If the participant requires a delay in pembrolizumab dosing, 
administration of mRNA-5671/V941 may also be delayed based on an assessment of 
relationship to study treatment(s). Any irAEs associated with mRNA-5671/V941 will follow 
the same guidelines presented in Table 5. 
6.6.4
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue) 
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab or Study Interventions
AEs associated with pembrolizumab or study interventions 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 or study interventions 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 or study 
interventions, 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. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
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 
(CTCAEv4.0)
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 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 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)
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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.
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 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 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer anti-
hyperglycemic 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 a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
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
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irAEs
Toxicity Grade 
(CTCAEv4.0)
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 b
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
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.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs (eg, 
vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
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 reaction are provided in Table 6.
Table 6
Guidelines for Pembrolizumab Infusion Reaction Dose Modification and 
Treatment
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, 
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 h (±30 
minutes) prior to infusion 
of pembrolizumab with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
Acetaminophen 500 to 
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 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension 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.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section
8.11.4.
Participants may discontinue study intervention at any time for any reason or be dropped 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to 
discontinue study intervention.
•
The participant interrupts study intervention administration for more than 12
consecutive weeks (exception if the Sponsor approves treatment continuation).
•
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.
•
Unacceptable adverse experiences as described in Section 8.4.
•
Intercurrent illness other than another malignancy that prevents further administration 
of study intervention.
•
Confirmed radiographic disease progression outlined in Section 8.2.1.5 (exception if 
the Sponsor approves treatment continuation)
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
•
Noncompliance with study intervention or procedure requirements
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•
Recurrent Grade 2 pneumonitis
•
Completion of 35 treatments (approximately 2 years) with pembrolizumab
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 treatment 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. 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.
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension study.
Participants in the survival follow-up phase will not be rolled-over.
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.
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•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
•
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, including any extra 
assessments that may be required over the duration of the study, can be found in the 
Procedures 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.
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 
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protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
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, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee
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 written informed consent. At the time of intervention 
allocation/randomization, site personnel will add the intervention/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
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the participant has enrolled in the study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and events of clinical interest (ECIs) should be 
recorded as defined in Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study treatment(s), the 
study treatment(s) should be discontinued and the participant will move into the survival 
follow-up phase; if a participant initiates a new anticancer therapy within 30 days after the 
last dose of the trial treatment, the 30-day Safety Follow-up visit should occur before the first 
dose of the new therapy. 
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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the
participant for all procedures occurring after treatment allocation/randomization.  Once a 
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treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study medication will be monitored by the investigator and/or study staff. 
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered. More details regarding the 
administration of mRNA-5671/V941 and pembrolizumab can be found in the accompanying 
Procedures Manual and Pharmacy Manual.
8.1.8.1
Timing of Dose Administration
Refer to Sections 6.1 and 6.2.1 for details regarding administration of study intervention.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End of Treatment/Discontinuation Visit should be performed (at the time of 
withdrawal). Any AEs that are present at the time of withdrawal should be followed in 
accordance with the safety requirements outlined in Section 8.4.
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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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. 
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8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
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.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Tumor imaging should be acquired by computed tomography (CT, strongly preferred). 
Magnetic resonance imaging (MRI) should be used when CT is contraindicated or for 
imaging in the brain. The same imaging technique regarding modality and use of contrast 
should be used in a participant throughout the trial to optimize the visualization of existing 
and new tumor burden. Required anatomical images as well as the process for image 
collection and transmission to the central imaging vendor can be found in the Site Imaging 
Manual (SIM).
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically 
relevant to enable a broader sampling of tumor burden.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
allocation.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of allocation. 
Participants with previously treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging (confirmed by 
magnetic resonance imaging (MRI) if MRI was used at prior imaging, or confirmed by 
computed tomography (CT) imaging if CT used at prior imaging) for at least 4 weeks prior to 
the first dose of trial treatment. Any neurologic symptoms must have returned to baseline and 
participants must have no evidence of new or enlarging brain metastases, and have not used 
steroids for brain metastases for at least 14 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as participants with 
carcinomatous meningitis are excluded regardless of clinical stability.
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8.2.1.2
Tumor Imaging During the Study
The first on study imaging assessment should be performed at 9 weeks (63 days ± 7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 9 weeks or 
more frequently if clinically indicated. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. Imaging should continue to be performed 
until disease progression is identified by the Investigator, the start of new anticancer 
treatment, withdrawal of consent, or death, whichever occurs first. 
PR and CR should be confirmed by a repeat imaging assessment. The imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan (ie, 9 weeks later), whichever is clinically indicated. 
Participants will then return to regular scheduled imaging every 9 weeks, starting with the 
next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 4 
weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 8 
weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed, provided they have met the 
conditions detailed in Section 8.2.1.5. Participants who receive confirmatory imaging do not 
need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
Participants who have confirmed disease progression by iRECIST, as assessed by the site, 
will discontinue the treatment.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (every 9 weeks) until the start of a new 
anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or the 
end of the study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by investigator assessment as the primary measure for assessment 
of tumor response, date of disease progression, and as a basis for all protocol guidelines 
related to disease status (eg, discontinuation of study intervention). Although RECIST 1.1 
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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.
8.2.1.5
iRECIST Assessment of Disease
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, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
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 intervention at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. In order to continue to receive study 
intervention after initial radiologic PD, the participant must sign an additional informed 
consent form (see Section 8.1.1.1). 
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in Section
8.2.1.2.
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A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 7.
Table 7
Imaging and Treatment Requirements After First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study intervention 
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
confirms PD (iCPD) 
by iRECIST per 
investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iPR=iRECIST partial 
response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; 
PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1.
8.2.2
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status as indicated in the SoA.
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical
history. The time points for full physical exam are described in the SoA. After the first dose 
of trial treatment, new clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For visits that do not require a full physical exam per the SoA, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study intervention. New clinically significant abnormal findings should 
be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs when indicated in the SoA. Vital 
signs include temperature, pulse, respiratory rate, weight, and blood pressure. Height will be 
measured at Screening only.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures at Screening as 
specified in the SoA. Clinically significant abnormal findings should be recorded as medical 
history. Additional ECGs may be performed as clinically 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 Procedures Manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
intervention, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. 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 Study 
Procedures Manual. Refer to the SoA for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study treatment. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. Predose laboratory safety tests can be conducted up to 
72 hours prior to dosing. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution. Laboratory 
tests do not need to be repeated after the end of treatment if laboratory results are within 
normal range.
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8.3.5
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulations.
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.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation/randomization through 30 days 
after cessation of study intervention must be reported by the investigator.
•
All AE meeting serious criteria, from the time of intervention
allocation/randomization through 120 days after cessation of study intervention or 
30 days after cessation of study intervention if the participant initiates new 
anticancer therapy, whichever is earlier, must be reported by the investigator.
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•
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 120 days following cessation of study 
intervention, 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 the time specified above must be reported immediately to the Sponsor if 
the event is considered related to study intervention.
Investigators are not obligated to actively seek AE or SAE 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 8.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 8
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
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
Non-Serious 
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/therapeutic 
vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential 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
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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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 AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
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. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
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 must trigger 
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).
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
For this study, an overdose of mRNA-5671/V941 will be defined as any dose exceeding the 
prescribed dose for mRNA-5671/V941 by ≥20% of the indicated dose.
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No specific information is available on the treatment of overdose of mRNA-5671/V941. In 
the event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated. If desired by the 
investigator, resumption of treatment should be discussed with the clinical monitor.
8.6
Pharmacokinetics
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, sample collections 
for analysis of antidrug antibodies (ADA) and PK are currently planned as shown in the SoA. 
Blood samples will be obtained to measure PK of serum pembrolizumab. The 
pembrolizumab serum maximum concentration (Cmax) and minimum concentration (Cmin) at 
planned visits and times will be summarized. If ongoing ADA and/or PK results continue to 
be consistent with existing ADA and/or PK data from other pembrolizumab clinical studies, 
it may be decided to discontinue or reduce further sample collection in this study. Should this 
occur, it will be communicated by an administrative memo.
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling. Based 
on PK data obtained in this study as well as PK data obtained from other studies, a 
population PK analysis will be performed to characterize PK parameters (clearance [CL], 
volume of distribution [V]) and evaluate the effect of extrinsic and intrinsic factors to support 
proposed dosing regimen. Pharmacokinetic data will also be used to explore the exposure 
response relationships for pembrolizumab antitumor activity/efficacy as well as safety in the 
proposed participant population, if feasible. The results of these analyses, if performed, will 
be reported separately. 
8.6.1
Blood Collection for PK, ADA, and Biomarkers
8.6.1.1
Blood Collection for PK
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedures Manual. Pharmacokinetic samples should be drawn according to the PK 
collection schedule for all participants. Every effort should be taken to collect samples at 30 
days after end of study intervention.
8.6.1.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedures Manual. Antidrug antibody samples should be drawn according to the ADA 
collection schedule for all participants as indicated in the SoA. Every effort should be taken 
to collect samples at 30 days after end of study intervention for ADA. Simultaneous PK 
sampling is required for interpretation of ADA analysis.
8.6.1.3
Blood Collection for Biomarkers
Sample collection, storage, and shipment instructions for plasma and whole blood biomarker 
samples will be provided in the Procedures Manual.
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8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
provided in the Procedures Manual.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
DNA for future research
•
Leftover tumor
•
Leftover RNA
•
Leftover Peripheral Blood Mononuclear Cells from immunogenicity assessment
•
Leftover blood from Blood for TCR (DNA) analysis
•
Leftover plasma or derivative from ctDNA analysis
•
Leftover serum from PK and ADA analyses
8.9
Planned Genetic Analysis Sample Collection
Sample collection, storage, and shipment instructions for the Planned Genetic Analysis 
samples will be provided in the Procedures Manual.
Samples should be collected for planned analysis of associations between genetic variants in 
germline/tumor DNA and drug response. If a documented law or regulation prohibits (or 
local IRB/Independent Ethics Committee [IEC] does not approve) sample collection for these 
purposes, then such samples should not be collected at the corresponding sites. Leftover 
DNA extracted from planned genetic analysis samples will be stored for future biomedical 
research only if participant signs the Future Biomedical Research consent.
8.10
Biomarkers
8.10.1
Pre-screening Biomarker Samples
8.10.1.1
Tumor KRAS Mutation Testing
Routine standard of care tumor KRAS mutation assessment by local testing should have been 
performed prior to consideration for study participation and should be used for eligibility 
determination. If a patient is being considered for participation in Part 2 of this study and
tumor KRAS mutation testing has not been previously performed, Sponsor consultation 
should occur. Sponsor approval would subsequently be required in order to perform local 
testing for tumor KRAS mutations on study in Pre-screening (see the Procedures Manual).
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8.10.1.2
Human Leukocyte Antigen Typing
Participants with KRAS mutated tumors being considered for enrollment in Part 2 of the 
study must undergo HLA typing during Pre-screening. Details regarding HLA testing can be 
found in the Procedures Manual. Results from this testing must be received by the site before 
a participant can be entered into the Screening phase for Part 2 of the study.
Note: If the patient has not undergone prior local tumor KRAS mutation testing, the timing of 
HLA testing in relation to KRAS mutation testing in Pre-screening (if on-study KRAS 
mutation testing has been approved by the Sponsor) must also be discussed with and 
approved by the Sponsor.
8.10.2
Archival Tumor Sample
All participants must provide an archival tumor sample during the Screening phase in order 
to be eligible for the study. KRAS mutational analysis, as well as other analyses, will be 
performed utilizing this sample. Details regarding the collection, shipment, and/or storage of 
these samples can be found in the Procedures Manual.
8.10.3
Blood Samples
Blood should be collected predose at the timepoints outlined in Section 1.3 – Schedule of 
Activities. Further details are provided in the Procedures Manual.
8.10.4
Immunogenicity Assessment
The assessment of immunogenicity of the mRNA-5671/V941 therapeutic vaccine is a 
secondary objective of this study.
8.10.4.1
PBMC Collection
Whole blood will be collected at specified time points from each study participant for 
isolation and cryopreservation of PBMC for immunogenicity assessment (unless a 
leukapheresis pack has been collected at a comparable time point [Section 8.10.4.2]). These 
PBMC will be utilized in immune assays to assess responses against KRAS mutant epitopes 
potentially induced by vaccination with mRNA-5671/V941. Further details are provided in 
the Procedures Manual.
8.10.4.2
Leukapheresis
Participants receiving combination therapy (mRNA-5671/V941 + pembrolizumab) either in 
Arm B of Part 1 or in Part 2 may undergo optional leukapheresis during Screening and on 
Day 8 of Cycle 4, but only if the clinical site has the capability to perform this procedure and 
facilities are available to isolate and cryopreserve PBMC from the collected leukapheresis 
within the specified time window (see the Procedures Manual for details). These collected 
cells will be utilized for immune assays to evaluate the immunological response against 
KRAS mutant epitopes potentially induced and expanded by vaccination with mRNA-
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5671/V941. Additional details regarding the collection, storage, and/or shipment of the 
collected leukapheresis pack can be found in the Procedures Manual.
In the event that a screening leukapheresis is collected from a given participant, the screening 
whole blood sample for isolation of PBMC for immunogenicity assessment should not be 
drawn from that participant. Similarly, if a Day 8 Cycle 4 leukapheresis is collected, the 
whole blood collections for isolation of PBMC for immunogenicity assessment on both Day 
8 of Cycle 4 and Day 1 of Cycle 6 should not be performed.
8.10.5
Exploratory Analyses
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 in this study, as specified in the SoA. Sample 
collection, storage, and shipment instructions for the exploratory biomarker specimens will 
be provided in the Procedures Manual. 
•
Archival tumor tissue
•
Blood for Genetic Analysis
•
Blood for PBMC immunogenicity assessment
•
Blood for RNA analysis
•
Blood for TCR (DNA) 
•
Blood for ctDNA analysis
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8. 
8.11.1
Pre-screening (Part 2 only)
For Part 2 of the study, approximately 50 days prior to treatment allocation, potential 
participants will undergo pre-screening procedures to determine their eligibility based on 
results of prior local tumor KRAS mutational testing (see Section 8.10.1.1) and on HLA 
typing (see Section 8.10.1.2).
Pre-screening procedures are to be completed within 21 days prior to screening procedure 
initiation. Pre-screening procedures may be repeated if needed after consultation with and 
approval by the Sponsor. Once Part 2 eligibility requirements regarding KRAS mutational 
status and HLA type are confirmed, potential participants should have screening procedures 
performed without delay. 
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8.11.2
Screening
Approximately 28 days prior to treatment allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements of the study. Screening procedures may 
be repeated after consultation with the Sponsor. Written consent must be obtained prior to 
performing any protocol-specific procedure.
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study intervention except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. An exception is hepatitis testing which may be done up to 28 days prior 
to the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).
•
Baseline radiological evaluations must be done within 28 days prior to the first dose 
of study intervention.
•
Archival tumor sample collection may have occurred at any point prior to the first 
dose of study intervention. 
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments 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/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number. Assessments performed as part of the screening evaluations and within 3 
days prior to the first dose of study treatment are not required to be repeated on Day 1 of 
Cycle 1.
8.11.3
Treatment Period/Vaccination Visit
Visit requirements are outlined in the SoA. Specific procedure-related details are provided in 
Section 8.1.
8.11.4
End of Treatment/Discontinuation Visit
The End of Treatment/Discontinuation Visit should occur at the time study intervention is 
discontinued for any reason. If the Discontinuation Visit occurs 30 days from the last dose of 
study intervention, at the time of the mandatory Safety Follow-up Visit, the Discontinuation 
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Visit procedures and any additional Safety Follow-up procedures should be performed. Visit 
requirements are outlined in Section 1.3. Additional details regarding participant withdrawal 
and discontinuation are presented in Section 7.
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension study.
Participants in the survival follow-up phase will not be rolled-over.
8.11.5
Post-treatment Visit
8.11.5.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded (up to 30 days 
following end of treatment). Participants with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new anticancer therapy, 
whichever occurs first. SAEs that occur within 120 days of the end of treatment or before 
initiation of a new anticancer treatment should also be followed and recorded. 
8.11.5.2
Imaging Follow-up Visit(s)
Participants who discontinue treatment for reasons other than verified PD should continue 
with imaging assessments per the protocol defined schedule until: (1) PD is verified or 
further confirmed by the investigator, (2) initiation of a new anti-cancer treatment, (3) death, 
(4) withdrawal of consent, or (5) study conclusion or early termination, whichever occurs 
first.
8.11.5.3
Survival Follow-up Visits
Participants, who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to an 
efficacy interim analysis, and/or final analysis. All participants who are not known to have 
died prior to the request for these additional survival status time points will be contacted at 
that time.
Participants on active treatment with pembrolizumab monotherapy in the post-treatment 
phase are discontinued and may be enrolled in to a pembrolizumab extension study. 
Participants in the survival follow-up phase will not be rolled-over.
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8.11.6
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Full details are in the Statistical Analysis Plan (SAP), Sections 9.2 to 9.12.
Study Design Overview
Phase 1 trial of mRNA-5671/V941 monotherapy (Arm A) and mRNA-
5671/V941 in combination with pembrolizumab (Arm B) in participants with 
advanced/metastatic solid tumors. The study applies a modified TPI design 
for dose finding.
Treatment Assignment
Participants will be allocated centrally through IVRS/IWRS to single agent 
mRNA-5671/V941 and mRNA-5671/V941 coadministered with 
pembrolizumab.
Analysis Populations
Safety (Primary): All-Subjects-as-Treated (AsaT)
Pharmacodynamic (Secondary): Per-Protocol (PP)
Efficacy (Secondary and Exploratory): Full Analysis Set (FAS) 
Primary Endpoint(s)

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to an AE
Secondary Endpoints

Objective response is a confirmed CR or PR.

Presence of and changes in the quantity of mutant KRAS-specific T cells 
in the blood.
Statistical Methods for 
Efficacy/ Immunogenicity/ 
ORR in participants treated with mRNA-5671/V941 monotherapy (Arm A) 
and mRNA-5671/V941 in combination with pembrolizumab (Arm B) will be 
estimated using an exact method based on the binomial distribution (Clopper-
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Pharmacokinetic Analyses
Pearson interval) together with its 95% confidence interval.
Methods for the rest of the efficacy analyses are documented in the sSAP.
Summary statistics will be provided for the immunogenicity parameters.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints as appropriate. 
The pool-adjacent-violators-algorithm [Ji Y, Li Y, Bekele BN 2007] will be 
used to estimate the DLT rates across doses. The estimate of the DLT rate 
among participants treated at RP2D of mRNA-5671/V941 and the 80% 
Bayesian credible intervals for the estimate will be provided for each 
treatment arm.
Interim Analyses
An interim analysis for part 2 will be conducted after about 60% of 
enrollment in each tumor cohort.
Multiplicity
No multiplicity adjustment is planned in this Phase 1 trial.
Sample Size and Power 
The overall sample size for this study depends on the observed DLT profiles 
of mRNA-5671/V941 monotherapy and mRNA-5671/V941 in combination 
with pembrolizumab. A target sample size of 100 participants will be used for 
study planning purposes. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned. 
Allocation to treatment will not be randomized.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3 – Objectives/Hypotheses 
and Endpoints.
9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity Endpoints
Objective response rate is the secondary endpoint in this study. Objective response rate is 
defined as the proportion of participants in the analysis population who experience complete 
response (CR) or partial response (PR) using RECIST 1.1 criteria as assessed by investigator 
review. 
Other efficacy endpoints (eg, PFS, OS) are exploratory endpoints in this trial and details of 
the analysis plan will be documented in the sSAP. Progression-free survival (PFS) is defined 
as the time from the first dose of study medication to the first documented disease 
progression (PD), using RECIST 1.1 criteria as assessed by investigator review, or death due 
to any cause, whichever occurs first. Overall survival (OS) is defined as the time from the 
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first dose of study medication to death due to any cause. Participants who did not die will be 
censored on the date of last study assessment or contact.
Immunogenicity endpoints may include the following: 1) Presence of and changes in the 
quantity of mutant KRAS-specific T cells in the blood and 2) TCR clonality and diversity in 
the blood.
9.4.2
Safety Endpoints
The primary safety endpoint is the incidence of DLTs. In addition, safety and tolerability will 
be assessed by clinical review of all relevant parameters including AEs, laboratory tests, and 
vital signs.
A description of safety measures is provided in Section 8.3 – Safety Assessments.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The All-Subjects-as-Treated (AsaT) population will be used for the analysis of safety data in 
this study. The AsaT population consists of all participants who received at least 1 dose of 
study treatment. 
The DLT evaluable population includes AsaT participants that meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 6.6.2 for details. 
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Data from participants who crossover from monotherapy to the combination therapy will be 
presented separately.
9.5.2
Pharmacokinetic/Immunogenicity Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of PK and immunogenicity
data in this study. The PP population consists of the subset of participants who complied with 
the protocol sufficiently to ensure that their data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance includes such 
considerations as exposure to treatment, availability of measurements, and the absence of 
major protocol violations. Any participants or data values excluded from the analyses will be 
identified, along with the reasons for exclusion, in the CSR. At the end of the study, all 
participants who were compliant with the study procedures and have available data from at 
least 1 treatment will be included in the PP analysis dataset.
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9.5.3
Efficacy Analysis Populations
The Full Analysis Set (FAS) population will be used for the analyses of secondary and 
exploratory efficacy data in this study. It consists of participants with centrally-confirmed 
tumor KRAS mutations, with a baseline scan that demonstrated measurable disease by the 
investigator’s assessment, and who were administered at least 1 dose of study medicine.
Participants from the dose finding phase in the combination arm (Arm B) who are treated at 
the RP2D and meet the dose expansion eligibility criterion will be pooled together with
participants enrolled in the dose expansion in a supportive analysis.
Data from participants who crossover from monotherapy to the combination therapy will be 
presented separately.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
9.6.1
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
Adverse events will be summarized by counts and frequencies for each dose level. 
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose limiting toxicities will be listed and summarized by dose level. The pool adjacent 
violators-algorithm [Ji Y, Li Y, Bekele BN 2007], which forces the DLT rate estimates to be 
nondecreasing with increasing dose levels and pools adjacent violators for weighted 
estimates by sample size, will be used to estimate the DLT rates across doses in each 
treatment arm. The estimate of the DLT rate among participants treated at the RP2D and the 
80% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate 
will be provided.
9.6.2
Statistical Methods for Efficacy Analysis
ORR, along with the confidence interval, will be estimated using an exact method based on 
the binomial distribution (Clopper-Pearson method). The statistical methods for other 
efficacy endpoints are exploratory nature and will be documented in the sSAP.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
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9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Pharmacokinetic parameters of pembrolizumab will be summarized by planned visit and time 
for each dose separately. 
Pharmacokinetics and pharmacodynamics modeling analyses will be documented in the 
sSAP.
9.7
Interim Analyses
Due to low prevalence of KRAS mutant and selected HLA typing population, the accrual is 
expected to be slow. A futility analysis will be conducted after about 60% of enrollment in 
each tumor cohort. For example, if no response is observed among the 9 participants in the 
non-MSI-H CRC or pancreatic cohort, or less than 7 responses out of 24 participants in the 
NSCLC cohort, enrollment to the tumor cohort may be stopped. The totality of data across 
the cohorts will be assessed to stop the trial early for futility.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
The planned total sample size for Part 1 dose finding is approximately 30 participants. The 
actual sample size could be less given that the therapeutic vaccine is expected to have a 
tolerable toxicity profile. The planned sample size for Part 2 efficacy expansion is 70 
participants (40 for NSCLC, 15 for non-MSI-H CRC and 15 for pancreatic). 
While there is no formal hypothesis testing in this study, preliminary efficacy in the Part 2 
expansion will be assessed with the pruning and pooling method [Chen, C., et al 2016]. With 
70 participants by the aforementioned allocation, the study has approximately 83% power for 
detecting a 15% improvement of ORR over historical control (pembrolizumab monotherapy) 
in at least 1 of the 3 tumor indications, while controlling the Type I error for the global null 
hypothesis under 5%. The ORR for historical control in the KRAS mutated population is 
assumed to be 1% for non-MSI-H CRC, 1% for pancreatic adenocarcinoma, and 20 to 25%
for NSCLC. 
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial. Any deviation 
from protocol-directed administration will be reported.
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9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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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 and Dohme Corp., a subsidiary of Merck & Co., Inc. (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 (Institutiona 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 report form 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
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.
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.6
Compliance with Law, Audit, and Debarmen
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 good clinical practice); 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.
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10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the 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 
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investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 9 will be performed by the local laboratory.
•
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 9
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive Chemistry 
Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT or PTT
WBC (total and 
differential)d
Aspartate aminotransferase
Specific gravity 
Total T3 (or Free T3 
[FT3]), Total T4 (or Free 
T4[FT4]), and TSHb
RBC
Bicarbonate
Microscopic exam, if 
abnormal results are noted
Absolute 
lymphocyte countc
Calcium
Absolute 
neutrophil countc
Chloride
Creatinine
Anti-HCVd
Glucose
HCV viral loadd
Phosphorus
Anti-HBsd
Potassium
HbsAgd
Sodium
Anti-HBc (total and 
IgM)d
Total bilirubin  
HbeAgd
Direct bilirubin
Anti-Hbed
Total protein
HIV testingd
Blood urea nitrogen
a.
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1.  Pregnancy tests must be 
repeated prior to every cycle if required or as specified per local regulatory guidance.
b.
T3 is preferred; if not available, Free T3 may be tested. 
c.
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
d.
Assessment should be based on history unless testing is required by local regulation.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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, 
device, diagnostic agent, or protocol specified procedure whether investigational 
(including placebo or active comparator product) or marketed, manufactured by, 
licensed by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
•
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.”
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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 8.4.7 for protocol-specific exceptions.
10.3.2
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
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.
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
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 timeframe 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
10.3.4
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.
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•
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
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4.0. 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
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the causality 
noted on the AE form, ensures that a medically qualified assessment of causality was 
done. This initialed document must be retained for the required regulatory time frame. 
The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test product and the AE based 
upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor’s product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors.
-
Dechallenge: Was the Sponsor’s product discontinued or 
dose/exposure/frequency reduced?
-
If yes, did the AE resolve or improve?
-
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.)
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-
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 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the Sponsor’s 
product or drug class pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets 
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
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.
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•
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every 
event before the initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
•
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each AE causality to the combination regimen 
or to a single agent of the combination. In general, causality attribution should be 
assigned to the combination regimen (ie, to all agents in the regimen). However, 
causality attribution may be assigned to a single agent if in the investigator’s opinion, 
there is sufficient data to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, 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.
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•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next 
section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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.
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
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 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following 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.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration. 
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception as described in Table 
10 during the protocol-defined time frame in Section 5.1.
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Table 10
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen- containing) hormonal contraceptionb,c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●Progestogen only hormonal contraceptionb,c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen- only contraceptive implantb,c 
●Intrauterine hormone-releasing system (IUS)b
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner 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.
●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
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
c
If hormonal contraception efficacy is potentially decreased due to interaction with study intervention, 
condoms must be used in addition to the hormonal contraception during the intervention period and for at 
least 120 days after the last dose of study intervention. If locally required, in accordance with Clinical 
Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to those 
which inhibit ovulation.
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. Additional pregnancy testing will be performed as indicated in the SoA, and as required 
locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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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 with which drugs/vaccines may interact

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 
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 participants' 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 sex, 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 using 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 FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the 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 study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the 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 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 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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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 Council on Harmonisation [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
Not Applicable
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained (using iRECIST for participant management 
(see Table 7). This decision by the investigator should be based on the participant’s overall 
clinical condition.
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 intervention at  
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment.
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
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 nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). 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 nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, 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 calculated, 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 Imaging
On the confirmatory imaging, 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
-
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
-
For nontarget 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
-
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 nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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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 imaging 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 imaging 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.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit , an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3.
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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
-
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.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
-
If nontarget 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
-
New lesions appear for the first time
-
Additional new lesions appear
-
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
-
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 Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), 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 a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Abbreviations
Abbreviation
Definition
Abscopal
a phenomenon in the treatment of metastatic cancer where localized treatment 
of a tumor causes not only a shrinking of the treated tumor, but also a shrinking 
of tumors outside the scope of the localized treatment.
ADA
anti-drug antibody
ADME
absorption, distribution, metabolism, and excretion
AE
adverse event
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
AMP
adenosine monophosphate
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ART
anti-retroviral therapy
AsaT
all-subjects-as-treated
AST
aspartate aminotransferase
ATD
accelerated titration design
AUC
area under the curve
C
cycle
CARPA
complement activation-related pseudoallergy
CBC
complete blood count
CBR
carbonyl reductase
CD
cluster of differentiation (eg, CD3, CD8, CD28)
CDN
cyclic dinucleotide
cGAMP
cyclic GMP-AMP
cGAS
cyclic (guanosine monophosphate-adenosine monophosphate)
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID
Coronavirus disease
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF/eCRF
case report form/electronic case report form
CRS
cytokine release syndrome
CT
computed tomography
CTCL
cutaneous T-cell lymphoma
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T lymphocyte-associated antigen 4
CXCL11
C-X-C motif chemokine 11  
CxCy
Cycle x Day y
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxynucleic acid
ECG
electrocardiograph
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Abbreviation
Definition
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EOT
end of treatment
FAS
Full Analysis Set
FBR
future biomedical research
FDA
U.S. Food and Drug Administration
FDAA
Food and Drug Administration Amendments Act
FDG
fluorodeoxyglucose
FIH
first-in-human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GMP
guanosine monophosphate 
GRI
growth rate inhibition
GVHD
graft-versus-host disease
HbsAg/HBV
Hepatitis B surface antigen/Hepatitis B virus
HCV
Hepatitis C virus
hCG
human chorionic gonadotropin
HED
human equivalent doses
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HLA-A
human leukocyte antigen A
HLA-C
human leukocyte antigen C
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IFN
interferon
IFNα
interferon alpha
IFNγ
interferon gamma
Ig
immunoglobulin
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IL-6
interleukin-6
IM
intramuscular
INR
international normalized ratio
IP-10
interferon gamma-induced protein 10 
irAE
immune-related adverse event
IRF3
interferon regulatory transcription factor-3
iRECIST
immune Response Evaluation Criteria In Solid Tumors
ISCL
International Society for Cutaneous Lymphomas 
IT
intratumoral
IV
intravenous
IVD
in vitro diagnostic
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Abbreviation
Definition
IVRS/IWRS
integrated web response system
IWG
International Working Group
KRAS
Kirsten RAt Sarcoma
LDH
lactate dehydrogenase
LLOQ
less than the limit of detection
LNP
lipid nanoparticle
mAb
monoclonal antibody
MAD
maximum administered dose
MCP-1
monocyte chemoattractant protein-1
MCP-2
monocyte chemoattractant protein-2
MHC
major histocompatibility complex
MIP-1α
macrophage inflammatory protein-1 alpha
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme
MSI
microsatellite instability
MSI-H
microsatellite instability-high
mSWAT
modified Severity Weighted Assessment Tool
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NCI
National Cancer Institute 
NF-κB
nuclear factor-κB
NOAEL
no-observed adverse effect level
NSCLC
non-small-cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBMC
peripheral blood mononuclear cell
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death-1 ligand 1
PD-L2
programmed cell death-1 ligand 2
PET
positron emission tomography
PFS
progression-free survival
PK
pharmacokinetic
PO
per os (by mouth)
PP
per-protocol
PR
partial response
PT
prothrombin time
Q1W
once a week
Q3W
every three weeks 
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse events
SNP
single nucleotide polymorphism
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Abbreviation
Definition
SoA
schedule of activities
SOP
standard operating procedure
SPD
sum of the products of the greatest diameters
sSAP
Supplemental Statistical Analysis Plan
STING
stimulator of interferon genes
SUSAR
suspected unexpected serious adverse reactions
TBK1
tumor necrosis factor receptor-associated factors (TRAF)-associated nuclear 
factor (NF)-κB activator
TCR
T-cell receptor
TNF-α
tumor necrosis factor-alpha
TSH
thyroid stimulating hormone
ULN
upper limit of normal
VS
vital signs
WOCBP
women of childbearing potential
WT
wild-type
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REFERENCES
[Ashktorab, H., et al 2016]
Ashktorab H, Ahuja S, Kannan L, Llor X, 
Ellis NA, Xicola RM, et al. A meta-
analysis of MSI frequency and race in 
colorectal cancer. Oncotarget. 2016 Apr 
23;7(23):34546-57.
[04V8BD]
[Boland, C. R. 2010]
Boland CR, Goel A. Microsatellite 
instability in colorectal cancer. 
Gastroenterology. 2010 Jun;138(6):2073-
87.e3.
[046LXW]
[Chemnitz, J. M., et al 2004]
Chemnitz JM, Parry RV, Nichols KE, 
June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-
based switch motif of programmed death 
1 upon primary human T cell stimulation, 
but only receptor ligation prevents T cell 
activation. J Immunol 2004;173:945-54.
[00VMPN]
[Chen, C., et al 2016]
Chen C, Li XN, Yuan S, Antonijevic Z, 
Kalamegham R, Beckman RA. Statistical 
design and considerations of a phase 3 
basket trial for simultaneous investigation 
of multiple tumor types in one study. Stat 
Biopharm Res. 2016;8(3):248-57.
[05FXP3]
[Chen, D. S. 2013]
Chen DS, Mellman I. Oncology meets 
immunology: the cancer-immunity cycle. 
Immunity 2013;39:1-10.
[03WNCG]
[Coelho, T., et al 2013]
Coelho T, Adams D, Silva A, Lozeron P, 
Hawkins PN, Mant T, et al. Safety and 
efficacy of RNAi therapy for transthyretin 
amyloidosis. N Engl J Med. 2013 Aug 
29;369(9):819-29.
[04V6WG]
[Cox, A. D., et al 2014]
Cox AD, Fesik SW, Kimmelman AC, 
Luo J, Der CJ. Drugging the undruggable 
RAS: mission possible? Nat Rev Drug 
Discov. 2014 Nov;13(11):828-51.
[04V7WQ]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J 
Clin Oncol 2010;28(29):4531-8.
[058SQL]
08B833

PRODUCT: V941 
146
PROTOCOL/AMENDMENT NO.: 001-08 
V941-001-08 FINAL PROTOCOL
24-MAR-2022
[Dudley, M. E., et al 2005]
Dudley ME, Wunderlich JR, Yang JC, 
Sherry RM, Topalian SL, Restifo NP, et 
al. Adoptive cell transfer therapy 
following non-myeloablative but 
lymphodepleting chemotherapy for the 
treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 
2005;23(10):2346-57.
[00VMPR]
[Fitzgerald, K. 2014]
Fitzgerald K, Frank-Kamenetsky M, 
Shulga-Morskaya S, Liebow A, 
Bettencourt BR, Sutherland JE, et al. 
Effect of an RNA interference drug on the 
synthesis of proprotein convertase 
subtilisin/kexin type 9 (PCSK9) and the 
concentration of serum LDL cholesterol 
in healthy volunteers: a randomised, 
single-blind, placebo-controlled, phase 1 
trial. Lancet. 2014 Jan 4;383(9911):60-
68.
[04R58P]
[Francisco, L. M., et al 2010]
Francisco LM, Sage PT, Sharpe AH. The 
PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 
2010;236:219-42.
[058SQP]
[Greenwald, R. J., et al 2005]
Greenwald RJ, Freeman GJ, Sharpe AH. 
The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[00VMQL]
[Hodi, F. S., et al 2014]
Hodi FS, Ribas A, Daud A, Hamid O, 
Robert C, Kefford R, et al. Patterns of 
response in patients with advanced 
melanoma treated with Pembrolizumab 
(MK-3475) and evaluation of immune-
related response criteria (irRC). J 
Immunother Cancer. 2014;2(Suppl 
3):P103.
[0465RW]
[Hunder, N. N., et al 2008]
Hunder NN, Wallen H, Cao J, Hendricks 
DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with 
autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 
2008;358(25):2698-703.
[00VMPX]
08B833

PRODUCT: V941 
147
PROTOCOL/AMENDMENT NO.: 001-08 
V941-001-08 FINAL PROTOCOL
24-MAR-2022
[Jamieson, D., et al 2016]
Jamieson D, Griffin MJ, Sludden J, Drew 
Y, Cresti N, Swales K, et al. A phase I 
pharmacokinetic and pharmacodynamic 
study of the oral mitogen-activated 
protein kinase kinase (MEK) inhibitor, 
WX-554, in patients with advanced solid 
tumours. Eur J Cancer. 2016 Nov;68:1-
10.
[04V5NH]
[Ji Y, Li Y, Bekele BN 2007]
Ji Y, Li Y, Bekele BN. Dose-finding in 
phase l clinical trials based on toxicity 
probability intervals. Clin Trials 
2007;4:235-44.
[03TFYL]
[Ji, Y. 2013]
Ji Y, Wang S-J. Modified toxicity 
probability interval design: a safer and 
more reliable method than the 3 + 3 
design for practical phase I trials. J Clin 
Oncol 2013;31:1-12.
[03FL3C]
[Kempf, E., et al 2016]
Kempf E, Rousseau B, Besse B, Paz-Ares 
L. KRAS oncogene in lung cancer: focus 
on molecularly driven clinical trials. Eur 
Respir Rev. 2016 Mar;25(139):71-6.
[04V62S]
[Knudsen, M. L., et al 2014]
Knudsen ML, Ljungberg K, Kakoulidou 
M, Kostic L, Hallengard D, Garcia-
Arriaza J, et al. Kinetic and phenotypic 
analysis of CD8+ T cell responses after 
priming with alphavirus replicons and 
homologous or heterologous booster 
immunizations. J Virol. 2014 
Nov;88(21):12438-51.
[04V8D9]
[Le, D. T., et al 2015]
Le DT, Uram JN, Wang H, Bartlett BR, 
Kemberling H, Eyring AD, et al. PD-1 
Blockade in tumors with mismatch repair 
deficiency. N Engl J Med. Forthcoming 
2015.
[045JGH]
08B833

PRODUCT: V941 
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PROTOCOL/AMENDMENT NO.: 001-08 
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[Lee, D. W., et al 2014]
Lee DW, Gardner R, Porter DL, Louis 
CU, Ahmed N, Jensen M, et al. Current 
concepts in the diagnosis and 
management of cytokine release 
syndrome. Blood. 2014 Jul 
10;124(2):188-95. Erratum in: Blood. 
2015 Aug 20;126(8):1048.
[04L35Q]
[Lee, D. W., et al 2015]
Lee DW, Kim KJ, Han SW, Lee HJ, Rhee 
YY, Bae JM, et al. KRAS mutation is 
associated with worse prognosis in stage 
III or high-risk stage II colon cancer 
patients treated with adjuvant FOLFOX. 
Ann Surg Oncol. 2015 Jan;22:187-94.
[04V4HJ]
[Ning, C., et al 2017]
Ning C, Liang M, Liu S, Wang G, 
Edwards H, Xia Y, et al. Targeting ERK 
enhances the cytotoxic effect of the novel 
PI3K and mTOR dual inhibitor VS-5584 
in preclinical models of pancreatic 
cancer. Oncotarget. 2017 May 
15;8(27):44295-311.
[04V8D3]
[Okazaki, T., et al 2001]
Okazaki T, Maeda A, Nishimura H, 
Kurosaki T, Honjo T. PD-1 
immunoreceptor inhibits B cell receptor-
mediated signaling by recruiting src 
homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc 
Natl Acad Sci U S A 2001;98(24):13866-
71.
[00VMQ6]
[Parry, R. V., et al 2005]
Parry RV, Chemnitz JM, Frauwirth KA, 
Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors 
inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 
2005;25(21):9543-53.
[00VMQ7]
[Prior, I. A., et al 2012]
Prior IA, Lewis PD, Mattos C. A 
comprehensive survey of Ras mutations 
in cancer. Cancer Res. 2012 May 
15;72(10):2457-67.
[04V4HL]
08B833

PRODUCT: V941 
149
PROTOCOL/AMENDMENT NO.: 001-08 
V941-001-08 FINAL PROTOCOL
24-MAR-2022
[Pylayeva-Gupta, Y., et al 
2011]
Pylayeva-Gupta Y, Grabocka E, Bar-Sagi 
D. RAS oncogenes: weaving a 
tumorigenic web. Nat Rev Cancer. 2011 
Nov;11(11):761-74.
[04V7W8]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T 
cells. Immunol Rev 2009;229:114-25.
[00VMQ9]
[Seymour, L., et al 2017]
Seymour L, Bogaerts J, Perrone A, Ford 
R, Schwartz LH, Mandrekar S, et al. 
iRECIST: guidelines for response criteria 
for use in trials testing 
immunotherapeutics. Lancet Oncol. 2017 
Mar;18(3):e143-52.
[04P9RV]
[Sharma, P. 2015]
Sharma P, Allison JP. Immune 
checkpoint targeting in cancer therapy: 
toward combination strategies with 
curative potential. Cell. 2015 Apr 
9;161(2):205-14.
[04V5QX]
[Sheppard, K-A, et al 2004]
Sheppard K-A, Fitz LJ, Lee JM, 
Benander C, George JA, Wooters J, et al. 
PD-1 inhibits T-cell receptor induced 
phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to 
PKCtheta. FEBS Lett. 2004;574:37-41.
[00VMQC]
[Soares, K. C., et al 2015]
Soares KC, Rucki AA, Wu AA, Olino K, 
Xiao Q, Chai Y, et al. PD-1/PD-L1 
blockade together with vaccine therapy 
facilitates effector T-cell infiltration into 
pancreatic tumors. J Immunother. 2015 
Jan;38(1):1-11.
[04V720]
[Szebeni, J. 2014]
Szebeni J. Complement activation-related 
pseudoallergy: a stress reaction in blood 
triggered by nanomedicines and 
biologicals. Mol Immunol. 2014 
Oct;61(2):163-73.
[04R3Z5]
08B833

PRODUCT: V941 
150
PROTOCOL/AMENDMENT NO.: 001-08 
V941-001-08 FINAL PROTOCOL
24-MAR-2022
[Taube, J. M., et al 2012]
Taube JM, Anders RA, Young GD, Xu H, 
Sharma R, McMiller TL, et al. 
Colocalization of inflammatory response 
with B7-H1 expression in human 
melanocytic lesions supports an adaptive 
resistance mechanism of immune escape. 
Sci Transl Med 2012;4(127):1-10.
[03X2NQ]
[Topalian, S. L., et al 2016]
Topalian SL, Taube JM, Anders RA, 
Pardoll DM. Mechanism-driven 
biomarkers to guide immune checkpoint 
blockade in cancer therapy. Nat Rev 
Cancer. 2016 May;16(5):275-87.
[04V7Q2]
[Tran, E., et al 2016]
Tran E, Robbins PF, Lu YC, Prickett TD, 
Gartner JJ, Jia L, et al. T-cell transfer 
therapy targeting mutant KRAS in cancer. 
N Engl J Med. 2016 Dec 8;375(23):2255-
62.
[04V6WJ]
[U.S. Department of Health 
and Human Services 2015]
US DHHS, US FDA, CBER. 
Considerations for the design of early-
phase clinical trials of cellular and gene 
therapy products: guidance for industry. 
June 2015.
[04V64B]
[Wang, Q. J., et al 2016]
Wang QJ, Yu Z, Griffith K, Hanada K, 
Restifo NP, Yang JC, et al. Identification 
of T-cell receptors targeting KRAS-
mutated human tumors. Cancer Immunol 
Res. 2016 Mar;4(3):204-14.
[04V4HK]
[Wolchok, J. D., et al 2009]
Wolchok JD, Hoos A, O'Day S, Weber 
JS, Hamid O, LebbéC, et al. Guidelines 
for the evaluation of immune therapy 
activity in solid tumors: immune-related 
response criteria. Clin Cancer Res 
2009;15(23):7412-20.
[00VMNZ]
[Zeitouni, D., et al 2016]
Zeitouni D, Pylayeva-Gupta Y, Der CJ, 
Bryant KL. KRAS mutant pancreatic 
cancer: no lone path to an effective 
treatment. Cancers. 2016 Apr 
18;8(4):45[22 p.].
[04V63P]
08B833

PRODUCT: V941 
151
PROTOCOL/AMENDMENT NO.: 001-08 
V941-001-08 FINAL PROTOCOL
24-MAR-2022
[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia 
S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory 
receptor programmed death-1. Immunity 
2004;20:337-47.
[00VMQJ]
08B833