A 3-Arm, Randomized, Blinded, Active-Controlled, Phase II Study of RO7121661, a PD1-TIM3 Bispecific Antibody and RO7247669, a PD1-LAG3 Bispecific Antibody, Compared With Nivolumab in Participants With Advanced or Metastatic Squamous Cell Carcinoma of the Esophagus
Phase: PHASE2
Conditions: Advanced or Metastatic Esophageal Squamous Cell Carcinoma
Sponsor: Hoffmann-La Roche

 
Official Title: 
A 3-Arm, Randomized, Blinded, Active-Controlled, Phase II Study of 
RO7121661, a PD1-TIM3 Bispecific Antibody and RO7247669, a 
PD1-LAG3 Bispecific Antibody, Compared with Nivolumab in 
Participants with Advanced or Metastatic Squamous Cell Carcinoma 
of the Esophagus 
NCT Number: 
NCT04785820 
Document Date: 
Protocol Amendment Version 3: 02-Feb-2022 
 
 
 

FINAL PROTOCOL APPROVAL 
CONFIDENTIAL 
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd (or under its control) and therefore, is provided to you in confidence as
an investigator, potential investigator, or consultant, for review by you, your staff, and an
applicable Ethics Committee or Institutional Review Board. It is understood that this information 
will not be disclosed to others without written authorization from Roche except to the extent 
necessary to obtain informed consent from persons to whom the drug may be administered. 
RO7121661, RO7247669, Nivolumab—F. Hoffmann-La Roche Ltd 
1/Protocol BP42772, Version 3 
PROTOCOL 
TITLE: 
A 3-ARM, RANDOMIZED, BLINDED, 
ACTIVE-CONTROLLED, PHASE II STUDY OF 
RO7121661, A PD1-TIM3 BISPECIFIC 
ANTIBODY AND RO7247669, A PD1-LAG3 
BISPECIFIC ANTIBODY, COMPARED WITH 
NIVOLUMAB IN PARTICIPANTS WITH 
ADVANCED OR METASTATIC SQUAMOUS 
CELL CARCINOMA OF THE ESOPHAGUS 
PROTOCOL NUMBER: 
BP42772 
VERSION: 
3 
EUDRACT NUMBER: 
2020-004606-60 
IND NUMBER: 
142906 (LAG3), 142844 (TIM3) 
TEST PRODUCT: 
RO7121661, RO7247669, Nivolumab 
SPONSOR: 
F. Hoffmann-La Roche Ltd
DATE FINAL: 
08 December 2020
DATE AMENDED: 
See electronic stamp below
Company Signatory
Approver's Name
Title
Date and Time (UTC)
02-Feb-2022 15:45:22

RO7121661, RO7247669, Nivolumab—F. Hoffmann-La Roche Ltd 
2/Protocol BP42772, Version 3 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A 3-ARM, RANDOMIZED, BLINDED, 
ACTIVE-CONTROLLED, PHASE II STUDY OF 
RO7121661, A PD1-TIM3 BISPECIFIC 
ANTIBODY AND RO7247669, A PD1-LAG3 
BISPECIFIC ANTIBODY, COMPARED WITH 
NIVOLUMAB IN PARTICIPANTS WITH 
ADVANCED OR METASTATIC SQUAMOUS 
CELL CARCINOMA OF THE ESOPHAGUS 
PROTOCOL NUMBER: 
BP42772  
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2020-004606-60 
IND NUMBER: 
142906 (LAG3), 142844 (TIM3) 
TEST PRODUCT: 
RO7121661, RO7247669, Nivolumab 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
 
 
Please keep the signed original form in your study files and return a copy to your local 
Site Monitor. 
 
 

RO7121661, RO7247669, Nivolumab—F. Hoffmann-La Roche Ltd
3/Protocol BP42772, Version 3
PROTOCOL AMENDMENT, VERSION 3
RATIONALE
Protocol BP42772 Version 2 has been mainly amended to stop recruitment into the 
RO7121661 arm. Changes to the protocol, along with a rationale for each change, are 
summarized below.

Sections 1.2, 3, 4.1, 6.3, 9.1, 9.3.2, and 9.4 have been amended to reflect the 
decision to stop recruitment into the RO7121661 arm. The decision to stop 
recruitment for RO7121661 was based on strategic considerations and not based 
on emerging safety and/or efficacy data. The benefit/risk assessment for 
RO7121661 remains unchanged. The study will not be unblinded and 
participants already randomized to the RO7121661 arm prior to this decision will 
continue to receive treatment with RO7121661 as long as participants are
experiencing clinical benefit, as assessed by the Investigator, in the absence of 
unacceptable toxicity or symptomatic deterioration attributed to disease 
progression after an integrated assessment of radiographic data, biopsy results 
(if available), and clinical status for a maximum of 24 months. Participants who 
meet the criteria for disease progression per RECIST v1.1 will be permitted to 
continue study treatment if they meet all criteria for treatment beyond 
progression.

Sections 3, 4.1, 8.1.1, and 9.3.2 have been amended to remove the endpoint of 
iRECIST from the protocol since tumor assessment data are no longer planned 
to be analyzed according to iRECIST criteria. 

In Section 5.1 (Inclusion Criteria), inclusion criterion #4 has been amended to 
improve clarity.

In Section 5.2 (Exclusion Criteria), exclusion criterion #5 has been amended to 
clarify that not all patients with a risk of fistula need to be excluded.

Table 6 in the Guidelines for Management of Immune-Mediated Myocarditis 
events (Appendix 7) has been updated following a health authorities request to 
include all grades immune-mediated myocarditis in the Guidelines for 
Management of Immune-Mediated Myocarditis events.
Additional minor changes have been made to improve clarity and consistency. 
Substantial new information appears in Book Antiqua italics. This amendment represents 
cumulative changes to the original protocol.

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4.2.2
Justification for Nivolumab Dose and Schedule..................... 43
4.3
End of Study Definition .......................................................... 43
5.
STUDY POPULATION................................................................................ 43
5.1
Inclusion Criteria.................................................................... 44
5.2
Exclusion Criteria................................................................... 47
5.3
Lifestyle Considerations......................................................... 50
5.4
Screen Failures ..................................................................... 50
5.5
Recruitment Procedures........................................................ 51
6.
TREATMENTS............................................................................................ 51
6.1
Treatments Administered....................................................... 51
6.1.1
Pre-medication ...................................................................... 52
6.2
Preparation/Handling/Storage/Accountability ........................ 52
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 54
6.3.1
Method of Treatment Assignment.......................................... 54
6.3.2
Blinding.................................................................................. 55
6.4
Treatment Compliance .......................................................... 55
6.5
Concomitant Therapy ............................................................ 56
6.5.1
Permitted Therapy................................................................. 56
6.5.2
Prohibited Therapy ................................................................ 56
6.6
Dose Modification.................................................................. 57
6.7
Treatment after the End of the Study..................................... 57
7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................. 58
7.1
Discontinuation of Study Treatment....................................... 58
7.1.1
Treatment after Disease Progression .................................... 59
7.1.2
Temporary Interruption .......................................................... 59
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 60
7.3
Lost to Follow-Up................................................................... 61
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 61
8.1
Efficacy Assessments............................................................ 62
8.1.1
Tumor and Response Evaluations......................................... 62

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8.1.2
Clinical Outcome Assessment............................................... 63
8.1.2.1
Data Collection Methods for Clinical Outcome 
Assessments ......................................................................... 64
8.1.2.2
Description of Clinical Outcome Assessment 
Instruments............................................................................ 65
8.2
Safety Assessments .............................................................. 66
8.2.1
Physical Examinations........................................................... 66
8.2.2
Vital Signs.............................................................................. 67
8.2.3
Electrocardiograms................................................................ 67
8.2.4
Eastern Cooperative Oncology Group 
Performance Status............................................................... 68
8.2.5
Royal Marsden Hospital Risk Score ...................................... 68
8.2.6
Transthoracic Echocardiogram or MUGA.............................. 68
8.2.7
Clinical Safety Laboratory Assessments................................ 68
8.2.8
Medical History and Demographic Data ................................ 69
8.3
Adverse Events and Serious Adverse Events ....................... 69
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event 
Information............................................................................. 70
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events ..................................................................... 70
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events ..................................................................... 71
8.3.3.1
Investigator Follow-Up........................................................... 71
8.3.3.2
Sponsor Follow-Up ................................................................ 71
8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events ..................................................................... 71
8.3.4.1
Emergency Medical Contacts................................................ 72
8.3.5
Pregnancy ............................................................................. 72
8.3.6
Non-Serious Adverse Events of Special Interest................... 72
8.3.7
Management of Specific Adverse Events .............................. 73
8.3.7.1
Infusion-Related Reactions.................................................... 73
8.3.7.2
Immune-mediated Adverse Events........................................ 74
8.4
Treatment of Overdose.......................................................... 75
8.5
Pharmacokinetics .................................................................. 75

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8.6
Immunogenicity Assessments ............................................... 76
8.7
Pharmacodynamics and Biomarkers Analyses...................... 76
8.7.1
Genetic and Genomic Analyses ............................................ 78
8.7.1.1
Whole Genome/Exome/Targeted DNA Analysis ................... 78
8.7.1.2
Transcriptome Analysis ......................................................... 79
8.8
Pharmacodynamics and Biomarker Samples........................ 79
8.8.1
Mandatory Samples............................................................... 80
8.8.2
Optional Samples .................................................................. 81
8.9
Samples for Research Biosample Repository ....................... 82
8.9.1
Overview of the Research Biosample Repository.................. 82
8.9.2
Sample Collection.................................................................. 83
8.10
Health Economics/Medical Resource Utilization 
and Health Economics........................................................... 84
8.11
Timing of Study Assessments ............................................... 84
8.11.1
Screening and Pre-treatment Assessments .......................... 84
8.11.2
Assessments during Treatment............................................. 84
8.11.3
Assessments at Treatment Discontinuation Visit................... 85
8.11.4
Follow-Up Assessments ........................................................ 85
8.11.5
Assessments at Unscheduled Visits...................................... 85
9.
STATISTICAL CONSIDERATIONS ............................................................ 86
9.1
Sample Size Determination ................................................... 86
9.2
Populations for Analyses ....................................................... 87
9.3
Statistical Analyses................................................................ 87
9.3.1
Demographics and Baseline Characteristics ......................... 87
9.3.2
Efficacy Analyses .................................................................. 88
9.3.3
Safety Analyses..................................................................... 89
9.3.4
Pharmacokinetic Analyses..................................................... 90
9.3.5
Immunogenicity Analyses...................................................... 91
9.3.6
Pharmacodynamic Analyses ................................................. 91
9.3.7
Pharmacokinetic/Pharmacodynamic 
Relationships......................................................................... 92
9.3.8
Other Analyses...................................................................... 92
9.3.8.1
Exploratory Analyses of PRO-CTCAE................................... 92

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9.4
Interim Analyses .................................................................... 93
9.5
Summaries of Conduct of Study............................................ 93
10. REFERENCES ........................................................................................... 94
11. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.................................................................................... 99
LIST OF TABLES
Table 1
Schedule of Activities.................................................................. 22
Table 2
Hourly Schedule of Assessments ............................................... 24
Table 3
Schedule of Assessment for Patient-Reported Outcomes.......... 26
Table 4
Estimands ................................................................................... 35
Table 5
Objectives and Endpoints ........................................................... 35
Table 6
Summary of Treatments Administered........................................ 52
Table 7
Recommendations for Infusion-related Reaction Prevention 
and Management........................................................................ 74
Table 8
Analysis Populations................................................................... 87
Table 9
Efficacy Statistical Analysis Methods.......................................... 88
Table 10
Safety Statistical Analysis Methods ............................................ 90
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 21
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations........ 100
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting........................................................... 110
Appendix 3
Procedures for Recording Adverse Events .............................. 118
Appendix 4
Clinical Laboratory Tests ......................................................... 124
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................ 127
Appendix 6
New Response Evaluation Criteria in Solid Tumors 
Version 1.1 Modified Excerpt from Original Publication with 
Addition of Supplementary Explanations .................................. 132

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Appendix 7
Risks Associated with Study Drugs and Guidelines for 
Management of Adverse Events Associated with Study 
Drugs ........................................................................................ 143
Appendix 8
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)........ 163
Appendix 9
European Organisation for Research and Treatment of 
Cancer Quality-of-Life Questionnaire for Esophageal Cancer 
(QLQ-OES18) ........................................................................... 165
Appendix 10
European Organisation for Research and Treatment of 
Cancer Item Library 97 (EORTC IL97)...................................... 166
Appendix 11
Patient Global Impression of Change and its Importance 
(PGI-CI)..................................................................................... 167
Appendix 12
Patient Global Impression of Severity (PGI-S)......................... 168
Appendix 13
Patient-Reported Outcomes Common Terminology Criteria 
for Adverse Events (PRO-CTCAE) ........................................... 169
Appendix 14
Correction Formulas for QTc Intervals ..................................... 171

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
2L
Second-line
ADA
Anti-drug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
BML
Below measurable limit
BP
Blood pressure
BsAb
Bispecific antibody
C1D1
Cycle 1 Day 1
CNS
Central nervous system
COVID-19
Coronavirus disease 2019
CPI
Checkpoint inhibitor
CR
Complete response
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
DCR
Disease control rate
DLT
Dose-limiting toxicities
DNA
Deoxyribonucleic acid
DoR
Duration of response
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EEA
European Economic Area
eCOA
Electronic clinical outcome assessment
ECOG
Eastern Cooperative Oncology Group
EIH
Entry-into-human
EORTC
European Organisation for Research and Treatment of 
Cancer
ESCC
Esophageal squamous-cell carcinoma
EU
European Union

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Abbreviation
Definition
FDA
Food and Drug Administration
FFPE
Formaldehyde fixed-paraffin-embedded 
FPI
First participant in
FSH
Follicle-stimulating hormone
GHS
Global health status
HBsAg
Hepatitis B surface antigen
HBcAb
Total hepatitis B core antibody
HCV
Hepatitis C
HIPAA
Health Insurance Portability and Accountability Act
HLH
Hemophagocytic lymphohistiocytosis
HIV
Human immunodeficiency virus
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IgA
Immunoglobulin A
IgE
Immunoglobulin E
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL97
Item library 97
IMP
Investigational medicinal product
imAE
Immune-mediated adverse event
IND
Investigational New Drug (application)
INR
International normalized ratio
IRB
Institutional Review Board
iRECIST
Immune response evaluation criteria in solid tumors
IRR
Infusion-related reaction
ITT
Intent-to-treat
IUD
Intrauterine device
IV
Intravenous
IxRS
Interactive (voice/web) response system
JMC
Joint Monitoring Committee
LAG3
Lymphocyte-activation gene 3
LDH
Lactate dehydrogenase
LDL
Low-density lipoproteins
LH
Luteinizing hormone
MAS
Macrophage activation syndrome

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Abbreviation
Definition
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
MUGA
Multiple-gated acquisition scans
NCI
National Cancer Institute
NGS
Next generation sequencing
NK
Natural killer
NSAESI
Non-serious adverse event of special interest
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Pharmacodynamic
PD1
Anti–programmed death-1
PFS
Progression-free survival
PGI-CI
Patient Global Impression of Change and its 
Importance
PGI-S
Patient Global Impression of Severity
PK
Pharmacokinetic
PR
Partial response
PRO
Patient-reported outcome (also refers to participants)
PRO-CTCAE
Patient-Reported Outcomes Common Terminology 
Criteria for Adverse Events
PT
Prothrombin time
Q2W
Every 2 weeks
QLQ-C30
Quality-of-life questionnaire
QLQ-OES18
Quality-of-life questionnaire for esophageal cancer
QRS
QRS complex
QT
QT interval
QTc
QT corrected for heart rate
QTcF
QT corrected for heart rate using the Fridericia’s 
correction factor
RBR
Research biosample repository
RECIST
Response evaluation criteria in solid tumors
RNA
Ribonucleic acid
RR
RR interval
SAE
Serious adverse event
SARS-CoV-2
Sudden acute respiratory syndrome coronavirus 2

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Abbreviation
Definition
SDR
Stable disease rate
SoA
Schedule of activities
TIM3
T cell immunoglobulin and mucin domain 3
TMB
Tumor mutational burden
TnI
Troponin I
TnT
Troponin T
TSH
Thyroid-stimulating hormone
TTE
Transthoracic echocardiogram
ULN
Upper limit of normal
U.S.
United States
WES
Whole exome sequencing
WMS
Whole metagenomic sequencing
WGS
Whole genome sequencing
WOCBP
Women of childbearing potential

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1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A 3-ARM, RANDOMIZED, BLINDED, ACTIVE-CONTROLLED,
PHASE II STUDY OF RO7121661, A PD1-TIM3 BISPECIFIC 
ANTIBODY AND RO7247669, A PD1-LAG3 BISPECIFIC 
ANTIBODY, COMPARED WITH NIVOLUMAB IN PARTICIPANTS 
WITH ADVANCED OR METASTATIC SQUAMOUS CELL 
CARCINOMA OF THE ESOPHAGUS
SHORT TITLE
A PHASE II STUDY OF RO7121661 AND RO7247669 COMPARED 
WITH NIVOLUMAB IN ADVANCED OR METASTATIC SQUAMOUS 
CELL CARCINOMA OF THE ESOPHAGUS
PROTOCOL NUMBER:
BP42772
VERSION:
3
TEST PRODUCT:
RO7121661, RO7247669, Nivolumab
PHASE:
II
RATIONALE
Cancer remains a major cause of death worldwide despite several new agents providing survival 
benefits to patients. Many cancer indications have a poor prognosis and the management of 
most advanced solid tumors remains challenging because of the high rate of tumor recurrence or 
the development of distant metastases.
Despite the effectiveness of PD1/L1 checkpoint inhibitor (CPI) therapy in various tumor types 
including esophageal squamous-cell carcinoma (ESCC), additional treatment options targeting 
immune checkpoints are needed, because the majority of patients eventually progress after an 
initial response or fail to respond to PD1/L1 checkpoint blockade.
By targeting both PD1 and TIM3 or LAG3 on dysfunctional tumor-specific T lymphocytes, the 
PD1-TIM3 and PD1-LAG3 bispecific antibodies aim to restore an effective anti-tumor 
immune-response and provide survival benefit to more patients with cancer than currently 
available agents do. PDL1 expression in ESCC ranges from 15% to 83% in tumor cells and from 
13% to 31% in tumor-infiltrated immune cells. Studies with nivolumab, pembrolizumab, and other 
PD1 inhibitors demonstrated benefit over chemotherapy in the second-line (2L) ESCC 
population leading to market authorizations in that setting (e.g., in the U.S., EU, Japan, South 
Korea, and other jurisdictions). Both TIM3 and LAG3 have been shown to be expressed on 
tumor-infiltrating lymphocytes in patients with ESCC. RO7121661 and RO7247669 may 
therefore have the potential to be a therapeutic option for patients with ESCC.
The purpose of this study is to assess the efficacy of RO7121661 and RO7247669 compared 
with nivolumab to address a significant unmet medical need in patients with unresectable 
advanced or recurrent ESCC who are refractory or intolerant to one prior line of chemotherapy.

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OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the efficacy of
RO7247669 compared with
nivolumab.

OS, defined as the time from randomization to death from 
any cause 
Secondary
To evaluate the safety and 
tolerability of RO7121661and 
RO7247669 compared with
nivolumab.

Nature, frequency, and severity of adverse events (AEs) 
graded according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0
To evaluate the efficacy of 
RO7247669 compared with
nivolumab.

Objective response rate (ORR), defined as the proportion 
of participants with an objective response (i.e., complete 
response [CR] or partial response [PR]), according to 
RECIST v1.1

Disease control rate (DCR), defined as ORR stable 
disease rate (SDR)

Duration of response (DoR) for participants with ORR, 
defined as the time from the first occurrence of a
documented objective response to disease progression 
according to RECIST v1.1 or death from any cause, 
whichever occurs first

Progression-free survival (PFS) defined as the time from 
randomization to the first occurrence of progression as 
determined by the Investigator according to RECIST v1.1
or death during the treatment period or within 60 days of 
the last tumor assessment after treatment discontinuation 
from any cause, whichever occurs first

Proportion of participants reporting clinically meaningful 
improvement in global health status/quality of life, 
emotional functioning, social functioning and dysphagia as 
measured by the European Organisation for Research 
and Treatment of Cancer (EORTC) Quality-of-life 
questionnaire (QLQ)-C30, IL97, and OES-18, defined as 
an improvement of at least 10 points
To investigate the pharmacokinetics 
(PK) of RO7247669 and nivolumab.

Serum concentrations, PK profiles and parameters for 
RO7121661, RO7247669, and nivolumab
To evaluate the immune response 
after administration RO7247669 and 
nivolumab.

Incidence and titer of RO7121661, RO7247669 or 
nivolumab anti-drug antibodies (ADAs) during the study 
relative to the prevalence of ADA at baseline
To assess treatment-induced 
pharmacodynamic changes (PD 
Biomarkers) in peripheral blood and 
tumor microenvironment

Changes from baseline in the phenotype and activation 
status (CD4/CD8 HLA-DR+Ki67+) of T-cell subsets in the 
peripheral blood

Changes from baseline such as CD8 T-cell infiltration, 
proliferation (CD8+Ki67+) in the tumor microenvironment
To assess baseline characteristics in 
the tumor microenvironment as 
predictive biomarkers of response

Baseline PDL1, CD8+PD1+, CD8+TIM3+, and 
CD8+LAG3+ expression in the tumor microenvironment

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home. This specifically applies to days where no other hospital assessments are required—i.e.,
C1D8 and C5D8.
Participant samples, including archival and fresh tumor tissue, serum, plasma, and blood 
samples, will also be collected for biomarker assessments. 
Safety assessments will include the incidence, nature, and severity of AEs, and other 
protocol-specified tests such as laboratory abnormalities that are deemed critical to the safety 
evaluation of the study.
After study treatment discontinuation and disease progression per RECIST v1.1, survival 
follow-up information will be collected by means of telephone calls, participant medical records, 
and/or clinic visits approximately every 3 months until death, lost to follow-up, or study 
termination by the Sponsor, whichever occurs first. All participants will be periodically contacted 
for survival and new anti-cancer therapy information unless the participant requests to be 
withdrawn from follow-up (this request must be documented in the source documents and signed 
by the Investigator). If the participant withdraws from the study, study staff may use a public 
information source (e.g., county records) when permissible to obtain information about survival 
status.
The IMPs are: RO7121661 (2100 mg Q2W IV), RO7247669 (2100 mg Q2W IV), and nivolumab
(240 mg Q2W IV).
Length of Study
The duration in each period of the study for each participant will be as follows:

Screening: Days -28 to -1.

Treatment Period: Cycle 1 Day 1 up to a maximum of 24 months.

Survival follow-up: 90 (7) days after last treatment with study drug; then every 
3 months (14 days) until death, loss to follow-up, or study termination by the Sponsor.
End of Study
The end of the study will occur when all of the following criteria have been met:

The required number of deaths for the primary analysis of OS has been observed.

The last participant, last visit has occurred.
Data Monitoring Committee
A Joint Monitoring Committee (JMC) will review available safety data periodically and make 
recommendations regarding study conduct to ensure the safety of patients enrolled in the study. 
The JMC will consist of designated Sponsor personnel and independent clinical expert(s) (i.e., 
expert[s] independent from the Sponsor). The JMC Chair will be a medical oncologist who is 
neither the Medical Monitor nor associated with the study. Other JMC members will include, but
not be limited to, a drug-safety scientist and biostatistician. The responsibility, membership, and 
communication flow of the JMC is further described in the JMC Charter.
PARTICIPANT POPULATION
The study population consists of male and female participants with advanced or metastatic 
ESCC who are not indicated for radical resection and who are refractory or intolerant to 
fluoropyrimidine- or taxane- and platinum-based regimen.

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Key Inclusion Criteria (for details, see Section 5.1 of the protocol)

Participants with advanced or metastatic, histologically confirmed ESCC.

Patients who are not indicated for radical resection and have previously received 1 line 
of treatment in non-curative intention prior to randomization. The prior line must be 
either a fluoropyrimidine- and platinum- or a taxane- and platinum-based regimen, and 
patients must have experienced progressive disease after at least 3 cycles or be 
unable to tolerate potential side effects of this treatment.
Patients who did not receive treatment in the non-curative setting but received a 
fluoropyrimidine-/taxane and platinum-based drug regimen in curative intent may be 
allowed. This includes patients who had either radical resection in conjunction with 
chemotherapy including neo-adjuvant/adjuvant therapy (radiotherapy) or patients 
who were treated with chemo-radiation (including patients who underwent 
chemo-radiation followed by salvage surgery).

If recurrence or progression was confirmed by imaging or by pathological 
assessment of a biopsy within 24 weeks after the last dose of the treatment, 
patients are eligible and do not require an additional line of therapy in the non-
curative setting.

If recurrence or progression occurred later than 24 weeks after the last dose of the 
treatment, patients need to be exposed to an additional line of fluoropyrimidine-
/taxane- and platinum-based drugs in the non-curative setting to be eligible for the 
study—unless the Investigator considers the patient not eligible for the re-exposure 
with fluoropyrimidine/taxane and platinum-based drugs.

The last dose of chemotherapy or the last radiation treatment (whichever occurs 
later) should be considered for the determination of the time-point of recurrence or 
progression after chemo-radiation.

Radiologically measurable disease according to RECIST v1.1. Previously irradiated 
lesions should not be counted as target lesions unless clearly progressed after the 
radiotherapy.

Eastern Cooperative Oncology Group Performance Status 0-1.

A life expectancy of 12 weeks.

Tissue samples must be provided for analysis of PD-L1 tumor positivity using the PDL1 
IHC 28-8 pharmDx assay. Testing will be done centrally and results must be obtained 
prior to stratification. 

Adequate visceral organ functions

AEs from any prior radiotherapy, chemotherapy, or surgical procedure must have 
resolved to Grade 1, except alopecia (any grade), vitiligo, endocrinopathy managed 
with replacement therapy, and Grade 2 peripheral neuropathy.

Adequate contraception
Key Exclusion Criteria

Pregnancy, lactation, or breastfeeding.

Known hypersensitivity to any of the components of RO7121661, RO7247669, or 
nivolumab, including but not limited to, hypersensitivity to Chinese hamster ovary cell 
products or other recombinant human or humanized antibodies.

Patients with significant malnutrition. Patients whose nutrition has been well controlled 
for 28 days prior to randomization may be enrolled.

Evidence of complete esophageal obstruction not amenable to treatment.

Higher risk of bleeding or fistula caused by esophageal lesions invading adjacent 
organs (aorta or tracheobronchial tree). Patients with manageable fistula may be 
included at the Investigator's discretion.

Symptomatic central nervous system (CNS) metastases.

RO7121661, RO7247669, Nivolumab—F. Hoffmann-La Roche Ltd
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
Spinal cord compression not definitively treated with surgery and/or radiation or without 
evidence that disease has been clinically stable for 14 days prior to randomization.

Active or history of carcinomatous meningitis/leptomeningeal disease.

Asymptomatic CNS primary tumors or metastases if they have requirement for steroids 
or enzyme-inducing anticonvulsants in the last 28 days prior to randomization.

Uncontrolled tumor-related pain. 

Patients with an active second malignancy. 

Evidence of significant, uncontrolled concomitant diseases that could affect compliance 
with the protocol or interpretation of results.

Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent.

Significant cardiovascular/cerebrovascular disease within 6 months prior to 
randomization.

Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not 
limited to tuberculosis [TB] and typical mycobacterial disease), parasitic, or other 
infection (excluding fungal infections of nail beds) or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of 
the course of antibiotics, except if for tumor fever) within 28 days prior to 
randomization.

Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease.

Major surgical procedure or significant traumatic injury (excluding biopsies) within 
28 days prior to randomization, or anticipation of the need for major surgery during the 
course of the study.

Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation of 
the results or render the participant at high risk from treatment complications.

Dementia or altered mental status that would prohibit informed consent.

Uncontrolled pleural effusion (with the exception of participants with indwelling 
catheters, e.g., PleurX), pericardial effusion, or ascites requiring recurrent drainage 
procedures (expected to occur once monthly or more frequently). 

Active or history of autoimmune disease or immune deficiency.

Positive HIV test at screening.

Positive hepatitis B surface antigen (HBsAg) or positive total hepatitis B core antibody 
(HBcAb) test at screening. Participants with a positive HBsAg or total HBcAb test 
followed by a negative hepatitis B virus (HBV) DNA test at screening are eligible.

Positive hepatitis C virus (HCV) antibody test at screening. Participants with a positive 
HCV antibody test followed by a negative HCV RNA test at screening are eligible.

Prior cancer therapy with any immunomodulatory agents including CPIs (such as 
anti-PDL1/PD1, anti-CTLA-4, anti-LAG3, anti-TIM3).

Vaccination with live vaccines within 28 days prior to randomization, or anticipation that 
a live attenuated vaccine will be required during the study.

Treatment with therapeutic oral or IV antibiotics within 14 days prior to randomization.

Concurrent therapy with any other investigational drug (defined as treatment for which 
there is currently no regulatory authority-approved indication) 28 days or 5 half-lives 
of the drug, whichever is shorter, prior to randomization.

Treatment with immune-modulating and immune suppressive agents/medication 
5 half-lives or 28 days (whichever is shorter) prior to randomization.

Regular immunosuppressive therapy (i.e., for organ transplantation, chronic 
rheumatologic disease). 

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
Radiotherapy within the last 28 days before start of study drug treatment is not allowed, 
with the exception of limited palliative radiotherapy.

Prior treatment with adoptive cell therapies, such as CAR-T therapies.
NUMBER OF PARTICIPANTS
 
plus an estimated number of patients enrolled in the RO7121661 arm at the time of switching 
from 3 to 2 arms.
CONCOMITANT MEDICATIONS
As a general rule, no concomitant medication will be permitted, with the exception of medications 
to treat AEs, unless the rationale for exception is discussed and clearly documented between the 
Investigator and the Sponsor.
Use of the following therapies is prohibited during the study and for at least 28 days or 
5 half-lives of the drug, whichever is shorter, prior to randomization and during study treatment, 
unless otherwise specified below:

Investigational or unlicensed/unapproved agents.

Therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, and radiotherapy [with the 
exception of limited palliative radiotherapy], as well as herbal therapy or traditional 
Chinese medicines with anti-cancer activity in the label), whether Health Authority-
approved or experimental.

Chronic use of steroids (inhaled and topical steroids are permitted) at baseline of 
10 mg of prednisone/day (or equivalent). Concurrent high doses of systemic 
corticosteroids.

Administration of a live, attenuated vaccine or anticipation that such a live attenuated 
vaccine will be required during the study or within 4 months after the administration of 
the final dose of the study drug.

Systemic immunostimulatory agents (including, but not limited to, interferons and IL-2) 
because these agents could potentially increase the risk for autoimmune conditions 
when given in combination with CPIs.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) because these agents 
could potentially alter the efficacy and safety of the study drug.

Adoptive cell therapies, such as CAR-T therapies.

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Table 1
Schedule of Activities
Cycle length 14 days
Screening
On dosing days of all 
treatment Cyclesa
Cycle 1 - 5 
Day 8
Treatment 
Discontinuation
Follow-up 
Day (D)
D -28 to D -1
(unless otherwise 
indicated)
Every 14 Days 
(-1/+3 days)
(± 1 day)
≤ 30 Days after
Last Dose
90 (±7 days) post last dose, then 
every 3 months (±2 weeks)
At the time of event
≥48 hours after the 
onset of an IRR
Informed consent (incl. RBR)
x
8.2.8
Medical history and demography
x
8.2.5
Royal Marsden Risk Score
x
6.1
Study drug administration 
x
6.5
Previous and concomitant treatments
x
x
8.3
Adverse events
x
x
x
8.2.1
Physical examination
x
x
x
Weight only
8.2.1
Height
x
8.2.2
Vital signsb
x
x
x
8.2.3
12-lead ECG
x
x
x
x
8.2.4
ECOG performance status
x
x
x
8.2.6
TTE or MUGA
x
8.1.2
PRO-assessments
8.8.2
Nutritional assessment (optional)
C1, C4 and upon 
occurrence of colitis
8.1.1
Tumor assessment
(CT scan of chest, abdomen, pelvis, brain, 
and other regions as clinically indicated)
8.11.4
Post-study survival and anti-cancer 
therapies
x
Viral serology
x
Quantitative immunoglobulins
x
Hematology
x
x
x
x
Blood chemistry
x
x
x
x
Coagulation
x
x
x
x
Lipid panel 
x
C1 and then every 4 cycles
x
Thyroid function
x
C3 and then every 3 cycles
Auto-antibody panel
x
In case of suspected Grade 
≥ 2 imAEs
In case of suspected 
imAEs
Urinalysis
x
x
x
IgE/tryptase
xd
xd
Pregnancy test
x
(blood test, 
D -7 to D -1)
C2 and then 
every 4 weeks
(blood or urine)
x
(blood or urine) 
xe (5 months after the last dose)
8.5
PK 
x
8.6
ADA
PD plasma 
x
PD serum 
x
PD whole blood flow cytometry
x
Whole Blood RNA
bTMB/ctDNA
8.7.1
WGS
8.8.1
Archival tumor sample
Fresh tumor biopsy (optional)
Tongue scrape (optional)
Stool sample (optional)
8.9
RBR sample (saliva DNA)
Local Laboratory Assessments
8.2.7 
and 
Appendix 4
Central Laboratory Assessments
Refer to Hourly Schedule of Assessments for specific sample collection timepoint details
8.8.1
8.8.2
continuous
Refer to the PRO assessments table for specific Timepoint Details
Protocol 
Section
In case of Grade ≥2 IRR, suspected 
anaphylaxis, or Grade ≥ 2 suspected imAEs
Screening Assessments
IMP Administration
Clinical Assessments

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Table 1
Schedule of Activities (cont.)
Abbreviations: ADA Anti-drug antibody; AE Adverse event; C Cycle; D Day;
ECOG Eastern Cooperative Oncology Group; imAE Immune-mediated adverse event; 
IMP Investigational medicinal product; IRR Infusion-related reaction; MUGA Multiple-
Gated Acquisition Scans; PD Pharmacodynamic; PK Pharmacokinetic; PRO Patient-
reported outcome; RBR Research biosample repository; TTE Transthoracic 
echocardiogram; WGS Whole genome sequencing.
a)
During the study treatment period, assessments scheduled on the days of study treatment 
infusions should be performed before the start of infusion unless otherwise noted. Laboratory 
results have to be available prior the initiation of treatment.
b)
Vital signs include pulse rate, respiratory rate, blood pressure, and temperature at every 
assessment and blood oxygen saturation pre-dose at visits where tumor assessments are 
performed. For the first infusion, vital signs should be determined within 60 minutes before 
and 30 (10) minutes after the end of infusion. Vital signs will also be collected during the 
first infusion (every 15 [5] minutes). During subsequent infusions, vital signs should be 
determined within 60 minutes before the infusion, during each infusion only as clinically 
indicated and within 15 (10) minutes after the end of each infusion. Additional vital signs 
should be collected during the infusion, if clinically indicated, or if symptoms occurred with 
the prior infusion. Blood oxygen saturation by pulse oximetry at baseline screening and pre-
dose at every visit where tumor assessments are performed.
c)
Participants who discontinue treatment for reasons other than radiographic disease 
progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue 
scheduled tumor assessments at the frequency described above until radiographic disease 
progression per RECIST v1.1, initiation of a new anti-cancer therapy, withdrawal of consent, 
death, or study termination by Sponsor, whichever occurs first. Thus, tumor assessments are 
to continue according to the schedule in participants who discontinue treatment for reasons 
other than disease progression or loss of clinical benefit. 
d)
Tryptase and total IgE should be analyzed for participants who experience a Grade 3 IRR 
during the first study treatment administration or for participants who experience a Grade 
2 IRR for the first time with the second or subsequent study drug infusion or with clinical 
signs of hypersensitivity reaction at any time of the conduct of the study. A second sample for 
IgE/tryptase analysis should be collected at least 48 hours after the onset of the reaction to 
rule out the possibility of an anaphylactic reaction.
e)
An at-home pregnancy test will be provided. The test has to be conducted 5 months after the 
final dose (for women of childbearing potential), and the site will inquire about the result 
during the second follow up.

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Table 2
Hourly Schedule of Assessments
Q2W regimen; 
Cycle length 
14 days
Screening
Treatment 
Discontinuation
Day
Day 8
Day 8
Scheduled 
Time (h)a
PreDose
EOI
4
168
PreDose
EOI
4
PreDose
EOI
PreDose
EOI
PreDose
EOI
4
168
PreDose
EOI
At Visit
Protocol 
Section
Time Window
-4h
+ 10 min
+/- 1 h
 +/- 24 h
-4h
+ 10 min
+/- 1 h
-4h
+ 10 min
-4h
+ 10 min
-4h
+ 10 min
+/- 1 h
 +/- 24 h
-4h
+ 10 min
8.5
 PK Sample
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
8.6
ADA 
x
x
x
x
x
C7 and then every 3 cycles
x
PD Serum
x
x
x
x
At the time of tumor assessment
x
PD Plasma 
x
x
x
x
C9 and then every 3 cycles
x
Whole Blood 
Flow 
Cytometry 
x
x
x
x
x
x
C9 and then every 3 cycles
x
Whole Blood 
RNA 
x
x
bTMB/ctDNA 
x
x
x
8.7.1
WGS
x
8.8.1
Archival 
Tumor Sample
x
Fresh Tumor 
Biopsy 
(Optionalb)
x
x
(+2/ -1 day[s])
Tongue 
Scrape 
(Optionalc)
x
(+0/ -5 day[s])
x
(+0/ -5 day[s])
Stool Sample 
(Optionalc)
x
(+0/ -5 day[s])
x
(+0/ -5 day[s])
8.9
RBR Sample
(Saliva DNA)
Optionald
x
8.8.1
8.8.2
Day 1
Subsequent Cycles
Day 1
Day 1
Day 1
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Day 1
Day 1

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Table 2
Hourly Schedule of Assessments (cont.)
Abbreviations: ADA Anti-drug antibody; C Cycle; EOI End of infusion; h Hour; PD Pharmacodynamic; PK Pharmacokinetic; 
Q2W Every two weeks; RBR Research biosample repository; WGS Whole genome sequencing.
a)
Assessments (e.g., pre-dose) should be performed relative to the start of the study drug infusion except for those at EOI time-points.
b)
As exception, a mandatory baseline fresh biopsy is required to be collected in case no suitable archival tissue sample is available to assess the 
PD-L1 positivity of a participant’s tumor (see Section 5.1)
c)
An additional sample should be taken upon occurrence of colitis, as assessed and confirmed by the Investigator.
d)
Samples for RBR DNA saliva will be collected on Day 1 from all participants who signed RBR ICF prior to study drug infusion. If the RBR DNA 
saliva sample is not collected during the scheduled visit, it may be collected at any time during the conduct of the clinical study.

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Table 3
Schedule of Assessment for Patient-Reported Outcomes 
Abbreviations: C Cycle. PRO Patient-reported outcome.
a)
All PRO instruments are required to be administered before the participant receives any information on 
disease status, prior to the performance of non-PRO assessments, and prior to the administration of 
study treatment, unless otherwise specified. In scenarios where assessments (e.g., blood draws) are 
done at a different location than the one providing treatment or when they are done on a different day 
than study treatment administration, laboratory assessments can be completed before the completion 
of PRO instruments as long as results have not been discussed with participants.
b)
On days where no site visit is planned, remote completion of PROs is accepted.
Cycle length 14 
days
Day (D)
QLQ-C30a
QLQ-IL97a
QLQ-OES18a
PGI-CIa
PGI-Sa
PRO-CTCAEa
Day 1
x
x
x
x
x
Day 8 
(± 1 day)
xb
Day 1
x
x
x
Day 8 
(± 1 day)
xb
Day 1
x
x
x
x
x
Day 8 
(± 1 day)
xb
Day 1
x
x
x
Day 8 
(± 1 day)
xb
Day 1
x
x
x
Day 8 
± 1 day)
xb
Cycle 6
Day 1
x
x
x
x
x
Cycle 7
Day 1
x
x
x
Cycle 8
Day 1
x
x
x
Cycle 9
Day 1
x
x
x
x
x
Subsequent 
cycles
Day 1
C10 and then every  
6 cycles
x
C12 and then 
every 6 cycles
C12 and then 
every 6 cycles
x
Treatment 
Discontinuation
≤ 30 Days after
Last Dose
x
x
x
x
x
Follow-up 
90 (±7 days) 
post last dose, 
then every 3 
months
 (±2 weeks)
Every 3 months 
during the 1st year 
post discontinuationb
Every 3 months 
during the 1st year 
post discontinuationb
At 1st follow-up 
onlyb
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5

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2.
INTRODUCTION
RO7121661, an anti-programmed death-1 (PD1)/T-cell immunoglobulin and mucin 
domain 3 (TIM3) bispecific antibody (BsAb) and RO7247669, an anti 
PD1/lymphocyte-activation gene 3 (LAG3) BsAb, were designed to target dysfunctional 
tumor antigen-specific T lymphocytes (expressing PD1 and TIM3 or LAG3 respectively) 
in order to establish or restore an effective anti-tumor immune response in patients with 
cancer with a high unmet medical need.
This Phase II study in patients with squamous cell carcinoma of the esophagus (ESCC)
aims to evaluate the efficacy of RO7121661 and RO7247669 compared to nivolumab.
2.1
STUDY RATIONALE
Cancer remains a major cause of death worldwide despite several new agents providing 
survival benefits to patients. Many cancer indications have a poor prognosis and the 
management of most advanced solid tumors remains challenging because of the high 
rate of tumor recurrence or the development of distant metastases.
Despite the effectiveness of PD1/L1 checkpoint inhibition (CPI) therapy in various tumor 
types including ESCC (Kato et al. 2019; Kim et al. 2019), additional treatment options 
targeting immune checkpoints are needed, because the majority of patients eventually 
progress after an initial response or fail to respond to the PD1/L1 checkpoint blockade.
By targeting both PD1 and TIM3 or LAG3 on dysfunctional tumor-specific 
T lymphocytes, the PD1-TIM3 and PD1-LAG3 BsAbs aim to restore an effective 
anti-tumor immune-response and provide survival benefit to more patients with cancer
than currently available agents do. PDL1 expression in ESCC ranges from 15% to 83% 
in tumor cells and from 13% to 31% in tumor-infiltrated immune cells (Jiang et al. 2017; 
Lam et al. 2017; Guo et al.2017; Qu et al. 2016). Studies with nivolumab, 
pembrolizumab, and other PD1 inhibitors demonstrated benefit over chemotherapy in 
the second-line (2L) ESCC population leading to market authorizations in that setting
(e.g., in the U.S, EU, Japan, South Korea, and other jurisdictions). Both TIM3 and LAG3 
have been shown to be expressed on tumor-infiltrating lymphocytes in patients with 
ESCC (Zhang et al. 2018; Wang et al 2019; Zhao et al. 2020). RO7121661 and 
RO7247669 may therefore have the potential to be a therapeutic option for patients with 
ESCC.
The purpose of this study is to assess the efficacy of RO7121661 and RO7247669
compared with nivolumab to address a significant unmet medical need in patients with 
unresectable advanced or recurrent ESCC who are refractory or intolerant to one prior 
line of chemotherapy.
The rationale for the study design is provided in Section 4.1.4.

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2.2
BACKGROUND
2.2.1
Background on Esophageal Carcinoma
Esophageal cancer is the seventh most common cancer and the sixth most common 
cause of death from cancer worldwide (Bray et al. 2018). The incidence, prevalence, and 
histologic type of esophageal cancer varies between geographic regions. ESCC 
accounts for 70% of cases of esophageal cancer globally and is particularly common in 
a so-called “esophageal cancer belt,” which stretches from northern China through the 
central Asian republics to Northern Iran. Adenocarcinoma is the predominant histologic 
type in Western countries (United States and Europe). Adenocarcinoma and squamous 
cell carcinoma have differing biologic pathways and are therefore treated differently.
Advanced esophageal cancer is a rapidly fatal disease. More than two-thirds of patients 
diagnosed with esophageal cancer will have advanced or metastatic disease, with a 
median survival of 8 to11 months and an expected 5-year survival rate of 5% (Drahos 
et al 2013; Lin et al 2016; Kato et al. 2019; Kim et al. 2019). The impact of esophageal
cancer on patients is multifaceted. Most affected individuals present with physical 
symptoms, primarily dysphagia (Daly et al. 2000), which can result in unintentional 
weight loss and loss of appetite; less common symptoms include chest pain, dyspnea, 
and gastrointestinal reflux. However, patients also frequently report poor emotional 
wellbeing, and in particular, high rates of anxiety and depression (Bergquist et al. 2007). 
Each of these patient-reportable issues has a significant impact on patients’ quality of
life. These data, combined with the relative lack of highly effective treatments, are 
indicative of the large unmet medical need in patients diagnosed with advanced 
esophageal cancer.
2.2.2
TREATMENT FOR ADVANCED ESOPHAGEAL SQUAMOUS
CELL CARCINOMA
2.2.2.1
Chemotherapy
There is no consensus on the optimal regimen for first-line treatment of advanced 
esophageal cancer globally. For ESCC in particular, there are no data from recent 
randomized controlled studies. However, combination chemotherapy is typically given as 
first-line treatment. Treatment regimens for ESCC commonly consist of cisplatin in 
combination with paclitaxel or 5-fluorouracil (5-FU) (Lordick and Janjigian 2016; 
Kitagawa et al. 2019; NCCN 2019; NHCPRC 2019): These regimens are associated with 
objective response rates (ORRs) ranging from 20% to 48%, 5-year survival rates of less 
than 10%, and significant toxicity rates (Grünberger et al. 2007). There are regional 
preferences for the chemotherapy of choice, which may be based on the toxicity profile
of each agent.

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In the 2L setting, single-agent chemotherapy is an established option based on patient 
benefit-risk assessment (Lordick et al 2016; Muro et al 2019; NCCN 2019; Kitagawa et 
al. 2019). Although 2L treatments with docetaxel and paclitaxel are used for patients with 
advanced ESCC that has progressed after first-line chemotherapy, they are associated 
with hematological, gastrointestinal, and neurological toxicities (Jimenez et al. 2011);
with poor long-term survival (Kato et al. 2011; Muro et al. 2004).
2.2.2.2
Anti-PD1 Therapy 
More recently, positive Phase 3 data have been shown with three anti-PD1 treatments in 
2L ESCC.
Data from the ATTRACTION-3 study demonstrated the survival benefit of nivolumab 
versus Investigator-selected chemotherapy (paclitaxel or docetaxel) in patients with 
ESCC (Kato et al. 2019). In the intent-to-treat (ITT) population, overall survival (OS) was 
statistically significantly prolonged in the nivolumab arm compared with that in the 
chemotherapy arm. The survival benefit with nivolumab occurred regardless of patients’ 
level of tumor PDL1 expression despite a numerically greater clinical benefit in patients 
with tumor PDL1 expression of at least 1% versus those with less than 1%.
Pembrolizumab showed positive data in ESCC in the Keynote-181 study compared to an 
Investigator’s choice of paclitaxel, docetaxel or irinotecan (Kojima et al. 2019). While the 
OS benefit over chemotherapy was only statistically significant in patients with a 
combined positive score 10, the hazard ratio in the overall ESCC population was 
0.78 (0.63-0.96) compared with chemotherapy, marginally missed statistical significance 
based on pre-specified statistical boundaries.
Likewise, camrelizumab provided positive data as 2L treatment of ESCC in the ESCORT 
study compared with Investigator’s choice of either docetaxel or irinotecan (Huang et al.
2020). Camrelizumab significantly improved OS compared with chemotherapy. 
Subgroup analysis showed that clinical benefits of camrelizumab were observed in all 
PDL1 expression subgroups, and patients with higher PDL1 expression appeared to 
derive more benefit than those with low PDL1 expression.
Overall, these data indicate that CPIs (such as anti-PD1) demonstrate single-agent 
activity in 2L ESCC and treatment with anti-PD1 agents and is an approved treatment 
option in a variety of countries. 

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2.2.3
Background on RO7121661
RO7121661 is a novel, Fc-silent, IgG1-based BsAb in the 1 1 format that incorporates 
monovalent binding to the checkpoint receptors PD1 and TIM3. Use of a natural IgG-like 
monovalent heterodimeric IgG1 format allows avidity for simultaneous binding to PD1 
and TIM3 when both receptors are co-expressed. RO7121661 binds with monovalent 
high affinity to a glycopeptide-epitope on PD1 and with low affinity to TIM3 to induce an 
avidity-driven selectivity effect for binding to T-cells in the tumor microenvironment that 
co-expresses both PD1 and TIM3 or to T-cells expressing PD1 alone. This preferential 
binding avoids the targeting of other TIM3 expressing cells such as myeloid or natural 
killer (NK) cells.
An additional feature of RO7121661 is the specifically engineered, IgG1-based,
Fc-region that prevents binding to Fc-gamma receptors by introduction of PGLALA 
mutations (Kabat et al. 1991; Schlothauer et al. 2016). This avoids drug-shaving and 
thus tumor-associated macrophage resistance mechanisms, which have been observed 
with IgG4-based antibodies such as pembrolizumab and nivolumab (Arlauckas et al.
2017).
RO7121661 is currently being evaluated in the entry-into-human (EIH) Study NP40435.
The available nonclinical and clinical data provide a strong rationale for evaluating the 
potential clinical benefit of RO7121661 in patients with ESCC.
A detailed description of the chemistry, pharmacology, and safety of RO7121661 is 
provided in the RO7121661 Investigator’s Brochure.

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2.2.4
Background on RO7247669
RO7247669 is a novel, Fc-silent IgG1-based BsAb in 1 1 format that incorporates 
monovalent binding to the checkpoint receptors, PD1 and LAG3. Use of a natural 
IgG-like monovalent heterodimeric IgG1 format allows one to make use of avidity (e.g.,
simultaneous binding to PD1 and LAG3). RO7247669 BsAb is engineered to 
preferentially bind to T-cells in the tumor microenvironment that co-express both PD1 
and LAG3, or to a lesser extent either PD1 or LAG3 alone. RO7247669 binds with 
monovalent high affinity to a PD1 glycoepitope and binds with monovalent high affinity to 
a novel epitope (E3) on LAG3 Domain 1. Although RO7247669 binds with high affinities 
to PD1 and LAG3, RO7247669 induces an avidity driven selectivity effect for binding to 
T-cells in the tumor microenvironment that co-express both PD1 and LAG3. Preferential 
binding to T-cells in the tumor microenvironment avoids the targeting of other LAG3 
expressing cells such as regulatory T cells in the tumor and in the periphery (which do 
not express high levels of PD1). Monovalent binding to LAG3 reduces internalization of 
the antibody (Ab) upon binding to the T-cell surface. The retention time of monovalent
RO7247669 on T-cell surface is higher when simultaneously bound to PD1 and LAG3. 
As for RO7121661, PGLALA mutations have been introduced into the IgG1-based Fc-
region RO7247669 to avoid drug-shaving and thus tumor-associated macrophage 
resistance mechanisms.
.
 
 
 
 
 
As of the cutoff date, 15 October 2020, the DCR in Part A of the study was 51.5% 
(17 out of 33 evaluable participants) and the ORR was 6.1 % (2 out of 33 participants).
Responses were observed in one participant with breast cancer and one participant with 
non-small cell lung cancer. Amongst the participants dosed at the proposed dose of 
2100 mg Q2W, 6 out of 11 participants had a best response of stable disease or better 
(DCR 54.5%) including two participants (one participant with breast cancer and one 
participant with head and neck cancer) with an unconfirmed partial response at their first 
on treatment tumor assessment.
The available nonclinical and clinical data provide a strong rationale for evaluating the 
potential clinical benefit of RO7247669 in patients with ESCC.
A detailed description of the chemistry, pharmacology, and safety of RO7247669 is 
provided in the RO7247669 Investigator’s Brochure.

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2.2.5
Background on nivolumab
Nivolumab is a human monoclonal antibody that targets the human PD1 receptor.
Nivolumab is approved for the treatment of several cancer types, including unresectable 
advanced, recurrent or metastatic ESCC after prior fluoropyrimidine- and platinum-based 
chemotherapy in the U.S., EU, Japan, South Korea, and other jurisdictions.
For detailed information, please refer to the nivolumab EU SmPC.
2.3
BENEFIT/RISK ASSESSMENT
Clinical data emerging in the field of tumor immunotherapy have demonstrated that 
therapies focused on enhancing T-cell responses against cancer can result in a 
significant survival benefit in patients with metastatic cancer, including ESCC. Recent
Heath Authority approvals in 2L ESCC of the PD1 inhibitors nivolumab, pembrolizumab,
and camrelizumab validate the inhibition of the immune checkpoint pathways for 
achieving clinical benefit in ESCC. Nevertheless, a significant unmet medical need 
remains in patients in the 2L setting with advanced or metastatic ESCC. Despite recent 
advancements, the median OS for patients treated with PD1 inhibitors in the 2L is 
reported to be between 8.3 and 10.9 months (Kato et al. 2019; Kim et al. 2019; Huang 
et al. 2020). 
It is hypothesized that dual checkpoint inhibition may result in enhanced and/or more 
durable responses than either therapy modality alone. Thus, compared to monospecific 
PD1/PDL1 directed antibodies, one might expect a better efficacy primarily coming from 
targeting both PD1 and TIM3- or LAG3-mediated immune-resistance mechanisms. 
PDL1 expression in ESCC ranges from 15% to 83% in tumor cells and from 13% to 31% 
in tumor-infiltrated immune cells (Jiang et al. 2017; Lam et al. 2017; Guo et al. 2017; Qu 
et al. 2016) and PD1 inhibition resulted in benefit in the ESCC population 
(Section 2.2.2.2). Both TIM3 and LAG3 have been shown to be expressed on 
tumor-infiltrating lymphocytes in patients with ESCC (Zhang et al. 2018; Wang et al.
2019; Zhao et al. 2020). As the TIM3 and LAG3 pathways are associated with immune 
dysfunction, these findings suggest that TIM3 and LAG3 blockade to restore T-cell 
function could potentially improve clinical outcomes for patients. Both molecules have 
demonstrated single-agent activity in the respective EIH studies (Sections 2.2.3
and 2.2.4). RO7121661 and RO7247669 may therefore have the potential to be a 
therapeutic option for patients with ESCC.

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Overall, both RO7121661 and RO7247669 have been well tolerated at the proposed 
dose/schedule of 2100 mg Q2W; AEs have been manageable, and the safety profile is 
observed to be consistent across different solid tumor indications as well as with 
approved PD1 directed antibodies (Sections 2.2.3 and 2.2.4). Precaution against general 
risks for patients have been taken into account in the safety measures for this study, 
which include the definition of the inclusion/exclusion criteria (Section 5), and rules for 
treatment interruption and withdrawal from study (Section 7). Recommendations for the 
prophylaxis and the management of specific and known PD1/PDL1-mediated AEs can 
be found in Section 8.3.7 and Appendix 7.
Advanced or metastatic ESCC is an incurable disease with a high unmet need for 
improved medical intervention. Taking into account the preliminary efficacy and 
manageable safety profiles, as well as the potential for improved outcomes due to their 
mechanisms of action of dual checkpoint inhibition, treatment with RO7121661 and 
RO7247669 has therapeutic potential in solid tumors such as ESCC. Based on the 
considerations above, currently available data and the planned safety monitoring and 
management guidance, the proposed study treatments are considered to have an 
appropriate benefit/risk profile for the population included in this study.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of RO7121661 and RO7247669 is provided 
in the respective Investigator’s Brochures.
Nivolumab has demonstrated efficacy in ESCC and is an approved 2L treatment option.
More detailed information about the known and expected benefits in the context of 
potential risks and reasonably expected AEs of nivolumab is provided in the EU SmPC.
COVID-19 Benefit-Risk Assessment
In the setting of the coronavirus disease (COVID-19) pandemic, patients with 
comorbidities (including those with ESCC) are a more vulnerable population. Infection 
with sudden acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been 
associated with higher morbidity and mortality in patients with cancer in some 
retrospective analyses. It is unclear how immunotherapy affects the incidence or severity 
of COVID-19. It is not anticipated that treatment with RO7121661 or RO7247669 will 
increase the risk of infection with SARS-CoV-2. Severe COVID-19 is associated with a 
cytokine release syndrome (CRS) involving the inflammatory cytokines IL-6, IL-10, IL-2, 
and interferon-gamma. RO7121661 and RO7247669 have a low risk of CRS and, while 
it is not known, there may be a potential for an increased risk of an enhanced 
inflammatory response if a participant develops SARS-CoV-2 infection while receiving 
RO7121661 or RO7247669. Clinical studies with RO7121661 and RO7247669 are 
ongoing during this pandemic and, although the study numbers are small, neither has
shown any increased risk of developing COVID-19 or of having a worse outcome in 
participants receiving treatment with RO7121661 or RO7247669.

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There are limited data concerning the possible interactions between cancer 
immunotherapy treatment and SARS-CoV-2 vaccination. It is recognized that human 
immune responses are highly regulated and that immune-modifying therapies may 
positively or negatively affect the efficacy and safety of SARS-CoV-2 vaccination 
(Society for Immunotherapy for Cancer [SITC] 2020).
Per recommendations of the National Comprehensive Cancer Network(NCCN 2021) 
COVID-19 Vaccination Advisory Committee, SARS-CoV-2 vaccination is recommended 
for all patients with cancer receiving active therapy (including immune checkpoint 
inhibitors), with the understanding that there are limited safety and efficacy data in such 
patients (NCCN 2021). Given the lack of clinical data, currently no recommendations can 
be made regarding the optimal sequence of SARS-CoV-2 vaccination in patients who 
are receiving cancer immunotherapy (SITC 2020). For patients enrolling in this study 
and receiving study treatment, a decision to administer the vaccine to a patient should 
be made on an individual basis by the Investigator in consultation with the patient.
In alignment with clinical practice procedures, factors to consider when making the 
individualized decision for a given patient receiving study treatment to receive SARS-
CoV-2 vaccination include the following: the risk of SARS-CoV-2 infection and potential 
benefit from the vaccine, the general condition of the patient and potential complications 
associated with SARS-CoV-2 infection, underlying disease, and the severity of COVID-
19 outbreak in a given area or region.
SITC and NCCN recommendations (SITC 2020; NCCN 2021), along with institutional 
guidelines, should be used by the Investigator when deciding on administering SARS-
CoV-2 vaccines. When administered, SARS-CoV-2 vaccines must be given in 
accordance with the approved or authorized vaccine label. Receipt of the SARS-CoV-2 
vaccine is considered a concomitant medication and should be documented as such 
(see Section 6.5).
3.
OBJECTIVES AND ENDPOINTS
The primary objective is expressed in the estimand framework through the 5 attributes 
as described in Table 4.

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Table 4
Estimands
Attribute
Study Definitions
Population 
Patients with unresectable advanced or recurrent ESCC who are 
refractory or intolerant to one prior line of chemotherapy
Primary endpoint (variable)
Overall survival
Treatments

Experimental: 2100 mg Q2W RO7121661

Experimental: 2100 mg Q2W RO7247669

Active comparator: 240 mg Q2W nivolumab
Intercurrent events and their 
handling
New anti-cancer therapy and treatment discontinuation, handled via 
treatment policy (intercurrent event is ignored)
Summary measure
Hazard ratios
The objectives and corresponding endpoints are provided in Table 5.
Table 5
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the efficacy of
RO7247669 compared with
nivolumab.

OS, defined as the time from randomization to death 
from any cause 
Secondary
To evaluate the safety and tolerability 
of RO7121661 and RO7247669 
compared with nivolumab.

Nature, frequency, and severity of adverse events 
(AEs) graded according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0
To evaluate the efficacy of
RO7247669 compared with
nivolumab.

Objective response rate (ORR), defined as the 
proportion of participants with an objective response 
(i.e., complete response [CR] or partial response [PR]), 
according to RECIST v1.1

Disease control rate (DCR), defined as ORR stable 
disease rate (SDR)

Duration of response (DoR) for participants with ORR, 
defined as the time from the first occurrence of a
documented objective response to disease progression 
according to RECIST v1.1 or death from any cause, 
whichever occurs first

Progression-free survival (PFS) defined as the time 
from randomization to the first occurrence of 
progression as determined by the Investigator
according to RECIST v1.1 or death during the 
treatment period or within 60 days of the last tumor 
assessment after treatment discontinuation from any 
cause, whichever occurs first

Proportion of participants reporting clinically meaningful 
improvement in global health status/quality of life, 
emotional functioning, social functioning and dysphagia 

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as measured by the European Organisation for 
Research and Treatment of Cancer (EORTC) 
Quality-of-life questionnaire (QLQ)-C30, IL97, and 
OES-18, defined as an improvement of at least 
10 points
To investigate the pharmacokinetics 
(PK) of RO7247669 and nivolumab.

Serum concentrations, PK profiles and parameters for 
RO7121661, RO7247669, and nivolumab
To evaluate the immune response 
after administration of RO7247669 
and nivolumab.

Incidence and titer of RO7121661, RO7247669 or 
nivolumab anti-drug antibodies (ADAs) during the study 
relative to the prevalence of ADA at baseline
To assess treatment-induced 
pharmacodynamic changes (PD 
Biomarkers) in peripheral blood and 
tumor microenvironment

Changes from baseline in the phenotype and activation 
status (CD4/CD8 HLA-DR+Ki67+) of T-cell subsets in 
the peripheral blood

Changes from baseline such as CD8 T-cell infiltration, 
proliferation (CD8+Ki67+) in the tumor 
microenvironment
To assess baseline characteristics in 
the tumor microenvironment as 
predictive biomarkers of response

Baseline PDL1, CD8+PD1+, CD8+TIM3+, and 
CD8+LAG3+ expression in the tumor 
microenvironment
Exploratory
To evaluate the efficacy of
RO7121661 and RO7247669 
compared with nivolumab.

Changes in disease-related symptoms, function, and 
health-related quality of life as measured by the 
EORTC QLQ-C30, IL-97, and OES-18

Proportion of responses on the PGI-CI and PGI-S
To evaluate the efficacy of 
RO7121661 compared with 
nivolumab.

OS, defined as the time from randomization to death 
from any cause 

ORR, DCR, DoR, PFS as defined above according to 
RECIST v1.1 

Proportion of participants reporting clinically 
meaningful improvement in global health 
status/quality of life, emotional functioning, social 
functioning and dysphagia as measured by the 
EORTC QLQ-C30, IL97, and OES-18, defined as an 
improvement of at least 10 points
To investigate the PK of RO7121661

Serum concentrations, PK profiles and parameters for 
RO7121661.
To evaluate the immune response 
after administration of RO7121661

Incidence and titer of RO7121661 ADAs during the 
study relative to the prevalence of ADA at baseline
To correlate anti-tumor activity of 
RO7121661, RO7247669, and 
nivolumab with PK and exploratory 
safety biomarkers.

Compare anti-tumor activity by RECIST with PK 
parameters, safety events, and exploratory safety
biomarkers (including genetic and genomic analyses).
To explore potential 
pharmacodynamics and predictive 
biomarkers associated with the anti-
tumor activity of RO7121661, 
RO7247669, and nivolumab

PD Biomarkers: Changes from baseline such as Treg 
profile, cytotoxic T cells in the tumor microenvironment,
and immune cell subsets such as Tregs and 
central/effector memory subsets 

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24 months. Participants who meet the criteria for disease progression per RECIST v1.1 
will be permitted to continue study treatment if they meet all criteria for treatment beyond 
progression (Section 7.1.1).
regardless of treatment delays until radiographic disease 
progression per RECIST v1.1, initiation of a new anti-cancer therapy, withdrawal of 
consent, death, or study termination by the Sponsor, whichever occurs first
(Section 8.1.1). Thus, tumor assessments are to continue according to the schedule in 
participants who discontinue treatment for reasons other than disease progression or 
loss of clinical benefit. For participants who continue treatment after progressive 
disease, tumor assessments are to continue according to schedule until study treatment 
is discontinued. At the Investigator’s discretion, tumor assessments may be repeated at 
any time if progressive disease is suspected. 
Response will be assessed according to RECIST v1.1 (Appendix 6). Objective response 
at a single time-point will be determined by the Investigator according to RECIST v1.1. 
All primary imaging data used for tumor assessments may be collected by the Sponsor; 
centralized, blinded independent review of response endpoints by an independent 
review facility may be conducted.
The primary comparison of interest are the hazard ratio of OS of each experimental arm 
compared to nivolumab, assessing the superiority of the experimental arms over the 
active comparator treatment. The primary comparison of OS will be made regardless of 
whether participants withdraw from treatment or receive new anti-cancer therapy prior to 
disease progression. In order not to confound the OS endpoint, crossover from any of 
the treatment arms to another arm will not be allowed. 
During the study, participants will be asked to complete patient-reported outcome (PRO) 
questionnaires at the beginning of the study, during study treatment, at treatment 
discontinuation, and during survival follow-up (Section 8.1.2). These will assess disease 
and treatment-related symptoms, as well as functioning and overall health-related quality 
of life. 
During the study, serum samples will be collected to monitor RO7121661, RO7247669, 
and nivolumab pharmacokinetics (PK) and to detect the presence of antibodies to 
RO7121661, RO7247669, or nivolumab (Section 8.5 and Section 8.6). Blood samples 
for PK analysis may be collected at the participant’s home. This specifically applies to 
days where no other hospital assessments are required—i.e., C1D8 and C5D8.
Participant samples, including archival and fresh tumor tissue, serum, plasma, and blood 
samples, will also be collected for biomarker assessments (Section 8.7 and Section 8.8).

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Safety assessments will include the incidence, nature, and severity of AEs, and other 
protocol-specified tests such as laboratory abnormalities that are deemed critical to the 
safety evaluation of the study (Section 8.2).
After study treatment discontinuation and disease progression per RECIST v1.1, survival 
follow-up information will be collected by means of telephone calls, participant medical 
records, and/or clinic visits approximately every 3 months until death, lost to follow-up, or 
study termination by the Sponsor, whichever occurs first (Section 8.11.4). All participants 
will be periodically contacted for survival and new anti-cancer therapy information unless 
the participant requests to be withdrawn from follow-up (this request must be 
documented in the source documents and signed by the Investigator). If the participant
withdraws from the study, study staff may use a public information source (e.g., county 
records) when permissible to obtain information about survival status (Section 7.2).
4.1.1
Length of the Study
The duration in each period of the study for each participant will be as follows:

Screening: Days -28 to -1.

Treatment Period: Cycle 1 Day 1 up to a maximum of 24 months.

Survival follow-up: 90 (7) days after last treatment with study drug; then every 
3 months (14 days) until death, loss to follow-up, or study termination by the 
Sponsor.
4.1.2
Communication Strategy
The Sponsor and Investigators will be in regular contact throughout the study by 
email/telephone/fax, as per normal interactions during the conduct of a clinical study,
and the Sponsor will arrange teleconferences and meetings to discuss study status.
The Sponsor will be available 24 hours a day to discuss any medical or study-related 
issues that may arise during the conduct of this study.
4.1.3
Joint Monitoring Committee
A Joint Monitoring Committee (JMC) will review available safety data periodically and 
make recommendations regarding study conduct to ensure the safety of patients 
enrolled in the study. The JMC will consist of designated Sponsor personnel and 
independent clinical expert(s) (i.e., expert[s] independent from the Sponsor). The JMC
Chair will be a medical oncologist who is neither the Medical Monitor nor associated with 
the study. Other JMC members will include, but not be limited to, a drug-safety scientist
and biostatistician. The responsibility, membership, and communication flow of the JMC 
is further described in the JMC Charter.

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4.1.4
Scientific Rationale for Study Design
The study rationale is provided in Section 2.1.
In this study, the primary efficacy endpoints will be OS. This study will test the 
hypothesis that treatment with RO7247669 will prolong OS compared to treatment with 
nivolumab. Improvement in OS is generally accepted as the best measure of clinical 
benefit for patients with solid tumors. Prior studies with anti-PD1 treatments in 2L
CPI-naïve ESCC showed inconsistent results for other commonly used endpoints such 
as ORR and PFS, which do not necessarily correlate with the observed OS benefits.
This study is blinded. Investigators, site staff, and participants will be unaware of the 
treatment allocation. Rationale for the blinded design is reducing potential bias in the 
assessment of disease recurrence/progression, PROs, and safety.
Nivolumab was chosen as active comparator for this study (Section 2.2.5). Given the 
positive data and approval of nivolumab for patients with ESCC after prior 
fluoropyrimidine- and platinum-based chemotherapy, independent of PDL1 expression, 
nivolumab was considered the best comparator for the anticipated patient population in 
this study. 
4.1.5
Rationale for Study Population
This study will enroll patients with advanced or metastatic ESCC who are not indicated 
for radical resection and who are refractory or intolerant to one prior line of
fluoropyrimidine- or taxane- and platinum-based regimen regardless of tumor PDL1 
expression.
As described in Section 2.2, combination chemotherapy consisting of cisplatin together 
with paclitaxel or 5-FU is typically given as first-line treatment for ESCC. Chemotherapy 
options in the 2L setting for patients with ESCC are associated with considerable toxicity 
and poor long-term survival. At the same time, anti-PD1 treatments have demonstrated 
a clinically meaningful improvement in OS over chemotherapy for 2L ESCC. In 
Keynote-181, patients with both adenocarcinoma and squamous histology were 
included. However, OS was only positive for patients in the subgroup with a combined 
positive score 10. The clinical benefits observed in the 2L ESCC population with 
nivolumab as well as camrelizumab occurred regardless of patients’ level of tumor PDL1 
expression. Despite the results for pembrolizumab in 2L esophageal cancer not reaching 
statistical significance in the ITT patient population, the data show a clear trend towards 
a clinical benefit over chemotherapy in accordance to the studies with nivolumab and 
camrelizumab. These data suggest that CPI treatment provides clinical benefit in the 2L
setting for patients with esophageal cancer with squamous histology, but independent of
tumor PDL1 expression.

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Based on these data, 2L patients with ESCC not indicated for radical resection and who 
are refractory or intolerant to fluoropyrimidine/taxane- and platinum-based treatment,
independent of their tumor PDL1 expression will be eligible to enroll in the current study.
4.1.6
Rationale for Biomarker Assessments
The main hypothesis is that additional checkpoint blockade via PD1-TIM3 or PD1-LAG3
will re-invigorate exhausted T cells and lead to an increase in CD8 T-cell infiltration and 
proliferation in the tumor microenvironment. As such, treatment-induced biomarker 
exploration will focus on changes from baseline associated with anti-PD1-LAG3, 
anti-PD1-TIM3, and anti-PD1 therapy in both the tumor microenvironment and peripheral 
blood. In peripheral blood, serial blood sampling will also be done to assess kinetic 
changes in immune cellular profiles and selected cytokines, and examined for 
association with treatment with RO7121661, RO7247669, and nivolumab. Samples for 
pharmacodynamics (PD) and biomarker research will be collected as described in the 
SoAs (Section 1.3), and with respect to analyses and samples detailed in Section 8.7
and Section 8.8.
To explore predictive markers of response for RO7247669 or RO7121661, the initial 
hypothesis focuses on association of response with baseline PDL1, CD8+TIM3+, 
CD8+LAG3+, and PD1 expression. Other exploratory biomarkers considered to identify 
potential predictive markers also include assessing baseline immune-cell
subsets/effector gene signatures in the peripheral blood and tumor microenvironment, 
oral, and gut microbiomes, or other soluble markers (such as bTMB, ctDNA, etc.).
Additional biomarkers may be measured if initial data lead to a strong scientific rationale
for these measurements.
4.1.7
Rationale for Non-Standard Clinical Outcome Assessments
Cancer treatments, particularly combination therapies, can produce significant 
symptomatic AEs. Recent research has shown that clinicians may underreport the 
incidence and severity of symptoms experienced by patients receiving treatment for 
cancer (Fromme et al. 2004; Trotti et al. 2007; Pakhomov et al. 2008; Basch et al. 2010; 
Quinten et al. 2011; Atkinson et al. 2012; Basch et al. 2014). Collecting side effect 
tolerability information directly from patients can provide a complementary understanding 
of treatment characteristics and their effects. 
In order to evaluate the tolerability of RO7121661 and RO7247669, and the experience 
with nivolumab, participants will be asked to report on their experience with
6 treatment-related symptoms selected from the validated PRO-CTCAE item bank 
(Appendix 13). These symptoms were identified as being salient to patients' experience 
with RO7121661, RO7247669, and nivolumab, based on available safety data from the 
nivolumab label or initial studies of RO7121661 and RO7247669.

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Additional items related to the safety profile of these drugs (e.g., diarrhea, fatigue, 
nausea, decreased appetite) are included in the other measures (European Organisation 
for Research and Treatment of Cancer [EORTC] QLQ_C30, OES-18, Item library 97 
(IL97), Patient Global Impression of Change and its Importance (PGI-CI) and Patient 
Global Impression of Severity (PGI-S); Appendix 8, Appendix 9, Appendix 10,
Appendix 11, and Appendix 12) included in the study. These other measures (EORTC 
QLQ_C30, OES-18, IL97, PGI-CI and PGI-S) are included to understand the impact of 
the disease on patients, support the use of more targeted assessments, and determine 
meaningful change thresholds.
4.2
JUSTIFICATION FOR RO7121661 DOSE AND SCHEDULE
A fixed dosing regimen of 2100 mg Q2W was selected as the dose for this study for 
RO7121661. 
 
 During the dose-escalation in Part A of the 
study, no specific safety concern associated with RO7121661 was identified. In total,
one single DLT (Grade 3 TnT increased) was reported and observed at the highest 
1200-mg dose group, and no MTD was reached. Anti-tumor activity, as measured by 
radiographic PRs, was observed at the selected dose for this study. A two 
compartmental PK linear model predicts the exposure data well, particularly at the higher 
dose range. A dose regimen of 2100 mg Q2W is predicted to result in a trough 
concentration of 320 μg/mL, the predicted EC95 from an ex vivo SEB cytokine assay, 
in 62% of participants. 
In addition, RO7121661 was well tolerated in both the dose-range finding and GLP 
monkey toxicology studies up to the highest dose evaluated (150 mg/kg). Toxicology 
findings were consistent with reported findings in cynomolgus monkey studies with 
marketed CPIs.
Supporting data for the selected dose can be found in the RO7121661 Investigator’s 
Brochure.
 
 
 
 
 
 

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4.2.2
Justification for Nivolumab Dose and Schedule
The approved dose and schedule for ESCC of 240 mg Q2W was selected for this study 
for nivolumab. This dose and schedule was used in the ATTRACTION-3 study (Kato 
et al. 2019).
For detailed information, please refer to the nivolumab EU SmPC.
4.3
END OF STUDY DEFINITION
The end of the study will occur when all of the following criteria have been met:

The required number of deaths for the primary analysis of OS has been 
observed.

The last participant, last visit has occurred.
The Sponsor has the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 

The incidence or severity of AEs in this or other studies indicates a potential 
health hazard to patients. 

Unsatisfactory patient enrollment.

Inaccurate or incomplete data recording.
The Sponsor will notify the Investigator if the Sponsor decides to discontinue the study.
If the Sponsor decides to terminate the study, participants who are still receiving study 
treatment or are undergoing survival follow-up may be enrolled in an extension study, if 
available.
5.
STUDY POPULATION
The study population rationale is provided in Section 4.1.5.
This study will enroll male and female participants with advanced or metastatic ESCC
who are not indicated for radical resection and who are refractory or intolerant to 
fluoropyrimidine- or taxane- and platinum-based regimen.
Prospective approval of protocol deviations, 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:
General Criteria
1.
Able and willing to provide written informed consent and to comply with the study 
protocol according to ICH and local regulations.
2.
Age 18 years.
Disease-Specific Criteria
3.
Participants with advanced or metastatic, histologically confirmed ESCC.
4.
Patients who are not indicated for radical resection and have previously received 
1 line of treatment in non-curative intention prior to randomization. The prior line 
must be either a fluoropyrimidine- and platinum- or a taxane- and platinum-based 
regimen, and patients must have experienced progressive disease after at least 
3 cycles or be unable to tolerate potential side effects of this treatment.
Patients who did not receive treatment in the non-curative setting but received a 
fluoropyrimidine-/taxane and platinum-based drug regimen in curative intent may 
be allowed. This includes patients who had either radical resection in conjunction 
with chemotherapy including neo-adjuvant/adjuvant therapy (radiotherapy) or 
patients who were treated with chemo-radiation (including patients who 
underwent chemo-radiation followed by salvage surgery).

If recurrence or progression was confirmed by imaging or by pathological 
assessment of a biopsy within 24 weeks after the last dose of the treatment,
patients are eligible and do not require an additional line of therapy in the 
non-curative setting.

If recurrence or progression occurred later than 24 weeks after the last dose 
of the treatment, patients need to be exposed to an additional line of 
fluoropyrimidine-/taxane- and platinum-based drugs in the non-curative 
setting to be eligible for the study—unless the Investigator considers the 
patient not eligible for the re-exposure with fluoropyrimidine/taxane and 
platinum-based drugs.

The last dose of chemotherapy or the last radiation treatment (whichever 
occurs later) should be considered for the determination of the time-point of 
recurrence or progression after chemo-radiation.
5.
Radiologically measurable disease according to RECIST v1.1. Previously irradiated 
lesions should not be counted as target lesions unless clearly progressed after the 
radiotherapy.
6.
ECOG Performance Status 0-1.
7.
A life expectancy of 12 weeks.

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8.
Tissue samples must be provided for analysis of PD-L1 tumor positivity using the 
PDL1 IHC 28-8 pharmDx assay. Testing will be done centrally and results must be 
obtained prior to stratification. 

Expression will be determined in a fresh tumor biopsy collected during 
study screening or a possibly available archival sample, provided that 
the latter is not older than 12 months. 

Tumor tissue should be of good quality based on total and viable tumor 
content and must be evaluated for PDL1 expression.

Patients whose tumor tissue is not evaluable for PDL1 expression are 
not eligible.
Medical Conditions
9.
Adequate cardiovascular function:

New York Heart Association (NYHA) Heart Failure Stage 2.

Baseline-corrected QT (QTcF) interval 470 ms.

Resting systolic blood pressure (BP) 150 mmHg and diastolic 
BP 100 mmHg (average of 3 readings on 2 sessions with short break 
between sessions; no clinically significant hypertension).

Resting heart rate between 45-100 bpm (no clinically significant 
tachycardia).

LVEF 50% assessed by either transthoracic echocardiogram (TTE) or 
MUGA (TTE preferred test) within 6 months prior to randomization.

TnT or I (TnI) institutional upper limit of normal (ULN). Patients with TnT 
or TnI levels between 1 and 2 ULN will be permitted to enter the 
study if repeat levels are 1 ULN. If repeat levels are between 1 and 
2 ULN, the patients need to undergo a cardiac evaluation and can be 
considered for treatment in case of no clinically significant findings.
10. AEs from any prior radiotherapy, chemotherapy, or surgical procedure must have 
resolved to Grade 1, except alopecia (any grade), vitiligo, endocrinopathy
managed with replacement therapy, and Grade 2 peripheral neuropathy.
11. Adequate hematological function: 

Neutrophil count of 1.5 109 cells/L (1500/L).

Platelet count of 100 109/L (100,000/L) without transfusion.

Hemoglobin 9 g/dL (90 g/L).

Lymphocyte count of 0.5 109 cells/L (500/L).
12. Adequate liver function: total bilirubin 1.5 ULN; aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), and alkaline phosphatase 
(ALP) 2.5 ULN; with the following exceptions:

Participants with known Gilbert disease: serum total bilirubin level 3 ULN.

Participants with documented liver metastases: AST and ALT 5 ULN.

Participants with documented liver or bone metastases: ALP 5 ULN.

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13. Adequate renal function: serum creatinine 1.5 ULN or creatinine clearance by 
eGFR by MDRD formula 50 mL/min for participants in whom, in the Investigator’s 
judgment, serum creatinine levels do not adequately reflect renal function. 
14. Additional adequate laboratory parameters obtained: 

Serum albumin 25 g/L (2.5 g/dL).

For participants not receiving therapeutic anticoagulation: Prothrombin time 
(PT) and activated partial thromboplastin time 1.5 ULN.

For participants receiving therapeutic anticoagulation: stable anticoagulant 
regimen.
Contraception
15. Male and/or female participants:
The contraception and abstinence requirements are intended to prevent exposure of 
an embryo to the study treatment. The reliability of sexual abstinence for male 
and/or female enrollment eligibility needs to be evaluated in relation to the duration 
of the clinical study and the preferred and usual lifestyle of the participant. Periodic 
abstinence (e.g., calendar, ovulation, symptom-thermal, or post-ovulation methods) 
and withdrawal are not acceptable methods of contraception.
Female Participants: A female participant is eligible to participate if she is not 
pregnant, not breastfeeding, and at least one of the following conditions applies:

Not a woman of childbearing potential (WOCBP).

WOCBP, who:
o
Agree to remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive methods that result in a failure rate of 1% per year during 
the treatment period and for at least 5 months after the final dose of study 
drug.
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal occlusion, male sterilization, established proper use 
of hormonal contraceptives that inhibit ovulation, hormone-releasing 
intrauterine devices and copper intrauterine devices.
o
Have a negative pregnancy test (blood) within the 7 days prior to 
randomization.
Male Participants: During the treatment period and for at least 5 months after the 
final dose of study drug, agreement to: 

Remain abstinent (refrain from heterosexual intercourse) or use 
contraceptive measures such as a condom plus an additional contraceptive 
method that together result in a failure rate of 1% per year, with partners 
who are women of childbearing potential.

With pregnant female partners, remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures such as a condom to avoid 
exposing the embryo.

Refrain from donating sperm during this period.

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5.2
EXCLUSION CRITERIA
Participants are excluded from the study if any of the following criteria apply:
General Exclusion Criteria
1.
Pregnancy, lactation, or breastfeeding.
2.
Known hypersensitivity to any of the components of RO7121661, RO7247669, or 
nivolumab, including but not limited to, hypersensitivity to Chinese hamster ovary 
cell products or other recombinant human or humanized antibodies.
Medical Conditions
3. Patients with significant malnutrition. Patients whose nutrition has been well 
controlled for 28 days prior to randomization may be enrolled.
4. Evidence of complete esophageal obstruction not amenable to treatment.
5. Higher risk of bleeding or fistula caused by esophageal lesions invading adjacent 
organs (aorta or tracheobronchial tree). Patients with manageable fistula may be 
included at the Investigator's discretion.
6. Symptomatic central nervous system (CNS) metastases. Patients with previously 
treated brain metastases may participate provided they:

Are stable (without evidence of progression by computed tomography (CT)
or magnetic resonance imaging (MRI) for at least 28 days prior to 
randomization).

Have no evidence of new or enlarging brain metastases for at least 28 days
prior to randomization.

Are off systemic steroids for at least 28 days prior to randomization.
7.
Spinal cord compression not definitively treated with surgery and/or radiation or 
without evidence that disease has been clinically stable for 14 days prior to 
randomization.
8.
Active or history of carcinomatous meningitis/leptomeningeal disease.
9.
Asymptomatic CNS primary tumors or metastases if they have requirement for 
steroids or enzyme-inducing anticonvulsants in the last 28 days prior to 
randomization.
10. Uncontrolled tumor-related pain. Participants requiring pain medication must be on a 
stable regimen at study entry.
11. Patients with an active second malignancy. Concurrent malignancy exceptions 
include: curatively treated carcinoma in situ of the cervix, good-prognosis ductal 
carcinoma in situ of the breast, basal- or squamous-cell skin cancer, Stage I 
melanoma, or low-grade, early-stage localized prostate cancer and any previously 
treated early stage non-hematological malignancy that has been in remission for at 
least two years.
12. Evidence of significant, uncontrolled concomitant diseases that could affect 
compliance with the protocol or interpretation of results, including diabetes mellitus, 
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deficiency, or other diseases with ongoing fibrosis (such as scleroderma, pulmonary 
fibrosis, emphysema, neurofibromatosis, palmar/plantar fibromatosis, etc.).
13. Encephalitis, meningitis, or uncontrolled seizures in the year prior to informed 
consent.
14. Significant cardiovascular/cerebrovascular disease within 6 months prior to 
randomization, including any of the following:

Hypertensive crisis/encephalopathy.

Unstable angina.

Transient ischemic attack/stroke.

Congestive heart failure (for NYHA classification, refer to inclusion criteria).

Serious cardiac arrhythmia requiring treatment (exceptions are atrial 
fibrillation, paroxysmal supraventricular tachycardia).

History of thromboembolic events (such as myocardial infarction, stroke or 
pulmonary embolism).
15. Known active or uncontrolled bacterial, viral, fungal, mycobacterial (including but not 
limited to tuberculosis [TB] and typical mycobacterial disease), parasitic, or other 
infection (excluding fungal infections of nail beds) or any major episode of infection 
requiring treatment with IV antibiotics or hospitalization (relating to the completion of 
the course of antibiotics, except if for tumor fever) within 28 days prior to 
randomization.
16. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, and 
inherited liver disease.
17. Major surgical procedure or significant traumatic injury (excluding biopsies) within 
28 days prior to randomization, or anticipation of the need for major surgery during 
the course of the study.
18. Any other diseases, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the 
interpretation of the results or render the participant at high risk from treatment 
complications.
19. Dementia or altered mental status that would prohibit informed consent.
20. Uncontrolled pleural effusion (with the exception of participants with indwelling 
catheters, e.g., PleurX), pericardial effusion, or ascites requiring recurrent 
drainage procedures (expected to occur once monthly or more frequently). 
21. Active or history of autoimmune disease or immune deficiency with the following 
exceptions:

Participants with a history of autoimmune-mediated hypothyroidism or 
endocrinopathy who are stable on thyroid-replacement hormone or 
appropriate replacement therapy are eligible for the study.

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
Participants with controlled Type 1 diabetes mellitus who are on an insulin 
regimen are eligible for the study.

Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., participants with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are 
met:
o
Rash must cover 10% of body surface area.
o
Disease is well controlled at baseline and requires only low-potency 
topical corticosteroids.
o
No occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, 
biologic agents, oral calcineurin inhibitors, or high-potency or oral 
corticosteroids within the previous 12 months.
22. Positive HIV test at screening.
23. Positive hepatitis B surface antigen (HBsAg) or positive total hepatitis B core 
antibody (HBcAb) test at screening. Participants with a positive HBsAg or total 
HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening are 
eligible.

The HBV DNA test will only be performed for participants who have a 
positive HBsAg or total HBcAb test.
24. Positive hepatitis C virus (HCV) antibody test at screening. Participants with a 
positive HCV antibody test followed by a negative HCV RNA test at screening are 
eligible.

The HCV RNA test will be performed only for participants who have a 
positive HCV antibody test.
Prior/Concomitant Therapy
25. Prior cancer therapy with any immunomodulatory agents including CPIs (such as 
anti-PDL1/PD1, anti-CTLA-4, anti-LAG3, anti-TIM3).
26. Vaccination with live vaccines within 28 days prior to randomization, or anticipation 
that a live attenuated vaccine will be required during the study 
27. Treatment with therapeutic oral or IV antibiotics within 14 days prior to 
randomization.
28. Concurrent therapy with any other investigational drug (defined as treatment for 
which there is currently no regulatory authority-approved indication) 28 days or 
5 half-lives of the drug (whichever is shorter) prior to randomization.
29. Treatment with immune-modulating and immune suppressive agents/medication 
5 half-lives or 28 days (whichever is shorter) prior to randomization, with the 
following exceptions:

The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) is allowed.

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
Participants who have received acute and/or low-dose systemic 
immunosuppressive medications (e.g., a one-time dose of dexamethasone 
for nausea or chronic use of 10 mg/day of prednisone or dose-equivalent 
corticosteroid) are allowed.
30. Regular immunosuppressive therapy (i.e., for organ transplantation, chronic 
rheumatologic disease). 
31. Radiotherapy within the last 28 days before start of study drug treatment is not 
allowed, with the exception of limited palliative radiotherapy.
32. Prior treatment with adoptive cell therapies, such as CAR-T therapies.
5.3
LIFESTYLE CONSIDERATIONS
Participants will be expected to follow protocol requirements for contraception 
(Appendix 5) and study center rules during visits, but there are no other lifestyle 
restrictions during the study. There are no study-specific restrictions to meals and dietary 
requirements.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the study but 
are not subsequently randomized to study treatment.
All screening evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before entering the study. The Investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screening failure. In case of uncertain or questionable results, any of 
the tests performed during screening may be repeated prior to randomization to confirm 
eligibility.
One re-screening is allowed for participants who were screened in the study and met 
study inclusion/exclusion criteria but failed to be randomized within 28 days after the 
start of screening period because of an administrative reason. Participants who do not 
initially meet all eligibility criteria for participation in the study may also qualify for one 
re-screening at the Investigator’s discretion. Patients are not required to re-sign the 
consent form if they are re-screened within 60 days after previously signing the consent 
form. In order to re-screen such participants, all inclusion and exclusion criteria should 
be re-evaluated and all applicable screening assessments repeated if done more than
28 days prior to randomization unless a longer period is specified for certain 
assessments elsewhere.
Biopsy samples will only be entered in the eCRF and analyzed for enrolled participants. 
In the event that a fresh biopsy is taken during the screening period and the participant 
is not enrolled into the study, the formaldehyde-fixed paraffin-embedded (FFPE) biopsy 
block can be returned to the site upon site request.

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5.5
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment using pre-screening enrollment 
logs and Institutional Review Board (IRB)/Ethics Committee (EC) approved recruitment 
strategies prior to consenting to take place on this study.
6.
TREATMENTS
Study intervention is defined as any investigational product (including placebo) or 
marketed product intended to be administered to a study participant according to the 
study protocol.
The investigational medicinal products (IMPs) for this study are RO7121661, 
RO7247669, and nivolumab. All IMPs required for completion of this study will be 
provided by the Sponsor. All study drug administration will be done at the study center 
under supervision of site staff.
Cases of accidental overdose or medication error, along with any associated AEs, 
should be reported as described in Section 5.2 of Appendix 2.
6.1
TREATMENTS ADMINISTERED
The administered treatments are summarized in Table 6. Guidelines for dosage 
modification and treatment interruption or discontinuation are provided in Section 6.6
and Section 7.1.2, respectively.
All study drugs will be administered IV. A 0.2 μm or 0.22 μm inline filter must be 
mandatorily used with the infusion set during administration.
The initial dose of study drug will be delivered over 60 10 minutes (the infusion may be 
slowed or interrupted for participants who experience infusion-associated symptoms; 
Section 8.3.7.1), followed by a 60-minute observation period. If the 60-minute infusion is 
tolerated without infusion-associated AEs, all subsequent infusions may be delivered 
over 30 10 minutes, followed by a 30-minute observation period. 
For additional details, refer to the Pharmacy Manual.

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Table 6
Summary of Treatments Administered
Study Treatment 
Name:
RO7121661
RO7247669
Nivolumab
IMP and NIMP
IMP
IMP
IMP
Dose Formulation:
Liquid
Liquid
Liquid
Unit Dose 
Strength(s)/Dosage 
Level(s):
300mg/6mL
300 mg/6mL
240 mg/24mL
Dose:
2100 mg
2100 mg
240 mg
Route of 
Administration:
IV infusion
IV infusion
IV infusion
Sourcing:
Provided centrally 
by the Sponsor
Provided centrally 
by the Sponsor
Provided centrally 
by the Sponsor
Packaging and 
Labeling:
Study treatment will 
be provided in vials.
Each vial will be 
labeled as required 
per country 
requirement.
Study treatment will 
be provided in vials.
Each vial will be 
labeled as required 
per country 
requirement.
Study treatment will 
be provided in vials.
Each vial will be 
labeled as required 
per country 
requirement.
6.1.1
Pre-medication
No pre-medication is foreseen prior to the first administration of study drug.
However, if administered, all pre-medications should be captured as concomitant 
medications in the participant’s electronic Case Report Form (eCRF). Please refer to 
Section 8.3.7.1 for details on pre-medications in case of Grade 2 IRRs.
Participants who experienced a Grade 2 infusion-related reaction (IRR) on a previous 
infusion should be pre-medicated for subsequent infusions. Pre-medication regimens for 
future cycles may be reduced or if the participants do not experience Grade 2 or higher 
IRR events with the current infusion (Section 8.3.7.1).
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the Sponsor’s clinical study supplies 
department and bear a label with the identification required by local law, the protocol 
number, drug identification and dosage.
The packaging and labeling of the study medication will be in accordance with the 
Sponsor’s standard and local regulations.

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The study site should follow all instructions included with each shipment of IMP. The
investigational site will acknowledge receipt of IMPs and confirm the shipment condition 
and content. Any damaged shipments will be replaced. The unblinded pharmacist or 
designee must confirm that appropriate temperature conditions have been maintained 
during transit for all IMPs received and that any discrepancies have been reported and 
resolved before use of the IMPs. All IMPs 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 unblinded pharmacist and authorized staff.
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs.
The study site (i.e., unblinded pharmacist or other authorized personnel) is responsible 
for maintaining records of IMP delivery to the site, IMP inventory at the site, IMP use by 
each patient, and disposition or return of unused IMP, thus enabling reconciliation of all 
IMP received, and for ensuring that patients are provided with doses specified by the 
protocol. Upon arrival of the IMPs at the site, site personnel will complete the following:

Check the IMPs for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Study Monitor upon 
discovery.
The qualified individual responsible for dispensing the study treatment will prepare the 
correct dose according to the Pharmacy Manual.
Only participants enrolled in the study may receive study treatment and only authorized 
site staff may supply or administer study treatment. All study treatments must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to authorized site 
staff.
The investigational site is responsible for study treatment accountability, reconciliation, 
and record maintenance (i.e., receipt, reconciliation and final disposition records).
For information on IMP handling (including preparation, storage, and accountability),
refer to the Pharmacy Manual and/or the Investigator's Brochure. 

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IMPs will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure (SOP) or returned to the Sponsor with the appropriate 
documentation. The site's method of IMP destruction must be agreed upon by the 
Sponsor. Local or institutional regulations may require immediate destruction of used 
IMP for safety reasons. The site must obtain written authorization from the Sponsor 
before any IMP is destroyed, and IMP destruction must be documented on the 
appropriate form. Accurate records of all IMPs received at, dispensed from, returned to, 
and disposed of by the study site should be recorded on the drug accountability log.
Refer to the Pharmacy Manual and/or the applicable Investigator's Brochure for 
information on IMP formulation, IMP handling, including preparation and storage, and 
accountability.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
This is a Phase II, randomized, blinded, active-controlled study. After written informed 
consent has been obtained and eligibility has been established (including determination 
of tumor PD-L1 status by central testing), the study site will obtain the participant's 
identification number and blinded treatment assignment from the interactive response 
system (IxRS). An IxRS User Guide will be provided to each site.
Using a permuted-block randomization method, participants will be randomized to 
receive either RO7121661, RO7247669, or nivolumab in a 
randomization ratio or –
after the decision to stop enrollment into the RO7121661 arm – to receive either 
RO7247669 or nivolumab in a 
 randomization ratio.
Eligible participants will be stratified by the following criteria:



These stratification factors were chosen because of their known or suspected potential 
to affect prognosis of treatment outcome with anti-PD1 treatment in ESCC. Prospective 
stratification by these factors will minimize differences in the three treatment arms due to 
sources other than the study drug.
Participants should receive their first dose of study drug on the day of randomization or 
at the latest on the day after randomization.

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6.3.2
Blinding
Investigators and participants will remain blinded to each participant’s assigned study 
treatment throughout the course of the study. In order to maintain this blind, an 
otherwise uninvolved, unblinded pharmacist will be responsible for the reconstitution and 
dispensation of all study treatment and will endeavor to ensure that there are no 
differences in time taken to dispense following randomization. Because of the size of the 
study, use of IxRS, randomization, blinding, and expected lack of substantial emergency 
unblinding, collected data will be protected from any biases that would arise from 
subjectivity in the reporting of the outcome measures. To further protect the integrity of 
the study, the results of interim safety and efficacy analyses will not be made known to 
the Investigators.
Treatment codes should not be broken except in emergency situations. This includes 
the decision to stop recruitment into the RO7121661 arm of the study. The study will 
not be unblinded and patients already randomized to the RO7121661 arm prior to this 
decision will continue to receive treatment with RO7121661. If the Investigator wishes 
to know the identity of the study drug for any other reason, the Investigator should 
contact the Medical Monitor directly.
If emergency unblinding is necessary for participant management (e.g., in the case of a 
serious AE (SAE) for which participant management might be affected by knowledge of 
treatment assignment), the Investigator will be able to break the treatment code by 
contacting the IxRS. This emergency unblinding may occur without prior authorization 
from the Sponsor. However, the Investigator should document and provide an 
explanation to the Sponsor for any premature unblinding (e.g., unblinding due to an SAE 
or accidental unblinding). 
As per Health Authority reporting requirements, the Sponsor's drug safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
that are considered by the Investigator or Sponsor to be related to study drug. The 
participant may continue to receive treatment, and the Investigator and participant will 
remain blinded to treatment assignment.
6.4
TREATMENT COMPLIANCE
The unblinded pharmacist will prepare the correct treatment according to the 
randomization schedule. This individual will write the date dispensed and participant 
number on the study-treatment-vial label and on the Drug Accountability Record. This 
individual will also record the study treatment number received by each participant 
during the study. The Drug Accountability Record should be kept in a restricted area, not 
accessible to blinded study site personnel or the blinded site monitor. For details, please 
refer to the Pharmacy Manual.

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6.5
CONCOMITANT THERAPY
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines,
approved dietary and herbal supplements, nutritional supplements) used by a participant 
within 7 days of study screening must be recorded along with reason for use, dates of 
administration (including start and end dates) and dosage information (including dose 
and frequency).
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the Investigator and recorded on the 
Concomitant Medications eCRF.
All medication administered to manage AEs should be recorded on the Adverse Event 
eCRF.
6.5.1
Permitted Therapy
Participants are permitted to use the following therapies during the study:

Oral contraceptives with a failure rate of 1% per year.

Hormone-replacement therapy.

Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable 
dose or low-molecular-weight heparin).

Inactivated influenza vaccinations.

Megestrol acetate administered as an appetite stimulant.

Inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone).

Acute and/or low-dose systemic immunosuppressive medications (e.g., a 
one-time dose of dexamethasone for nausea or chronic use of 10 mg/day of 
prednisone or dose-equivalent corticosteroid).

Limited field palliative radiotherapy is allowed at any time during the study, 
except for days where study drug is administered.
Concomitant use of herbal therapies is not recommended because their PK, safety 
profiles, and potential drug-drug interactions are generally unknown. However, herbal 
therapies not intended for the treatment of cancer may be used during the study at the 
discretion of the Investigator.
6.5.2
Prohibited Therapy
As a general rule, no concomitant medication will be permitted, with the exception of 
medications to treat AEs, unless the rationale for exception is discussed and clearly 
documented between the Investigator and the Sponsor.

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Use of the following therapies is prohibited during the study and for at least 28 days or 
5 half-lives of the drug, whichever is shorter, prior to randomization and during study 
treatment, unless otherwise specified below:

Investigational or unlicensed/unapproved agents.

Therapy intended for the treatment of cancer (including, but not limited to, 
chemotherapy, hormonal therapy, immunotherapy, and radiotherapy [with the 
exception of limited palliative radiotherapy as described in Section 6.5.1], as well 
as herbal therapy or traditional Chinese medicines with anti-cancer activity in the 
label), whether Health Authority-approved or experimental.

Chronic use of steroids (inhaled and topical steroids are permitted) at baseline of 
10 mg of prednisone/day (or equivalent). Concurrent high doses of systemic 
corticosteroids.

Administration of a live, attenuated vaccine or anticipation that such a live 
attenuated vaccine will be required during the study or within 4 months after the 
administration of the final dose of the study drug.

Systemic immunostimulatory agents (including, but not limited to, interferons and 
IL-2) because these agents could potentially increase the risk for autoimmune 
conditions when given in combination with CPIs.

Systemic immunosuppressive medications (including, but not limited to, 
cyclophosphamide, azathioprine, methotrexate, and thalidomide) because these 
agents could potentially alter the efficacy and safety of the study drug.

Adoptive cell therapies, such as CAR-T therapies.
6.6
DOSE MODIFICATION
Dose modifications, including dose reductions, will not be allowed in this study.
6.7
TREATMENT AFTER THE END OF THE STUDY
Currently, the Sponsor does not have any plans to provide RO7121661, RO7247669, 
nivolumab, or any other study treatments or interventions to the participants after the 
end of the study or when participants discontinue or have been withdrawn from the 
study. The Sponsor will evaluate whether to continue providing RO7121661 and/or 
RO7247669 to participants after the main study is over, in accordance with the Roche 
Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf

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7.
DISCONTINUATION OF STUDY, STUDY TREATMENT AND
PARTICIPANT DISCONTINUATION/WITHDRAWAL
An excessive rate of withdrawals (either participants discontinuing study treatment or 
withdrawing from the study) can render the study non-interpretable. Therefore, 
unnecessary withdrawal of participants should be avoided and efforts should be taken to 
motivate participants to comply with all the study-specific procedures as outlined in this 
protocol.
Details on study and site closures are provided in Section 4 of Appendix 1 Study 
Governance Considerations Study.
7.1
DISCONTINUATION OF STUDY TREATMENT
For data to be collected at the time of treatment discontinuation and follow-up and for 
any further evaluations that need to be completed see the SoAs in
Section 1.3.Participants have the right to voluntarily withdraw from the study treatment at 
any time for any reason.
In addition, the Investigator has the right to discontinue a participant from study 
treatment for medical conditions that the Investigator or Sponsor determines, may 
jeopardize the participant’s safety if he/she continues with the study treatment.
Participants must permanently discontinue study treatment if they experience any of the 
following:

Intolerable toxicity related to study treatment, including development of an 
immune-mediated AE (imAE) determined by the Investigator to be unacceptable 
given the individual participant's potential response to therapy and severity of the 
event.

Any medical condition that may jeopardize the participant's safety if he or she 
continues study treatment.

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the participant.

Use of another non-protocol anti-cancer therapy.

Pregnancy.

Loss of clinical benefit as determined by the Investigator after an integrated 
assessment of radiographic and biochemical data, local biopsy results (if 
available), and clinical status (e.g., symptomatic deterioration such as pain 
secondary to disease).
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF. Participants who discontinue study treatment prematurely will not be 
replaced.

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Participants who discontinue study treatment will be asked to return to the clinic for 
treatment discontinuation visit (Section 8.11.3) 30 days after the final dose of study 
treatment and will undergo follow-up assessments (Section 8.11.4). The visit at which 
response assessment shows progressive disease may be used as the treatment
discontinuation visit. Participants who discontinue study treatment for any reason other 
than progressive disease or loss of clinical benefit will continue to undergo tumor 
response assessments as outlined in the SoAs (Section 1.3) until they start a new 
anti-cancer therapy.
After treatment discontinuation, information on survival status, new anti-cancer therapy 
and other assessments as applicable will be collected via telephone calls, participant
medical records, and/or clinic visits approximately every 3 months until death (unless the 
participant withdraws consent or the Sponsor terminates the study, Section 7.2). In 
particular, every effort should be made to obtain survival information on participants who 
withdraw from study treatment but have not withdrawn consent.
7.1.1
Treatment after Disease Progression
Because of the possibility of an initial increase in tumor burden caused by immune-cell 
infiltration in the setting of a T-cell response (termed “pseudoprogression”) with cancer 
immunotherapy, radiographic progression per RECIST v1.1 may not be indicative of true 
disease progression. During the study, participants who meet criteria for disease 
progression per RECIST v1.1 and show evidence of clinical benefit may continue study 
treatment at the Investigator’s discretion provided that the participants meet all of the 
following criteria: 

Absence of clinically important symptoms and signs (including worsening of 
laboratory values) indicative of disease progression

Investigator-assessed potential clinical benefit for the participant

The participant is tolerating study drugs.

No decline in ECOG Performance Status.

Absence of rapid progression of disease or of progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.
7.1.2
Temporary Interruption
Before permanently discontinuing study treatment (regardless of whether initiated by the 
participant, the Investigator, or Sponsor), an interruption should be considered. 
Participants who have temporarily interrupted study treatment should be considered to 
restart as soon as medically justified in the opinion of the Investigator.

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Study treatment may be temporarily suspended for up to 12 weeks to allow for resolution 
of toxicity to NCI CTCAE Grade2 for hematological toxicities or Grade1 for 
non-hematological toxicities (with the exception of a toxicity considered as non-study 
treatment related). If study treatment is withheld for 12 weeks, the participant will be 
discontinued from study treatment. 
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed, and the acceptable length of interruption should be discussed between the 
Investigator and the Medical Monitor. Minor elective surgery will generally be permitted
during the study with resumption of treatment as soon as possible post-procedure, 
assuming normal recovery. This can be done to avoid the discontinuation of participants 
who could potentially benefit from study treatment.
It should be noted that infusions/cycles not occurring at the anticipated schedule, are 
considered as delayed, not missed.
If a participant has a complete response (CR) or achieves maximum clinical benefit as 
determined by the Investigator and the Sponsor after an integrated assessment of 
radiographic data, biopsy results (if available), and clinical status, the study treatment 
may be paused at the discretion of the Investigator after discussion with the Medical 
Monitor. While the treatment is paused, assessments per SoA (Section 1.3) will be 
suspended, except for tumor assessments. The length of the treatment pause is to be 
included in the calculation of the maximum treatment period duration (24 months from 
C1D1 to discontinuation visit), as per Section 4.1.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. If a participant requests to be withdrawn from the study, this request must be 
documented in the source documents and signed by the Investigator. Participants will 
not be followed for any reason after consent has been withdrawn. However, the study 
staff may use a public information source (e.g., county records) to obtain information 
about survival status.
When a participant voluntarily withdraws from the study samples collected until the date 
of withdrawal will be analyzed, unless the participant specifically requests for these to be 
discarded or local laws require their immediate destruction. However, if samples have 
been tested prior to withdrawal, results from those tests will be used as part of the 
overall research data. A participant's withdrawal from this study does not, by itself, 
constitute withdrawal of samples donated to the Research Biosample Repository (RBR).

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Participants who withdraw from the study for any reasons will not be replaced.
For data to be collected at the time of study discontinuation, at follow-up visits, and for 
any further evaluations that need to be completed, refer to the SoAs (Section 1.3).
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow-up, the Investigator or designee 
must make every effort to regain contact with the participant. These contact 
attempts should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to 
have withdrawn from the study. Attempts to obtain survival information should 
continue. 
Discontinuation of sites or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their time-points are summarized in the SoAs (Section 1.3).
Accepted time windows are indicated, where applicable. In addition, any efficacy or 
safety assessments may be repeated as clinically indicated, at the Investigator’s 
discretion. Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine whether the participant should continue or 
discontinue study treatment.
Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count, tumor assessments) and obtained before signing of the Informed 
Consent Form (ICF) may be utilized for screening or baseline purposes provided that the 
procedure met the protocol-specified criteria and was performed within the time-frame
defined in the SoAs (Section 1.3).
Exceptional measures during the COVID-19 pandemic, such as adjustments in study 
visits, may be considered if in the overall best interest of the participant.

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Adjustments may include:

Use of alternative facility for assessments (e.g., local laboratory or imaging 
centers).

Replacement of a study visit with alternative methods for assessments (such as 
phone contacts or virtual visits to assess safety).

Postponement of a study visit or of individual assessments.
A robust benefit-risk assessment should be performed by the Investigator and discussed 
with the Medical Monitor. This assessment will be fully documented and any deviations 
to the protocol will be recorded in accordance with the Sponsor standard procedure.
8.1
EFFICACY ASSESSMENTS
8.1.1
Tumor and Response Evaluations
Tumor 
assessments should be performed at the described interval regardless of treatment 
delays until radiographic disease progression per RECIST v1.1 (Appendix 6), initiation of 
a new anti-cancer therapy, withdrawal of consent, death, or study termination by the 
Sponsor, whichever occurs first. Thus, tumor assessments are to continue according to 
schedule in participants who discontinue treatment for reasons other than disease 
progression or loss of clinical benefit. For participants who continue treatment after 
progressive disease, tumor assessments are to continue according to schedule until 
study treatment is discontinued. 
At the Investigator’s discretion, tumor assessments may be repeated at any time if 
progressive disease is suspected.
 
 
 Exceptions may apply at the discretion of the Investigator (e.g., in case of
suspected rapid tumor growth).
Participants who are treated beyond disease progression per RECIST v1.1 will undergo 
tumor assessments at the frequency described above until study treatment is 
discontinued.

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Screening assessments must include CT scans (with oral or IV contrast) or MRI scans of 
the chest, abdomen, pelvis, and head. A spiral CT scan of the chest may be obtained 
but is not a requirement. If a CT scan with contrast is contraindicated (e.g., in patients 
with impaired renal clearance), a non-contrast CT scan of the chest may be performed 
and MRI scans of the abdomen, pelvis, and head should be performed. A CT scan with 
contrast or MRI scan of the head must be done at screening to evaluate CNS metastasis 
in all patients (MRI scan must be performed if CT scan is contraindicated). An MRI scan 
of the head is required to confirm or refute the diagnosis of CNS metastases at baseline 
in the event of an equivocal CT scan. Bone scans and CT scans of the neck should also 
be performed if clinically indicated. If a CT scan for tumor assessment is performed in a 
positron emission tomography-CT scanner, the CT acquisition must be of full diagnostic 
quality and include CT contrast. Ultrasound and x-rays are not acceptable for monitoring 
target lesions. At the Investigator's discretion, other methods of assessment of 
measurable disease as per RECIST v1.1 may be used.
All measurable and evaluable lesions identified at screening should be re-assessed at 
each subsequent tumor evaluation. If the participant presents with a CNS metastasis at 
screening, on treatment tumor assessments must also contain a CT or MRI scan of the 
head. If the participant has no brain metastasis at screening, then CT/MRI scan of the 
head is only indicated if symptoms suggest potential brain disease. Objective response 
at a single time-point will be determined by the Investigator according to RECIST v1.1.
Tumor measurements should be made by the same Investigator/radiologist for each 
participant to the extent that this is feasible and using the assessment technique or 
procedure throughout the study (e.g., the same contrast protocol for CT scans). 
All primary imaging data used for tumor assessments may be collected by the Sponsor; 
centralized, blinded independent review of response endpoints by an independent 
review facility per RECIST v1.1 may be conducted.
8.1.2
Clinical Outcome Assessment
PRO instruments will be completed to more fully characterize the clinical profile of 
RO7121661 and RO7247669 compared with nivolumab. PRO data will be collected
through use of the following instruments:
European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life 
questionnaire (QLQ-C30).

EORTC quality-of-life questionnaire for esophageal cancer (QLQ-OES18).

Selected items from the EORTC Item Library (IL97).

Patient Global Impression of Change and its Importance (PGI-CI).

Patient Global Impression of Severity (PGI-S).

Patient-Reported Outcomes Common Terminology Criteria for Adverse Events 
(PRO-CTCAE).

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8.1.2.1
Data Collection Methods for Clinical Outcome Assessments
PRO questionnaires will be completed at the clinic at specified time-points during the 
study (SoAs in Section 1.3). The PRO questionnaires will be completed by the 
participants at the investigational site or remotely on an electronic device or via 
telephone at time-points where no site visit is planned, as well as during the follow-up 
period. If the participant is unable to complete the questionnaire on his or her own, 
interview assessment is allowed but can only be conducted by site staff. Unless 
otherwise specified, the PRO questionnaires will be completed before the participant
receives any information on disease status, prior to the performance of non-PRO 
assessments, and prior to the administration of study treatment. The PRO 
questionnaires will be collected via a web-based solution.
The PRO questionnaires, translated into the local language as appropriate, will be 
completed through use of an electronic device provided by the Sponsor when possible. 
The device will be pre-programmed to enable the appropriate questionnaires to be 
administered in the correct order at each specified time-point. The electronic device and 
instructions for completing the questionnaires electronically will be provided by the site 
staff. The data will be transmitted to a centralized database maintained by the electronic 
device vendor. The data will be available for access by appropriate study personnel. In 
circumstances when the electronic device is not available (e.g., device failure or due to 
supply issues), a backup data collection method will be used.
During clinic visits, the PRO questionnaires should be administered as follows:

Participants' health status should not be discussed prior to completing the PRO 
questionnaires.

Sites must administer the official version of each questionnaire, as provided by 
the Sponsor. Questionnaires must not be copied from the protocol.

Sites should allow sufficient time for participants to complete the questionnaires, 
estimated to be 20 minutes at each specified visit.

Sites should administer the questionnaires in a quiet area with minimal 
distractions and disruptions.

Participants should be instructed to answer questions to the best of their ability; 
there are no right or wrong answers.

Site staff should not interpret or explain questions but may read questions 
verbatim upon request.

Participants should not obtain advice or help from others (e.g., family members 
or friends) when completing the questionnaires.
Reasons for non-completion of PROs by participants should be recorded in the 
electronic device by site staff. Reasons for non-completion will be pre-populated on the 

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device, and may include if the questionnaire is not available in the participants’ 
language. 
8.1.2.2
Description of Clinical Outcome Assessment Instruments
EORTC QLQ-C30
The QLQ-C30 is a validated and reliable self-reported measure (Aaronson et al. 1993; 
Fitzsimmons et al. 1999; Appendix 8.
It consists of 30 questions that assess five aspects of patient functioning (physical, 
emotional, role, cognitive, and social), global health status and quality of life (GHS/QoL), 
and nine symptoms (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite 
loss, constipation, diarrhea, and financial difficulties) with a recall period of the previous 
week. The functioning and symptoms items are scored on a 4-point scale that ranges 
from "not at all" to "very much," and the GHS/QoL items are scored on a 7-point scale 
that ranges from "very poor" to "excellent."
EORTC QLQ-OES18
The QLQ-OES18 is a validated and reliable self-reported measure that serves as a 
modular supplement to the QLQ-C30 for use in patients with esophageal cancer
(Blazeby et al. 2003; Appendix 9). It consists of 18 questions that assess four scales and 
six single items with a recall period of the previous week. The scoring for the 
QLQ-OES18 follows that of the QLQ-C30.
EORTC IL97
The IL97 is a reduced version of the QLQ-C30 that was created specifically for this study 
from the EORTC Quality of Life Group Item Library. It consists of 17 questions that 
assess two aspects of patient functioning (emotional and social), GHS/QoL, and six
symptoms (fatigue, nausea, vomiting, pain, appetite loss, and diarrhea) with a recall 
period of the previous week (Appendix 10). The scoring for the IL97 follows that of the 
QLQ-C30.
PGI-CI
The PGI-CI is a two-item, self-reported measure used to assess patients’ impression 
about changes to their overall health because of their cancer and the associated 
importance compared with when they began the study (Appendix 11). In the first item, 
the PGI-CI uses a 7-point response scale that ranges from “very much worse” to "very 
much improved" (adapted from Guy et al. 1976). In the second item, the PGI-CI uses a 
3-point response scale (“yes,” “no,” and “not applicable”) for patients to indicate if the 
change they experienced (and reported in the first item) was important to them.

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PGI-S
The PGI-S is a one-item, self-reported measure used to assess patients’ impression 
about how severely their overall health has been impacted because of their cancer 
during the preceding week (Appendix 12). The PGI-S utilizes a 5-point response scale 
that ranges from “very severe” to “none” (adapted from Guy et al. 1976).
PRO-CTCAE
The PRO-CTCAE is a validated item bank that is used to characterize the presence, 
frequency of occurrence, severity, and/or degree of interference with daily function of 
78 patient-reportable symptomatic treatment toxicities (Basch et al. 2014; Dueck et al. 
2015). The PRO-CTCAE contains 124 questions that are rated either dichotomously (for 
determination of presence versus absence) or on a 5-point Likert scale (for 
determination of frequency of occurrence, severity, and interference with daily function). 
Treatment toxicities can occur with observable signs (e.g., vomiting) or non-observable 
symptoms (e.g., nausea). The standard PRO-CTCAE recall period is the previous 7 
days. 
A subset of four symptoms deemed most applicable to the current treatments has been 
selected for this study (Appendix 13). Symptoms have been selected based on known 
adverse drug reactions, mechanism of action of the treatments under investigation, and 
recent work to identify common AEs associated with immunotherapies (King-Kallimanis 
et al. 2019; Hansen et al. 2020).
8.2
SAFETY ASSESSMENTS
Planned time-points for all safety assessments are provided in the SoAs (Section 1.3).
On dosing days, the safety assessments are to be performed prior to the study treatment 
administration. If the assessments have been performed within maximum 72 hours prior 
to dosing, they do not need to be repeated on the scheduled dosing day.
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-serious AEs of special interest (NSAESI); measurement of protocol-specified safety 
laboratory assessments; and measurement of protocol-specified vital signs, 
electrocardiograms (ECGs), and other protocol-specified tests that are deemed critical to 
the safety evaluation of the study.
8.2.1
Physical Examinations
A complete physical examination, performed at screening and all scheduled visits as 
indicated in the SoAs, will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, dermatological and neurological, musculoskeletal systems 
in addition to the head, eyes, ears, nose, throat, neck, and lymph node systems. Weight 
will also be measured and recorded. Height will only be collected at screening. Further 
examination of other body systems may be performed in case of evocative symptoms at 
the Investigator’s discretion.

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Limited, symptom-directed physical examinations should be performed at unscheduled
visits as clinically indicated. 
Changes from baseline abnormalities should be recorded in participant notes. New or 
worsened clinically significant abnormalities should be recorded as AEs on the Adverse 
Event eCRF.
8.2.2
Vital Signs
Vital signs will be recorded at the time-points specified in the SoAs. For vital sign 
assessments on infusion days it is not required to capture vital signs collected during the 
infusion in the eCRF unless abnormalities are observed.
Vital signs will include measurements of systolic and diastolic BP, respiratory rate, pulse 
rate, and body temperature while the participant is in a sitting or semi-supine position at 
every assessment.
Additionally, blood oxygen saturation will be measured by pulse oximetry at screening
and pre-dose at every visit where tumor assessments are performed.
8.2.3
Electrocardiograms
Single 12-lead ECG will be obtained as outlined in the SoAs using an ECG machine that 
automatically calculates the heart rate and measures PR interval, QRS complex, QT 
interval, and QT corrected for heart rate (QTc) interval.
Additional unscheduled ECG assessments should be performed in case of abnormalities 
and if clinical symptoms occur. ECGs for each participant should be obtained from the 
same machine whenever possible.
To minimize variability, it is important that participants be in a resting position for at least 
10 minutes prior to each ECG evaluation. Body position should be consistently
maintained for each ECG evaluation to prevent changes in heart rate. Environmental
distractions (e.g., television, radio, conversation) should be avoided during the pre-ECG
resting period and during ECG recording. ECGs should be performed prior to meals and
any scheduled vital sign measurements and blood draws, whenever logistically possible. 
To minimize variability between visits, it is also recommended that for a given patient, 
assessments should be conducted in the same order throughout the trial. In some 
cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.
For safety monitoring purposes, the Investigator or designee must review, sign, and date 
all ECG tracings. Paper or electronic copies will be kept as part of the participant’s 
permanent study file at the site. If considered appropriate by the Sponsor, ECGs may be 
analyzed retrospectively at a central laboratory.

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ECG characteristics, including heart rate, QRS duration, and PR and QT intervals, will 
be recorded on the eCRF. QTcB (Bazett’s correction, Appendix 14), QTcF (Fridericia’s 
correction, Appendix 14), and RR will be calculated by the Sponsor and recorded on the 
eCRF. Changes in T-wave and U-wave morphology and overall ECG interpretation will 
be documented on the eCRF. T-wave information will be captured as normal or 
abnormal, U-wave information will be captured in two categories: absent/normal or 
abnormal. 
8.2.4
Eastern Cooperative Oncology Group Performance Status
ECOG Performance Status will be assessed at screening, before each study treatment 
administration, and at the discontinuation visit as specified in the SoAs (Section 1.3). It is 
recommended, where possible, that a participant’s performance status will be assessed 
by the same person throughout the study.
8.2.5
Royal Marsden Hospital Risk Score
The Royal Marsden hospital risk score will be derived at screening for each participant 
(Arkenau et al. 2008). This risk-based score is derived from: 

Lactate dehydrogenase (LDH) ULN 0 versus LDH ULN 1

Albumin 35 g/L 0 versus 35 g/L 1

Site of metastasis 2 0 versus 2 1. 
8.2.6
Transthoracic Echocardiogram or MUGA
TTE or MUGA scans will be performed at screening as specified in the SoAs 
(Section 1.3) if no scan is available within 6 months prior to randomization. This may be 
further repeated at the Investigator’s discretion if there are signs or symptoms of 
cardiotoxicity.
8.2.7
Clinical Safety Laboratory Assessments
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. 
A list of clinical laboratory tests to be performed is provided in Appendix 4 and these 
assessments must be conducted in accordance with the separate laboratory manual and 
the SoAs (Section 1.3).
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the 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.

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
In the event of unexplained abnormal clinically significant laboratory test values, 
the tests should be repeated immediately and followed up until they have 
returned to the normal range and/or an adequate explanation of the abnormality 
is found.

If such values do not return to normal/baseline within a period judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified.

If laboratory values from non-protocol-specified laboratory assessments 
performed at the local laboratory require a change in participant management or 
are considered clinically significant by the Investigator (e.g., SAE, AE, or 
dose-modification), then the results must be recorded in the CRF.
Results of clinical laboratory testing will be recorded on the eCRF or be received as 
electronically produced laboratory reports submitted directly from the local or central 
laboratory.
Additional blood or urine samples may be taken at the discretion of the Investigator if the 
results of any test fall outside the reference ranges or clinical symptoms necessitate 
additional testing to monitor participant safety.
Where the clinical significance of abnormal laboratory results at screening is considered 
uncertain, screening laboratory tests may be repeated prior to randomization to confirm 
eligibility.
Based on continuous analysis of the data in this study and other studies, any sample 
type not considered to be critical for safety may be stopped at any time if the data from 
the samples collected do not produce useful information.
8.2.8
Medical History and Demographic Data
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history, 
use of alcohol and drugs of abuse and all medications (e.g., prescription drugs, OTC 
drugs, herbal or homeopathic remedies, nutritional supplements) used by the participant
within 7 days prior to the screening visit.
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The NSAESI and 
disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs 
are discussed in Section 8.3.6 and Section 8.3.7.
The Investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity and causality; see Appendix 2) are

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recorded on the Adverse Event eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3:
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Investigators will seek information on AEs at each participant’s contact. All AEs, whether 
reported by the participant or noted by study personnel, will be recorded in the 
participant’s medical record and on the Adverse Event eCRF as follows:
After informed consent has been obtained but prior to initiation of study treatment, 
only SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). Any other AE should not be reported.
After initiation of study treatment, all AEs, regardless of relationship to study 
treatment, will be reported until 30 days after the final dose of study treatment or until 
initiation of new systemic anti-cancer therapy, whichever occurs first. SAEs will continue 
to be reported until 90 days after the final dose of study treatment or until initiation of 
new systemic anti-cancer therapy, whichever occurs first. In addition, AEs of special 
interest will continue to be reported until 90 days after the final dose of study treatment, 
regardless of initiation of new systemic anti-cancer therapy. 
Post-study AEs and SAEs: The Investigator is not required to actively monitor 
participants for AEs after the end of the AE reporting period.
However, if the Investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study treatment, at any 
time after a participant has been discharged from the study, and the Investigator
considers the event to be reasonably related to the study treatment or study 
participation, the Investigator must promptly notify the Sponsor. For the procedure of 
reporting, see Appendix 2.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE
information at all participant evaluation time-points.

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8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The Investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the Investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study treatment or study-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the 
Adverse Event eCRF and in the participant’s medical record to facilitate source data 
verification. If, after follow-up, return to baseline status or stabilization cannot be 
established, an explanation should be recorded on the Adverse Event eCRF.
All pregnancies reported during the study should be followed until pregnancy outcome 
and reported according to the instructions provided in Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, NSAESIs, and pregnancies, the Sponsor or a designee may follow up by 
telephone, fax, electronic mail, and/or a monitoring visit to obtain additional event details
and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported 
event.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study treatment 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 treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/Independent Ethics 
Committees (IEC), and Investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions 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 (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the Investigator’s Brochure and will notify the IRB/IEC, 
if appropriate according to local requirements.

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For immediate and expedited reporting requirements from Investigator to Sponsor and 
from Sponsor to Health Authority, Investigators, IRB and EC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical Monitors is available 
24 hours a day, 7 days a week. Details will be available separately.
8.3.5
Pregnancy
Female participants of childbearing potential will be instructed to immediately inform the 
Investigator if they become pregnant during the study or within 5 months after the final
dose of study treatment.
Male participants will be instructed through the ICF to immediately inform the 
Investigator if their partner becomes pregnant during the study or within 5 months after 
the final dose of study drug. Male participants should refrain from donating sperm during
the treatment period and for at least 5 months after the final dose of study.
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest
NSAESI are required to be reported by the Investigator to the Sponsor immediately (i.e., 
no more than 24 hours after learning of the event; see Appendix 2 for reporting 
instructions).
NSAESI for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin 
or clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study treatment, as defined 
below:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a participant exposed to a medicinal product. This term applies only when a 
contamination of the study treatment is suspected.

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8.3.7
Management of Specific Adverse Events
Based on the mode of action, RO7121661and RO7247669are expected to show a 
safety profile that is similar to that of other CPIs including nivolumab. Toxicities from 
CPIs can include infusion-related reactions and imAEs. Toxicities associated or possibly 
associated with study treatment should be managed according to standard medical 
practice. Additional tests, such as autoimmune serology or biopsies, should be used to 
determine a possible immunogenic etiology as clinically indicated.
Measures will be taken to ensure the safety of participants in this study, including the 
use of stringent inclusion and exclusion criteria and close monitoring of participants 
during the study. Administration of study drug will be performed in a monitored setting in 
which there is immediate access to trained personnel and adequate equipment and 
medicine to manage potentially serious reactions. 
For events in which management guidelines are not covered in this protocol, participants 
should be managed as deemed appropriate by the Investigator according to best 
medical judgment and local medical guidelines. Clinical judgment may be applied, and 
risk/benefit consideration may suggest deviating from these guidelines. In this specific 
case, decisions on study treatments will be taken by the Investigator upon consultation 
with the Medical Monitor.
8.3.7.1
Infusion-Related Reactions
Administration of therapeutic antibodies may cause IRRs characterized by symptoms 
such as fever, chills, dizziness, hypertension, hypotension, dyspnea, restlessness, 
sweating, flushing, rash, tachycardia, tachypnea, headache, tumor pain, nausea, and/or 
vomiting. Respiratory and cardiac symptoms such as, bronchospasm, larynx, and throat 
irritation, wheezing, laryngeal edema and atrial fibrillation may also occur. Such 
reactions typically occur during or shortly after an infusion or within 24 hours after study 
treatment infusion, predominantly at the first infusion. The incidence and severity 
typically decrease with subsequent infusions.
Participants may also develop immunoglobulin (Ig)E-mediated hypersensitivity reactions. 
IRRs may be indistinguishable from an anaphylactic reaction; however, in case of 
IgE-mediated hypersensitivity, symptoms typically occur after previous exposure and 
very rarely with the first infusion. In case of confirmed IgE-mediated hypersensitivity 
reaction, treatment should be permanently discontinued.
No pre-medication is indicated for the administration of Cycle 1. However, participants 
who experience a Grade 2 should receive pre-medication for subsequent infusions. In 
case of Grade 3 or 4 IRRs related to study treatment, the participant should be 
permanently discontinued from the study treatment. If an IRR occurs during the infusion 
of study drug, refer to Table 7.

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Table 7
Recommendations for Infusion-related Reaction Prevention and 
Management
Infusion-Related 
Reactionsa
Guidance
Grades 1−2

Slow infusion to 50% or interrupt infusion.

Give supportive treatment.b

Upon symptom resolution may resume infusion (if interrupted) at 
50% starting rate. The infusion must remain at the lower rate resulting in 
symptom resolution for the remainder of the infusion.

For Grade 2 IRRs, subsequent cycles of study drug should be administered 
with pre-medication including acetaminophen/paracetamol and an 
antihistamine, such as diphenhydramine.
Notes:

For Grade 2 wheezing or urticaria, the participant must also be 
pre-medicated prior to subsequent doses (as described above).

If symptoms recur with the same or greater severity following the slower or 
interrupted infusion, the infusion must be stopped immediately. No further 
study drug will be administered for the cycle.
Grades 3-4

Discontinue infusion.

Give supportive treatment. b

Permanently discontinue study treatment.
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
a Refer to the NCI-CTCAE, v5.0 scale for the grading of symptoms.
b Supportive treatment: Participants should be treated with acetaminophen/paracetamol and an 
antihistamine, such as diphenhydramine, if they have not been administered in the last 4 hours. 
Intravenous fluids (e.g., normal saline) may be administered as clinically indicated. For bronchospasm, 
urticaria, or dyspnea, antihistamines, oxygen, corticosteroids (e.g., 100 mg IV prednisolone or 
equivalent), and/or bronchodilators may be administered per institutional practice.
8.3.7.2
Immune-mediated Adverse Events
Most imAEs observed with CPIs have been mild and self-limiting, however, such events 
should be recognized early and treated promptly to avoid potentially major 
complications. Any organ or tissue can be involved, although some imAEs occur much 
more commonly than do others. The most frequently occurring imAEs affect the skin, 
colon, endocrine organs, liver, and lungs. Others are very infrequent but may be very 
serious, even lethal, such as neurological disorders and myocarditis.
Discontinuation of study treatment may not have an immediate therapeutic effect, and in 
severe cases, immune-mediated toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNF-α inhibitors. Study 
treatment may be suspended for most Grade 2 toxicities, with consideration of resuming 
when symptoms revert to Grade 1 or less. Corticosteroids may be administered. Grade 3 
toxicities generally warrant suspension of study treatment and the initiation of high-dose 
corticosteroids (prednisone, 1-2 mg/kg/day, or methylprednisolone, 1-2 mg/kg/day). 
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refractory cases may require infliximab or other immunosuppressive therapy. In general, 
permanent discontinuation of study treatment is recommended with Grade 4 toxicities, 
with the exception of endocrinopathies that have been controlled by hormone 
replacement. The management guidelines for imAEs associated with study treatment
are provided in Appendix 7.
8.4
TREATMENT OF OVERDOSE
Study treatment overdose is the accidental administration of a drug in a quantity that is
higher than the assigned dose. An overdose or incorrect administration of study
treatment is not an AE unless it results in untoward medical effects (see Sections 5 and 
5.2 of Appendix 2 for further details).
Decisions regarding dose-interruptions will be made by the Investigator/treating 
physician in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
In the event of an overdose, the Investigator should:

Contact the Sponsor’s Medical Monitor immediately.

Closely monitor the participant for AEs/SAEs and laboratory abnormalities until 
resolved.

Obtain a blood sample for PK analysis as soon as possible.

Document the quantity of the excess dose.
Any dose of study treatment greater than the planned dose will be considered an 
overdose.
The Sponsor does not recommend specific treatment for an overdose.
8.5
PHARMACOKINETICS
Mandatory blood samples to evaluate concentrations of study treatment will be collected 
from an IV line from the arm opposite to that used for study treatment administration. 
The date and time of each sample collection will be recorded in the eCRF. 
RO7121661, RO7247669, and nivolumab levels will be analyzed by using validated 
assays. The PK samples will be taken as outlined in the SoAs (Section 1.3). Additional 
PK samples should be taken, if the participant experiences an infusion-related AE (such 
as an IRR) or if the participant experiences an AE leading to a delay in study drug 
administration. Blood samples for PK analysis may be collected at the participant’s 
home. This specifically applies to days where no other hospital assessments are 
required—i.e. C1D8 and C5D8. 
Remaining volumes of PK samples may be used for additional PK/anti-drug antibodies 
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analyses, or to help develop further blood tests for exploratory analysis (e.g., further 
characterization of immune responses), after they are used for the mentioned intended 
use and as deemed appropriate. 
The PK blood samples will be destroyed within 2 years after the date of final clinical 
study report or earlier depending on local regulations, unless participants give optional 
consent for further use of remaining samples as part of RBR after the end of the study. 
Details on sampling procedures, sample storage, and shipment are given in the sample 
documentation.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or other blinded personnel until the study has been unblinded.
8.6
IMMUNOGENICITY ASSESSMENTS
As the study drugs are human antibodies, there is a risk that ADAs against the study 
drugs could develop, potentially reducing their efficacy and/or potentially resulting in 
symptomatic hypersensitivity reaction, including immune-complex reactions.
Antibodies to the study drugs will be evaluated in blood samples collected from all 
participants according to the SoAs (Section 1.3). For each collected ADA sample, a 
corresponding PK sample will be collected at the same time-point for the determination 
of the study drug concentration. During the course of the study, ADA sampling time-
points may be modified based on emerging data to ensure the immunogenicity of 
RO7121661 and RO7247669 can be adequately characterized.
Validated screening, confirmatory, and titer assays will be employed to detect ADAs. 
The date and time of each sample will be recorded in the eCRF.
If required, remaining volumes of ADA samples may also be used for assay 
development/validation experiments, ADA characterization, for compound-related
exploratory analyses, or to help develop further blood tests, after they are used for the 
mentioned intended uses.
The blood samples will be destroyed within 2 years after the date of final clinical study 
report, or earlier, depending on local regulations unless participants give optional 
consent for further use of remaining samples as part of RBR after the end of the study.
Details on sampling procedures, sample storage, and shipment are documented in the 
sample documentation.
8.7
PHARMACODYNAMICS AND BIOMARKERS ANALYSES
Blood, tissue, tongue scrape, and stool samples will be collected as specified in the 
SoAs (Section 1.3). Details on processes for collection and shipment of these samples 
can be found in the Laboratory Flow Chart.

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Collected samples will be tested for protein, nucleic acid, or other tissue and/or blood 
derived biomarkers relating to the proposed mechanism of actions of RO7247669, 
RO7121661, and nivolumab. These may include, but are not limited to, cellular profiling, 
determination of the activation status of immune cells in blood and in the tumor, 
assessment of the oral and gut microbiome, as well as cytokines and/or other soluble 
markers of inflammation. Additional markers may be measured in case a strong scientific 
rationale for these analyses develops.
The specimens will also be used for research purposes to identify biomarkers useful for
predicting and monitoring response to the respective treatments, identifying biomarkers
useful for predicting and monitoring safety, assessing PD effects, and investigating 
mechanisms of therapy resistance.
Planned analyses include, but are not limited to:

Blood samples:
o
Blood samples for flow cytometry will be analyzed for changes in the 
numbers and activation status of lymphocyte subsets including but not 
limited to CD4+, CD8+, and/ or NK cells.
o
Blood samples for measurement of select cytokines/chemokines (e.g.,
IL-2Ra, IL-6, IL-8, and IP-10), and/or soluble markers (such as, but not 
limited to, sPD1, sLAG3, and/or sTIM3).
o
Blood for whole genome sequencing (WGS; Section 8.7.1.1). 
o
Blood for RNA extraction will be collected for gene expression analysis.
o
Blood for blood tumor mutation burden and ctDNA determination.

Tongue scrape and stool samples:
o
Examining the role of the gut and oral microbiome as a determinant of 
treatment response and safety for cancer immunotherapy via whole 
metagenomic sequencing (WMS) of microbial communities and 
calprotectin detection in stool samples.

Tumor tissue samples (archival samples and/or fresh biopsies):
o
Tumor tissue samples will be used for immunohistochemistry (IHC) 
and/or immunofluorescence (IF) analyses (such as, but not limited to, 
CD8, Ki67, PD1, LAG3, TIM3, and PDL1), as well as the assessment of 
tumor mutational burden (TMB), and tumor gene expression.
Analysis techniques may include, but are not limited to, flow cytometry,
immunohistochemistry, gene expression, and gene sequencing. DNA and/or RNA will be
extracted for exploratory biomarker research on genetic biomarkers (including, but not 
limited to, cancer-related genes and biomarkers associated with common molecular 
pathways or immune-related markers, and TMB.

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Residual plasma/serum samples (e.g., from PK and/or PD assessments) may be used 
for retrospective and longitudinal testing of bacterial or viral infection by serological 
methods (such as but not limited to SARS-CoV-2). This testing may be performed for 
each participant. In addition to serving as an important safety measure, these analyses 
will inform as to any association of bacterial or viral infection and response to treatment.
Based on continuous analysis of data any sample type, time-point, and/ or analysis not
considered critical may be stopped at any time if the data do not produce useful 
information. 
When a participant withdraws from the study, samples collected prior to the date of
withdrawal may still be analyzed, unless the participant specifically requests that the
samples be destroyed or local laws require destruction of the samples. However, if
samples have been tested prior to withdrawal, results from those tests will remain as
part of the overall research data.
Archival tumor blocks will be returned, unless notified by the site that they do not want 
them returned. Blood, tissue, and other residual material (slides, extracts, on-study 
blocks, etc.) will be destroyed within 2 years after the final closure of the clinical 
database unless the participant gives specific consent for the remainder of the material 
to be stored for optional exploratory research (RBR, Section 8.9).
Data arising from all biosamples including samples for analyses of inherited DNA will be
subject to the local confidentiality standards.
8.7.1
Genetic and Genomic Analyses 
Whole blood, tissue, tongue scrape, and stool samples for genetic analyses will be taken 
at the time-points mentioned in SoA (Section 1.3), with respect to the analyses 
described in Section 8.7. These samples will be destroyed no later than 2 years after the 
date of final clinical study report, unless the participant gives specific consent for the 
remainder of the residual material to be stored for optional potential exploratory research 
within the RBR (see Section 8.9).
8.7.1.1
Whole Genome/Exome/Targeted DNA Analysis
Blood, tissue samples (archival and/or fresh biopsies), tongue scrape, and stool samples 
will be collected for DNA extraction (Section 1.3). These samples may be sent to one or 
more laboratories for analysis of germline or somatic mutations via WGS, whole WMS of 
microbial communities, whole exome sequencing (WES), next-generation sequencing 
(NGS), or other targeted genomic analysis methods including (but not limited to) TMB 
and ctDNA determination.

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Genomics is increasingly informing researchers’ understanding of disease pathobiology. 
WGS, WES, WMS, and NGS provide a comprehensive characterization of the genome 
and, along with clinical data collected in this study, may increase the opportunity for 
developing new therapeutic approaches, and understanding genetic predisposition to
greater response or certain AEs after treatment. Data will be analyzed in the context of 
this study but may also be explored in aggregate with data from other studies. The 
availability of a larger dataset will assist in identification of important pathways, guiding 
the development of new, targeted agents.
Given the complexity and exploratory nature of these analyses, data and analyses will 
not be shared with Investigators or study participants unless required by law. 
Participants will not be identified by name or any other personally identifying information. 
Data arising from all biosamples, including samples for analyses of inherited DNA, will 
be subject to the confidentiality standards described in the sample documentation. 
8.7.1.2
Transcriptome Analysis
Archival and/or fresh tissue biopsies and blood samples (other matrices possible) will be 
collected as outlined in the SoAs (Section 1.3) for RNA extraction and subsequent gene 
expression profiling to enable the identification of PD biomarkers and markers predictive 
of treatment response.
8.8
PHARMACODYNAMICS AND BIOMARKER SAMPLES
All samples for PD and biomarker research should be collected as specified in the SoAs
(Section 1.3), with respect to the analyses described in Section 8.7. Details on 
processes for collection and shipment of these samples can be found in separate 
sample documentation.
Any remaining samples after the specified analyses may also be used for additional 
(assay) validation experiments. Samples may be used for research to develop methods, 
assays, prognostics, and/or companion diagnostics related to RO7247669 and/or 
RO7121661, disease process, pathways associated with disease state, and/or
mechanism of action of the study treatments. Note that as science and research is
evolving, the list of biomarkers that will be evaluated cannot be fully defined.
Based on continuous analysis of the data in this study and other studies, any sample 
type and/or analysis not considered critical for safety may be stopped at any time if the 
data from the samples collected does not produce useful information. 
Unless otherwise specified below, samples (including blood, slides, extracts, etc.) will be 
destroyed no later than 5 years after the date of final clinical study report. For 
participants who consent to RBR, leftover samples will be transferred to RBR 
(Section 8.9).

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For sampling procedures, storage conditions, and shipment instructions, see the sample 
flowchart and additional instruction documents.
8.8.1
Mandatory Samples
The following samples for PD and biomarker research are required and will be collected 
from all participants with respect to the analyses described in Section 8.7:

All PD blood samples as outlined in the SoAs (Section 1.3) for:
o
Flow cytometry analyses. 
o
Measurement of select cytokines/chemokines and/or soluble markers. 
o
Whole genome sequencing (Section 8.7.1.1). If this sample is missing on 
C1D1, it should be collected at the next scheduled visit, where possible. 
Collection of this sample is contingent on approval by relevant institutions 
in the respective countries/sites.
o
RNA extraction for gene expression analysis.
o
Blood tumor mutation burden and ctDNA determination.

FFPE archival tumor tissue is to be provided for all participants, if available.
o
In case no suitable archival tissue is available for central assessment of 
tumor PD-L1 positivity using the IHC 28-8 pharmDx assay, a mandatory 
fresh baseline biopsy will be required (Section 5.1 and Section 8.8.2).
o
The primary and the most recent metastasis (if both are available) should
be submitted for analysis, and the tissue sample should not be older than 
12 months. Ideally, these samples should include the invasive margin. 
o
Tumor blocks are preferred but unstained slides containing freshly cut, 
serial sections will be accepted.
o
Acceptable samples include core needle biopsies for deep tumor tissue or 
excisional, incisional, punch, or forceps biopsies for cutaneous, 
subcutaneous, or mucosal lesions.
o
Fine-needle aspiration, brushing, cell pellet from effusions, bone 
metastases, and lavage samples are not acceptable.
o
Archival tumor blocks will be returned to the sites when requested by the 
Investigator or at the end of the study, unless notified by the site that they 
do not want them returned.

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8.8.2
Optional Samples
Upon consent, the following optional samples for biomarker research should be collected 
from participants as outlined in the SoAs (Section 1.3), with respect to the analyses 
described in Section 8.7).

Tongue scrape and stool samples for the assessment of the participant’s oral and 
gut microbiome as well as calprotectin detection
o
Dietary intake is a central determinant of changes in the microbiota. A 
nutritional assessment will therefore be performed as indicated in the 
SoAs to better correlate the profiles of the microbiota for participants who 
consent to provide these optional samples.
o
Screening samples of participants who are not enrolled in the study will 
be destroyed.

Fresh tumor biopsies at baseline and as indicated in the SoAs:
o
Collection of tumor biopsies should be guided by ultrasound, CT scan, or 
other methods according to the location of the selected lesion using a 
16-gauge needle (preferred) to provide cores, ideally, of at least 20 mm in 
length or equivalent size. Ideally, 4 (minimum 2) core biopsies should be 
obtained at each time-point (at the physician’s discretion). In order to 
mitigate the potential risk associated with tumor biopsies, all participants
required to have a biopsy must have tumor lesions from which biopsies 
can be safely obtained, as per clinical judgment of the treating physician.
o
Fresh screening samples should generally be collected after eligibility is 
confirmed. Post-dose samples can be collected 2/1 day(s) from 
scheduled time-point. If the participant progresses and discontinues 
treatment prior to the on-treatment biopsy day, the tumor biopsy should 
be taken at the time of treatment discontinuation. An additional biopsy at 
the time of PR, stable disease, progression, or at any other time-point of 
interest based on participants’ course of disease may be taken after 
discussion between the Investigator and the Sponsor. A minimum interval 
of 4 weeks is necessary between the collections of optional tumor 
biopsies.
o
Baseline and on-treatment biopsies should be preferably taken from the 
same tumor lesion (metastasis) to ensure comparability. If the sample 
cannot be collected from the same lesion (e.g., lesion disappears after 
treatment) then preferably the biopsy should be collected from the same 
organ, if possible.
o
Fine-needle aspiration is not acceptable. The biopsies will be taken from
accessible tumor locations, including, but not limited to, skin, lymph 
nodes, rectum, liver, etc. Bone biopsies and trans-bronchial biopsies are 
not acceptable.

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o
Use of available existing biopsies at the sites prior to the participant’s 
entry in the study should be discussed with the Sponsor (i.e., biopsy 
should have recently been obtained as part of diagnosis biopsy and 
participants should have not received any tumor treatment after this 
collection).
o
In the event that a fresh biopsy is taken during the screening period and 
the participant is not enrolled into the study, the fixed and embedded 
biopsy (FFPE block) can be returned to the site upon site request. The 
site must confirm that a written consent is obtained from the participant 
before return request submission to the Sponsor. If the participant does 
enroll in the study, fresh biopsies will not be returned to the site.
o
The Sponsor will continuously assess the need for making the biopsies 
mandatory, and additional participants may be enrolled to ensure that 
sufficient paired fresh biopsy samples are evaluable to conclude the 
intended PD analyses.
The ICF will contain a separate section that addresses the use of remaining samples for 
optional exploratory research. A separate signature will be required to document a 
participant's agreement to allow any remaining samples to be used for optional 
exploratory research.
8.9
SAMPLES FOR RESEARCH BIOSAMPLE REPOSITORY
8.9.1
Overview of the Research Biosample Repository
The Roche RBR is a centrally administered group of facilities for the long-term storage of 
human biologic samples, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides). The collection, storage, and analysis of the RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future.
Samples for the RBR will be collected from participants who give specific consent to 
participate in this optional RBR. Collected RBR samples will be used to achieve the 
following objectives:

To study the association of biomarkers with efficacy or progressive disease.

To identify safety biomarkers that are associated with susceptibility to developing 
AEs or can lead to improved AE monitoring or investigation.

To increase knowledge and understanding of disease biology and drug safety.

To study treatment response, including drug effects and the processes of drug 
absorption and disposition. 

To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays.

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8.9.2
Sample Collection
The following samples will be collected for identification of genetic (inherited) 
biomarkers:

Saliva for DNA extraction
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to RO7121661, RO7247669, 
diseases or drug safety:

Leftover plasma samples

Leftover serum samples

Leftover blood samples

Leftover fresh or archival tumor tissue samples and unstained slides

Leftover blood samples for DNA extraction

Leftover genetic material such as DNA and RNA
The samples collected for DNA extraction include, but is not limited to, genomic analysis 
and may be sent to one or more laboratories for analysis of germline or somatic 
mutations via WGS, WES, NGS, or other genomic analysis methods.
Genomics is increasingly informing researcher's understanding of disease pathobiology. 
WGS provides a comprehensive characterization of the genome and, along with clinical 
data collected in this study, may increase the opportunity for developing new therapeutic 
approaches. Data will be analyzed in the context of this study but may also be explored 
in aggregate with data from other studies. The availability of a larger dataset will assist in 
identification of important pathways, guiding the development of new targeted agents.
Upon RBR consent, samples may be used for DNA extraction to enable whole 
genome/exome sequencing WGS/WES and other genomic analysis.
Samples may be sent to one or more laboratories for analysis of germline or somatic 
mutations via WGS/WES, or other genomic analysis methods. WGS and WES provide a 
comprehensive characterization of the genome and exome, respectively, and, along with 
clinical data collected in this study, may increase the opportunity for developing new 
therapeutic approaches or new methods for monitoring efficacy and safety or predicting 
which patients are more likely to respond to a drug or develop AEs.
Participants will not be identified by name or any other personally identifying information. 
Data generated from RBR samples will be analyzed in the context of this study but may
also be explored in aggregate with data from other studies. The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development.

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For all samples, dates of consent, and sample collection should be recorded on the 
associated RBR page of the eCRF. Details on processes for collection and shipment of 
these samples can be found in separate sample documentation.
RBR samples will be stored and used until they are depleted or come to end of their 
retention period and are thus destroyed. The RBR storage period will be in accordance 
with the IRB/EC‑approved ICF and applicable laws (e.g., Health Authority 
requirements).
The repository samples will be subject to the confidentiality standards (as described 
under Confidentiality in Appendix 1).
8.10
HEALTH ECONOMICS/MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
8.11
TIMING OF STUDY ASSESSMENTS
8.11.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. ICFs for enrolled 
participant and for participants who are not subsequently enrolled will be maintained at 
the study site.
All screening, and all pre-treatment assessments (related to entry criteria), must be 
completed and reviewed to confirm that 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.
An Eligibility Screening Form documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator and kept at the investigational site.
Screening and pre-treatment assessments will be performed within 28 days prior to 
randomization, unless otherwise specified. Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within 28 days prior to 
randomization may be used (and do not need to be repeated for screening).
8.11.2
Assessments during Treatment
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified be permitted to be allocated a new randomization number and
re-enroll in the study.

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All assessments must be performed as per SoAs (Section 1.3). Assessments scheduled 
on the day of study treatment administration should be performed prior to administration 
of study treatment, unless otherwise noted in the SoAs. PRO questionnaires will be 
completed before the participant receives any information on disease status, prior to the 
performance of non-PRO assessments, and prior to the administration of study 
treatment.
8.11.3
Assessments at Treatment Discontinuation Visit
Participants who discontinue study treatment early will be asked to return to the clinic 
30 days after the final dose of study drug for a follow‑up visit. The visit at which 
response assessment shows progressive disease may be used as the treatment 
discontinuation visit.
8.11.4
Follow-Up Assessments
As part of the post-treatment follow-up, the sites will provide to the Sponsor every 
3 months with an update on survival status and new anti-cancer therapies of each 
participant who has completed or discontinued from the study. The survival follow-up will 
be performed for the first time 90 days (7 days) post last dose of study treatment and 
then every 3 months (2 weeks). The sites will use a designated section of the eCRF for 
this purpose. Post-treatment follow-up visits can be done at site, over the phone, or 
participant medical records. In addition, all participants will be asked to complete PROs 
every 3 months during the first year post discontinuation. 
For participants who discontinue treatment for reasons other than disease progression 
or loss of clinical benefit tumor assessments are to continue according to schedule until
they start new anti-cancer therapy.
After the treatment discontinuation visit, AEs should be followed as outlined in 
Section 8.3.1 and Section 8.3.3.
8.11.5
Assessments at Unscheduled Visits
If clinically indicated, any sample or assessment specified in the SoAs can be performed 
any time as unscheduled sample or assessment at the discretion of the Investigator.
In case of Grade 2 IRRs or Grade 3 IRRs, suspected anaphylaxis, or Grade 3 
suspected imAEs, the assessments as per SoAs (Section 1.3) are to be performed.

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9.
STATISTICAL CONSIDERATIONS
The data will be analyzed by the Sponsor and/or designated contract research 
organization. Any data analysis carried out independently by the Investigator should be 
submitted to the Sponsor before publication or presentation. The data will be 
summarized with respect to demographic and baseline characteristics, efficacy, safety, 
PK, and biomarkers observations and measurements. The core analysis will focus on the 
OS comparison of RO7247669 against nivolumab and take place when approximately 
 
OS events have been observed in these two arms of the study. The additional data for 
any participant continuing to receive study treatment or being followed for survival past 
this time (as allowed by the protocol) will be further summarized in a subsequent 
extension report once the study is terminated.
9.1
SAMPLE SIZE DETERMINATION
This study was designed to provide an assessment of the efficacy and safety of 
RO7121661 and RO7247669. The primary purpose is the estimation of the OS hazard 
ratios (HR) of RO7247669 against nivolumab. 
The planned number of enrolled participants was 255, randomized 
 into 3 arms. 
With the decision to stop enrollment into the RO7121661 arm, the study sample size 
has been re-estimated to reflect the new randomization scheme (new participants will be 
randomized 
 to either RO7247669 or nivolumab).
 
 
 
 
 
 
 
 
 
 
 
 

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9.2
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined in Table 8.
Table 8
Analysis Populations
Population
Description
Intent-to-treat
All randomized participants will be included in the intent-to-treat 
population.
Safety
All participants randomized to study treatment and who received any 
amount of the study treatment, whether prematurely withdrawn from the 
study or not, will be included in the safety analysis. 
Pharmacokinetic
All participants who have received at least one dose of study treatment 
and who have data from at least one post-dose sample will be included 
in the PK analysis population. Participants will be excluded from the PK 
analysis population if they significantly violate the inclusion or exclusion 
criteria, deviate significantly from the protocol, or if data are unavailable 
or incomplete which may influence the PK analysis. Excluded cases will 
be documented together with the reason for exclusion. All decisions on 
exclusions from the analysis will be made prior to database closure.
Immunogenicity
Participants who had at least one pre-dose or at least one post-dose 
ADA assessment will be included and analyzed according to the 
treatment they actually received or were allocated to receive. The 
relationship between ADA status and safety, efficacy, PK, and biomarker 
endpoints will be analyzed and reported descriptively via subgroup 
analyses.
PRO-evaluable 
population
All randomized participants with a non-missing baseline assessment 
and at least one post-baseline assessment for the respective PRO 
will be included in the PRO-evaluable population.
ADA Anti-drug antibody; PK Pharmacokinetic; PRO Patient-reported outcome.
9.3
STATISTICAL ANALYSES
A technical document describing the statistical analyses plan will provide more details 
on the statistical analyses.
9.3.1
Demographics and Baseline Characteristics
Study enrollment, study drug administration, reasons for study drug discontinuation, and 
reasons for discontinuation from the study will be summarized by treatment arm. Major 
protocol deviations, including major deviations with regard to the inclusion and exclusion 
criteria, will be summarized by treatment arm.
Demographic (including age, sex, and self-reported race/ethnicity) and baseline disease 
characteristics (e.g., ECOG Performance Status) will be summarized overall and by 
treatment arm.
Descriptive statistics (mean, median, standard deviation, and range) will be presented 
for continuous data, and frequencies and percentages will be presented for categorical 
data, as appropriate.

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Baseline measurements are the last available data obtained prior to the participant 
receiving the study treatment.
9.3.2
Efficacy Analyses
The efficacy analyses will include all participants in the ITT population, with participants 
grouped according to the treatment assigned at randomization (Table 9).
Descriptive statistics for the various endpoints will be provided for all 3 arms. 
However, since the primary aim has shifted from comparing the 2 experimental arms to 
nivolumab to only compare the RO7247669 arm to nivolumab, the statistical models 
will only include participants assigned to RO7247669 and nivolumab.
Table 9
Efficacy Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Primary
OS 
OS is defined as the time from randomization to death from any cause. Data for 
participants who are alive at the time of the data cutoff will be censored at the last 
date they were known to be alive. Data from participants without post-baseline 
information will be censored at the date of randomization.
Kaplan-Meier methods will be used to estimate median OS for each treatment arm 
and the 95% CIs for median OS will be computed using the Brookmeyer and 
Crowley method. The stratified Cox proportional hazard model will be used to 
estimate the hazard ratio for RO7247669 versus nivolumab (i.e., the magnitude of 
the treatment effect) and the corresponding 95% confidence interval, stratified by 
the protocol-defined stratification factors.
Secondary
ORR and DCR based on RECIST 
ORR is defined as the proportion of participants who have achieved an objective 
response, characterized by a CR or PR according to RECIST v1.1.
Objective response will be evaluated by treatment arm, and participants without 
post-baseline overall response assessments will be counted as non-responders. 
DCR is defined as ORR stable disease rate (SDR).
An estimate of ORR for each treatment group as well as of the difference between 
the ORR of each experimental arm compared with the active comparator will be 
computed along with its 95% CI. The Mantel-Haenszel test will be used to 
compare the ORR of RO7247669 and the active comparator at the two-sided 
significance level of 20%, stratified by the protocol-defined stratification factors.
PFS based on RECIST
PFS defined as the time from randomization to the first occurrence of progression 
as determined by the Investigator according to RECIST v1.1 or death during the 
treatment period or within on study (i.e., within 60 days of the last study treatment
tumor assessment) after treatment discontinuation, whichever occurs first. 
Participants who have not experienced disease progression at the time of analysis 
and who have not died during the treatment period or within 60 days of the last 
tumor assessment after treatment discontinuation will be censored at the time of 
the last tumor assessment. Participants with no post-baseline tumor assessment 
will be censored at the date of randomization.
The requirement that participants without a radiographic disease progression per 
RECIST v1.1 are still followed for the tumor assessments until progression or 
when the participant starts a new anti-cancer therapy (whatever occurs first), 
means that: 

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Endpoint
Statistical Analysis Methods
- intercurrent events of treatment discontinuations in absence of disease 
progression per RECIST 1.1 do not per se censor the PFS observation, since the 
participant will still undergo tumor assessments (treatment policy strategy)
- intercurrent events of new anticancer therapy imply instead that the PFS 
observation is censored at the last available tumor assessment before the new 
anticancer treatment starts, therefore assuming that participants who experience 
this intercurrent event have the same risk as those who did not (hypothetical 
strategy). 
PFS will be compared between treatment arms with use of the stratified log-rank 
test.
The HR and its 95% CI for PFS will be estimated using a stratified Cox 
proportional-hazards model. Kaplan-Meier methodology will be used to estimate 
the median PFS for each treatment arm, and Kaplan-Meier curve will be 
constructed to provide a visual description of the difference between treatment 
arms.
DoR based on RECIST
DoR is defined as the time from the first occurrence of a documented objective 
response to disease progression according to RECIST v1.1 or death from any 
cause, whichever occurs first. 
The analysis of DoR will include only participants who achieved an objective 
response to study treatment. DoR will be estimated using the Kaplan-Meier 
methodology. As the determination of DoR is based on a non-randomized subset 
of participants, no formal hypothesis testing will be performed.
Proportion of participants reporting clinically meaningful improvements in 
PRO measures
The proportion of participants in each treatment group reporting clinically 
meaningful improvement (defined as 10 points) in global health status/quality of 
life, emotional functioning, social functioning and dysphagia as measured by the
EORTC QLQ-C30, IL-97, and OES-18 will be computed.
An estimate of this proportion for each treatment group as well as of the difference 
between proportions of each experimental arm compared to the active comparator
will be computed along with its 95% CI.
CI Confidence interval; CR Complete response; DCR Disease control rate; DoR Duration 
of response; EORTC European Organisation for Research and Treatment of Cancer;
HR Hazard ratio; IL97 Item Library 97; OS Overall survival; PFS Progression-free 
survival; PR Partial response; PRO Patient-reported outcomes; RECIST Response 
evaluation criteria in solid tumors.
9.3.3
Safety Analyses
All safety analyses will be based on the safety analysis population grouped according to 
the treatment assigned at randomization (Table 10).
Safety analyses will include all participants randomized to study treatment and who 
received any amount of the study treatment, whether prematurely withdrawn from the 
study or not. Safety analyses will be performed by treatment arm and will be based on 
actual treatment received. Drug exposure will be summarized, including duration.
Verbatim description of AEs will be mapped to the MedDRA terms. Severity for all AEs 
will be graded by the Investigator according to the NCI CTCAE v5.0. All AEs will be 

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summarized by treatment arm and NCI CTCAE grade. In addition, SAEs and AEs 
leading to study treatment discontinuation or interruption will be summarized 
accordingly. Multiple occurrences of the same event will be counted once at the 
maximum severity. Laboratory data with values outside of the normal ranges will be 
identified. In addition, selected laboratory data, including ADA results, will be 
summarized by treatment arm. Deaths and causes of deaths will be summarized.
Table 10 Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Adverse events
The original terms recorded on the eCRF by the Investigator for AEs will be 
coded by the Sponsor.
Adverse events will be summarized by mapped term and appropriate 
thesaurus level.
Clinical laboratory 
tests
All clinical laboratory data will be stored on the database in the units in 
which they were reported. Laboratory test values will be presented in 
International System of Units (SI units; Système International d’Unités) by 
individual listings with flagging of abnormal results.
Shifts in NCI CTCAE v5.0 grades from baseline to the worst grade 
observed during treatment and summary tables of change from baseline 
over time based on SI units will be presented for selected laboratory 
parameters. Individual participant listings (abnormal values or out of range) 
will be produced. For details on standard reference ranges and data 
transformation and the definition of laboratory abnormalities, see
Appendix 4. Additional figures/tables/listings will be produced as deemed 
appropriate.
Vital signs
Vital signs data will be presented by individual listings with flagging of 
values outside the normal ranges and flagging of abnormalities. In addition, 
tabular summaries will be used, as appropriate.
ECG data analysis ECG data will be presented by individual listings. In addition, tabular 
summaries will be used, as appropriate.
Concomitant 
medications
The original terms recorded on the participants’ eCRF by the Investigator 
for concomitant medications will be standardized by the Sponsor by utilizing 
a mapped term and appropriate drug dictionary level.
Concomitant medications will be presented in summary tables and listings.
AE Adverse event; ECG Electrocardiogram; eCRF Electronic case report form; 
NCI CTCAE National Cancer Institute Common Terminology Criteria for Adverse Events; 
SI units Système International d’Unités.
9.3.4
Pharmacokinetic Analyses
Analyses will be carried out on the PK analysis population. All PK parameters will be 
presented by listings and descriptive summary statistics (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum) separately by treatment group.

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Individual and mean serum RO7121661, RO7247669, and nivolumab versus time data 
will be tabulated and plotted by treatment group. Graphical displays of PK data may also 
be provided. The serum pharmacokinetics of RO7121661, RO7247669 and nivolumab
will be summarized by estimating total exposure (area under the curve), maximum 
concentration, total clearance, volume of distribution at steady‑state, and terminal 
half-life, as appropriate for the data collected. Estimates for these parameters will be 
tabulated and summarized. Inter‑participant variability and drug accumulation will be 
evaluated.
9.3.5
Immunogenicity Analyses
The immunogenicity analyses will include all participants with at least one ADA 
assessment, irrespective of whether or not the participant receives any treatment
(Shankar et al., 2014).
The numbers and proportions of ADA-positive participants and ADA-negative
participants at baseline (baseline prevalence) and after study drug administration (post-
baseline incidence during both the treatment and follow-up periods) will be summarized.

Participants are considered to be ADA positive if they are ADA negative at 
baseline but develop an ADA response following study drug administration 
(treatment-induced ADA response), or if they are ADA positive at baseline and 
the titer of one or more post-baseline samples is greater than the titer of the 
baseline sample by a scientifically reasonable margin such as at least 4-fold 
(treatment-enhanced ADA response).

Participants are considered to be ADA negative if they are ADA negative at 
baseline and all post-baseline samples are negative, or if they are ADA positive 
at baseline but do not have any post-baseline samples with a titer that is greater 
than the titer of the baseline sample by a scientifically reasonable margin such as 
at least 4-fold (treatment unaffected).
The relationship between ADA status and safety, efficacy, PK, and biomarker endpoints 
may be analyzed and reported descriptively via subgroup analyses.
9.3.6
Pharmacodynamic Analyses
All PD parameters will be presented by listings and descriptive summary statistics 
separately by treatment group.
All analyses of PD and exploratory biomarkers will be based on the safety analysis 
population (Section 9.2).
For the analysis of PD biomarkers, the primary evaluation will be based on the observed 
change from baseline. Both actual values and estimated parameters will be presented in 
summary tables and graphically as deemed appropriate.

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To assess predictability of a biomarker, the association between clinical outcome and 
the biomarker level or changes thereof will be explored.
9.3.7
Pharmacokinetic/Pharmacodynamic Relationships 
Exploratory graphical analyses of exposure-effect relationships may be produced for 
selected efficacy, PD, and/or safety measurements if appropriate. A PK/PD modelling 
approach may be considered in order to further explore the exposure-response 
relationship of selected response variables. Data will be explored using linear and/or 
exponential models, as appropriate, in non-linear mixed effect modelling software.
Additional PK analyses will be conducted as appropriate.
9.3.8
Other Analyses
Completion rates and reasons for missing data will be summarized for the QLQ-C30, 
QLQ-OES18, IL97, PGI-CI, and PGI-S at each treatment cycle by treatment arm and 
within the ITT population.
Visit mean summary and change from baseline analyses will be performed for all scales 
of the QLQ-C30, QLQ-OES18, and IL97. Summary statistics (e.g., number of 
participants, mean, standard deviation, median, minimum, maximum, 95% CI) of linearly 
transformed scores (per the EORTC scoring manual) will be calculated at all 
assessment time-points for each treatment arm. These analyses will be performed in the 
PRO-evaluable population.
Summary statistics (e.g., number of participants, proportions) will be calculated for the 
PGI-CI and PGI-S in the PRO-evaluable population.
9.3.8.1
Exploratory Analyses of PRO-CTCAE
PRO-CTCAE analyses will be primarily descriptive, with a focus on characterizing the 
pattern of symptomatic treatment toxicities over the course of the study. Results from 
these exploratory analyses will be presented separately from the other safety analyses.
PRO-CTCAE data will be analyzed at the item level in line with current NCI 
recommendations for data handling (Basch et al. 2014).
PRO-CTCAE data will be summarized over time. The proportion of missing data at each 
assessment time-point will also be summarized to facilitate interpretation of data.
The number and percentage of participants reporting each symptom and the change 
from baseline by category (frequency of occurrence, severity, interference) will be 
summarized at each assessment time-point by treatment arm. For items that are rated 
on a 5-point Likert scale, the maximum post-baseline score and change from baseline 
will be summarized by treatment arm. 
Graphical representation of PRO-CTCAE data over time will also be provided.

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9.4
INTERIM ANALYSES
For this study, blinded periodic analyses of cumulative safety data will be conducted by 
the JMC. 
In addition, given the hypothesis-generating nature of this study, 
 
 
 
 
 
 
The interim analysis will be performed and interpreted by Sponsor study team personnel 
who will have full access to unblinded data. Access to treatment assignment information 
will follow the Sponsor’s standard procedures.
A technical document describing the statistical analyses plan will provide more details 
on the planned interim analyses.
9.5
SUMMARIES OF CONDUCT OF STUDY
Enrollment, duration of survival follow-up, study drug administration, reasons for study 
drug discontinuation, and reasons for discontinuation from the study will be summarized 
by treatment arm for the ITT population. Major protocol deviations, including major 
deviations with regard to the inclusion and exclusion criteria, will be summarized by 
treatment arm for the ITT population.

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10.
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foradvanced or recurrent esophageal cancer in patients who had previously 
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patients (pts) with advanced/metastatic adenocarcinoma (AC) or squamous cell 
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2019;30(Suppl 9):,ix42-3.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following appendices are included in this section:
Appendix 1: Regulatory, ethical, and study oversight considerations
Appendix 2: Adverse events definitions and procedures for evaluating, follow-up, and 
reporting 
Appendix 3: Procedures for recording adverse events
Appendix 4: Clinical laboratory tests
Appendix 5. Contraceptive guidance and collection of pregnancy information
Appendix 6: New Response Evaluation Criteria in Solid Tumors Version 1.1
Appendix 7: Risks and guidelines for adverse events associated with study drugs
Appendix 8: EORTC QLQ-C30
Appendix 9: QLQ-OES18
Appendix 10: EORTC IL97
Appendix 11: PGI-CI
Appendix 12: PGI-S
Appendix 13: PRO-CTCAE
Appendix 14: Correction formulas for QTc intervals

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Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting). Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws. Studies 
conducted in the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC).
1.2.
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms (ICFs), any information to be given to the 
participant (e.g., advertisements, diaries etc.), and relevant supporting information must 
be submitted to the IRB/EC by the Principal Investigator and reviewed and approved by 
the IRB/EC before the study is initiated. In addition, any participant recruitment materials 
must be approved by the IRB/EC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. Investigators are also 
responsible for promptly informing the IRB/EC of any protocol amendments 
(Section 2.3.1 of this Appendix).
The Investigator should follow the requirements for reporting all adverse events to the 
Sponsor. Investigators may receive written IND safety reports or other safety‑related 
communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with Health Authority requirements 
and the policies and procedures established by their IRB/EC, and archived in the site’s 
study file.

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1.3.
INFORMED CONSENT
The Sponsor’s Master Informed Consent Form (and ancillary sample ICFs such as a 
Child’s Assent or Caregiver's Informed Consent Form, if applicable) will be provided to 
each site. If applicable, it will be provided in a certified translation of the local language. 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center. The Sponsor or its designee must review 
and approve any proposed deviations from the Sponsor's sample ICFs or any alternate 
Consent Forms proposed by the site (collectively, the “Consent Forms”) before IRB/EC 
submission. The final IRB/EC‑approved Consent Forms must be provided to the 
Sponsor for Health Authority submission purposes according to local requirements.
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. A copy of the ICF(s) signed by all parties must be provided to 
the participant or the participant’s legally authorized representative.
The ICFs must be signed and dated by the participant or the participant’s legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each participant shall document the informed consent process and 
that written informed consent was obtained prior to participation in the study.
The ICFs should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the participant to 
take part. The final revised IRB/EC-approved ICFs must be provided to the Sponsor for 
Health Authority submission purposes if required as per local regulations.
If the ICFs are revised (through an amendment or an addendum) while a participant is 
participating in the study, the participant or a legally authorized representative may be
re-consented by signing the most current version of the ICFs or the addendum, in 
accordance with applicable laws and IRB/EC policy. For any updated or revised ICFs, 
the case history or clinical records for each participant shall document the informed 
consent process and that written informed consent was obtained using the 
updated/revised ICFs for continued participation in the study. The study team will 
provide guidance for which participants need to re-consent in the event of an update to 
the ICF.
A copy of each signed ICF must be provided to the participant or the participant’s legally 
authorized representative. All signed and dated ICFs must remain in each participant’s 
study file or in the site file and must be available for verification by study monitors at any 
time.
A participant who is re-screened is not required to sign another ICF if the re-screening
occurs within 60 days from the previous ICF signature date.

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Consent to Participate in the Research Biosample Repository
The ICF will contain a separate section that addresses participation in the RBR. The
Investigator or authorized designee will explain to each participant the objectives, 
methods, and potential hazards of participation in the RBR. Participants will be told that 
they are free to refuse to participate and may withdraw their samples at any time and for 
any reason during the storage period. A separate, specific signature will be required to 
document a participant’s agreement to provide optional RBR samples. Participants who 
decline to participate will not provide a separate signature.
The Investigator should document whether or not the participant has given consent to 
participate by completing the RBR Sample Informed Consent eCRF.
In the event of death or loss of competence of a participant who is participating in the 
research, the participant's samples and data will continue to be used as part of the RBR.
For sites in the United States, each ICF may also include participant authorization to 
allow use and disclosure of personal health information in compliance with the U.S. 
HIPAA. If the site utilizes a separate Authorization Form for participant authorization for 
use and disclosure of personal health information under the HIPAA regulations, the 
review, approval, and other processes outlined above apply except that IRB review and 
approval may not be required per study site policies.
Approval by the Institutional Review Board or Ethics Committee
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the ICF by each site's 
IRB/EC and, if applicable, an appropriate regulatory body. If a site has not been granted 
approval for RBR sampling, this section of the protocol will not be applicable at that site

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Withdrawal from the Research Biosample Repository
Participants who give consent to provide samples for the RBR have the right to withdraw 
their samples at any time for any reason. If a participant wishes to withdraw consent to 
the testing of his or her samples, the Investigator must inform the Medical Monitor and 
Site Monitor in writing of the participant’s wishes using the RBR Withdrawal Form and, if 
the study is ongoing, must enter the date of withdrawal on the RBR Withdrawal of 
Informed Consent eCRF. The participant will be provided with instructions on how to 
withdraw consent after the study is closed. A participant's withdrawal from Study 
BP42772 does not, by itself, constitute withdrawal of samples from the RBR. Likewise, a 
participant’s withdrawal from the RBR does not constitute withdrawal from Study 
BP42772. Data already generated before time of withdrawal of consent to RBR will still 
be used.
1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
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. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
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.
Study data, which may include data on germline mutations, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study. These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease. In addition, redacted clinical study reports and 
other summary reports will be provided upon request.
Confidentiality for Research Biosample Repository
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local Health Authorities, and Roche monitors, 
representatives, and collaborators, as appropriate.

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Participant medical information associated with RBR samples is confidential and may 
only be disclosed to third parties as permitted by the ICF (or separate authorization for 
use and disclosure of personal health information) signed by the participant, unless 
permitted or required by law.
Data derived from RBR sample analysis on individual participants will generally not be 
provided to study Investigators unless a request for research use is granted. The 
aggregate results of any conducted research will be available in accordance with the 
effective Roche policy on study-data publication.
Genetic research data and associated clinical data may be shared with researchers who 
are not participating in the study or submitted to government or other health research 
databases for broad sharing with other researchers. Participants will not be identified by 
name or any other personally identifying information. Given the complexity and 
exploratory nature of these analyses, genetic data and analyses will not be shared with 
Investigators or participants unless required by law.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR sample data will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
Monitoring and Oversight Research Biosample Repository
Samples collected for the RBR will be tracked in a manner consistent with Good Clinical 
Practice by a quality-controlled, auditable, and appropriately validated laboratory 
information management system, to ensure compliance with data confidentiality as well 
as adherence to authorized use of samples as specified in this protocol and in the ICF. 
The Sponsor’s monitors and auditors will have direct access to appropriate parts of 
records relating to participant participation in RBR for the purposes of verifying the data 
provided to the Sponsor. The site will permit monitoring, audits, IRB/EC review, and 
Health Authority inspections by providing direct access to source data and documents 
related to the samples.
1.5.
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate Health Authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for one year after completion of the study.

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2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
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 (e.g., laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by 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.
2.1.2.
Clinical Outcome Assessment Data
2.1.2.1
Electronic Clinical Outcome Assessment Data
An electronic clinical outcome assessment (eCOA) device will be used to capture clinical 
outcome assessment data. The data will be transmitted automatically to a centralized 
database at the eCOA vendor via web or wireless transmission after data entry. The 
data may be reviewed by site staff via secure access to a web portal provided by the 
eCOA vendor.
The eCOA data will be collected using an electronic device provided by an eCOA
vendor. The device is designed for entry of data in a way that is attributable, secure, and 
accurate, in compliance with U.S. FDA regulations for electronic records (21 CFR Part 
11). In situations where there is no on-site visit required, remote options for eCOA 
completion (e.g., URL or phone) will be provided. System backups for data stored by the 
Sponsor and records retention for the study data will be consistent with the Sponsor’s 
standard procedures.

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2.1.3.
Source Data Records
Source documents (paper or electronic) are those in which participant data are recorded 
and documented for the first time. They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, clinical outcome assessments
(paper or eCOA), evaluation checklists, pharmacy dispensing records, recorded data 
from automated instruments, copies of transcriptions that are certified after verification 
as being accurate and complete, microfiche, photographic negatives, microfilm or 
magnetic media, X-rays, participant files, and records kept at pharmacies, laboratories, 
and medico‑technical departments involved in a clinical study.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described below.
To facilitate source data verification, the Investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IRB/EC review. The investigational site must also allow 
inspection by applicable Health Authorities.
2.1.4.
Use of Computerized Systems
When clinical observations are entered directly into an investigational site’s 
computerized medical record system (i.e., in lieu of original hardcopy records), the 
electronic record can serve as the source document if the system has been validated in 
accordance with Health Authority requirements pertaining to computerized systems used 
in clinical research. An acceptable computerized data collection system allows 
preservation of the original entry of data. If original data are modified, the system should 
maintain a viewable audit trail that shows the original data as well as the reason for the 
change, name of the person making the change, and date of the change.
2.1.5.
Safety Biomarker Data
Adverse event reports will not be derived from safety biomarker data by the Sponsor, 
and safety biomarker data will not be included in the formal safety analyses for this 
study.  In addition, safety biomarker data will not inform decisions on participant
management.

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2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after study completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local Health Authorities, whichever is longer. After that period, the documents may be 
destroyed, subject to local regulations. 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.
The Sponsor will retain study data for 25 years after the final study results have been 
reported or for the length of time required by relevant national or local Health Authorities.
2.3.
STUDY RECORDS
The Investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully reconstructed, including but not limited to the protocol, protocol 
amendments, ICFs, and documentation of IRB/EC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and Competent 
Authorities according to local regulatory requirements and timelines of each country 
participating in the study.
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IRB/EC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to participants or any non-substantial changes, as 
defined by regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
for approval prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator.
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 trials only in their entirety and not as individual center 
data. In this case, a coordinating Investigator will be designated by mutual agreement.

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Any formal publication of the study in which contribution of Sponsor personnel exceeded 
that of conventional monitoring will be considered as a joint publication by the 
Investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
2.3.3.
Dissemination of Clinical Study Data
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals. The Sponsor will 
comply with all requirements for publication of study results. Study data may be shared 
with others who are not participating in this study (for more details, see Section 2.3.5), 
and redacted clinical study reports and other summary reports will be made available 
upon request, provided the requirements of Roche's global policy on data sharing have 
been met.
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following web site:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf 
2.3.4.
Management of Study Quality
The Sponsor will implement a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring participant safety and data integrity. 
Prior to study initiation, the Sponsor will identify potential risks associated with critical 
trial processes and data and will implement plans for evaluating and controlling these 
risks. Risk evaluation and control will include the selection of risk-based parameters 
(e.g., adverse event rate, protocol deviation rate) and the establishment of quality 
tolerance limits for these parameters prior to study initiation. Detection of deviations from 
quality tolerance limits will trigger an evaluation to determine if action is needed. Details 
on the establishment and monitoring of quality tolerance limits will be provided in a 
Quality Tolerance Limit Management Plan.
2.3.5.
Site Inspections
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and eCRFs. The Investigator will 
permit national and local Health Authorities, Sponsor monitors, representatives, and 
collaborators, and the IRBs/ECs to inspect facilities and records relevant to this study.

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3.
ADMINISTRATIVE STRUCTURE
For information of the Joint Monitoring Committee, see Section 4.1.3 of the protocol.
4.
STUDY AND SITE CLOSURE
The Sponsor (or designee) has the right to close the study site or terminate this study at 
any time. Reasons for terminating the study may include, but are not limited to, the 
following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to participants.

Participant enrollment is unsatisfactory.
The Sponsor will notify the Investigator and Health Authorities if the study is placed on 
hold, or if the Sponsor decides to discontinue the study or development program.
Study sites will be closed upon study completion. A study site is considered closed when 
all required documents and study supplies have been collected and a study-site closure 
visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP 
guidelines.

Inadequate recruitment of participants by the Investigator.

Discontinuation of further study treatment development.

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Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a participant or clinical investigation participant
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.
An adverse event can therefore be:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.
Events Meeting the AE Definition:

Deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 
or other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads 
to a change in study treatment or concomitant treatment or discontinuation from 
study treatment (see Appendix 3, Section 4).

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 treatment administration even 
though it may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies).

"Lack of efficacy" or "failure of expected pharmacological action" per se will not 
be reported as an AE or SAE unless the progression is unexpectedly accelerated 
and not in line with the natural history of the disease. If the “Lack of efficacy” 
would not require safety reporting such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting 
from lack of efficacy will be reported as AE or SAE if they fulfill the definition of an 
AE or SAE.
Events NOT Meeting the AE Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

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
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is an AE.

Situations where 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.
2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any 
dose:

Results in death.

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 was more severe.

Requires inpatient hospitalization or prolongation of existing 
hospitalization (see Appendix 3).
In general, hospitalization signifies that the participant has been admitted to the 
hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect.

Other significant events:

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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 
one 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.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event.
The Investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
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 redacted 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. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
3.1.
ASSESSMENT OF SEVERITY
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a pre-defined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events [NCI CTCAE] criteria); the event itself may be of relatively minor medical 
significance (such as severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the Investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event.

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The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 1
Adverse Event Severity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily livinga
3
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily livingb,c
4
Life-threatening consequences or urgent intervention indicatedd
5
Death related to adverse eventd
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.
Note: Based on the NCI CTCAE (v5.0), which can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick
_Reference_8.5x11.pdf
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 6 of this appendix for reporting instructions), per the definition of 
serious adverse event in Section 2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 6 for 
reporting instructions), per the definition of serious adverse event in Section 2. Grade 4 
laboratory abnormalities would only be reported as SAEs if these meets one or more of the 
conditions outlined in Section 2 (Definition of Serious Adverse Events) of this appendix.
3.2.
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether an adverse event is considered to be related to the study treatment, 
indicating "yes" or "no" accordingly. The following guidance should be taken into 
consideration:

Temporal relationship of event onset to the initiation of study treatment.

Course of the event, considering especially the effects of discontinuation of study 
treatment, or reintroduction of study treatment.

Known association of the event with the study treatment or with similar 
treatments.

Known association of the event with the disease under study.

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
Presence of risk factors in the participant or use of concomitant medications 
known to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with 
the occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF AES AND SAES
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Medical 
Monitor 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.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology.
New or updated information will be recorded in the originally completed eCRF.
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
5.
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The Investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the Investigator learns of the event. The following is a list 
of events that the Investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study treatment:

Serious adverse events

Non-serious adverse events of special interest (NSAESI)

Pregnancies (see Section 8.3.5).
The Investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

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
Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IRB/EC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS, AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
Events that Occur prior to Study Treatment Initiation
After informed consent has been obtained but prior to initiation of study treatment, only 
serious adverse events caused by a protocol-mandated intervention should be reported. 
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to Investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Treatment Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study treatment (Section 8.3.1), Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to Investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
After the end of the adverse event reporting period (see Section 8.3.1), all deaths, 
regardless of cause, should be reported through use of the Long-Term Survival Follow-
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In addition, if the Investigator becomes aware of a SAE that is believed to be related to 
prior study treatment, the event should be reported directly to the Sponsor or its 
designee, either by faxing or by scanning and emailing the SAE Reporting Form using 
the fax number or email address provided to Investigators.
5.2
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose: accidental administration of a drug in a quantity that is
higher than the assigned dose.

Medication error: accidental deviation in the administration of a drug.
o
In some cases, a medication error may be intercepted prior to 
administration of the drug.
Special situations are not in themselves adverse events, but may result in adverse 
events. Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF. If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event). For this study, adverse events 
associated with special situations should be recorded as described below for each 
situation:

Accidental overdose: Enter the adverse event term. Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the adverse event 
term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the adverse event term. 
Check the "Accidental overdose" and "Medication error" boxes. 
In addition, all special situations associated with the study drugs, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF and 
should be recorded as described below:

Accidental overdose: Enter the “Blinded Drug” and "accidental overdose" as the
event term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the 
drug administered and a description of the error (e.g., wrong dose administered, 
wrong dosing schedule, incorrect route of administration, wrong drug, expired 
drug administered) as the event term. Check the "Medication error" box.

Medication error that qualifies as an overdose: Enter the drug name and 
"accidental overdose" as the event term. Check the "Accidental overdose" and 

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"Medication error" boxes. Enter a description of the error in the additional case 
details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache. The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and NSAESI against 
cumulative product experience to identify and expeditiously communicate possible new 
safety findings to Investigators, IRBs, ECs, and applicable Health Authorities based on 
applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the documents listed below:
Drug
Document
RO7121661
RO7121661 Investigator's Brochure
RO7247669
RO7247669 Investigator’s Brochure
Nivolumab
EU SmPC
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the Investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.

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Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF. Avoid colloquialisms and abbreviations.
Only one AE term should be recorded in the event field on the Adverse Event eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
1.1.
INFUSION-RELATED REACTIONS
Adverse events that occur during or after study drug administration and are judged to be 
related to study treatment infusion should be captured as a diagnosis (e.g., 
infusion-related reaction [IRR]) on the Adverse Event eCRF. If possible, avoid 
ambiguous terms such as “systemic reaction.” Associated signs and symptoms should 
be recorded on the dedicated Infusion-Related Reaction eCRF. If a participant 
experiences both a local and systemic reaction to the same dose of study drug, each 
reaction should be recorded separately on the Adverse Event eCRF, with signs and 
symptoms also recorded separately on the dedicated Infusion-Related Reaction eCRF.
1.2.
OTHER ADVERSE EVENTS
For AEs other than IRRs (see Section 1.1), a diagnosis (if known) should be recorded on 
the Adverse Event eCRF rather than individual signs and symptoms (e.g., record only 
liver failure or hepatitis rather than jaundice, asterixis, and elevated transaminases). 
However, if a constellation of signs and/or symptoms cannot be medically characterized 
as a single diagnosis or syndrome at the time of reporting, each individual event should 
be recorded on the Adverse Event eCRF. If a diagnosis is subsequently established, all 
previously reported AEs based on signs and symptoms should be nullified and replaced 
by one AE report based on the single diagnosis, with a starting date that corresponds to 
the starting date of the first symptom of the eventual diagnosis.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events. However, medically significant AEs occurring secondary to an 
initiating event that are separated in time should be recorded as independent events on 
the Adverse Event eCRF. For example:

If vomiting results in mild dehydration with no additional treatment in a healthy 
adult, only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported 
separately on the eCRF.

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
If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF.

If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF.
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent AE is one that extends continuously, without resolution, between participant 
evaluation time-points. Such events should only be recorded once on the Adverse Event 
eCRF. The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens. If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this.
A recurrent AE is one that resolves between participant evaluation time-points and 
subsequently recurs. Each recurrence of an AE should be recorded separately on the 
Adverse Event eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention (e.g., potassium supplementation for 
hypokalemia) or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all laboratory findings. Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5 times the upper limit of normal [ULN]
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded 
on the Adverse Event eCRF.

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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium", as opposed to "abnormal potassium"). If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE. For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.”
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported 
as an AE if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

Clinically significant in the Investigator’s judgment.
It is the Investigator’s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury. 

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Therefore, Investigators must report as an adverse event the occurrence of either of the 
following:

Treatment-emergent ALT or AST3ULN in combination with total 
bilirubin2ULN.

Treatment-emergent ALT or AST3ULN in combination with clinical jaundice.

For participants who have liver metastases or are receiving hepatotoxic 
concomitant medications, Investigators must report as an AE the occurrence of 
either of the following:
o
Treatment-emergent ALT or AST 5 ULN value in combination with 
total bilirubin 2 ULN (of which 35% is direct bilirubin).
o
Treatment-emergent ALT or AST 5 ULN value in combination with 
clinical jaundice.
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Appendix 2) and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event), either as an SAE or a non-serious adverse event of special interest 
(Section 8.3.6).
7.
DEATHS
For this protocol, mortality is an efficacy endpoint. Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5 of Appendix 2) that are
attributed by the Investigator solely to progression of squamous cell carcinoma of the 
esophagus should be recorded only on the Death Attributed to Progressive Disease
eCRF. All other on-study deaths, regardless of relationship to study treatment, must be 
recorded on the Adverse Event eCRF and immediately reported to the Sponsor (see
Section 5 of Appendix 2).
Death should be considered an outcome and not a distinct event. The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF. Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF. If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
8.
PREEXISTING MEDICAL CONDITIONS
A preexisting medical condition is one that is present at the screening visit for this study. 
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.

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A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study. When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”).
9.
LACK OF EFFICACY OR WORSENING OF ADVANCED OR 
METASTATIC SQUAMOUS CELL CARCINOMA OF THE 
ESOPHAGUS
Events that are clearly consistent with the expected pattern of progression of the 
underlying disease should not be recorded as AEs. These data will be captured as 
efficacy assessment data only. In most cases, the expected pattern of progression will 
be based on criteria (e.g., RECIST. In rare cases, the determination of clinical 
progression will be based on symptomatic deterioration. However, every effort should be 
made to document progression using objective criteria. If there is any uncertainty as to 
whether an event is due to progressive disease, it should be reported as an AE.
10.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as an SAE (per the definition of serious adverse event in Appendix 2), 
except as outlined below.
An event that leads to hospitalization under the following circumstances should not be 
reported as an AE or am SAE:

Hospitalization for respite care.

Planned hospitalization required by the protocol (e.g., for study treatment 
administration).

Hospitalization for a preexisting condition, provided that all of the following 
criteria are met:
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The participant has not suffered an AE.

Hospitalization due solely to progression of the underlying cancer.
An event that leads to hospitalization under the following circumstances is not
considered to be an SAE, but should be reported as an adverse event instead:

Hospitalization for an AE that would ordinarily have been treated in an outpatient 
setting had an outpatient clinic been available.

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11.
PATIENT-REPORTED OUTCOME DATA (COA DATA 
REPORTED DIRECTLY BY PATIENTS)
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data.

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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 1 will be performed by the local laboratory unless otherwise 
specified.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2, respectively, 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 1
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, 
differential count (neutrophils, eosinophils, basophils, monocytes, 
lymphocytes, other cells).
Clinical chemistry

Sodium, potassium, chloride, bicarbonate (only required if 
considered standard of care for the site and in situations where the
participant’s safety is at risk), glucose, urea or blood urea nitrogen, 
serum creatinine, protein, serum albumin, phosphate, calcium, total 
and direct bilirubin, alkaline phosphatase, alanine aminotransferase, 
aspartate aminotransferase, urate, lactate dehydrogenase, creatine 
kinase, creatine kinase MB, troponin I and/or troponin T, eGFR 
determined using the MDRD formulaa, GGT, magnesium, CRP, 
ferritin.
Coagulation

INR or prothrombin time and activated partial prothrombin time;
additional coagulation parameters (i.e., antithrombin III [antigenic or 
chromogenic], fibrinogen, fibrin degradation products, D-dimer) may 
be assessed according to clinical judgment.
Viral serology

HIV, hepatitis B surface antigen (HBsAg), total hepatitis B core 
antibody (HBcAb), hepatitis C virus (HCV) antibody.
Lipid panel

Cholesterol, LDL cholesterol, high-density lipoprotein cholesterol, 
triglycerides.
Thyroid hormones

Free T4, TSH, free T3 (alternatively total T3 if free T3 is not 
performed)
Quantitative 
immunoglobulins

IgA, IgG, IgM, IgE 
Pregnancy test

All women of childbearing potential (including those who have had a 
tubal occlusion/ ligation) will have a blood pregnancy test at 
screening. During the study treatment, a pregnancy test (urine or 
blood) will be performed as indicated in the SoA and at least every 4 
weeks. An additional at-home pregnancy test will be conducted 5 
months after the final dose, as indicated in the SoA. If a urine 
pregnancy test is positive, it must be confirmed by a blood 
pregnancy test.

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Laboratory 
Assessments
Parameters
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein or albumin, blood, ketones 

If there is a clinically significant positive result (confirmed by a positive 
repeated sample), urine will be sent to the laboratory for microscopy 
and culture. If there is an explanation for the positive dipstick results 
(e.g., menses), it should be recorded and there is no need to perform 
microscopy and culture.

Microscopic examination (sediment, red blood cells, white blood cells, 
casts, crystals, epithelial cells, bacteria), if blood or protein is 
abnormal.
Other tests

sCD25 (optional, only in case of a suspected hemophagocytic 
lymphohistiocytosis/macrophage activation syndrome)

IgE and tryptase (only in case of IRRs or anaphylaxis; see SoAs in 
Section 1.3).
Auto-antibody panel

Anti-nuclear antibody, anti-double-stranded deoxyribonucleic acid 
(DNA), circulating anti-neutrophil cytoplasmic antibody (cANCA), and 
perinuclear anti-neutrophil cytoplasmic antibody (pANCA) (panel 
based on local availability).

The auto-antibody panel will be assessed, if possible locally. If not 
available locally the test can be done centrally.

In participants who develop signs and/or symptoms suggestive of 
autoimmune disease while on treatment or Grade 2 
immune-mediated AEs, the auto-antibody panel should be repeated.

Participants with confirmed positive serology of at least one of the 
auto-antibody panel during the course of the study should be 
discussed between Medical Monitor and Investigators, and if judged 
clinically relevant could be referred to a specialist to exclude an 
underlying autoimmune disease.
a Estimated GFR = 175 standardized Scr −1.154 age−0.203 1.212 [if black] 0.742 [if female];
Scr (serum creatinine) mg/dL; age years.
In case of Grade 2 IRR, samples as indicated in Section 1.3 of the protocol are to be 
analyzed by the local laboratory. 
In case IgE or tryptase cannot be analyzed locally, the tests can be done centrally.
The results of each test must be entered into the CRF.
Investigators must document their review of each laboratory safety report.
Based on continuous analysis of the data in this study, any sample type not considered 
to be critical for safety may be stopped at any time if the data from the samples collected 
does not produce useful information.

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Additional Statistical Considerations for Clinical Laboratory Data
Standard Reference Ranges and Transformation of Data
Potential analysis considerations for analyzing laboratory data includes the use of 
standard reference ranges and potential transformation of data for specific laboratory
tests. 
In this scenario, Roche standard reference ranges, rather than the reference ranges of 
the Investigator, can be used for specific parameters. For these parameters, the 
measured laboratory test result will be assessed directly using the Roche standard 
reference range. Certain laboratory parameters will be transformed to Roche’s standard 
reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of Investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.
Definition of Laboratory Abnormalities
For all laboratory parameters included in the analysis described above, there exists a 
Roche predefined standard reference range. Laboratory values falling outside this 
standard reference range will be labeled “H” for high or “L” for low in participant listings 
of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for these laboratory parameters. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.

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Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile. The definition of childbearing potential may be adapted for 
alignment with local guidelines or requirements.
Women in the following categories are considered to be women of 
non-childbearing potential
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A post-menopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the post-menopausal range may be used to confirm a 
post-menopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single FSH measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of post-menopausal status before study enrollment.

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2.
CONTRACEPTION GUIDANCE
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
use highly effective method of contraception consistently and correctly as described in 
Table 1 below.
Per ICH M3(R2), highly effective methods of birth control are defined as those, alone or 
in combination, that result in a low failure rate (i.e. less than 1% per year) when used 
consistently and correctly as described in Table 1 below.
Table 1
Highly Effective Contraceptive 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 contraception associated with 
inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
Highly Effective Methods That Are User-Independent
(Failure rate of 1% per year)

Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion/ ligation
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 treatment. 
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.

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Acceptable Birth Control Methods Which May Not Be Considered As Highly Effective
(Failure rate of 1% per year when used consistently and correctly)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the
primary mode of action

Male or female condom with or without spermicide b

Cap, diaphragm or sponge with spermicide b
a)
Hormonal contraception may be susceptible to interaction with the IMP, which may reduce 
the efficacy of the contraception method.
Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.
b)
A combination of male condom with either cap, diaphragm or sponge with spermicide 
(double barrier methods) are also considered acceptable, but not highly effective, birth 
control methods. i.e., when the risk of teratogenicity and genotoxicity is unlikely.
3.
PREGNANCY TESTING
For WOCBP enrolled in the study, blood sample and urine pregnancy tests will be 
performed according to Schedule of Activity tables (see Section 1.3). If a urine 
pregnancy test is positive, it must be confirmed by a blood pregnancy test.
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected and according to local practice.
4.
COLLECTION OF PREGNANCY INFORMATION
Male participants with partners who become pregnant
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study or within 
5 months after the final dose of study drug (see Section 8.3.5 Pregnancy).

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Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to study treatment. The
Investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the site, the pregnant partner would need to sign an Authorization for 
Use and Disclosure of Pregnancy Health Information to allow for follow-up on her 
pregnancy. If the authorization has been signed, the Investigator should update the 
Clinical Trial Pregnancy Reporting Form with additional information on the course and 
outcome of the pregnancy when available. An Investigator who is contacted by the male 
participant or his pregnant partner may provide information on the risks of the pregnancy 
and the possible effects on the fetus, to support an informed decision in cooperation with 
the treating physician and/or obstetrician. The female partner will be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and 
child will be forwarded to the Sponsor. Monitoring of the participant’s partner should 
continue until conclusion of the pregnancy. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.
Female participants who become pregnant
The Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5 Pregnancy). 
Information will be recorded on the appropriate form and submitted to the Sponsor within
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The Investigator will collect follow-up 
information on the participant and the neonate, which will be forwarded to the Sponsor. 
Monitoring of the participant should continue until conclusion of the pregnancy. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.
While pregnancy itself is not considered to be an AE or SAE, and should not be 
recorded on the AE eCRF, any pregnancy complication will be reported as an AE or 
SAE. A spontaneous abortion is always considered to be an SAE and will be reported as 
such. Any post-study pregnancy related SAE considered reasonably related to the study 
treatment by the Investigator, will be reported to the Sponsor as described in 
Appendix 2. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting.
Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment.

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ABORTIONS
Any spontaneous abortion should be classified as a serious adverse event (as the 
Sponsor considers spontaneous abortions to be medically significant events), recorded 
on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no more 
than 24 hours after learning of the event; see Section 5 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as serious adverse event, recorded on the Adverse Event eCRF, and reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5 of Appendix 2).
Elective or therapeutic abortion not associated with an underlying maternal or 
embryofetal toxicity (e.g., induced abortion for personal reasons) does not require 
expedited reporting but should be reported as outcome of pregnancy on the Clinical Trial 
Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female participant or female 
partner of a male participant exposed to study treatment should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event).

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Appendix 6
New Response Evaluation Criteria in Solid Tumors Version 1.1 
Modified Excerpt from Original Publication with Addition of 
Supplementary Explanations
1.
MEASURABILITY OF TUMOR AT BASELINE
1.1
DEFINITIONS
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows: 
1.1.1
Measurable Tumor Lesions
Tumor lesions must be accurately measured in at least one dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of: 

10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm). 

10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 

20 mm by chest x-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be not greater than 5 mm). At baseline and in follow-up, only 
the short axis will be measured and followed. See also Section 2.2 on ‘Baseline 
documentation of target and non-target lesions’ for information on lymph node 
measurement. 
1.1.2 Non-measurable Tumor Lesions
Non-measurable tumor lesions encompass small lesions (longest diameter10 mm or 
pathological lymph nodes with 10 to 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: 
leptomeningeal disease, ascites, pleural or pericardial effusion, inﬂammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identiﬁed by physical exam that is not measurable by 
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1.1.3 Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment: 
Bone lesions:

Bone scan, positron emission tomography scan, or plain ﬁlms are not considered 
adequate imaging techniques to measure bone lesions. However, these techniques 
can be used to conﬁrm the presence or disappearance of bone lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identiﬁable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the deﬁnition of measurability described above. 

Blastic bone lesions are non-measurable. 
Cystic lesions:

Lesions that meet the criteria for radiographically deﬁned simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) because 
they are, by deﬁnition, simple cysts. 

‘Cystic lesions’ thought to represent cystic metastases, can be considered as 
measurable lesions if they meet the deﬁnition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions. 
Lesions with previous local treatment: 

Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.
1.2
TARGET LESIONS: SPECIFICATIONS BY METHODS OF 
MEASUREMENTS 
1.2.1
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed. All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 
1.2.2 Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identiﬁed and reported lesion at baseline and during study. Imaging 
based evaluation should always be the preferred option. 

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Clinical lesions: Clinical lesions will only be considered measurable when they are 
superﬁcial and 10 mm diameter as assessed using calipers (e.g., skin nodules). For 
the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested. 
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint, because CT is more sensitive than x-ray, particularly in identifying 
new lesions. However, lesions on chest x-ray may be considered measurable if they are 
clearly deﬁned and surrounded by aerated lung.
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has deﬁned measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less. 
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable. 
If before enrollment it is known that a participant is unable to undergo CT scans with 
intravenous contrast because of allergy or renal insufficiency, the decision as to whether 
a non-contrast CT or MRI (without intravenous contrast) will be used to evaluate the 
participant at baseline and during study, should be guided by the tumor type under 
investigation and the anatomic location of the disease. For participants who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, should
also be based on the tumor type, anatomic location of the disease and should be 
optimized to allow for comparison to the previous studies if possible. Each case should 
be discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the participant should be considered not evaluable from that point 
forward.
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. 
2.
TUMOR RESPONSE EVALUATION
2.1.
ASSESSMENT OF OVERALL TUMOR BURDEN AND 
MEASURABLE DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and use this as a comparator for subsequent 
measurements. Measurable disease is deﬁned by the presence of at least one 
measurable lesion (as detailed in Section 1.1.1).

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2.2.
BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of ﬁve lesions total (and a maximum of 2 lesions per organ) representative of 
all involved organs should be identiﬁed as target lesions and will be recorded and 
measured at baseline.
This means in instances where participants have only one or 2 organ sites involved a 
maximum of 2 (one site) and 4 lesions (2 sites), respectively, will be recorded. Other 
lesions (albeit measurable) in that organ will be recorded as non-measurable lesions 
(even if size is 10 mm by CT scan).
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, but in addition should be 
reproducible in repeated measurements. It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion which can be measured reproducibly should be selected.
Lymph nodes merit special mention because they are normal anatomical structures 
which may be visible by imaging even if not involved by tumor. As noted in Section 1.1.1,
pathological nodes which are deﬁned as measurable and may be identiﬁed as target 
lesions must meet the criterion of a short axis of ≥15 mm by CT scan. Only the short 
axis of these nodes will contribute to the baseline sum. The short axis of the node is the 
diameter normally used by radiologists to judge if a node is involved by solid tumor. 
Nodal size is normally reported as 2 dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal, or coronal). The smaller of these measures is the short 
axis. For example, an abdominal node which is reported as being 20 mm 30 mm has a 
short axis of 20 mm and qualiﬁes as a malignant, measurable node. In this example, 
20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis ≥10 mm but15 mm) should be considered non-target lesions. 
Nodes that have a short axis 10 mm are considered non-pathological and should not 
be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added 
into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease.

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All other lesions (or sites of disease) including pathological lymph nodes should be 
identiﬁed as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare 
cases ‘unequivocal progression’ (see also Section 2.3.4).
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
2.3.
RESPONSE CRITERIA
This section provides the deﬁnitions of the criteria used to determine objective tumor 
response for target lesions. 
2.3.1.
Evaluation of Target Lesions 

Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis 
to 10 mm.

Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters. 

Progressive Disease: At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study including baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
2.3.2.
Special Notes on the Assessment of Target Lesions
Lymph nodes: Lymph nodes identiﬁed as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to below 10 mm on study. This means 
that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, because a normal lymph node is 
deﬁned as having a short axis of10 mm. 

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Target lesions that become ‘too small to measure’: while on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at 
each subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes 
lesions or lymph nodes which are recorded as target lesions at baseline become so faint 
on CT scan that the radiologist may not feel comfortable assigning an exact measure 
and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form:

If it is the opinion of the radiologist that the lesion has probably disappeared, the 
measurement should be recorded as 0 mm.

If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) should 
be ticked (Note: It is less probable that this rule will be used for lymph nodes 
because they usually have a deﬁnable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned in this circumstance as well and BML should also be 
ticked). 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm and in that case BML should not be ticked (BML is 
equivalent to a less than sign <).
Lesions that split or coalesce on treatment: when non-nodal lesions ‘fragment’, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum. Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the ‘coalesced lesion’. 
2.3.3.
Evaluation of Non-target Lesions 
This section provides the deﬁnitions of the criteria used to determine the tumor response 
for the group of non-target lesions. While some non-target lesions may actually be 
measurable, they need not be measured and instead should be assessed only 
qualitatively at the time-points speciﬁed in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions (and, if applicable, 
normalization of tumor marker level). All lymph nodes must be non-pathological in size 
(10 mm short axis).

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Non-CR/Non-progressive disease: Persistence of one or more non-target lesion(s) 
and/or maintenance of tumor marker level above the normal limits.
Progressive Disease: Unequivocal progression (see Section 2.3.4) of existing non-target 
lesions. The appearance of one or more new lesions is also considered progression.
2.3.4.
Special Notes on Assessment of Progression of Non-target 
Disease 
When the participant also has measurable disease: in this setting, to achieve 
‘unequivocal progression’ on the basis of the non-target disease, there must be an 
overall level of substantial worsening in non-target disease in a magnitude that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target 
disease in the face of SD or PR of target disease will therefore be extremely rare. 
When the participant has only non-measurable disease: this circumstance arises in 
some phase III trials when it is not a criterion of study entry to have measurable disease. 
The same general concepts apply here as noted above, however, in this instance there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden. Because worsening in non-target disease cannot be 
easily quantiﬁed (by deﬁnition: if all lesions are truly non-measurable) a useful test that 
can be applied when assessing participants for unequivocal progression is to consider if 
the increase in overall disease burden based on the change in non-measurable disease 
is comparable in magnitude to the increase that would be required to declare 
progressive disease for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include an increase in a pleural 
effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease from localized to 
widespread, or may be described in protocols as ‘sufficient to require a change in 
therapy’. If ‘unequivocal progression’ is seen, the participant should be considered to 
have had overall progressive disease at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease 
makes it impossible to do so; therefore, the increase must be substantial. 

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2.3.5.
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no speciﬁc criteria for 
the identiﬁcation of new radiographic lesions; however, the ﬁnding of a new lesion 
should be unequivocal: i.e., not attributable to differences in scanning technique, change 
in imaging modality or ﬁndings thought to represent something other than tumor (for 
example, some ‘new’ bone lesions may be simply healing or ﬂare of preexisting lesions). 
This is particularly important when the participant’s baseline lesions show partial or 
complete response. For example, necrosis of a liver lesion may be reported on a CT 
scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identiﬁed during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans conﬁrm 
there is deﬁnitely a new lesion, then progression should be declared using the date of 
the initial scan. 
2.4
EVALUATION OF RESPONSE 
2.4.1
Time-Point Response (Overall Response)
It is assumed that at each protocol speciﬁed time-point, a response assessment occurs. 
A summary of the overall response status calculation at each time-point for participants 
who have measurable disease at baseline is provided in Table 1. 
When participants have non-measurable (therefore non-target) disease only, Table 2 is 
to be used.

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Table 1
Time-Point Response – Target (w/wo non- target) Lesions
Abbreviations: w/wowith or without.
Table 2
Time-Point Response – Non-Target Lesions only
2.4.2
Missing Assessments and Not Evaluable Designation
When no imaging/measurement is done at all at a particular time-point, the participant is 
not evaluable at that time-point. If only a subset of lesion measurements is made at an 
assessment, usually the case is also considered not evaluable at that time-point, unless 
a convincing argument can be made that the contribution of the individual missing 
lesion(s) would not change the assigned time-point response. This would be most likely 
to happen in the case of progressive disease. 

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For example, if a participant had a baseline sum of 50 mm with 3 measured lesions and 
during study only 2 lesions were assessed, but those gave a sum of 80 mm, the 
participant will have achieved progressive disease status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done, 
or could not be assessed because of poor image quality or obstructed view, the 
Response for Target Lesions should be “Unable to Assess” because the participant is 
not evaluable. Similarly, if one or more non-target lesions are indicated as ‘not 
assessed’, the response for non-target lesions should be “Unable to Assess” (except 
where there is clear progression). Overall response would be “Unable to Assess” if either 
the target response or the non-target response is “Unable to Assess” (except where this 
is clear evidence of progression) as this equates with the case being not evaluable at 
that time-point.
2
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’ size (10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted 
earlier, this means that participants with CR may not have a total sum of ‘zero’ on the 
case report form (CRF). 
Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be
reported as ‘symptomatic deterioration’. Every effort should be made to document 
objective progression even after discontinuation of treatment. Symptomatic deterioration 
is not a descriptor of an objective response: it is a reason for stopping study therapy. 
The objective response status of such participants is to be determined by evaluation of 
target and non-target disease as shown in Table 1 and Table 2. 
For equivocal ﬁndings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is conﬁrmed, the date of 
progression should be the earlier date when progression was suspected. In studies 
where participants with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should be also captured under target or non-target 
lesions as appropriate. This is to avoid wrong assessments of complete overall response 
by statistical programs while the primary is still present but not evaluable.

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References
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47.

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Appendix 7
Risks Associated with Study Drugs and Guidelines for 
Management of Adverse Events Associated with Study Drugs
Toxicities associated or possibly associated with study drug treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology.
Although most immune-mediated AEs observed with immunomodulatory agents have 
been mild and self-limiting, such events should be recognized early and treated promptly 
to avoid potential major complications. Discontinuation of study drug may not have an 
immediate therapeutic effect, and in severe cases, immune-mediated toxicities may 
require acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The Investigator should consider the benefitrisk balance a given participant may be 
experiencing prior to further administration of study drug. The decision to re-challenge 
patients with study drug should be based on the Investigator’s assessment of benefit-risk 
and documented by the Investigator (or an appropriate delegate). The Medical Monitor 
will be available to advise as needed.
MANAGEMENT GUIDELINES
PULMONARY EVENTS
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates may be
associated with the administration of study drug. Participants will be assessed for 
pulmonary signs and symptoms throughout the study and also have computed 
tomography (CT) scans of the chest performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension. Management guidelines for pulmonary events are provided in Table 1.

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Table 1
Management Guidelines for Pulmonary Events, Including 
Pneumonitis
Event
Management
Pulmonary 
event, Grade 1 

Continue study drug and monitor closely.

Re-evaluate on serial imaging.

Consider participant referral to pulmonary specialist.
Pulmonary 
event, Grade 2 

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to pulmonary and infectious disease specialists and consider 
bronchoscopy or BAL.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.

For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary 
event, Grade 3 
or 4

Permanently discontinue study drug and contact Medical Monitor.

Bronchoscopy or BAL is recommended.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
BAL Bronchoscopic alveolar lavage.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.
HEPATIC EVENTS
Immune-mediated hepatitis may be associated with the administration of study drug.
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment. Management guidelines for hepatic events are provided in Table 2.
Participants with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have liver function tests (LFTs) performed immediately and reviewed 
before administration of the next dose of study drug.
For participants with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate.

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Table 2
Management Guidelines for Hepatic Events
Event
Management
Hepatic event, Grade 1

Continue study drug.

Monitor LFTs until values resolve to within normal limits
or to baseline values.
Hepatic event, Grade 2
All events:

Monitor LFTs more frequently until return to baseline 
values. 
Events of 5 days’ duration:

Withhold study drug for up to 12 weeks after event 
onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event resolves to Grade 1 or better, resume study 
drug. b

If event does not resolve to Grade 1 or better while 
withholding study drug, permanently discontinue study 
drug and contact Medical Monitor.
Hepatic event, Grade 3 or 4

Permanently discontinue study drug and contact Medical 
Monitor.

Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of 
hepatic injury. 

Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.

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Event
Management
In participants with liver lesions
AST/ALT is within normal limits at 
baseline and increases 
to > 3 ULN to ≤10 ULN 
or 
AST/ALT is > ULN to ≤3 ULN at 
baseline and increases 
to >5 ULN to ≤10 ULN 
or 
AST/ALT is >3 ULN to 5 ULN at 
baseline and increases to > 
8 ULN to ≤10 ULN 
Monitor LFTs more frequently until return to baseline 
values. 

Withhold study drug for up to 12 weeks after event 
onseta.
Events of > 5 days' duration: 

Consider initiating treatment with 1−2 mg/kg/day 
prednisone or equivalent. 

If event resolves to baseline, resume study drug b.

If event does not resolve to baseline while withholding 
study drug, permanently discontinue study drug and 
contact Medical Monitor.
AST or ALT increases to >10×ULN 
or total bilirubin increases to > 
3×ULN

Permanently discontinue study drug and contact Medical 
Monitor

Consider patient referral to GI specialist for evaluation 
and liver biopsy to establish etiology of hepatic injury.

Initiate treatment with 1−2 mg/kg/day prednisone or 
equivalent

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent.
If event resolves to baseline, taper corticosteroids over 
≥1 month.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE Common 
Terminology Criteria for Adverse Events; GI Gastrointestinal; LFT Liver function test; 
NCI National Cancer Institute; ULN -Upper limit of normal. 
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE 
and are applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.

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GASTROINTESTINAL EVENTS
Immune-mediated colitis may be associated with the administration of study drug. 
Management guidelines for diarrhea or colitis are provided in Table 3.
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies. For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (e.g., increased C-reactive protein, 
platelet count, or bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) 
with colonic biopsy, with three to five specimens for standard paraffin block to check for 
inflammation and lymphocytic infiltrates to confirm colitis diagnosis. 
Table 3
Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis)
Event
Management
Diarrhea or 
colitis, Grade 1

Continue study drug.

Initiate symptomatic treatment.

Endoscopy is recommended if symptoms persist for 7 days.

Monitor closely.
Diarrhea or 
colitis, Grade 2

Withhold study drug for up to 12 weeks after event onset. a

Initiate symptomatic treatment.

Participant referral to GI specialist is recommended.

For recurrent events or events that persist 5 days, initiate treatment with 
12 mg/kg/day oral prednisone or equivalent. 

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.
Diarrhea or 
colitis, Grade 3

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to GI specialist for evaluation and confirmatory biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.
Diarrhea or 
colitis, Grade 4

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to GI specialist for evaluation and confirmation biopsy.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent and 
convert to 12 mg/kg/day oral prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
GI Gastrointestinal, IV Intravenous.

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a Study Drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.
ENDOCRINE EVENTS
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders may 
be associated with the administration of study drug. Management guidelines for 
endocrine events are provided in Table 4.
Participants with unexplained symptoms such as headache, fatigue, myalgias, 
impotence, constipation, or mental status changes should be investigated for the 
presence of thyroid, pituitary, or adrenal endocrinopathies. The participant should be 
referred to an endocrinologist if an endocrinopathy is suspected. Thyroid-stimulating 
hormone (TSH) and free triiodothyronine and thyroxine levels should be measured to 
determine whether thyroid abnormalities are present. Pituitary hormone levels and 
function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating 
hormone, testosterone, prolactin, adrenocorticotropic hormone levels, and 
adrenocorticotropic hormone stimulation test) and magnetic resonance imaging (MRI) of 
the brain (with detailed pituitary sections) may help to differentiate primary pituitary 
insufficiency from primary adrenal insufficiency.
Table 4
Management Guidelines for Endocrine Events
Event
Management
Asymptomatic 
hypothyroidism

Continue study drug.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism

Withhold study drug.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider participant referral to endocrinologist.

Resume study drug when symptoms are controlled and thyroid 
function is improving.
Asymptomatic 
hyperthyroidism

TSH 0.1 mU/L and 0.5 mU/L:

Continue study drug.

Monitor TSH every 4 weeks.

TSH 0.1 mU/L:

Follow guidelines for symptomatic hyperthyroidism.

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Event
Management
Symptomatic 
hyperthyroidism

Withhold study drug.

Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed.

Consider participant referral to endocrinologist.

Resume study drug when symptoms are controlled and thyroid 
function is improving.

Permanently discontinue study drug and contact Medical Monitor for 
life-threatening immune-mediated hyperthyroidism.
Symptomatic adrenal 
insufficiency, 
Grade 24 

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to endocrinologist.

Perform appropriate imaging.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event resolves to Grade 1 or better and participant is stable on 
replacement therapy, resume study drug. b

If event does not resolve to Grade 1 or better or participant is not 
stable on replacement therapy while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.
Hyperglycemia, 
Grade 1 or 2 

Continue study drug.

Investigate for diabetes. If participant has Type 1 diabetes, treat as a 
Grade 3 event. If participant does not have Type 1 diabetes, treat as 
per institutional guidelines.

Monitor for glucose control.
Hyperglycemia, 
Grade 3 or 4

Withhold study drug.

Initiate treatment with insulin.

Monitor for glucose control.

Resume study drug when symptoms resolve and glucose levels are 
stable.
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study 
drug, permanently discontinue study drug and contact Medical 
Monitor.

For recurrent hypophysitis, treat as a Grade 4 event.

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Event
Management
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

Initiate hormone replacement if clinically indicated.
IV Intravenous; MRI Magnetic resonance imaging; TSH Thyroid-stimulating hormone.
a
Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period must be based on the assessment of benefit-risk by the Investigator and 
in alignment with the protocol requirement for duration of treatment and documented by the Investigator.
The Medical Monitor will be available to advise as needed.
b
If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.

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OCULAR EVENTS
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). 
Management guidelines for ocular events are provided in Table 5.
Table 5
Management Guidelines for Ocular Events
Event
Management
Ocular event, 
Grade 1 

Continue study drug.

Participant referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If symptoms persist, treat as a Grade 2 event.
Ocular event, 
Grade 2

Withhold study drug for up to 12 weeks after event onset. a

Participant referral to ophthalmologist is strongly recommended.

Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.
Ocular event, 
Grade 3 or 4

Permanently discontinue study drug and contact Medical Monitor

Refer participant to ophthalmologist.

Initiate treatment with 12 mg/kg/day oral prednisone or equivalent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.

 
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IMMUNE-MEDIATED MYOCARDITIS 
Immune-mediated myocarditis should be suspected in any participant presenting with 
signs or symptoms suggestive of myocarditis, including, but not limited to, laboratory 
(e.g., B-type natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, 
palpitations, fatigue, decreased exercise tolerance, or syncope. Immune-mediated 
myocarditis needs to be distinguished from myocarditis resulting from infection 
(commonly viral, e.g., in a participant who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of preexisting cardiac 
conditions, or progression of malignancy. 
All participants with possible myocarditis should be urgently evaluated by performing 
cardiac enzyme assessment, an ECG, a chest x-ray, an echocardiogram, and/or a 
cardiac MRI as appropriate per institutional guidelines. A cardiologist should be 
consulted. An endomyocardial biopsy may be considered to enable a definitive diagnosis 
and appropriate treatment, if clinically indicated. 
Participants with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 6. 
Table 6 
Management Guidelines for Immune-Mediated Myocarditis 
Event 
Management 
Immune-mediated 
myocarditis (all 
grades) 
 Permanently discontinue study drug and contact Medical Monitor.  
 Refer participant to cardiologist. 
 Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
 Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.  
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over   1 month. 
ECMO  Extracorporeal membrane oxygenation; IV  Intravenous; VAD  Ventricular assist 
device. 
 

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PANCREATIC EVENTS
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, may be associated with the administration of study drug. The 
differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate 
work-up should include an evaluation for ductal obstruction, as well as serum amylase 
and lipase tests. Management guidelines for pancreatic events, including pancreatitis, 
are provided in Table 7.
Table 7
Management Guidelines for Pancreatic Events, Including 
Pancreatitis
Event
Management
Amylase and/or 
lipase elevation, 
Grade 2
Amylase and/or lipase 1.52.0 ULN:

Continue study drug.

Monitor amylase and lipase weekly.

For prolonged elevation (e.g.,3 weeks), consider treatment with 
10 mg/day oral prednisone or equivalent.
Asymptomatic with amylase and/or lipase 2.05.0 ULN:
Treat as a Grade 3 event.
Amylase and/or 
lipase elevation, 
Grade 3 or 4

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to GI specialist.

Monitor amylase and lipase every other day.

If no improvement, consider treatment with 12 mg/kg/day oral prednisone 
or equivalent.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.

For recurrent events, permanently discontinue study drug and contact 
Medical Monitor.
Immune-mediated
pancreatitis, 
Grade 2 or 3

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.

For recurrent events, permanently discontinue study drug and contact 
Medical Monitor.

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Event
Management
Immune-mediated
pancreatitis, 
Grade 4

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to GI specialist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
GI Gastrointestinal; IV Intravenous; ULN Upper limit of normal.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.
DERMATOLOGIC EVENTS
Treatment-emergent rash may be associated with the study drug. A dermatologist 
should evaluate persistent and/or severe rash or pruritus. A biopsy should be considered 
unless contraindicated. Management guidelines for dermatologic events are provided in
Table 8.

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Table 8
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic 
event, Grade 1 

Continue study drug.

Consider treatment with topical corticosteroids and/or other symptomatic 
therapy (e.g., antihistamines).
Dermatologic 
event, Grade 2 

Continue study drug.

Consider participant referral to dermatologist.

Initiate treatment with topical corticosteroids.

Consider treatment with higher-potency topical corticosteroids if event 
does not improve.
Dermatologic 
event, Grade 3 

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to dermatologist.

Initiate treatment with 10 mg/day oral prednisone or equivalent, increasing 
dose to 12 mg/kg/day if event does not improve within 4872 hours.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study 
drug, permanently discontinue study drug and contact Medical Monitor.
Dermatologic 
event, Grade 4

Permanently discontinue study drug and contact Medical Monitor.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.
NEUROLOGIC DISORDERS
Myasthenia gravis and Guillain-Barré syndrome may be observed with study drug. 
Participants may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic work-up is essential for an accurate characterization to differentiate between 
alternative etiologies. Management guidelines for neurologic disorders are provided in
Table 9.

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Table 9
Management Guidelines for Neurologic Disorders
Event
Management
Immune-mediated 
neuropathy, 
Grade 1

Continue study drug.

Investigate etiology.
Immune-mediated
neuropathy, 
Grade 2 

Withhold study drug for up to 12 weeks after event onset. a

Investigate etiology.

Initiate treatment as per institutional guidelines.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor.
Immune-mediated
neuropathy, 
Grade 3 or 4

Permanently discontinue study drug and contact Medical Monitor.

Initiate treatment as per institutional guidelines.
Myasthenia gravis 
and Guillain-Barré
syndrome (any 
grade)

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to neurologist.

Initiate treatment as per institutional guidelines.

Consider initiation of 12 mg/kg/day oral or IV prednisone or equivalent.
IV Intravenous.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to 10 mg/day oral 
prednisone or equivalent before study drug can be resumed.
IMMUNE-MEDIATED MENINGOENCEPHALITIS
Immune-mediated meningoencephalitis may be associated with the administration of 
study drug. Immune-mediated meningoencephalitis should be suspected in any 
participant presenting with signs or symptoms suggestive of meningitis or encephalitis, 
including, but not limited to, headache, neck pain, confusion, seizure, motor or sensory 
dysfunction, and altered or depressed level of consciousness. Encephalopathy from 
metabolic or electrolyte imbalances needs to be distinguished from potential
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of 
malignancy, or secondary to a paraneoplastic process.
All participants being considered for meningoencephalitis should be urgently evaluated 
with a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
edema. If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted.

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Participants with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in Table 10.
Table 10 Management Guidelines for Immune-Mediated
Meningoencephalitis
Event
Management
Immune-mediated
meningoencephaliti
s, all grades

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to neurologist.

Initiate treatment with 12 mg/kg/day IV methylprednisolone or equivalent 
and convert to 12 mg/kg/day oral prednisone or equivalent upon 
improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
IV Intravenous.
RENAL EVENTS
Immune-mediated nephritis may be associated with the administration of study drug. 
Eligible participants must have adequate renal function, and renal function, including 
serum creatinine, should be monitored throughout study treatment. Participants with 
abnormal renal function should be evaluated and treated for other more common 
etiologies (including prerenal and postrenal causes, and concomitant medications such 
as non-steroidal anti-inflammatory drugs). Refer the participant to a renal specialist if 
clinically indicated. A renal biopsy may be required to enable a definitive diagnosis and 
appropriate treatment.
Participants with signs and symptoms of nephritis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 11.

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Table 11 Management Guidelines for Renal Events
Event
Management
Renal event, 
Grade 1

Continue study drug.

Monitor kidney function, including creatinine, closely until values resolve to 
within normal limits or to baseline values. 
Renal event, 
Grade 2

Withhold study drug for up to 12 weeks after event onset. a

Refer participant to renal specialist.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor. 
Renal event, 
Grade 3 or 4

Permanently discontinue study drug and contact Medical Monitor. 

Refer participant to renal specialist and consider renal biopsy.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral prednisone. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before study drug can be resumed.

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IMMUNE-MEDIATED MYOSITIS
Immune-mediated myositis may be associated with the administration of study drug. 
Myositis or inflammatory myopathies are a group of disorders sharing the common 
feature of inflammatory muscle injury; dermatomyositis and polymyositis are among the 
most common disorders. Initial diagnosis is based on clinical (muscle weakness, muscle 
pain, rash in dermatomyositis), biochemical (serum creatine kinase increase), and 
imaging (electromyography/MRI) features, and is confirmed with a muscle biopsy.
Participants with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 12.
Table 12 Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated
myositis, Grade 1

Continue study drug.

Refer participant to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated
myositis, Grade 2

Withhold study drug for up to 12 weeks after event onset a and contact 
Medical Monitor.

Refer participant to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If corticosteroids are initiated and event does not improve within 48 hours 
after initiating corticosteroids, consider adding an immunosuppressive 
agent.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor. 

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Event
Management
Immune-mediated
myositis, Grade 3

Withhold study drug for up to 12 weeks after event onset a and contact 
Medical Monitor.

Refer participant to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines. Respiratory support may be 
required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if participant is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume study drug. b

If event does not resolve to Grade 1 or better while withholding study drug, 
permanently discontinue study drug and contact Medical Monitor. 

For recurrent events, treat as a Grade 4 event.
Immune-mediated
myositis, Grade 4

Permanently discontinue study drug and contact Medical Monitor.

Refer participant to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines. Respiratory support may be 
required in more severe cases.

Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement.

If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 1 month.
IV Intravenous.
a Study drug may be withheld for a longer period (i.e., 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral prednisone. The 
acceptable length of the extended period must be based on the assessment of benefit-risk by 
the Investigator and in alignment with the protocol requirement for duration of treatment and 
documented by the Investigator. The Medical Monitor will be available to advise as needed.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before study drug can be resumed.

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HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS AND MACROPHAGE 
ACTIVATION SYNDROME
Immune-mediated reactions may involve any organ system and may lead to 
hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome 
(MAS). 
Patients with suspected HLH should be diagnosed according to published criteria by 
McClain and Eckstein (2014). A patient should be classified as having HLH if five of the 
following eight criteria are met:

Fever 38.5°C

Splenomegaly

Peripheral blood cytopenia consisting of at least two of the following:
–
Hemoglobin 90 g/L (9 g/dL) (100 g/L [10 g/dL] for infants aged 
4 weeks)
–
Platelet count 100 109/L (100 000/L)
–
ANC 1.0109/L (1000/L)

Fasting triglycerides 2.992 mmol/L (265 mg/dL) and/or fibrinogen 1.5 g/L 
(150 mg/dL)

Hemophagocytosis in bone marrow, spleen, lymph node, or liver

Low or absent natural killer cell activity

Ferritin 500 mg/L (500 ng/mL)

Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated 2 standard 
deviations above age-adjusted laboratory-specific norms
Participants with suspected MAS should be diagnosed according to published criteria for 
systemic juvenile idiopathic arthritis by Ravelli et al. 2016. A febrile patient should be 
classified as having MAS if the following criteria are met: 

Ferritin 684 mg/L (684 ng/mL)

At least two of the following:
–
Platelet count 181 109/L (181,000/µL)
–
AST 48 U/L
–
Triglycerides 1.761 mmol/L (156 mg/dL)
–
Fibrinogen 3.6 g/L (360 mg/dL)
Participants with suspected HLH or MAS should be treated according to the guidelines in 
Table 13.

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Table 13 Management Guidelines for Suspected Hemophagocytic 
Lymphohistiocytosis or Macrophage Activation Syndrome
Event
Management
Suspected HLH
or MAS

Permanently discontinue study drug and contact Medical 
Monitor. 

Consider patient referral to hematologist.

Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines.

Consider initiation of IV corticosteroids, an 
immunosuppressive agent, and/or anti-cytokine therapy.

If event does not respond to treatment within 24 hours, contact 
Medical Monitor and initiate treatment as appropriate 
according to published guidelines (La Rosée 2015; Schram 
and Berliner 2015; La Rosée et al. 2019).

If event resolves to Grade 1 or better, taper corticosteroids 
over 1 month.
HLH Hemophagocytic lymphohistiocytosis; IV Intravenous; MASMacrophage activation 
syndrome.
REFERENCES
La Rosée P. Treatment of hemophagocytic lymphohistiocytosis in adults. Hematology 
Am Soc Hematol Educ Protram. 2015:190–6.
La Rosée P, Horne A, Hines M, et al. Recommendations for the management of 
hemophagocytic lymphohistiocytosis in adults. Blood 2019;133:2465–77.
McClain KL, Eckstein O. Clinical features and diagnosis of hemophagocytic 
lymphohistiocytosis. Up to Date [resource on the Internet]. 2014 [updated 29 
October 2018; cited: 17 May 2019]. Available from: 
https://www.uptodate.com/contents/clinical-features-and-diagnosis-of-
hemophagocytic-lymphohistiocytosis.
Ravelli A, Minoia F, Davi S, et al. 2016 classification criteria for macrophage activation 
syndrome complicating systemic juvenile idiopathic arthritis: a European League 
Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology 
International Trials Organisation Collaborative Initiative. Ann Rheum Dis 
2016;75:481–9.
Schram AM, Berliner N. How I treat hemophagocytic lymphohistiocytosis in the adult 
patient. Blood 2015;125:2908–14.

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Appendix 8
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire (EORTC QLQ-C30)

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Appendix 9
European Organisation for Research and Treatment of Cancer 
Quality-of-Life Questionnaire for Esophageal Cancer 
(QLQ-OES18)

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Appendix 10
European Organisation for Research and Treatment of Cancer 
Item Library 97 (EORTC IL97)

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Appendix 13
Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events (PRO-CTCAE)
NCI PRO-CTCAE ™ ITEMS
Item Library Version 1.0
English
Form Created on 06 October 2020
As individuals go through treatment for their cancer, they sometimes experience different 
symptoms and side effects. For each question, please select the one response that best 
describes your experiences over the past 7 days.
1a.  In the last 7 days, what was the SEVERITY of your SHORTNESS OF BREATH at its WORST?
Ο None
Ο Mild
Ο Moderate
Ο Severe
Ο Very severe
1b.  In the last 7 days, how much did your SHORTNESS OF BREATH INTERFERE with your usual 
or daily activities?
Ο Not at all
Ο A little bit
Ο Somewhat
Ο Quite a bit
Ο Very much
2a.  In the last 7 days, what was the SEVERITY of your COUGH at its WORST?
Ο None
Ο Mild
Ο Moderate
Ο Severe
Ο Very severe
2b.  In the last 7 days, how much did COUGH INTERFERE with your usual or daily activities?
Ο Not at all
Ο A little bit
Ο Somewhat
Ο Quite a bit
Ο Very much
3a.  In the last 7 days, did you have any RASH?
Ο Yes
Ο No
4a.  In the last 7 days, what was the SEVERITY of your ITCHY SKIN at its WORST?
Ο None
Ο Mild
Ο Moderate
Ο Severe
Ο Very severe
5a.  In the last 7 days, how OFTEN did you have ACHING MUSCLES?
Ο Never
Ο Rarely
Ο Occasionally
Ο Frequently
Ο Almost 
constantly
5b.  In the last 7 days, what was the SEVERITY of your ACHING MUSCLES at their WORST?
Ο None
Ο Mild
Ο Moderate
Ο Severe
Ο Very severe
5c.  In the last 7 days, how much did ACHING MUSCLES INTERFERE with your usual or daily 
activities?
Ο Not at all
Ο A little bit
Ο Somewhat
Ο Quite a bit
Ο Very much

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6a.  In the last 7 days, how OFTEN did you have ACHING JOINTS (SUCH AS ELBOWS, KNEES, 
SHOULDERS)?
Ο Never
Ο Rarely
Ο Occasionally
Ο Frequently
Ο Almost 
constantly
6b.  In the last 7 days, what was the SEVERITY of your ACHING JOINTS (SUCH AS ELBOWS, 
KNEES, SHOULDERS) at their WORST?
Ο None
Ο Mild
Ο Moderate
Ο Severe
Ο Very severe
6c.  In the last 7 days, how much did ACHING JOINTS (SUCH AS ELBOWS, KNEES, SHOULDERS) 
INTERFERE with your usual or daily activities?
Ο Not at all
Ο A little bit
Ο Somewhat
Ο Quite a bit
Ο Very much

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Appendix 14
Correction Formulas for QTc Intervals
Fridericia’s correction for QTc Measurement - QTcF
QTcF (ms)
QT (ms)
3
1000
/)
ms
(
RR
Example:
QTcF of a subject with a QT of 386 ms and a RR of 848 ms
QT (ms)386
RR (ms)848
QT (ms)
408 ms
3
1000
/)
ms
(
RR
Bazett’s correction for QTc Measurement - QTcB
QTcB (ms)
QT (ms)
1000
/)
ms
(
RR
Example:
QTcB of a subject with a QT of 386 ms and a RR of 848 ms
QT (ms)386
RR (ms)848
QT (ms)

419 ms
                 
1000
/)
ms
(
RR