Conditions: Biliary Tract Cancer Cholangiocarcinoma Gallbladder Cancer
Keywords: M7824 Bintrafusp alfa (proposed INN) Transforming growth factor-beta First-line Platinum-Based Chemotherapy Programmed death-ligand 1 Metastatic Biliary Tract Cancer Cholangiocarcinoma Gallbladder cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 159
Healthy volunteers: no

Brief summary:
The study to evaluate M7824 monotherapy in participants with advanced or metastatic biliary tract cancer (BTC) who failed or were intolerant to first-line (1L) chemotherapy.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: M7824
Intervention descriptions: intervention 1: Participants received an intravenous infusion of 1200 milligrams (mg) M7824 once every 2 weeks until confirmed disease progression, death, unacceptable toxicity or study withdrawal.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
A Phase II, Multicenter, Open-label Study to 
Investigate the Clinical Efficacy of M7824 
Monotherapy 
in 
Participants 
With 
Locally 
Advanced or Metastatic Biliary Tract Cancer Who 
Fail or are Intolerant to First-line Platinum-Based 
Chemotherapy
Study Number:
MS200647_0047
Merck Compound:
M7824
Merck Registered Compound Name in 
Japan:
Not applicable
Study Phase:
Phase II
Short Title:
Phase II Study of M7824
Monotherapy in 
Participants With Locally Advanced or Metastatic 
Biliary Tract Cancer Who Fail or are Intolerant to 
First-line Platinum-Based Chemotherapy
Coordinating Investigator:
 
Sponsor Name and Legal Registered 
Address:
For all countries, except the USA and Japan:
Merck KGaA
Frankfurter Str. 250
Darmstadt, Germany
In the USA:
EMD Serono Research & Development Institute, 
Inc.
An affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA, 01821, USA
In Japan:
Merck Biopharma Co., Ltd.: Japan
(Affiliate of Merck KGaA, Darmstadt, Germany)
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
Regulatory 
Agency 
Identifying 
Numbers:
IND:
EudraCT: 2018-003707-19
ClinicalTrials.gov: NCT03833661
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Protocol Version:
22 June 2021/Version 5.0
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
08-Nov-2018
1.1-VHP
Region-specific amendment
(European Union for countries
participating in the Voluntary 
Harmonisation Procedure [VHP])
15-Jan-2019
1.2-FDA
Region-specific amendment (United 
States Food and Drug Administration 
request)
01-Feb-2019
1.3-CHN
Country-specific amendment (China)
31-May-2019
2.0
Global Protocol Amendment
26-Aug-2019
3.0
Global Protocol Amendment
10-Oct-2019
3.1-CHN
Country-specific amendment (China)
14-Mar-2020
4.0
Global Protocol Amendment
20-Oct-2020
4.1
Country-specific amendment (China)
21-Oct-2020
5.0
Global Protocol Amendment
22-Jun-2021
Protocol Version 5.0 (22 June 2021)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The primary purpose of this amendment is to update the risk classification.
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Section # and Name
Description of Change
Brief Rationale
Title Page
Removed “Medical Responsible” field
Removed “Replaces Version” and 
“Approval Date” rows.
To be consistent with current Sponsor 
protocol template (Version 15).
2.3 Benefit/Risk 
Assessment
Risk classification has been revised 
and the list of events has been 
updated accordingly.
The statement referring to the number 
of patients treated with M7824 
monotherapy has been removed.
The risk reclassification was based on 
in-depth analysis of a pooled safety 
dataset of N = 765 participants who 
received M7824 monotherapy at 1200 mg 
Q2W.
The information on the number of 
patients treated with M7824 is provided in 
the IB.
5 Study Population
Appendix 2 Study 
Governance
Edits related to informed consent 
process.
To be consistent with current Sponsor 
protocol template (Version 15).
6.9 Management of 
Adverse Events of Special 
Interest and other Potential 
Risks
Appendix 4 Adverse 
Events: Definitions and 
Procedures for Recording, 
evaluating, Follow-up, and 
Reporting
Risk categorization has been revised
and the list of events has been 
updated accordingly.
The risk reclassification was based on in-
depth analysis of a pooled safety dataset 
of N = 765 participants who received 
M7824 monotherapy at 1200 mg Q2W.
6.9.1 Infusion-related 
Reactions Including 
Immediate Hypersensitivity
Infusion-related reactions are
reclassified from “important identified 
risk” to “identified risk” for M7824.
6.9.2 Immune-related 
Adverse Events
Risk categorization has been revised
and the list of events has been 
updated accordingly.
6.9.3 TGF-β Inhibition 
Mediated Skin Reactions
Skin Adverse Events have been 
renamed to TGF-β Inhibition Mediated 
Skin Reactions.
6.9.4 Anemia
Term “treatment-related anemia 
events” has been revised to “anemia” 
and reclassified from “important 
potential risk” to “important identified 
risk” for M7824.
6.9.5 Bleeding Events
Bleeding events are reclassified from 
“potential risk” to “important identified 
risk” for M7824.
6.9.6.1 Impaired Wound 
Healing
The risk name “Alterations in Wound 
Healing or Repair of Tissue Damage” 
has been changed to “Impaired
Wound Healing”.
7.3 Lost to Follow-up
Edits are done related to Lost to 
Follow-up information.
To be consistent with current Sponsor 
protocol template (Version 15).
Note: Minor changes have been performed throughout the protocol to address consistency pertaining to major 
changes made in the protocol or to add further clarity and precision.
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
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permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................6
List of Tables
..............................................................................................................9
List of Figures
............................................................................................................10
1
Protocol Summary ..............................................................................11
1.1
Synopsis..............................................................................................11
1.2
Schema................................................................................................14
1.3
Schedule of Activities.........................................................................14
2
Introduction.........................................................................................26
2.1
Study Rationale...................................................................................26
2.2
Background.........................................................................................26
2.3
Benefit/Risk Assessment ....................................................................28
3
Objectives and Endpoints ...................................................................28
4
Study Design.......................................................................................30
4.1
Overall Design....................................................................................30
4.2
Scientific Rationale for Study Design ................................................31
4.3
Justification for Dose..........................................................................33
4.4
End of Study Definition......................................................................33
5
Study Population.................................................................................33
5.1
Inclusion Criteria ................................................................................34
5.2
Exclusion Criteria...............................................................................37
5.3
Lifestyle Considerations .....................................................................40
5.4
Screen Failures....................................................................................40
6
Study Intervention(s) ..........................................................................40
6.1
Study Intervention Administration .....................................................41
6.2
Study Intervention Preparation, Handling, Storage, and 
Accountability.....................................................................................41
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................42
6.3.1
Study Intervention Assignment ..........................................................42
6.3.2
Blinding ..............................................................................................42
6.4
Study Intervention Compliance..........................................................42
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6.5
Concomitant Therapy .........................................................................43
6.5.1
Rescue Medicine.................................................................................43
6.5.2
Permitted Medicines...........................................................................43
6.5.3
Prohibited Medicines..........................................................................44
6.5.4
Other Interventions.............................................................................44
6.6
Dose Selection and Modification........................................................45
6.6.1
Adverse Drug Reactions Requiring Treatment Modification.............45
6.7
Study Intervention After the End of the Study...................................47
6.8
Special Precautions.............................................................................47
6.9
Management of Adverse Events of Special Interest and other 
Potential Risks ....................................................................................47
6.9.1
Infusion-Related Reactions Including Hypersensitivity.....................47
6.9.2
Immune-Related Adverse Events .......................................................50
6.9.3
TGF-β Inhibition Mediated Skin Reactions .......................................52
6.9.4
Anemia................................................................................................53
6.9.5
Bleeding Events..................................................................................54
6.9.5.1
Mucosal/Non-Tumor Bleeding...........................................................54
6.9.5.2
Tumor Bleeding..................................................................................55
6.9.6
Other Potential Risks..........................................................................55
6.9.6.1
Impaired Wound Healing ...................................................................55
6.9.6.2
Embryofetal Toxicity..........................................................................55
6.9.6.3
Disease Specific Risk: Hepatic Impairment .......................................55
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................56
7.1
Discontinuation of Study Intervention................................................56
7.1.1
Temporary Discontinuation................................................................56
7.1.2
Rechallenge.........................................................................................56
7.1.2.1
Treatment Beyond Initial Progression................................................57
7.1.2.2
Treatment Beyond Confirmed Progression ........................................57
7.1.2.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression............................................................................58
7.2
Participant Discontinuation/Withdrawal from the Study ...................58
7.3
Lost to Follow-up ...............................................................................60
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8
Study Assessments and Procedures....................................................60
8.1
Efficacy Assessments and Procedures................................................61
8.1.1
Tumor Response.................................................................................61
8.2
Safety Assessments and Procedures ...................................................64
8.2.1
Physical Examinations and Vital Signs..............................................65
8.2.2
Electrocardiograms.............................................................................65
8.2.3
Clinical Safety Laboratory Assessments ............................................65
8.2.4
Review Committees............................................................................66
8.3
Adverse Events and Serious Adverse Events.....................................66
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................67
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...67
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............67
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....68
8.3.5
Pregnancy ...........................................................................................68
8.4
Treatment of Overdose .......................................................................69
8.5
Pharmacokinetics................................................................................69
8.9
Health Economics...............................................................................72
8.10
Immunogenicity Assessments ............................................................72
9
Statistical Considerations....................................................................73
9.1
Statistical Hypotheses.........................................................................73
9.2
Sample Size Determination ................................................................73
9.3
Populations for Analyses ....................................................................75
9.4
Statistical Analyses.............................................................................75
9.4.1
Efficacy Analyses ...............................................................................75
9.4.1.1
Analysis of Primary Endpoint ............................................................75
9.4.1.2
Analysis of Secondary and 
 Endpoints............................76
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9.4.2
Safety Analyses ..................................................................................78
9.4.3
Other Analyses....................................................................................79
9.4.4
Sequence of Analyses.........................................................................81
10
References...........................................................................................82
11
Appendices .........................................................................................84
Appendix 1
Abbreviations......................................................................................84
Appendix 2
Study Governance...............................................................................87
Appendix 3
Contraception......................................................................................95
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................97
Appendix 5
Clinical Laboratory Tests .................................................................101
Appendix 6
Management of irAEs.......................................................................102
Appendix 8
Protocol Amendment History...........................................................141
Appendix 9
Sponsor Signature Page....................................................................154
Appendix 10
Coordinating Investigator Signature Page........................................155
Appendix 11
Principal Investigator Signature Page...............................................156
List of Tables
Table 1
Schedule of Activities.........................................................................15
Table 2
M7824 Pharmacokinetic, Immunogenicity Sampling........................25
Table 3
Study Objectives and Endpoints.........................................................29
Table 4
Treatment Modification of M7824 for Symptoms of 
Infusion-Related Reactions Including Immediate Hypersensitivity...49
Table 5
Evaluation Guidance of Suspected Anemia .......................................54
Table 6
Pharmacokinetic Parameters...............................................................70
Table 8
Confidence Intervals for Different Objective Response Rates...........74
Table 9
Analysis Populations ..........................................................................75
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List of Figures
Figure 1
Overall Study Design Schema............................................................14
Figure 2
Spectra of Molecular Alterations in Biliary Tract Cancers ................32
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1
Protocol Summary
1.1
Synopsis
Protocol Title: 
A Phase II, Multicenter, Open-label Study to Investigate the Clinical Efficacy of M7824 
Monotherapy in Participants With Locally Advanced or Metastatic Biliary Tract Cancer Who Fail 
or are Intolerant to First-line Platinum-Based Chemotherapy
Short Title:
Phase II Study of M7824 Monotherapy in Participants With Locally Advanced or Metastatic 
Biliary Tract Cancer Who Fail or are Intolerant to First-line Platinum-Based Chemotherapy
Rationale:
There is no established second-line therapy for biliary tract cancer (BTC) as the standard of care 
according to the National Comprehensive Cancer Network and European Society for Medical 
Oncology guidelines. M7824 (bintrafusp alfa) targets the programmed death-ligand 1 (PD-L1) and 
transforming growth factor β, the 2 major mechanisms of immunosuppression in the tumor 
microenvironment and provides a rationale to overcome the resistance of checkpoint inhibitor 
monotherapy. A preclinical study showed that M7824 demonstrated enhanced antitumor activity 
and prolonged survival compared with checkpoint inhibitors in in vivo models. A clinical study of 
M7824 showed a promising result with a clinical efficacy signal of 23.3% (7 of 30 participants) 
confirmed objective response rate (ORR) assessed by Investigators and 20% assessed by 
Independent Review Committee (IRC) in second-line BTC. Therefore, the current clinical study 
is supported by scientific evidence and promising clinical efficacy data with the goal of fulfilling 
an unmet medical need and bringing clinical benefits to patients.
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Primary
!
To evaluate clinical efficacy of M7824 based on 
ORR
!
Confirmed objective response (OR) according to 
Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) assessed by IRC
Secondary
!
To evaluate clinical efficacy of M7824 based on 
duration of response (DOR)
!
DOR assessed from complete response (CR) or 
partial response (PR) until progression of disease 
(PD), death, or last tumor assessment assessed by 
IRC
!
To evaluate clinical efficacy of M7824 based on 
durable response rate (DRR)
!
Durable response of at least 6 months according to 
RECIST 1.1 assessed by IRC
!
To evaluate clinical safety of M7824
!
Occurrence of treatment-emergent adverse events 
(TEAEs) and treatment-related adverse events 
(AEs), including adverse events of special interest 
(AESIs)
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Objectives
Endpoints (Outcome Measures)
!
To evaluate clinical efficacy based on 
progression-free survival (PFS)
!
PFS according to RECIST 1.1 assessed by IRC
!
To evaluate ORR, DOR, DRR and PFS by 
Investigator read
!
OR, DOR, DRR, and PFS according to RECIST 1.1 
assessed by Investigator read
!
To evaluate clinical efficacy based on overall 
survival (OS)
!
OS
!
To characterize the pharmacokinetic (PK) profile of 
M7824
!
The concentration observed immediately at the end 
of infusion (CEOI) of M7824
!
The concentration observed immediately before next 
dosing (corresponding to pre-dose or trough 
concentration [Ctrough] for multiple dosing) of M7824
!
To characterize the immunogenicity of M7824
!
Immunogenicity of M7824 as measured by antidrug 
antibody (ADA) assay, from Screening through 
12 weeks (± 2 weeks) after last treatment
!
To evaluate clinical efficacy of M7824 based on 
ORR, DOR, and DRR according to PD-L1 
expression and microsatellite instability (MSI) 
status retrospectively
!
Confirmed OR according to RECIST 1.1 assessed by 
IRC according to PD-L1 expression and MSI status
!
DOR and durable response of at least 6 months 
according to RECIST 1.1 assessed by IRC according 
to PD-L1 expression and MSI status
Overall Design:
This is a Phase II, multicenter, international, single-arm, open-label, study to evaluate M7824 
monotherapy in participants with locally advanced or metastatic BTC who failed or were intolerant 
to first-line chemotherapy.
The study plans to enroll 141 eligible BTC participants. The participants will be included from the
USA, Europe, and Asian countries with competitive enrollment. The study will enroll 3 major 
subtypes of BTC, including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma,
and gallbladder cancer, with a minimum of 30 participants in each subtype. If one subtype does 
not reach a minimum of 30 participants by the end of competitive enrollment of 141 participants, 
the study will continue to enroll only in this subtype to reach 30 participants. 
Participants will receive M7824 at a dose of 1200 mg once every 2 weeks until confirmed PD, 
death, unacceptable toxicity, or study withdrawal.
This study includes: 
! 28-day Screening period.
! Treatment until confirmed PD per RECIST 1.1, death, unacceptable toxicity, or study 
withdrawal. In the case of PD, treatment may continue past the initial determination of PD or 
confirmed PD if the participant’s performance status has remained at least stable, and if in the 
opinion of the Investigator, the participant will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol. Participants who have experienced a confirmed
CR should continue treatment for a maximum of 24 months after confirmation of response. If 
the Investigator believes that a participant with confirmed CR may benefit from treatment 
beyond 24 months, it may be permissible to continue treatment after discussion with the 
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Medical Monitor and the Sponsor Medical Responsible. Participants with stable disease or PR 
should continue treatment until disease progression or any other discontinuation criterion is 
met.
! Safety Follow-up will continue until 12 weeks after the last dose of M7824. The 12-week Safety 
Follow-up is allowed to be conducted via phone calls or patient chart reviews unless there is 
medical necessity requiring a clinical visit.
! Long-term Follow-up should be performed every 12 weeks after the Safety Follow-up
according to the Schedule of Activities. Long-term Follow-up can be performed by chart 
reviews or telephone calls.
! Survival Follow-up will continue until each participant was followed up for at least 3 years after 
the End-of-Treatment.
Number of Participants: 
The planned total sample size is 141 participants based on the following assumptions:
1. ORR of 18%
2. Alpha = 0.025 (1-sided) for the Exact test of the null hypothesis of an ORR ≤10%.
Under the given assumptions, the power to reject the null hypothesis at the primary analysis is 
80%.
Statistical Analysis:
There will be 2 data cutoff time points in this study:
! An 
per BTC subtype will be performed once 
15 participants of each subtype have reached at least one postbaseline tumor assessment. Each 
subtype will be analyzed separately once criteria are met.
! The primary analysis will be conducted 9 months after the accrual of the last of 141 planned 
participants.
! Second analysis for DRR and DOR will be conducted 15 months after the accrual of the last of 
141 planned participants. The analysis will comprise a full evaluation of all efficacy and safety 
endpoints.
Study Intervention Groups and Duration: 
The study duration for a participant is estimated to be up to 3 years. This includes a 28-day 
Screening period (decision will be made in this period for participants’ study inclusion if all 
eligibility criteria are met); a treatment duration until confirmed PD, unacceptable toxicity, or
study withdrawal occurs, a 28-day Safety Follow-up visit and a 12-week Safety Follow-up phone 
call after the last dose of M7824.
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Involvement of Special Committee(s): Yes
The following committees will be involved in the study: Independent Data Monitoring Committee 
(IDMC), IRC, and Study Steering Committee.
To ensure participants’ safety during the study, an external IDMC will periodically review safety 
data. The IDMC will be composed of a minimum of 3 voting members, including an independent 
biostatistician, and 2 independent oncologists (BTC experts). The full membership, mandate, and 
processes of the IDMC are detailed in the IDMC charter.
1.2
Schema
The overall study design is shown in Figure 1.
Figure 1
Overall Study Design Schema
2L=second-line, BTC=biliary tract cancer, DOR=duration of response, DRR=durable response rate, IV=intravenous, 
, N=number of participants, ORR=objective response rate, OS=overall survival,
PD-L1=programmed death-ligand 1, PFS=progression-free survival, Q2W=every 2 weeks.
1.3
Schedule of Activities
The Schedule of Activities is provided in Table 1. The M7824 pharmacokinetic and 
immunogenicity sampling times are provided in Table 2.
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Table 1
Schedule of Activities
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Administrative Procedures
Written 
informed 
consent
X
Inclusion/
exclusion 
criteria/
Enrollment (if 
eligible)
X
Xa
Enrollment will be after the confirmation of 
fulfilling all inclusion criteria and without 
matching any exclusion criterion.
a Confirmation of eligibility is required prior 
to dosing on W1D1.
Demographic 
data
X
Medical history 
X
Medical history should include history of 
BTC with stages at diagnosis, tumor 
locations (intrahepatic, extrahepatic, and 
gallbladder cancer) environmental / 
occupational exposure to chemicals and 
baseline medical condition.
Prior 
anticancer 
drug/radio-
therapy /
procedures for 
Baseline visit
X
Prior anticancer procedures and therapies 
should at least include prior adjuvant 
therapy, surgical resection and recurrence, 
and details on first-line chemotherapy 
agents, treatment duration, and treatment 
responses.
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Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Documentation 
of concomitant 
medication 
and 
procedures
X
X
X
X
X
X
X
X
Q2W
X
X
Documentation 
of non-protocol 
related 
hospitalization, 
emergency 
room visits, 
and outpatient 
hospital visits
X
X
X
X
X
X
X
Q2W
X
X
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Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Tumor Biopsies/Archival Tissue Collection
Document No. 
Object No. 
CCI
CCI
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
18/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Premedication and M7824 Drug Administration
Premedication 
and M7824
administration
Xd
Xd
Xd
Xd
Xd
Xd
Xd
Q2Wd
d See Section 6.9.1 for premedication 
details. The first 15 participants will not 
receive premedication before first and 
second M7824 infusions to establish 
whether mandatory use of premedication
is required. If two or more Grade 2 
infusion-related reactions are seen during 
the first 2 infusions for the first 15 
participants, IDMC will determine if 
mandatory premedication is needed. Study 
enrollment will continue in parallel to this 
review and sites will be notified 
accordingly if premedication becomes a 
requirement.
If IDMC determines mandatory 
premedication is justified, premedication 
with an antihistamine and with 
paracetamol (acetaminophen) (e.g., 25 to 
50 mg diphenhydramine and 500 to 650 
mg paracetamol [acetaminophen] IV or 
oral equivalent) prior to each dose of 
M7824 is mandatory for the first 
2 infusions. After 2 infusions, 
premedication is optional and at the 
discretion of the Investigator. If Grade 2 
infusion-related reactions are seen during 
the first 2 infusions, then premedication 
should not be stopped. Steroids as 
premedication are not permitted.
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
19/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Safety Assessments
Documentation 
of AEse
X
X
X
X
X
X
X
X
Q2W
X
X
Xe
Xe
AEs will be documented at each study visit 
(see Appendix 4) for safety assessment.
Any SAE assessed as related to study 
intervention must be reported whenever it 
occurs, irrespective of the time elapsed 
since the last administration of study 
intervention.
e The 12-week Safety Follow-up and Long-
term Follow-up should be conducted via 
telephone calls or patient chart reviews 
unless there is medical necessity requiring 
a clinical visit.
See Sections 8.3.1, 8.3.2 and Appendix 4
for definition of the AE reporting period 
and Follow-up. 
Physical 
examination
X
X
X
X
X
X
X
X
Q2W
X
X
Complete physical examination at 
Screening; at least focused physical 
examinations should be performed at 
subsequent clinical visits per local 
standard practice.
Skin 
assessment
X
X
X
Q6W
X
X
Xf
f The 12-week Safety Follow-up is to be 
conducted via a telephone call unless 
there is medical necessity requiring a 
clinical visit.
Vital signs
X
X
X
X
X
X
X
X
Q2W
X
X
Including weight and height (height at 
Screening only).
ECOG PS
X
Xg
X
X
X
X
X
X
Q2W
X
X
g ECOG PS 0 or 1 is required at W1D1.
12-lead ECG
X
X
X
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
20/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
SpO2
X
X
X
X
X
X
X
X
Q2W
X
X
Using pulse oximeter.
Laboratory Assessments
Virology 
serology
(HBV and
HCV)
X
As clinically indicated in participants with a history of HBV or HCV 
infection
HIV testing is not mandated for study 
inclusion; and if it is performed at any point 
in Screening or while on study, a site must 
consent the participant for HIV testing as 
per local standard guidance.
Hematology
X
X
X
X
X
X
X
X
Q2W
X
X
Details on blood tests under this category 
are listed in Appendix 5. Samples must 
also be drawn prior to study intervention
administration and results of selected 
laboratory tests (see Appendix 5) must be 
reviewed within 48 hours prior to dosing.
Full serum 
chemistry
X
X
X
X
X
X
X
X
Q2W
X
X
Full serum chemistry is listed in Appendix 
5. Samples must be drawn prior to dose 
administration and results of selected 
laboratory tests (see Appendix 5) must be 
reviewed within 48 hours prior to dosing.
Coagulation 
parameters 
(aPTT, 
prothrombin 
time and INR)
X
X
X
X
X
Q4W
X
X
See Appendix 5.
CA 19.9
X
X
X
X
Q6W
X
X
Urinalysis
X
X
X
Details on urinalysis under this category 
are listed in Appendix 5. Full urinalysis 
(dipstick plus microscopic evaluation) at 
the Screening only and a basic urinalysis 
(dipstick only) should be performed during 
treatment if clinically indicated.
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
21/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
β-HCG 
pregnancy test
X
X
X
X
X
Q4W
X
Xh
β-HCG should be determined from serum 
or highly sensitive urine β-HCG pregnancy 
test. Results of the most recent pregnancy 
test should be available prior to dosing of 
study intervention. See Section 5.1 and 
8.2.3 for details.
h participants should go to local laboratory
to perform pregnancy test. Clinical visit is 
not required. 
Free T4 and 
TSH
X
X
X
Q6W
X
KL-6, SP-A 
and SP-Di
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Q4Wi
after 
D85 
until 
PD
Xi
Xi
i Only applicable for Japanese sites.
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
22/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Patient Reported Outcomes (PRO)
Document No. 
Object No. 
CCI
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
23/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
Patient 
interviews
X
X
Participants will be asked to participate in 
an interview performed by a third-party 
vendor. Participants will be selected from 
all sites in the USA, Germany, and Korea.
Tumor Assessments
Tumor 
evaluation
/staging (CT 
scan/MRI/other 
established 
methods)
X
X
Q8W 
up to 
12 
month
s,
then 
Q12W
Xm
A brain CT/MRI scan should be done as 
clinically indicated at Screening. 
Confirmation of CR or PR should be 
performed preferably at the regularly 
scheduled assessment intervals, but no 
sooner than 4 weeks after the initial 
documentation. See Section 8.1.1.
The IRC should confirm measurable 
disease before enrollment as well as verify 
unconfirmed PD by Investigator read.
m In case treatment is discontinued due to 
another reason than PD, tumor 
assessments should be continued 
according to original protocol schedule 
until confirmed PD.
Subsequent 
anticancer 
therapy (any 
line)
X
X
X
Survival 
follow-upn
Xn
n Survival Follow-up will continue until 
each participant was followed up for at 
least 3 years after the End-of-Treatment.
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
24/156
Assessments 
& Procedures
Screen
-ing/ 
Base-
line
Treatment Phase
(± 3 days)
End-of-
Treatment 
Visit
Safety
Follow-up Visit
Long-
term 
Follow-
up
Notes
Day -28 
to First 
Treat-
ment
V1
V2
V3
V4
V5
V6
V7
Until 
PD
On the Day 
of or Within 
7 Days of 
Decision to 
Discontinue
28 Days 
(± 5 Days) 
After Last 
Treatment
12 Weeks 
(± 2 
Weeks) 
After Last 
Treatment
Every 
12 
Weeks 
(± 2 
Weeks)
W1
W3
W5
W7
W9
W11
W13
D1
D15 D29 D43 D57
D71
D85
PK, ADA and 
PK and ADA 
sampling
See Table 2 for PK and ADA sampling times
s 
 
ADA=antidrug antibody, AE=adverse events, aPTT= activated partial thromboplastin time, β-HCG=β-human chorionic gonadotropin, 
 
item module, BTC=biliary tract cancer, 
, CR=complete response, CT=computed tomography, D=Day, ECG=electrocardiogram, ECOG 
PS=Eastern Cooperative Oncology Group performance status, 
 
, 
, HBV=hepatitis B virus, HCC-18=Hepatobiliary Cancer 18 item module,
HCV=hepatitis C virus, HIV=human immunodeficiency virus, IDMC=Independent Data Monitoring Committee, INR=international normalized ratio, IRC=Independent 
review committee, IV=intravenous, MRI=magnetic resonance imaging, 
, PD=progression of disease, PD-L1=programmed death ligand 
1, PGIS=patient global impression of severity, PK=pharmacokinetics, PR=partial response, 
ome, Q2W=every 2 weeks, Q4W=every 4 
weeks, Q6W=every 6 weeks, Q12W=every 12 weeks, SAE=serious adverse event, SP-A=Surfactant protein A, SP-D=Surfactant protein D, SpO2=blood oxygen 
saturation, T4=thyroxine,
 TSH=thyroid-stimulating hormone, V=visit, W=Week, W1D1=Week 1 Day 1.
Document No. 
Object No. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
25/156
Table 2
M7824 Pharmacokinetic, Immunogenicity Sampling
M7824 
Measure
Screening /
Baseline 
Assessments
Treatment Phase
(± 3 days)
End-of-
Treatment
Visit
Safety Follow-up Visit
Notes
Day -28 to First 
Treatment
V1
V2
V3
V4
V7
Until 
Progression 
Pre-infusion
On the Day 
of or Within 
7 Days of 
Decision
Up to 28 
Days 
(± 5 days) 
After Last 
Treatment
12 Weeks 
(± 2 weeks) 
After Last 
Treatment
W1
W3
W5
W7
W13
D1
Pre/En
d 
Infusio
n
D15
Pre/End 
Infusion
D29
Pre/En
d 
Infusio
n
D43
Pre/End 
Infusion
D85
Pre/En
d 
Infusio
n
Blood 
sample for 
PK
X/X
X/-
X/X
X/-
X/-
Q6W up 
to/including 
W25, then 
Q12W
X
X
Samples for PK analysis to 
be taken before (pre) infusion 
(as close to the start of the 
infusion as possible), 
immediately after the 
completion of infusion (as 
close to the completion as 
possible but no later than 
30 minutes post end of 
infusion). The pre-dose 
sample should still be drawn 
even if dosing is ultimately 
deferred at the study visit. 
The exact time of each draw 
must be recorded. A protocol 
deviation will be defined by a 
sample not being drawn or 
time not being recorded.
Blood 
sample for 
ADA
X
X/-
X/-
X/-
X/-
Q6W up 
to/including 
W25, then 
Q12W
X
X
Pre-dose ADA samples to be 
collected within 2 hours prior 
to study intervention infusions 
as scheduled.
ADA=antidrug antibody, D=days, PK=pharmacokinetics, Q6W=every 6 weeks, Q12W=every 12 weeks; V=visit, W=Week.
Document No. 
Object No. 
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
26/156
2
Introduction
M7824 (bintrafusp alfa) is a first-in-class, intravenously administered bifunctional fusion protein 
that combines an antiprogrammed death-ligand 1 (anti-PD-L1) antibody and the soluble 
extracellular domain of the human transforming growth factor-β (TGF-β) receptor as a TGF-β 
neutralizing “trap” into a single molecule. M7824 is being developed for the treatment of 
participants with locally advanced or metastatic biliary tract cancer (BTC) who failed or are 
intolerant to first-line (1L) chemotherapy. Bintrafusp alfa is the international nonproprietary name 
for M7824.
M7824, as a monotherapy, has shown an acceptable safety profile and a promising clinical efficacy 
signal in a Phase Ib study of second-line (2L) BTC.
Detailed information on the chemistry, pharmacology, efficacy, and safety of M7824 is in the
Investigator’s Brochure (IB).
2.1
Study Rationale
There is no established 2L therapy for BTC as the standard of care according to the National 
Comprehensive Cancer Network (NCCN 2018) and European Society for Medical Oncology 
(Valle 2016) guidelines. The TGF-β pathway mutation is one of the key underlying molecular 
alterations of BTC tumorigenesis (Nakamura 2015). M7824 is designed to target PD-L1 and 
TGF-β, 2 of the major mechanisms of immunosuppression in the tumor microenvironment and
provides a rationale to overcome resistance of checkpoint inhibitor monotherapy. 
A preclinical study showed that M7824 demonstrated enhanced antitumor activities and prolonged 
survival compared with checkpoint inhibitors in in vivo models (Lan 2018). A clinical study of 
M7824 showed a promising result with a clinical efficacy signal of 23.3% (7 of 30 participants) 
confirmed objective response rate (ORR) by Investigator read and 20% by Independent Review 
Committee (IRC) in 2L BTC. Therefore, the current clinical study is supported by scientific 
evidence and promising clinical efficacy data with the goal of fulfilling an unmet medical need 
and bringing clinical benefits to patients.
2.2
Background
BTC is a heterogeneous group of rare tumors that include intrahepatic and extrahepatic 
cholangiocarcinoma (CCA) and gallbladder cancer (NCCN 2018; Valle 2016). Ampullary cancer 
can originate from the pancreas, duodenum, distal common bile duct, or the structures of the 
ampullary complex based on the anatomic location. For this reason, this study excludes ampullary 
cancer. There were approximately 12,190 estimated new cases and 3,790 estimated deaths in 2018 
in the USA (Siegel 2018). More than 90% of BTCs are adenocarcinomas (Hezel 2008). Most 
patients with BTC have advanced disease at presentation and relapse despite surgery; BTC cases 
have a poor prognosis, with an estimated 5-year overall survival (OS) of about 17.5% (Noone 
2018). The recurrence rates are about 67% at 24 months among the few patients who undergo 
curative resection (Jarnagin 2003). Unresectable BTC is treated with chemotherapy, but the 
median survival time is < 1 year (Valle 2010). For patients with advanced-stage or unresectable 
Document No. 
Object No.
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
27/156
BTCs, current standard of care is 1L systemic chemotherapy, that is a combination of gemcitabine 
and cisplatin. However, this 1L standard of care has limited effectiveness, with median OS < 1 year 
(Valle 2010). 
There is no established 2L therapy for BTC as the standard of care for 2L chemotherapy. Based
on an update of a systematic review published in 2014 (Lamarca 2014) from available literature 
conducted in August 2018, which included 2L BTC studies reporting ORR results for
chemotherapy alone or in association with an approved systemic anticancer therapy restricted to 
studies with > 20 participants (to avoid imprecise ORR estimates reported in smaller samples), 
32 studies were identified reporting outcomes for 2137 participants globally. The ORR estimate 
derived from a regression model with a random effect was 7.2% with a 95% confidence interval 
(CI) ranging from 5.5% to 9.2%. Using the upper limit of this CI we assumed the benchmark ORR 
to be 10%.
M7824 has shown promising clinical efficacy signal in BTC patients progressing after 
platinum-based 1L treatment (Study MS200647-0008). Thirty Asian participants were treated with 
M7824 at dose of 1200 mg every 2 weeks. As of 20 March 2018, 30 participants who had 
previously received 1L treatment for BTC, received M7824 for a median duration of 8.9 weeks 
(range: 2 to 57.6 weeks); 5 participants remained on treatment at the time of data cutoff. Seven 
participants had a confirmed objective response (OR) by Investigator read (ORR 23.3%) and
6 participants had a confirmed OR by IRC (ORR 20%), including 1 confirmation of response after 
cutoff. Per anatomical location, the ORR was 14.3% (1 out of 7) in study participants with 
extrahepatic CCA and 40% (4 out of 10) in study participants with intrahepatic CCA, 16.6% (2 out 
of 12) in study participants with gallbladder carcinoma. No responses were observed in ampullary 
cancer (0 out of 1). With a minimum follow-up of 8 months, the duration of response (DOR)
ranged from 0.7 to 6.9 months with 5 of 7 responses ongoing at the data cutoff date. Besides the 
confirmed ORR, 1 additional participant had an ongoing partial response (PR) for 7.6+ months
after initial progression. The observed clinical efficacy, therefore, compares favorably to the 
calculated benchmark of existing 2L treatment options and there is a strong rationale with 
preclinical and clinical data to justify further clinical development of M7824 in 2L BTC, with the 
potential to establish M7824 as the standard of care.
In the Phase I Asian 2L BTC study, 2 treatment-related Grade 5 interstitial lung disease (ILD)
events have been reported in Japanese participants with an incidence of approximately 6.6%: 1 on
treatment after 3 doses and 1 with Grade 3 ILD after 3 doses that recovered, and then worsened 
with fatal outcome 6 months after initial ILD diagnosis and last M7824 dose. These 2 cases of 
treatment-related Grade 5 interstitial pneumonitis represent an incidence of approximately 0.3% 
in overall M7824 studies (2 adverse events [AEs] reports out of more than 670 treated participants). 
According to the literature reference, a higher ILD incidence is observed in the Japanese 
population (Takada 2014; Azuma 2007; Vansteenkiste 2017). For proper and early detection of 
ILD/pneumonitis events occurring in Japanese participants, serum KL-6, surfactant protein A 
(SP-A), and surfactant protein D (SP-D) levels will be measured in study sites in Japan. Inclusion 
of these markers will potentially help to identify treatment-emergent lung toxicity early on, which 
can be further confirmed by imaging (Kubo 2013).
Document No. 
Object No.
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
28/156
2.3
Benefit/Risk Assessment
At the time of study initiation, in Study MS200647-0008, a Phase Ib study of 2L BTC, M7824 has
demonstrated promising clinical efficacy with a confirmed ORR of 23.3% (7 of 30 participants)
by Investigator read and 20% by IRC, suggesting that the clinical benefit could be substantially 
better than the historical benchmark. 
The following have been identified as important identified risks for M7824: Immune-related 
adverse events (immune-related pneumonitis, immune-related hepatitis, immune-related colitis, 
immune-related nephritis and renal dysfunction, immune-related endocrinopathies [thyroid 
disorders, adrenal insufficiency, Type 1 diabetes mellitus, pituitary disorders], immune-related 
rash and other immune-related adverse events (irAEs) [myositis, myocarditis, encephalitis]), TGF-
β inhibition mediated skin reactions, anemia and bleeding adverse events. Infusion-related 
reactions are classified as identified risk for the treatment with bintrafusp alfa.
The identified and potential risks with M7824 monotherapy across tumor types were overall 
manageable and no new safety signals emerged in the EMR200647-001/MS200647-0008 studies 
compared with therapies targeting PD-(L)1 or TGF-β. M7824 infusion-related reactions (IRRs) 
were similar to those seen with monoclonal antibodies. The overall M7824 related IRRs was
observed to be 5% with severity of low grade, well managed, and did not lead to permanent 
treatment discontinuation. The overall safety profile for irAEs is found to be consistent across 
M7824 studies and aligned with the known safety profile of approved anti-PD-(L)1 agents.
Dermatologic AEs related to TGF-β-inhibition (including keratoacanthomas [KA] and cutaneous 
squamous cell cancers) are an important identified risk with M7824 not seen with other 
programmed death-1 (PD-1)/PD-L1 antibodies. These lesions were previously observed in 
participants with genetic mutations in the TGF-β receptor (i.e., Ferguson-Smith syndrome), and 
participants treated with the TGF-β-targeting agent fresolimumab (Goudie 2011; Morris 2014). In 
the EMR200647-001/MS200647-0008 studies, treatment-emergent TGF-β inhibition mediated 
skin reactions were observed in approximately 7% of participants, were well-managed with simple 
excision (or spontaneous resolution) and did not require any participant to discontinue treatment. 
The risk of these lesions with M7824 was considered manageable in this study, especially in the 
context of encouraging clinical activity in several tumor types.
In view of the observed clinical efficacy in 2L BTC in M7824 and the manageable safety profile 
observed in the Phase I studies, the benefit/risk assessment is considered favorable to conduct this 
global study in 2L BTC participants, in consideration of the high unmet medical need and the 
current absence of an efficacious standard of care.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of M7824 can be found in Section 4.2 and the current IB. Based on the available 
nonclinical and clinical data to date, the conduct of the study, as specified in this protocol, is 
considered justifiable.
3
Objectives and Endpoints
The objectives and endpoints of M7824 monotherapy are shown in Table 3. 
Document No. 
Object No.
CCI
CCI


Bintrafusp Alfa (M7824)
Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
29/156
Table 3
Study Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
Primary
!
To evaluate clinical efficacy of M7824 based on 
objective response rate (ORR)
!
Confirmed objective response (OR) according to 
Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) assessed by
Independent Review Committee (IRC)
Secondary
!
To evaluate clinical efficacy of M7824 based on 
duration of response (DOR)
!
DOR assessed from complete response (CR) or 
partial response (PR) until progression of disease 
(PD), death, or last tumor assessment assessed by 
IRC
!
To evaluate clinical efficacy of M7824 based on 
durable response rate (DRR)
!
Durable response of at least 6 months according to 
RECIST 1.1 assessed by IRC
!
To evaluate clinical safety of M7824
!
Occurrence of treatment-emergent adverse events 
(TEAEs) and treatment-related adverse events, 
including adverse events of special interest 
(AESIs)
!
To evaluate clinical efficacy based on 
progression-free survival (PFS)
!
PFS according to RECIST 1.1 assessed by IRC
!
To evaluate ORR, DOR, DRR, and PFS by 
Investigator read
!
OR, DOR, DRR, and PFS according to 
RECIST 1.1 assessed by Investigator read
!
To evaluate clinical efficacy based on overall 
survival (OS)
!
OS
!
To characterize the pharmacokinetic (PK) 
profile of M7824
!
The concentration observed immediately at the 
end of infusion (CEOI) of M7824
!
The concentration observed immediately before 
next dosing (corresponding to pre-dose or trough 
concentration [Ctrough] for multiple dosing) of M7824
!
To characterize the immunogenicity of M7824
!
Immunogenicity of M7824 as measured by 
antidrug antibody (ADA) assay, from Screening 
through 12 weeks (± 2 weeks) after last treatment
!
To evaluate clinical efficacy of M7824 based on 
ORR, DOR and DRR according to programmed 
death-ligand 1 (PD-L1) expression and 
microsatellite instability (MSI) status
retrospectively
!
Confirmed OR according to RECIST 1.1 assessed 
by IRC according to PD-L1 expression and MSI 
status
!
DOR and durable response of at least 6 months 
according to RECIST 1.1 assessed by IRC 
according to PD-L1 expression and MSI status
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Objectives
Endpoints (Outcome Measures)
* Items noted above with an * symbol are not collected in sites in China.
4
Study Design
4.1
Overall Design
This is a Phase II, multicenter, international, single-arm, open-label study to evaluate M7824 
monotherapy in participants with locally advanced or metastatic BTC who failed or were intolerant 
to 1L chemotherapy.
The study plans to enroll 141 eligible BTC participants from USA, Europe, and Asian countries,
with competitive enrollment. The study will enroll 3 major subtypes of BTC: intrahepatic CCA, 
extrahepatic CCA, and gallbladder cancer, with a minimum of 30 participants enrolled per each 
subtype. If one subtype does not reach a minimum of 30 participants by the end of competitive 
enrollment of 141 participants, the study will continue to enroll only in this subtype to reach 
30 participants. Ampullary cancer is excluded from the study, since it originates from the pancreas, 
duodenum, distal common bile duct, or the structures of the ampullary complex.
Participants will receive M7824 at a dose of 1200 mg once every 2 weeks until confirmed 
progression of disease (PD), death, unacceptable toxicity, or study withdrawal. The primary 
objective is to evaluate the clinical efficacy of M7824 based on the ORR in 2L BTC. The secondary 
efficacy objectives are summarized in Figure 1. Tumor response evaluation based on RECIST 1.1 
(Eisenhauer 2009) will be performed every 8 weeks until 12 months after the first administration 
of M7824 and then every 12 weeks until confirmed disease progression.
Document No. 
Object No.
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This study includes: 
! 28-day Screening period
! Treatment until confirmed PD per RECIST 1.1, death, unacceptable toxicity, or study 
withdrawal. In the case of PD, treatment may continue past the initial determination of PD or 
confirmed PD if the participant’s performance status (PS) has remained at least stable, and if in 
the opinion of the Investigator, the participant will benefit from continued treatment and if other 
criteria are fulfilled as outlined in the protocol. Participants who have experienced a confirmed 
complete response (CR) should continue treatment for a maximum of 24 months after 
confirmation of response. If the Investigator believes that a participant with a confirmed CR 
may benefit from treatment beyond 24 months, it may be permissible to continue treatment after 
discussion with the Medical Monitor and the Sponsor Medical Responsible. Participants with 
stable disease or PR should continue treatment until disease progression or any other 
discontinuation criterion is met.
! Safety Follow-up will continue until 12 weeks after the last dose of M7824. The 12-week Safety 
Follow-up is allowed to be conducted via telephone calls or patient chart reviews unless there 
is medical necessity requiring a clinical visit.
! Long-term Follow-up should be performed every 12 weeks after the Safety Follow-up
according to the Schedule of Activities (Table 1). Long-term Follow-up should be performed 
by chart reviews or telephone calls.
! Survival Follow-up will continue until each participant was followed up for at least 3 years after 
the End-of-Treatment.
The overall study design is shown in Figure 1. A detailed Schedule of Activities is provided in
Section 1.3.
4.2
Scientific Rationale for Study Design
In benign and early-stage cancers, TGF-β acts as a potent inducer of cell growth arrest and 
apoptosis. In advance stage the TGF-β pathway promotes tumor progression and metastasis by 
promoting cancer cell motility, invasion, epithelial-to-mesenchymal transition, and cell stemness. 
TGF-β can function as both a tumor suppressor and tumor promoter. This functional switch is 
known as TGF-β paradox. The pathway is inactivated either through mutation, allelic loss of 
heterozygosity, or through epigenetic changes in various types of cancers. Cancer genomic 
analysis of 260 BTCs showed that 15% to 20% of BTC has TGF-β pathway mutations suggesting 
that the TGF-β pathway alteration has high selection pressure and is important in BTC 
tumorigenesis (Nakamura 2015). 
The TGF-β signaling inhibition is an emerging strategy for cancer therapy. TGF-β signaling 
influences the tumor microenvironment by promoting fibrosis, angiogenesis, and metastasis, and 
suppressing immune-related host response. TGF-β inhibition is considered primarily to normalize 
tumor microenvironment homeostasis by down-regulating stromal stimulation resulting from 
excess TGF-β production by tumor and tumor-related tissues, reduce immunosuppression, as well 
as suppress epithelial-to-mesenchymal transition that might further contribute to immune escape. 
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Spectra of molecular alterations in BTC (Nakamura 2015) are shown in Figure 2.
Figure 2
Spectra of Molecular Alterations in Biliary Tract Cancers
Source: Nakamura 2015.
M7824, as a monotherapy, has shown a manageable safety profile and promising clinical efficacy 
signal in 2L BTC. Thirty Asian participants with BTC refractory to platinum-based 1L treatment 
were treated with M7824 1200 mg every 2 weeks. As of 20 March 2018, the median treatment 
duration was 8.9 weeks (range: 2 to 57.6 weeks). Five participants remained on treatment. Seven 
participants had a confirmed OR by Investigator read (ORR 23.3%) and 6 participants had a 
confirmed OR by IRC (ORR 20%), including 1 confirmation of response after cutoff. With a 
minimum follow-up of 8 months, the DOR ranged from 0.7 to 6.9 months, with 5/7 responses 
ongoing at the data cutoff date. One additional participant had ongoing PR for 7.6+ month after 
initial progression. Therefore, there is a strong rationale with preclinical and clinical data to justify 
further clinical development of M7824 in 2L BTC with the potential to establish M7824 as the 
standard of care.
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Since there is no established standard of care for 2L BTC, a Phase II, multicenter, international, 
single-arm, open-label study to evaluate M7824 monotherapy in participants with locally advanced 
or metastatic BTC who fail 1L gemcitabine plus cisplatin chemotherapy has been proposed.
In this study participants who benefit from treatment will stay on treatment with frequent safety 
monitoring visits until unacceptable toxicity or loss of clinical benefit. Participants with confirmed 
CR will continue treatment for up to 24 months since confirmation of CR. In the M7824 program, 
participants have been exposed to M7824 beyond 12 months and the treatment was well tolerated. 
In Study MS200647-0008, some participants with OR had long lasting reduction in tumor size 
beyond 12 months under ongoing treatment. Treatment up to 24 months was also used with other 
checkpoint inhibitors published in 2L BTC (Ueno 2018). In addition, recent data showed 
continuous treatment beyond 12 months of nivolumab significantly improved progression-free 
survival (PFS) in non-small cell lung cancer compared to 12-month treatment duration 
(Spigel 2017).
4.3
Justification for Dose
The recommended Phase II dose (RP2D) for M7824 is 1200 mg administered as an intravenous
infusion once every 2 weeks. The selection of RP2D is based on the available clinical data from 
the Phase I Studies EMR200647-001 and MS200647-0008, including safety/tolerability, 
pharmacokinetic (PK), and pharmacodynamics (PD-L1 target occupancy in peripheral blood 
mononuclear cell and TGF-β plasma concentrations), as well as efficacy in 2L non-small cell lung 
cancer cohorts from the EMR200647-001 study. The selection of RP2D is also supported by 
population pharmacokinetic (PopPK) and exposure-response modeling and simulation. 
The completed and detailed data and analysis for dose justification can be found in IB. 
4.4
End of Study Definition
A participant has completed the study if he or she has completed all study parts, including the last 
visit or the last scheduled procedure shown in Section 1.3.
The end of the study is defined as the date when each participant was followed up for at least 
3 years after the End-of-Treatment.
The Sponsor may terminate the study at any time once access to study intervention for participants
still benefitting is provided via a rollover study, expanded access, marketed product or another 
mechanism of access as appropriate.
5
Study Population
The study will aim at enrolling a balanced number of participants across the 3 major subtypes of 
BTC (intrahepatic CCA, extrahepatic CCA, and gallbladder cancer), with a minimum of 
30 participants in each subtype. If one subtype does not reach a minimum of 30 participants by the 
end of competitive enrollment of 141 participants, the study will continue to enroll only in this 
subtype to reach 30 participants in principle. 
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The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to enroll 
only participants who are appropriate for the study, thereby ensuring that the study fulfills its 
objectives. All relevant medical and nonmedical conditions should be taken into consideration 
when deciding whether a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study activities that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative (where 
allowed by local laws and regulations) has provided written informed consent, as indicated in 
Appendix 2 (Study Governance).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are ≥18 years of age at the time of signing the informed consent. In Japan, if a participant 
is at least 18 but < 20 years of age, written informed consent from his/her parent or guardian 
will be required in addition to the participant’s written consent.
Type of Participant and Disease Characteristics
2. Are participants with histologically or cytologically confirmed locally advanced or 
metastatic BTC.
3. Availability of tumor (primary or metastatic) archival material or fresh biopsies is 
mandatory. Fine needle aspirates, transductal aspirates, or cell blocks are not acceptable. 
Endoscopic retrograde cholangiography or intraductal ultrasounds assisted biopsy is 
acceptable, needle or excisional biopsies, or resected tissue, are preferable. Tumor biopsies 
and tumor archival material must be suitable for biomarker assessment as described in the 
Laboratory Manual.
4. Participants with BTC must have failed or be intolerant to 1L systemic platinum-based 
chemotherapy administered for locally advanced or metastatic disease. Only one prior 
treatment line is allowed. Participants who received adjuvant platinum-based 
chemotherapy and had evidence of disease recurrence within 6 months of completion of 
the adjuvant treatment are also eligible. If recurrence occurs during or within 6 months 
after the adjuvant chemotherapy, adjuvant platinum-based chemotherapy is counted as 1L 
chemotherapy. 
5. Disease must be measurable with at least 1 unidimensionally measurable lesion by 
RECIST 1.1 and verified independently by IRC.
6. Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1 at study entry and Day 1 of 
treatment with M7824.
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7. Life expectancy ≥12 weeks as judged by the Investigator.
8. Adequate hematological function defined by white blood cell count ≥3 × 109/L with 
absolute neutrophil count ≥1.5 × 109/L, lymphocyte count ≥0.5 × 109/L, platelet count 
≥75 × 109/L, and hemoglobin (Hgb) ≥9 g/dL.
9. Adequate hepatic function defined by a total bilirubin level ≤1.5 × upper limit of normal 
(ULN), an aspartate aminotransferase level ≤2.5 × ULN, and an alanine aminotransferase
(ALT) level ≤2.5 × ULN. For participants with liver involvement in their tumor, aspartate 
aminotransferase ≤5.0 × ULN and ALT ≤5.0 × ULN is acceptable.
o
Participants with biliary obstruction should have an adequate biliary drainage with 
no evidence of ongoing infection. Biliary duct obstruction should be relieved by 
internal endoscopic drainage/stenting at least 2 weeks prior to dosing or by 
palliative bypass surgery or percutaneous drainage prior to study entry, and the 
participant should have no active or suspected infection. Participants fitted with a 
biliary stent should be clinically stable and free of signs of infection for ≥2 weeks 
prior to dosing.
10. Adequate coagulation function defined as prothrombin time (PT) or international 
normalized ratio (INR) ≤1.5 × ULN unless the participant is receiving anticoagulant 
therapy.
11. Albumin ≥3.0 g/dL.
12. Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) positive participants must be treated 
and on a stable dose of antivirals (e.g., entecavir, tenofovir, or lamivudine; adefovir or 
interferon are not allowed) at study entry and with planned monitoring and management 
including baseline HBV DNA quantity according to appropriate labeling guidance. 
Participants receiving active hepatitis C virus (HCV) therapy must be on a stable dose at 
study entry and with planned monitoring and management according to appropriate 
labeling guidance of an approved antiviral.
13. Adequate renal function defined by either creatinine ≤1.5 × ULN or an estimated 
creatinine clearance (CCr) > 40 mL/min according to the Cockcroft-Gault formula or by 
measure of CCr from 24-hour urine collection. 
o
CCr (mL/min) = (140-age) × weight (kg)/(72 × serum Cr jaffe)
o
If female, × 0.85
o
If Cr is measured by enzymatic method, add 0.2 and use as Crjaffe = 0.2 + Crenzyme.
Sex
14. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 4 months after the last dose of study intervention:
! Refrain from donating sperm
PLUS, either
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! Abstain from intercourse with a female
OR
! Use a male condom:
o
When having sexual intercourse with a woman of childbearing potential (WOCBP), 
who is not currently pregnant, and advise her to use a highly effective contraceptive 
method with a failure rate of < 1% per year, as described in Appendix 3, since a 
condom may break or leak
o
When engaging in any activity that allows for exposure to ejaculate.
15. A female is eligible if she is not pregnant or breastfeeding, and at least one of the following 
conditions applies:
! Not a WOCBP
OR
! If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate of < 1% 
per year), preferably with low user dependency, as described in Appendix 3 for the following 
time periods: 
o
Before the first dose of the study intervention, if using hormonal contraception: 

Has completed at least one 4-week cycle of an oral contraception pill and 
either had or has begun her menses
OR

Has used a depot contraceptive or extended-cycle oral contraceptive for 
least 28 days and has a documented negative pregnancy test using a highly
sensitive assay.
o
During the intervention period
o
After the study intervention period (i.e., after the last dose of study intervention is 
administered) for at least 2 months after the last dose of study intervention. 
The Investigator evaluates the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
!
Have a negative serum or highly sensitive urine pregnancy test, as required by local 
regulations, within 24 hours before the first dose of study intervention. If a urine test cannot 
be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
! Additional requirements for pregnancy testing during and after study intervention are in 
Section 8.2.3.
! The Investigator reviews the medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a female with an early undetected pregnancy.
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Informed Consent
16. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Ampullary cancer is excluded.
2.
Rapid clinical deterioration other than malignancy which, in the opinion of the Investigator, 
may predispose to inability to tolerate treatment or study procedures.
3.
Participants with active central nervous system (CNS) metastases causing clinical 
symptoms or metastases that require therapeutic intervention are excluded. Participants 
with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible 
unless they have fully recovered from treatment, demonstrated no progression for at least 
2 months, and do not require continued steroid therapy.
4.
Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but 
with the exception of transplants that do not require immunosuppression (e.g., corneal 
transplant, hair transplant).
5.
Other previous and/or intercurrent malignancy except for curatively treated cancers with 
no recurrence in > 3 years since treatment completion, or early cancers treated with curative 
intent, including cervical carcinoma in situ, superficial, noninvasive bladder cancer, or 
basal cell or squamous cell carcinoma in situ. Endoscopically resected early 
gastrointestinal cancers limited in mucosal layer (esophageal, gastric, and colorectal) that 
are without recurrence in > 1 year are allowed.
6.
Significant acute or chronic infections, including:
o
Uncontrolled biliary infection. Biliary tract obstruction should be released by 
stenting or percutaneous transhepatic biliary drainage.
o
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (no testing at Screening required). If an 
Investigator has a strong suspicion of HIV infection without known history for a 
participant in Screening, and the participant refuses testing, discuss with the 
Medical Monitor to assess eligibility. (Note: HIV testing is not mandated for study 
inclusion; however, if it is performed at any point in Screening or while on study, 
a site must consent the participant for HIV testing as per local standard guidance.)
o
Active tuberculosis infection (clinical symptoms, physical or radiographic, and 
laboratory findings).
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o
Active bacterial or fungal infection requiring intravenous systemic therapy (except 
as indicated, discuss alternative scenarios with the Medical Monitor).
7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent:
o
Participants with diabetes type 1, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid 
disease not requiring immunosuppressive treatment are eligible
o
Participants requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤10 mg of prednisone or equivalent per day
o
Administration of steroids for other conditions through a route known to result in a 
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is
acceptable.
8. History of non-infectious (e.g., drug-induced) ILD requiring systemic steroid treatment, or
current pneumonitis.
9. Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring 
hospitalization or precluding study therapy within 30 days before enrollment.
10. Known severe hypersensitivity (Grade ≥3 National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 5.0 [NCI-CTCAE v5.0]) to 
investigational product (M7824) or any components in their formulations, any history of 
anaphylaxis, or recent, within 5 months, history of uncontrolled asthma.
11. Persisting Grade > 1 NCI-CTCAE v5.0 toxicity (except alopecia and vitiligo) related to 
prior therapy; however, sensory neuropathy Grade ≤2 is acceptable.
12. Clinically significant cardiovascular/cerebrovascular disease as follows: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior 
to enrollment), unstable angina, congestive heart failure (≥New York Heart Association 
Classification Class II), or serious cardiac arrhythmia.
13. Clinically relevant diseases (e.g., inflammatory bowel disease) and/or uncontrolled 
medical conditions, which, in the opinion of the Investigator, might impair the participant’s 
tolerance or ability to participate in the study. Participants with history of bleeding diathesis 
or recent major bleeding events considered by the Investigator as high risk for study 
intervention are also excluded.
14. Any psychiatric condition that would prohibit the understanding or rendering of informed 
consent. 
Prior/Concomitant Therapy
15. Participants who are not eligible for or have not been treated with 1L systemic 
chemotherapy will be excluded.
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16. Systemic anticancer treatment after failing 1L platinum-based chemotherapy.
17. Concurrent treatment with nonpermitted drugs. 
18. Prior participation in a M7824 clinical trial.
19. Prior therapy with other immunotherapy or checkpoint inhibitors, such as anti-PD-1, 
anti-PD-L1, anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies. 
20. Prior therapy with any antibody or inhibitors targeting the TGF-β/TGF-β receptor pathway. 
21. Anticancer treatment within 21 days before the start of study intervention, e.g., 
cytoreductive therapy, radiotherapy involving > 30% of the bone marrow (with the 
exception of palliative bone-directed radiotherapy), immune therapy, or cytokine therapy. 
22. Anticancer treatment with antibody within 28 days before the start of study intervention. 
23. Systemic therapy with immunosuppressive agents within 7 days before the start of study
intervention; or use of any investigational drug within 28 days before the start of study
intervention. 
24. Vaccine administration within 4 weeks of M7824 administration. Vaccination with live 
vaccines while on study is prohibited. Administration of inactivated vaccines is allowed 
(e.g., inactivated influenza vaccines). 
Prior/Concurrent Clinical Study Experience
25. Participation in experimental clinical studies after failure of 1L systemic chemotherapy.
Diagnostic Assessments
26. Unable to tolerate computed tomography (CT) or magnetic resonance imaging (MRI) in 
the opinion of the Investigator and/or allergy to contrast material.
Other Exclusions
27. Major surgery within 28 days before the start of study intervention (excluding prior 
diagnostic biopsy and stenting/percutaneous transhepatic biliary drainage for releasing 
biliary tract obstruction). 
28. Pregnancy or breast feeding. 
29. Known active or recent alcohol or drug abuse within 2 years. 
30. Legal incapacity or limited legal capacity.
31. Other severe acute or chronic medical conditions.
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5.3
Lifestyle Considerations
No specific lifestyle or dietary restrictions are required throughout the study.
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants will be assigned a new participant number. Rescreening is 
allowed within 14 days since date of screen failure. Baseline tumor assessments must be repeated 
if outside of 28-day window from the first dose of study intervention. Participants can be 
rescreened only 1 (one) time after initial screen failure.
Participants who have an abnormal liver function test at Screening that may normalize with biliary 
drainage or stenting can be rescreened once appropriate drainage has been put in place (see 
inclusion criterion #9). For participants with other laboratory abnormalities that may resolve, 
concomitant medication that will be discontinued, or undergoing a prohibited procedure that will 
be completed, it is recommended to discuss with the Medical Monitor as to whether the participant
may be rescreened. 
In other situations, when a potential participant fails screening and wants to be rescreened, the site 
should contact the Medical Monitor to discuss whether the participant can be rescreened.
6
Study Intervention(s)
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol.
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6.1
Study Intervention Administration
Study Intervention Name:
M7824
Dose Formulation:
Sterile concentrate solution for infusion
Unit Dose Strength(s)/Dosage Level(s):
10 mg/mL in single-use glass vials
Route of Administration:
Intravenous infusion
Dosing Instructions:
Flat 
dose 
of 
1200 
mg 
over
1 hour 
(- 10 minutes/+ 20 minutes, i.e., over 50 to 80 
minutes) once every 2 weeks
Sourcing:
Provided centrally by the Sponsor
Supplier/Manufacturer:
Merck KGaA/
Packaging and Labeling:
Each vial will be packaged and labeled per all 
applicable regulatory requirements and Good 
Manufacturing Practice Guidelines
6.2
Study Intervention Preparation, Handling, Storage, and 
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
Upon receipt of the study intervention, the Investigator or designee must confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported and 
resolved before use. Also, the responsible person will check for accurate delivery. Further guidance 
and information for study intervention accountability are provided in the Pharmacy Manual.
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply it. All study intervention must be stored in a secure, environmentally controlled, 
and monitored (manual or automated) area, in accordance with the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff.
Dispensing will be recorded on the appropriate accountability forms so that accurate records will 
be available for verification at each monitoring visit.
Study intervention accountability records at the study site will include the following:
!
Confirmation of receipt, in good condition, and in the defined temperature range.
!
The inventory provided for the clinical study and prepared at the site.
!
The dose(s) each participant used during the study.
!
The disposition (including return, if applicable) of any unused study intervention.
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!
Dates, quantities, batch numbers, vial numbers, expiry dates, formulations, and the participant 
numbers.
The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and that all study intervention provided were fully 
reconciled.
Unused study intervention must not be discarded or used for any purpose other than the present 
study. No study intervention that is dispensed to a participant may be redispensed to a different 
participant.
A Study Monitor will periodically collect the study intervention accountability forms.
Destruction of used and unused study intervention should be performed at the site if allowed by 
local law only after Sponsor authorization. If that is not possible, the Sponsor/designee will be 
responsible.
Further guidance and information for the final disposition of unused study intervention is provided 
in the Operations Manual.
M7824 should be stored in a 
 (
) until use. M7824 must not be frozen and 
should be stored in the original packaging.
Additional instructions for the preparation, handling, storage, and disposal of M7824 will be 
provided in the Pharmacy Manual.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
The Sponsor or delegate will assign a unique participant identifier number to participants in 
chronological order at the time of informed consent signature. Participant identifiers will be 
comprised of digits representing the study number, the site number, and the participant number, 
which is allocated sequentially. Enrollment will utilize an Interactive Voice/Web Response 
System.
6.3.2
Blinding
Not applicable.
6.4
Study Intervention Compliance
In this study, participants will receive study intervention at the study site. Well-trained medical 
staff will monitor and perform the study intervention administration. The information of each study 
intervention administration, including the date, time, and dose of study intervention, will be 
recorded on the electronic case report forms (eCRF). The Investigator will make sure that the 
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information entered into the eCRF regarding study intervention administration is accurate for each 
participant. Any reason for noncompliance should be documented.
Noncompliance is defined as a participant missing > 1 infusion of study intervention for 
nonmedical reasons and barring any extenuating circumstances in the opinion of the Investigator.
Extenuating circumstances should be documented, and when possible, discussed with the Sponsor 
in advance. If 1 infusion is missed and the interval between the subsequent infusion and the last 
administered treatment is longer than 4 weeks for nonmedical reasons, the criterion of insufficient 
compliance is met as well.
Consequences of noncompliance may lead to discontinuation of study interventions as described 
in Section 7.1. In case of overdose, see Section 8.4.
6.5
Concomitant Therapy
Record in the eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Rescue Medicine
Not applicable.
6.5.2
Permitted Medicines
The only permitted medications are the following:
! Any medications (other than those excluded by the clinical study protocol) that are considered 
necessary for the participants’ welfare and will not interfere with the study intervention may be 
given at the Investigator’s discretion.
! Other drugs to be used for nonsteroid premedication as described in Table 1 (antihistamine and 
acetaminophen), treatment of anaphylactic reactions, IRRs, and severe hypersensitivity 
reactions/flu-like symptoms and irAEs.
! Blood transfusions and erythroid growth factors are permitted for Hgb ≤7 g/dL as clinically 
indicated and/or for life-threatening bleeding.
Any medicines that are considered necessary to protect the participant’s welfare in emergencies
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
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Permitted Procedures
Palliative bone-directed organ-sparing radiotherapy may be administered for clinical indications 
only during the study. The assessment of PD will be made according to RECIST 1.1 and not based 
on the necessity for palliative radiotherapy.
6.5.3
Prohibited Medicines
The following treatments must not be administered during Screening and for the duration 
of study intervention:
!
Immunotherapy, immunosuppressive drugs (i.e., chemotherapy or systemic corticosteroids 
except for short-term treatment of allergic reactions or for the treatment of irAEs), or other 
experimental pharmaceutical products. 
! Short-term administration of systemic steroid (i.e., for allergic reactions or the management 
of irAEs) is allowed. 
! Steroids with no or minimal systemic effect (topical, intranasal, intro-ocular, inhalation) are 
allowed.
! Hormone replacement with corticosteroids for adrenal insufficiency is allowed if the steroids 
are administered only for the purpose of hormonal replacement and at doses ≤10 mg or 
equivalent prednisone per day.
! Prophylactic use of corticosteroids for IRRs is prohibited.
! Concomitant local or regional treatment (radio/chemo-embolization) is not permitted.
! Vaccination with live vaccines while on study intervention is prohibited. Administration of 
inactivated vaccines is allowed (e.g., inactivated influenza vaccines).
!
If the administration of a nonpermitted concomitant drug becomes necessary during the study, 
the participant will be withdrawn from study intervention (the Sponsor may be contacted to 
discuss whether the study intervention must be discontinued).
!
Any traditional Chinese medication with approval for use as anticancer treatment (regardless 
of the type of cancer) will not be permitted. Traditional Chinese medication for indications 
other than anticancer treatment, such as supportive care, may be administered at the discretion 
of the Investigator.
!
Medications other than those specifically excluded in this study (see above) may be 
administered for the management of symptoms associated with the administration of M7824 
as required. These might include analgesics, antinausea medications, antihistamines, diuretics, 
antianxiety medications, and medication for pain management, including narcotic agents.
6.5.4
Other Interventions
The following procedures must not be performed, and supplements must not be taken during the 
study and within 28 days before the study. 
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! Major surgery (excluding prior diagnostic biopsy and stenting/percutaneous transhepatic biliary 
drainage for releasing biliary tract obstruction) within 4 weeks before the start of the study. 
Discuss with the Medical Monitor if unplanned major surgery is required on study to plan for 
timing of retreatment. Any diagnostic biopsies collected for clinical reasons during the study 
should be documented as a concomitant procedure including the outcome of available 
pathological reports.
! Herbal remedies with immuno-stimulating properties (e.g., mistletoe extract) or known to 
potentially interfere with major organ function (e.g., hypericin). 
6.6
Dose Selection and Modification
Participants will receive an intravenous infusion of M7824 at a dose of 1200 mg over 1 hour 
(- 10 minutes/+ 20 minutes, i.e., over 50 to 80 minutes) once every 2 weeks as detailed in the 
Schedule of Activities (Table 1).
Dose modification of M7824 is not allowed. Special precautions for monitoring of participants and 
management of IRRs/hypersensitivity, including premedication, modifications of the infusion rate 
and stopping of study intervention, are described in Section 6.9.
6.6.1
Adverse Drug Reactions Requiring Treatment Modification
Any adverse drug reaction (ADR) assessed as related to M7824 may require permanent or transient 
discontinuation of M7824 treatment. For the management of certain ADRs assessed to be irAEs, 
follow the American Society of Clinical Oncology (ASCO) guideline in Appendix 6. Single 
laboratory values out of the normal range that do not have any clinical correlate do not necessarily 
need treatment interruption. Questions or concerns with regard to management and/or follow-up
of ADRs should be discussed with the Medical Monitor.
Immune-related AEs, IRRs including hypersensitivity, anemia, TGF-β inhibition mediated skin 
reactions, and bleeding events are managed and followed up as described in their respective 
sections. Permanent study intervention discontinuation may be recommended, so the relevant 
section must be reviewed:
!
For suspected irAEs, irAE management and guidance is presented in Appendix 6. General 
management by NCI-CTCAE v5.0 toxicity grading, as per ASCO, is listed below: 
! Grade 1: study intervention should be continued with close monitoring, with the exception 
of some neurologic, hematologic, and cardiac toxicities.
! Grade 2: study intervention may be suspended for most Grade 2 toxicities, with 
consideration of resuming when symptoms revert to Grade 1 or less. Corticosteroids may be 
administered (initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent).
! Grade 3: study intervention is generally suspended and the high-dose corticosteroid 
treatment (prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) should be 
initiated. Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some 
refractory cases may require infliximab or other immunosuppressive therapy.
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!
Grade 4: in general, permanent discontinuation of study intervention is recommended, with 
the exception of endocrinopathies that have been controlled by hormone replacement.
!
IRRs and hypersensitivity reactions guidance are presented in Section 6.9.1.
!
Guidance on anemia is presented in Section 6.9.4. 
!
Guidance and management for TGF-β inhibition mediated skin reactions are discussed in 
Section 6.9.3. 
!
Guidance and management of bleeding events are discussed in Section 6.9.5.
In general, the following applies for ADRs related to M7824 that are not covered by the ASCO 
guideline:
Any Grade 4 ADRs require permanent treatment discontinuation, except endocrinopathies 
that have been controlled by hormone replacement, or single laboratory values out of normal 
range that do not have clinical relevance.
Any Grade 3 ADRs require treatment discontinuation, except for any of the following:
! Transient Grade 3 flu-like symptoms or fever that is controlled with medical management
! Transient Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to ≤Grade 1
! Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known or 
suspected tumors
! Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated with symptoms 
or clinical manifestations of pancreatitis
! Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or 
erythroid growth factor use
! Keratoacanthoma (KA) and cutaneous squamous cell carcinoma (cSCC).
Any Grade 2 ADRs should be managed as follows:
If a Grade 2 ADR resolves to Grade ≤ 1 by the day before the next infusion, study intervention 
may be continued.
If a Grade 2 ADR does not resolve to Grade ≤ 1 by the day before the next infusion, but it is 
manageable and/or not clinically relevant, the Medical Monitor should be consulted to assess if it 
is clinically reasonable to administer the following infusion.
Note that treatment recommendations regarding continuation, hold, or discontinuation by grade 
are different depending on the specific toxicity (see Appendix 6). Toxicity grading is assigned 
based on NCI-CTCAE v5.0. The ASCO guideline should be used only for the management of 
immune-related toxicity due to M7824.
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6.7
Study Intervention After the End of the Study
After a participant has completed the study, has withdrawn consent, or has been withdrawn early, 
symptom guided appropriate treatment will be administered, if required, in accordance with the 
study site’s standard of care and generally accepted medical practice and depending on the 
participant’s individual medical needs.
On withdrawal from the study, participants may receive whatever care they and their physicians 
agree upon.
6.8
Special Precautions
As a part of safety-related precautionary measures, a standardized risk management approach is 
planned for M7824 for IRRs, irAEs, TGF-β inhibition mediated skin reactions, anemia, and 
bleeding AEs. The approach is mainly based on the mechanism of PD-L1 inhibition and TGF-β
inhibition.
6.9
Management of Adverse Events of Special Interest and other 
Potential Risks
Adverse events of special interest (AESIs) are serious or non-serious AEs specific to the known 
mechanism of action of the study intervention that are of clinical interest requiring ongoing 
monitoring.
For this study, AESIs include the following:
! Infusion-related reactions including hypersensitivity
! Immune-related AEs
! TGF-β inhibition mediated skin reactions
! Anemia
! Bleeding AEs
6.9.1
Infusion-Related Reactions Including Hypersensitivity
Infusion-related reactions, including hypersensitivity, are defined in this section. Infusion-related 
reactions are AESIs and identified risks for M7824.
Infusion-Related Reactions
Infusion-related reactions are defined as any signs or symptoms experienced by participants during 
the infusion of pharmacologic or biologic agents or any event occurring during or within 1 day of 
study intervention administration. They are identified based on a list of Medical Dictionary for 
Regulatory Activities (MedDRA) preferred terms and criteria on the timely relationship to an 
infusion. Events are divided into reactions versus signs and symptoms:
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!
Reactions are considered when onset is on the day of infusion (during or after the infusion) or 
the day after the infusion (irrespective of resolution date) for IRR, drug hypersensitivity, 
anaphylactic reaction, hypersensitivity, and type 1 hypersensitivity.
!
Signs and symptoms of IRRs and hypersensitivity/allergic reactions are considered when onset 
is on the day of infusion (during or after the infusion) and resolved completely with the end 
date within 2 days after onset of (but not limited to) pyrexia, chills, flushing, hypotension, 
dyspnea, wheezing, back pain, abdominal pain, and urticaria.
Management of Infusion-Related Reactions
Based on the observed low IRR incidence in Phase I studies in over 670 participants treated with 
M7824 single agent, and with low-grade IRRs without leading to treatment discontinuation, the 
first 15 participants will not receive premedication before first and second M7824 infusions in this 
study in order to establish whether mandatory use of premedication is required. If IRR is observed
at the first or second infusion, premedication should be used for subsequent infusions at the 
discretion of the Investigator.
If two or more Grade 2 IRRs are seen during the first 2 infusions for the first 15 participants, an 
Independent Data Monitoring Committee (IDMC) will determine if mandatory premedication is 
needed. Study enrollment will continue in parallel to this review and sites will be notified 
accordingly if premedication will be required.
If IDMC determines mandatory premedication is justified in order to mitigate potential IRRs, 
premedication with an antihistamine and with paracetamol (acetaminophen) (e.g., 25 to 50 mg 
diphenhydramine and 500 to 650 mg paracetamol [acetaminophen] intravenous or oral equivalent) 
prior to each dose of M7824 is mandatory for the first 2 infusions. After the first 2 infusions, 
premedication is optional and at the discretion of the Investigator. If Grade 2 IRRs are seen during 
the first 2 infusions, then premedication should not be stopped. Steroids as premedication are not 
permitted.
Management of symptoms should follow the guidelines shown in Table 4.
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Table 4
Treatment Modification of M7824 for Symptoms of Infusion-Related 
Reactions Including Immediate Hypersensitivity
NCI-CTCAE v5.0 Grade
Treatment Modification 
Grade 1 – mild
!
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.
!
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.
Grade 2 – moderate
!
Therapy or infusion interruption indicated but if 
responds promptly to symptomatic treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, 
IV 
fluids); 
prophylactic medications indicated for ∀24 hours.
!
Stop the infusion of the study intervention caused 
IRR.
!
Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator. 
!
If symptoms resolve quickly or decreased to Grade 1, 
resume infusion at 50% of original rate with close 
monitoring of any worsening otherwise dosing held 
until 
resolution 
of 
symptoms 
with 
mandated 
premedication for the next scheduled visit. 
!
If worsens to Grade 3 or 4, follow treatment 
modification guidelines accordingly.
Grade 3 or Grade 4 – severe or life-threatening
!
Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.
!
Grade 4: Life-threatening consequences; urgent 
intervention indicated.
!
Stop the infusion of study intervention-caused IRR 
immediately and disconnect infusion tubing from the 
participant with additional appropriate medical 
measures and closely
monitor until deemed 
medically stable by the attending Investigator. 
Hospitalization 
and/or 
close 
monitoring 
is 
recommended
!
Administration of glucocorticoids may be required
!
Restart the medication taking out the drug that is the 
cause of IRRs from the next scheduled visit 
IRR=infusion-related reaction, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology 
Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
Once the M7824 infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain decreased 
for all subsequent infusions. For Grade 3 or 4 IRRs, M7824 discontinuation is mandated. 
For all types and grades of infusion reactions, details about drug physical constitution, method of preparation, and 
infusion must be recorded.
In the event of a Grade 2 IRR that does not improve or worsens after implementation of the 
treatment modifications indicated in Table 4 (including reducing the infusion rate by 50%), the 
Investigator may consider treatment with corticosteroids and the infusion should be stopped for 
that day. At the next infusion, the Investigator may consider the addition of H2 blocker 
antihistamines (e.g., famotidine or ranitidine), in addition to premedication, for select participants. 
However, prophylactic steroids are not permitted. At the next dose, if the participant has a second 
IRR Grade ≥2 on the slower infusion rate, with the addition of further medication to 
premedication, the infusion should be stopped, and the participant should be removed from the 
study intervention.
Hypersensitivity Reaction
If a hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council United Kingdom and can be found 
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at https://www.resus.org.uk/pages/reaction.pdf. Participants should be instructed to report any 
delayed reactions to the Investigator immediately.
Symptoms may include, but are not limited to: 
!
Impaired airway
!
Decreased oxygen saturation (< 92%)
!
Confusion
!
Lethargy
!
Hypotension
!
Pale/clammy skin
!
Cyanosis.
Management of hypersensitivity includes: 
!
Epinephrine injection and intravenous dexamethasone
!
Participant should be placed on cardiac, blood pressure, heart rate, and oxygen saturation 
monitoring immediately
!
Alert intensive care unit for possible transfer if required.
Prophylaxis of Flu-Like Symptoms:
For prophylaxis of flu-like symptoms, a nonsteroidal anti-inflammatory drug (NSAID), e.g., 
ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours 
after the start of each intravenous infusion.
6.9.2
Immune-Related Adverse Events
In general, the spectrum of irAEs is similar for M7824 compared with other checkpoint inhibitors. 
Immune-related AEs are considered AESIs. Effective risk management of these toxicities (irAEs) 
primarily caused due to inhibition of PD-L1 and PD-1 pathways is based on key recommendations 
(Champiat 2016). Participant education for on-time reporting of symptoms of potential irAEs and 
prompt clinical assessment is critical for effective management and quicker resolution of 
immune-mediated toxicities, thus preventing progression into severe forms of toxicity that 
otherwise may become life-threatening and difficult to manage or warrant permanent 
discontinuation from the study.
Immune-related AEs are specific to immunotherapies and vary by organ system.
The following immune-related AEs are important identified risks for M7824:
! Immune-related hepatitis
! Immune-related pneumonitis
! Immune-related colitis
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! Immune-related nephritis and renal dysfunction
! Immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, Type 1 diabetes 
mellitus, pituitary disorders)
! Immune-related rash
! Other immune-related events (myositis, myocarditis, encephalitis)
The following irAEs are important potential risks for M7824:
! Guillain-Barré syndrome
! Uveitis
! Pancreatitis
! Myasthenia gravis/myasthenic syndrome
The Medical Monitor may be involved as needed for follow-up. Details of the diagnostic work-up 
will be requested by the study team.
For treatment management of irAEs per NCI-CTCAE v5.0 criteria, refer to the ASCO Clinical 
Practice Guidelines and National Comprehensive Cancer Network (NCCN) irAE management 
guidelines.
The recommendations for irAE management are guided by the joint ASCO Clinical Practice 
Guidelines (Brahmer 2018) and NCCN guidelines, listed in Appendix 6.
Treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In general, 
management by NCI-CTCAE v5.0 grading, as per ASCO, is listed below:
!
Grade 1: study intervention should be continued with close monitoring, with the exception of 
some neurologic, hematologic, and cardiac toxicities. 
!
Grade 2: study intervention may be suspended for most Grade 2 toxicities, with consideration 
of resuming when symptoms revert to Grade 1 or less. Corticosteroids may be administered 
(initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent). 
!
Grade 3: study intervention is generally suspended and high-dose corticosteroids (prednisone 
1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) treatment should be initiated. 
Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory 
cases may require infliximab or other immunosuppressive therapy. 
!
Grade 4: in general, permanent discontinuation of study intervention is recommended, with the 
exception of endocrinopathies that have been controlled by hormone replacement.
Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 
syndrome, aplastic anemia, immune thrombocytopenia and acquired thrombotic thrombocytopenic 
purpura (TTP).
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For Grade 4 immune-related lymphopenia, permanent discontinuation of study intervention will 
be required, if lymphopenia is considered immune-related in nature, no clear alternative 
explanation exists for the event, and Grade 4 lymphopenia does not resolve within 14 days. 
Permanent discontinuation of study intervention is not required when the AE is manifest by a 
single laboratory value out of normal range without any clinical correlates. In this case, study 
intervention should be held until the etiology is determined. If the event is not considered 
immune-related and resolves to Grade ≤1 restarting of study intervention may be considered.
For additional organ/system specific management guidelines, see the guideline tables in 
Appendix 6.
Recommended guidance and management for specific irAEs are provided in the current NCCN 
guideline available at http://www.nccn.org.
6.9.3
TGF-β Inhibition Mediated Skin Reactions
TGF-β inhibition mediated skin reactions, including hyperkeratosis, KA, and/or cSCCs, are 
important identified risks and AESIs for M7824.
Skin assessments are performed at Baseline and every 6 weeks for all participants per Schedule of 
Activities (Table 1). Referral to a dermatologist is recommended in case of suspicious lesions. 
Baseline skin assessments include a detailed medical history of genetic or iatrogenic skin 
conditions, skin type, geographical location, significant UV exposure/sun damage of skin, and 
occupational or environmental exposure to radiation or chemicals.  
Skin AEs appear to be related to both mechanisms of M7824; anti-PDL1 and anti-TGF-β:
1. Immune-related skin AEs possibly mediated by PD-L1 inhibition (e.g., rash or 
maculopapular rash, distributed typically on trunk and uniformly on limbs). 
2. Immune-related skin AEs should be managed according to ASCO Clinical Practice 
Guidelines (Appendix 6). Treatment typically includes use of emollients, non-sedating 
antihistamines for pruritus, and targeted use of potent topical steroids to most inflamed 
lesions; oral corticosteroids can be used in highly symptomatic cases.
Skin AEs, possibly due to TGF-β inhibition, including hyperkeratosis, KA and/or cSCC, are 
important identified risks for M7824. The distribution of lesions tends to be in sun-exposed areas.
Management guidelines for potential TGF-β inhibition mediated skin reactions:
! Discontinuation or interruption is not required in most cases. Continuation of treatment should 
be evaluated by the Investigator. 
! Emollients may continue to be used
! Diagnostic and treatment plan should be developed in collaboration between Investigator and 
dermatologist. In general, treatment of TGF-β inhibition mediated skin reactions such as 
hyperkeratosis, KA, and cSCC should be based on local guidelines/standard of care. Lesion 
evaluation should include excision biopsy of one representative lesion to confirm diagnosis.
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! Treatment and follow-up for KA and cSCC will depend on number and localization of lesions. 
! For single lesions: 
o
Full excision may be recommended. 
! In case of multiple lesions or location not suitable for full excision: 
o
Other treatment options may be offered by the dermatologist, such as: 

Mohs surgery, cryotherapy, or other standard treatment options depending 
on the pathology. 

Use of retinoids if recommended by dermatologist, may be considered after 
discussion with Medical Monitor.
! Close clinical follow-up for re-evaluation, resolution or potential recurrence should be 
implemented.
! Spontaneous resolution of KA lesions without surgical intervention has been observed, 
typically occurring within weeks after discontinuing M7824.
! The number and localization of lesions, diagnosis (including histopathological diagnosis), 
treatment and outcome should be appropriately documented in the eCRF.
Consult with study Medical Monitor as needed for management of TGF-β inhibition mediated skin 
reactions.
6.9.4
Anemia
Anemia is an AESI (refer to IB) and important identified risk for M7824. Notably, there are many 
reasons for anemia in patients with advanced cancer, which is why a thorough investigation of new 
anemia cases of unspecified etiology is requested.
For new anemia events, items queried may include, but are not limited to, detailed relevant past 
medical and treatment history, bruising tendency, history of blood transfusions and/or dependency, 
and a request for an updated eCRF including details such as concomitant medications, all 
laboratory data, updated dosing information and recent tumor evaluation scans.
General guidance for anemia management and evaluation:
!
Participants must enter the study with Hgb values at least 9 g/dL; routine blood test parameters 
are required in the Schedule of Activities (Table 1).
!
All relevant hematologic testing for anemias should be done prior to a blood transfusion, if 
clinically feasible.
!
Transfusion should be performed at the discretion of the Investigator based on clinical 
assessment and considered when the participant experiences significant anemia. An attempt 
should be made to initiate work-up (as specified below) for the cause of anemia prior to 
transfusion, if clinically feasible, to not confound this work-up. In general, blood transfusions 
and erythroid growth factors are permitted for Hgb ≤7 g/dL and/or for life-threatening 
bleeding.
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Guidance for evaluation of suspected anemias is provided in Table 5.
Table 5
Evaluation Guidance of Suspected Anemia
Baseline Anemia Evaluation (Prior to Transfusion, if feasible)
CBC with differential (e.g., Hgb, hematocrit, MCV, reticulocytes counts, ANC).
Peripheral blood smear for cell morphological assessment.
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and other chemistries if indicated:
1.
Coagulation factors (PT, aPTT, INR)
2.
Urinalysis including culture
3.
Iron panel (TIBC, ferritin, Fe)
4.
Serum folate, B12 values
5.
TSH/hormonal panel
6.
Fecal-occult blood testing
7.
Erythropoietin.
Further Recommendation Based on Suspected Etiology (in Addition to Baseline Anemia Testing)
Unknown etiology, suspect 
possible hemolysis
Coombs test, fibrinogen, haptoglobin, d-dimer.
Consider hematology consultation.
Consider blood transfusion at clinical discretion.
Unknown etiology, suspect 
possible bleeding
Consider blood transfusion at clinical discretion.
Consider surgical/interventional radiology consultation.
Consider imaging, as clinically indicated (e.g., FAST scan, CT scan, MRI, angiography).
Consider endoscopy (upper/lower). 
Unknown etiology despite 
above work-up
Hematology consultation.
Consider bone marrow aspiration/morphologic evaluation.
ANC=absolute neutrophil count, aPTT=activated partial thromboplastin time, CBC=complete blood count, CT=computed 
tomography, FAST=Focused assessment with sonography for trauma, Fe=iron, Hgb=hemoglobin, INR=international 
normalized ratio, LDH=lactate dehydrogenase, LFT=liver function test, MCV=mean corpuscular volume, MRI=magnetic 
resonance imaging, PT=prothrombin time, TIBC=total iron binding capacity, and TSH=thyroid-stimulating hormone.
6.9.5
Bleeding Events
Bleeding events are AESIs and considered an important identified risk for M7824 (refer to the IB).
6.9.5.1
Mucosal/Non-Tumor Bleeding
Mucosal bleeding events of mild to moderate severity were observed in participants treated with 
M7824 in ongoing studies. Events may include epistaxis, hemoptysis, gingival bleeding, or 
hematuria amongst others. In general, these reactions resolve without discontinuation of treatment. 
For all participants:
For Grade 2 non-tumor bleeding, see Section 6.6.1 for general management of Grade 2 ADRs.
For Grade 3 non-tumor bleeding, study intervention must be permanently discontinued unless an 
alternative explanation can be identified (such as concomitant use of antithrombotic agents, 
traumatic event, etc.). In case of alternative explanations for the Grade 3 bleeding event, study 
intervention should be held until the event recovers to Grade ≤1.
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For Grade 4 non-tumor bleeding, treatment must be permanently discontinued if no alternative 
explanation is identified. 
6.9.5.2
Tumor Bleeding
Participants treated with M7824 were reported in lower frequencies, with Grade ≥ 3 hemorrhages 
including tumor bleeding.
For Grade ≥ 2 tumor bleeding, study intervention must be held until the event recovers to 
Grade ≤1. Treatment should be permanently discontinued if the Investigator considers the 
participant to be at risk for additional severe bleeding.
6.9.6
Other Potential Risks
6.9.6.1
Impaired Wound Healing 
Impaired wound healing is considered an important potential risk (a theoretical risk based on 
literature findings) for M7824, given the role of TGF-β in wound healing. Management should be 
discussed with the Medical Monitor for participants requiring surgery on study. It is recommended 
to hold study intervention for approximately 4 weeks post major surgery for observation. 
Postoperative wound healing will be closely monitored.
6.9.6.2
Embryofetal Toxicity
Embryofetal toxicities are a known risk of the PD-1/PD-L1 targeting class and are considered
important potential risks for M7824. Animal models link the PD-1/PD-L1 signaling pathway with 
maintenance of pregnancy through induction of maternal immune tolerance to fetal tissue. 
Embryofetal toxicity is an important potential risk of M7824. An appropriate contraception 
warning is provided as part of the inclusion criteria. Pregnant and breastfeeding women are not 
allowed in the M7824 study, and adequate contraceptive measures are recommended during the 
study to minimize or eliminate the potential risk to the developing fetus.
Respective safety measures comprise inclusion/exclusion criteria for participation in clinical 
studies with M7824, guidance for prevention, monitoring, and medical management of potential 
risks, as well as guidance on study intervention interruption or discontinuation.
6.9.6.3
Disease Specific Risk: Hepatic Impairment
Biliary tract cancer can cause obstructive cholestasis complicated by acute cholangitis. Acute 
cholangitis is a clinical syndrome characterized by fever, jaundice, and abdominal pain that 
develops as a result of stasis and infection in the biliary tract. Patients with acute cholangitis may 
develop septic shock and thus require frequent monitoring for evaluation of signs of shock. 
If biliary infection is suspected, the study intervention must be withheld. The Investigator should 
consider biliary drainage as well as treatment with antibiotics. If biliary tract infection is clinically 
improved, the study intervention can be resumed. 
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7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Participants will be withdrawn from study intervention for any of the following reasons:
!
A participant may withdraw from the study intervention at any time at his/her own request (i.e.,
withdrawal of consent), and without giving a reason.
!
Occurrence of an exclusion criterion, which is clinically relevant and affects the participant's 
safety, if discontinuation is considered necessary by the Investigator and/or Sponsor.
!
A participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons.
!
Confirmed PD per RECIST 1.1, with the exception that participants receiving treatment may 
continue past PD if the participant’s ECOG PS has remained stable, and if in the opinion of 
the Investigator, the participant will benefit from continued treatment (See Section 7.1.2.1).
!
Unacceptable toxicity
!
Some ADRs require withdrawal from treatment. See Section 6.6.1 for additional details.
!
Occurrence of pregnancy
!
Use of a nonpermitted concomitant drug as defined in Section 6.5.3, where the predefined 
consequence is withdrawal from the study intervention.
The Schedule of Activities specifies the data to collect at study intervention discontinuation and 
follow-up, and any additional evaluations that need to be completed.
Obstructive jaundice and/or biliary tract infection without radiological PD, should not be cause for 
study intervention discontinuation if patients can be treated with prompt biliary drainage.
7.1.1
Temporary Discontinuation
See Section 6.9 for information on temporary study intervention discontinuation.
7.1.2
Rechallenge
One reinitiation course of treatment after treatment discontinuation at the same dose and schedule 
is allowed at the discretion of the Investigator and upon agreement of the Study Medical 
Responsible for the following:
!
Participants who are experiencing CR at the time of discontinuation, and then subsequently 
develop disease progression after stopping therapy, but prior to the end of the study.
Prior to reinitiation, the Investigator will need to confirm that the benefit of reinitiating treatment 
outweighs any risk involved, such as that which led to initial treatment discontinuation. For 
participants with only stable disease at the time of discontinuation, the Investigator should confirm 
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that no other reasonable treatment options are available. In addition, to be eligible for reinitiation, 
the participant must not have previously withdrawn consent for this trial and should have been 
followed up with regular eCRF documented evaluation scans up to reinitiation of treatment.
A re-Baseline scan must be performed prior to reinitiation of study intervention. Additionally, 
relevant safety laboratory assessments, including both full hematology and full chemistry results 
within 2 weeks, must be available and verified. The clinical Investigator will determine whether 
additional evaluation and workup are required on a case-by-case basis. A discussion with the study 
team is warranted to determine whether PK/
 testing is indicated upon restarting 
treatment.
The participant should reinitiate treatment at the treatment phase visit where they left off according 
to the Schedule of Activities (Table 1). Participants who reinitiate treatment should stay on study 
and should be treated and monitored according the Schedule of Activities for the rest of the study. 
7.1.2.1
Treatment Beyond Initial Progression
Treatment with M7824 should continue from the initial determination of disease progression by 
the IRC (verified PD) according to RECIST 1.1 until confirmed PD if the following criteria are 
met:
!
No new unacceptable treatment or disease-related toxicity
!
Tolerance of study interventions
!
Stable or improving ECOG PS
!
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).
!
Participants must sign a separate informed consent to ensure that they are aware of being 
treated beyond initial progression.
If the treatment continues after the verified PD, a radiographic assessment should be performed to 
confirm the PD at the next scheduled imaging. 
7.1.2.2
Treatment Beyond Confirmed Progression
After confirmed PD, if the Investigator believes per clinical judgment that the participant continues 
to achieve clinical benefit by continuing treatment with M7824, the participant can remain in the 
study and continue to receive monitoring according to the Schedule of Activities. The decision to 
continue treatment beyond confirmed PD should be discussed with the Medical Monitor and 
documented in the study records.
To qualify for treatment beyond confirmed progression:
! Participants must sign a separate informed consent to ensure that they are aware of being treated 
beyond confirmed progression.
! Investigators must document clinical judgment to justify the continuation of study intervention
rather than other possible alternative treatments.
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Participants who continue treatment beyond progression will be evaluated for further tumor 
response as per the protocol Schedule of Activities (Table 1). Treatment should be discontinued 
permanently in case of any overall, meaningful and unequivocal further increase in tumor burden 
after confirmation of PD. As a general guidance, a meaningful increase, for example, may 
represent an approximately 10% increase in tumor burden, considering the totality of all existing 
target lesions, non-target lesion burden, existing new lesions, and any further new lesions. Note: 
This 10% increase is provided as a general guide to be interpreted considering the clinical 
condition of the participant and any other considerations which the Investigator feels relevant, such 
as the availability of alternative treatments. In unclear situations, the Investigator should consult 
with the Medical Monitor, and the wellbeing of the individual participant should be the key 
consideration in determining the continuation of study intervention after confirmed progression.
7.1.2.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression
If disease progression is due to brain metastasis, participants may continue study interventions 
after local treatment of the brain lesions provided that the above criteria are met in addition to the 
following:
! PD is verified by the IRC. 
! Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior to 
reinitiation of study interventions. 
! There are no ongoing neurological symptoms that are related to the brain localization of the 
disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable). 
! Participants must be either off steroids or on a stable or decreasing dose of ≤10 mg daily 
prednisone (or equivalent). 
! Benefit-risk assessment to continue study intervention is favorable after consideration of any 
alternative treatment options as assessed by the Investigator. 
In addition, if disease progression is mainly due to a metastatic lesion, which in the opinion of the 
Investigator may be treated with radiotherapy or surgically removed, participants may continue 
study interventions after the local treatment of such a lesion provided that:
! PD is verified by IRC. 
! It has been at least 2 weeks and the participant has fully recovered from the surgery or 
radiotherapy.
! Benefit-risk assessment to continue study intervention is favorable after consideration of any 
alternative treatment options as assessed by the Investigator.
7.2
Participant Discontinuation/Withdrawal from the Study
! A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons.
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! At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the Schedule of Activities. The Schedule of Activities specifies the data 
to collect at study discontinuation and follow-up, and any additional evaluations that need to be 
completed.
! If the participant withdraws consent for future involvement in the study, any data collected up 
to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed (refer to the ICF).
! A participant has the right at any time to request destruction of any biological samples taken. 
The Investigator must document this in the site study records.
The Investigator will secure the safety of the study participants and make every attempt to collect 
data.
In case of discontinuation/withdrawal from the study:
! At study intervention discontinuation, the day of End-of-Treatment will correspond to the day 
of withdrawal (or within 7 days).  
! The assessments scheduled for the End-of-Treatment visit should be performed, if possible, 
with a focus on the most relevant assessments and the appropriate eCRFs for the 
End-of-Treatment visit must be completed. 
! Participants will be asked to continue Safety and Survival Follow-ups, which include the 
collection of data on survival, 
, and subsequent 
anticancer therapy. After completion of the follow-up period or after the End-of-Treatment 
visit, whichever is applicable, the appropriate eCRF section for Study Termination must be 
completed.
If the participant is enrolled into a new study or any new therapy post-withdrawal from study 
intervention, the Safety Follow-up visit should be scheduled prior to the start of the new treatment 
irrespective of the 28-day Safety Follow-up period.
Survival follow-up will continue until each participant has been followed up for at least 3 years 
after End-of-Treatment.
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7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions will be taken if a participant fails to return to the study site for a required 
study visit:
! The site will 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 if the participant wants to or should continue in the study.
! Before a participant is deemed “lost to follow-up”, the Investigator or designee will make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner or caretaker (where allowed by local regulations) for
information. These contact attempts should be documented in the participant’s medical record.
! If the participant continues to be unreachable, he or she will be considered to have withdrawn 
from the study.
8
Study Assessments and Procedures
! Study assessments and procedures and their timing are summarized in the Schedule of Activities
(Table 1).
! No protocol waivers or exemptions are allowed.
! Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
! Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
! All Screening evaluations will be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a Screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for Screening 
failure.
! Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2 (Study 
Governance).
! Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for Screening or Baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the Schedule of Activities.
A maximum of 145 mL of blood will be collected in any one-month period from each participant 
in the study, including any extra assessments that may be required.
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8.1
Efficacy Assessments and Procedures
8.1.1
Tumor Response
Contrast-enhanced CT of chest/abdomen and pelvis covering the area from the superior extent of 
the thoracic inlet to the symphysis pubis is the first choice of imaging modality. If a participant 
should not receive iodinated contrast medium, or due to radiation protection reasons, MRI of the 
same area, using gadolinium enhancement according to local protocol as permitted in conjunction 
with unenhanced CT of the chest from the thoracic inlet to the inferior costophrenic recess should 
be done. The same method should be used per participant throughout the study.
A brain CT/MRI scan should be performed if clinically indicated by development of new specific 
symptoms. In this study, RECIST 1.1 was modified so that skin metastases cannot be used as target 
lesions using measurements by caliper but may be selected if they fulfill RECIST 1.1 requirements 
for target lesions using CT/MRI scan (refer to RECIST 1.1 criteria).
A central imaging laboratory will be used to read and interpret all CT/MRI data; however, 
treatment decisions will be made by the treating Investigator, except for verification of measurable 
disease at Baseline and verification of initial PD, which will be made by the IRC following a local 
site Investigator-assessed first radiologic evidence of PD. Response will be evaluated according to 
RECIST 1.1
 by the IRC. Tumor 
responses to treatment assessed according to RECIST 1.1 by the Investigator will be documented 
in the eCRF (all measurements should be recorded in metric notation). 
 
Baseline scans are taken within 28 days prior to treatment. Disease must be measurable with at 
least 1 unidimensionally measurable lesion by RECIST 1.1 and verified by independent image 
review. All the scans performed at Baseline need to be repeated at subsequent visits for tumor 
assessment using the same method. In general, lesions detected at Baseline need to be followed 
using the same imaging methodology and preferably the same imaging equipment at subsequent 
tumor evaluation visits.
Participants will be evaluated every 8 weeks with radiographic imaging to assess response to 
treatment within the first 12 months of the participant’s first dose, then every 12 weeks until 
confirmed disease progression, as scheduled in the Schedule of Activities (Table 1).
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8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting, and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, 
electrocardiogram (ECGs), and laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information).
The safety assessments will be performed according to the Schedule of Activities (Table 1). 
Periodic evaluations of the study data will be conducted by an IDMC to ensure safety and the 
validity and scientific merit of the study (see Section 8.2.4).
Ongoing events at the 12-week Safety Follow-up visit should continue to be monitored and 
documented until resolution or resolution with sequelae. All serious adverse events (SAEs) 
ongoing at the End-of-Treatment visit must be monitored and followed up by the Investigator until 
stabilization or until the outcome is known, unless the participant is documented as “lost to follow-
up”. Reasonable attempts to obtain this information must be made and documented. It is also the 
responsibility of the Investigator to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed.
If a liver function test is elevated in an HBV- or HCV-positive participant, HBV DNA or HCV 
ribonucleic acid (RNA) must be monitored to exclude the possibility of reactivation of viral 
hepatitis. In case of viral reactivation, follow the HBV and HCV management guidelines.
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8.2.1
Physical Examinations and Vital Signs
! Vital signs, physical examinations, and ECOG PS will be conducted at Screening and at 
subsequent visits as indicated in the Schedule of Activities (Table 1). These should be 
documented in the eCRF. 
! A complete physical examination at Screening will include, at a minimum, assessments of the
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height (at Screening 
Visit only) and weight will also be measured and recorded.
! A brief physical examination (at all other scheduled visits other than Screening) will include, 
at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and
spleen).
! Investigators should pay special attention to clinical signs related to previous serious illnesses.
! General status, such as asthenia or appetite, should be evaluated at Baseline, as these are usually 
affected. Pre-existing symptoms of underlying conditions and/or signs of infection should be 
investigated as clinically indicated.
! Abnormal findings are to be reassessed at subsequent visits.
! Vital signs including heart rate, body temperature, pulse rate, respiratory rate, and blood 
pressure will be assessed and recorded in the eCRF.
! Blood pressure and pulse measurements will be assessed with a completely automated device. 
Manual techniques will be used only if an automated device is not available.
! Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).
! Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse and respiratory rate.
! Blood oxygen saturation will be measured with a pulse oximeter and recorded in the eCRF.
8.2.2
Electrocardiograms
Single 12-lead ECGs will be obtained as outlined in the Schedule of Activities (Table 1) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals.
8.2.3
Clinical Safety Laboratory Assessments
! Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 5
at the time points listed in the Schedule of Activities (Table 1). All samples should be clearly 
identified. 
! Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations.
! The tests will be performed by the local laboratory.
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! The Sponsor will receive a list of the local laboratory normal ranges before shipment of study 
intervention. Any changes to the ranges during the study will be forwarded to the Sponsor or 
designated organization.
! The Investigator will review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents.
! If a participant has a clinically significant abnormal laboratory test value that is not present at 
Baseline, the test should be closely monitored until the test value has returned to the normal 
range or the Investigator has determined that the abnormality is chronic or stable. 
! The report of the results must be retained as a part of the participant’s medical record or source 
documents. 
! Serum KL-6, SP-A, and SP-D levels will be measured at sites in Japan for potential early 
detection of pneumonitis. Inclusion of these markers are for indicating potential lung-related 
toxicity only; further investigations, like chest CT, etc., will be performed for a confirmatory 
diagnosis.
! Pregnancy testing (serum or highly sensitive urine test, as required by local regulations) will be 
conducted at monthly intervals during study intervention administration and at the time points 
specified in the Schedule of Activities (Table 1), including at the end of relevant systemic 
exposure of the study intervention. 
8.2.4
Review Committees
The following committees will be involved in the study: IDMC, IRC, and Study Steering 
Committee.
Independent Data Monitoring Committee (IDMC)
To ensure participants’ safety during the study, an external IDMC will periodically review safety 
data. The IDMC will be composed of a minimum of 3 voting members, including an independent 
biostatistician, and 2 independent oncologists (BTC experts). The full details on membership, 
mandate, and processes of the IDMC are outlined in the IDMC charter. 
Independent Radiology (Review) Committee (IRC)
The IRC will be composed of a minimum of 3 members. The role of the IRC will be to review 
radiographic image findings, physical findings, and other clinical data for the determination of the 
best overall response (OR) and date of disease progression for each participant. The full 
membership, mandate, and processes of the IRC will be detailed in the IRC charter.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are in Appendix 4.
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8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until the 28-day Safety Follow-up visit, defined as 28 days (± 5 days) after 
the last study intervention administration. After this visit, all SAEs and non-serious 
treatment-related AEs should be documented until the last Safety Follow-up visit, defined as 
12 weeks (± 2 weeks) after the last study intervention. Ongoing events at the 12-week Safety 
Follow-up visit should continue to be monitored and documented until resolution or resolution 
with sequelae, unless the participant is documented as “lost to follow-up”.
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 4, whenever it occurs, irrespective of the time elapsed since the last administration of 
study intervention.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 4.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator.
Complete, accurate, and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using the appropriate SAE Report Form 
as specified in Appendix 4.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
Adverse events are recorded and assessed continuously throughout the study, as specified in 
Section 8.3.1 (Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information) and are assessed for their outcome at the 28-day Safety Follow-up visit.
All SAEs ongoing at the 28-day Safety Follow-up visit must be monitored and followed up by the 
Investigator until stabilization or until the outcome is known, unless the participant is documented 
as “lost to follow-up.” Reasonable attempts to obtain this information must be made and 
documented. It is also the responsibility of the Investigator to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed. Further information on follow-up 
procedures is given in Appendix 4 (Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reports).
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8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must report SAEs (particularly deaths) in accordance with applicable site-specific 
requirements to the Institutional Review Board (IRB) that approved the study.
In accordance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP)
and the Japanese ministerial ordinance on GCP, the Sponsor/designee will immediately inform all 
the study Investigators and the Heads of the study sites of findings that could adversely affect the 
safety of participants, impact the conduct of the study, or alter the IRB’s approval/favorable 
opinion to continue the study. In line with respective applicable regulations, the Sponsor/designee 
will immediately inform all the study Investigators and the Heads of the study sites of AEs that are 
both serious and unexpected and considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). In addition, per applicable regulations, the 
Sponsor/designee will inform the study Investigators and the Heads of the study sites of all SAEs 
that were reported to the Health Authorities. In accordance with the Japanese regulatory 
requirements concerning safety reporting, the Investigator should place copies of the Safety 
Reports in the Investigator Site File. The Head of the study site should also maintain copies of 
Safety Reports appropriately.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead Independent Ethic Committee (IEC)/IRB 
and will maintain records of these notifications. When direct reporting is not clearly defined by 
national or site-specific regulations, the Investigator will be responsible for promptly notifying the 
concerned IEC/IRB of any Safety Reports provided by the Sponsor/designee and of filing copies 
of all related correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
8.3.5
Pregnancy
Only pregnancies the Investigator considers to be related to the study intervention (e.g., resulting 
from a drug interaction with a contraceptive method) are AEs. However, all pregnancies with an 
estimated conception date during the period defined in Section 8.3.1 (Time Period and Frequency 
for Collecting Adverse Event and Serious Adverse Event Information) must be recorded in the AE 
page/section of the eCRF for both pregnancies in female participants and pregnancies in female 
partners of male participants. The Investigator must notify the Sponsor/designee in an expedited 
manner of any pregnancy using the Pregnancy Report Form, which must be transmitted by the 
same process specified for SAE reporting in Appendix 4, section on Reporting Serious Adverse 
Events.
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Investigators must actively follow-up, document, and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the participant sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event. Any abnormal outcome (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) must be reported in an expedited manner, as specified in 
Section 8.3.1, while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay and 
the participant must be followed as indicated above.
8.4
Treatment of Overdose
! For this study, any dose of M7824 greater than 2 times (i.e., > 2400 mg) than the planned dose 
administered within a 24-hour time period will be considered an overdose. Of note: In the 
dose-escalation study (EMR200647-001), participants safely received up to 30 mg/kg M7824 
every 2 weeks (including those with doses > 2400 mg) with no observed maximum tolerated 
dose (refer to the IB). Safety at significantly higher doses has not been clinically evaluated. 
! In case of overdose with clinical correlation, symptomatic treatment must be used; there are no 
known antidotes for the compound.
! In the event of an overdose, the study intervention infusion should be discontinued, and 
participants should be observed closely for any signs of toxicity. Supportive treatment should 
be provided if clinically indicated.
! Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and reported 
to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, following 
the procedure in Appendix 4, section on Reporting Serious Adverse Events.
! If an AE occurs resulting from an overdose, it should follow SAE reporting criteria as indicated 
in Appendix 4.
8.5
Pharmacokinetics
! Whole blood samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of M7824. Collection times are specified in the Schedule of Activities
(see Section 1.3; Table 2). The actual date and time (24-hour clock time) of each sample will 
be recorded to calculate actual time elapsed since the prior dose administration.
! The quantification of M7824 in serum will be performed using a validated assay method. 
Concentrations will be used to evaluate the PK of M7824.
! Remaining samples collected for analyses of M7824 concentration may also be used to evaluate 
immunogenicity and safety, or efficacy aspects related to concerns arising during or after the 
study.
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! Details on processes for collection and shipment of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF.
! PK and antidrug antibody (ADA) samples collected at the same time points may be used 
interchangeably if the dedicated sample has insufficient quantity as the participants will have 
consented to all collections and tests.
! PK samples will be collected according to Table 2.
The following PK parameters will be estimated and reported in the PK Analysis Set:
!
CEOI
!
Ctrough.
The PK parameters will be summarized using descriptive statistics. Individual as well as mean 
concentration-time plots will be depicted (Table 6).
The following PK parameters will be calculated, when appropriate.
Table 6
Pharmacokinetic Parameters
Symbol
Definition
CEOI
The concentration observed immediately at the end of infusion.
Ctrough
The concentration observed immediately before next dosing (corresponding to pre-dose or 
trough concentration for multiple dosing).
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Details on processes for collection and shipment of these samples are specified in the Laboratory 
Manual. The Sponsor will store the samples in a secure storage space with adequate measures to 
protect confidentiality. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICFs.
8.9
Health Economics
Not applicable.
8.10
Immunogenicity Assessments
! Whole blood samples of approximately 5 mL will be collected for detection of antibodies 
against M7824 in serum. Collection times are specified in the Schedule of Activities (see 
Section 1.3; Table 2). Samples will be collected prior to any M7824 administration on the same 
study day.
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9
Statistical Considerations
9.1
Statistical Hypotheses
The primary endpoint of the study is the confirmed OR according to RECIST 1.1, based on 
independent review of tumor assessments. 
The following null hypothesis will be tested:
: ORR ≤10%.
9.2
Sample Size Determination
The study aims at demonstrating an ORR > 10% in the intention-to-treat (ITT) population by 
means of an exact binomial test. 
The planned total sample size is 141 participants based on the following assumptions:
1. ORR of 18%
2. Alpha = 0.025 (1-sided) for the Exact test of the null hypothesis of an ORR ≤10%.
Under the given assumptions, the power to reject the null hypothesis at the primary analysis (PA)
is 80%.
An observed ORR of 15.6% (22/141) would achieve a positive ORR outcome and would lead to 
an exact 95% CI of (10%, 22.7%).
The 2-sided 95% Clopper-Pearson CIs for different observed values for the ORR are provided in 
Table 8.
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Table 8
Confidence Intervals for Different Objective Response Rates
N
N with CR/PR
ORR (%)
95% CI
141
15
10.6
6.1
16.9
20
14.2
8.9
21.1
21
14.9
9.5
21.9
22
15.6
10.0
22.7
25
17.7
11.8
25.1
30
21.3
14.8
29.0
35
24.8
17.9
32.8
CI=confidence interval, CR=complete response, N=number of participants, ORR=objective response rate,
PR=partial response.
Characterization of ORR in Individual BTC Subtypes
To characterize ORR in each individual BTC subtype (intrahepatic CCA, extrahepatic CCA and 
gallbladder cancer), subgroup analysis of ORR will be performed. With the planned overall sample 
size of 141 and assuming frequencies of 45% intrahepatic CCA, 30% extrahepatic CCA, and 25% 
gallbladder cancer, enrolment of at least 30 participants per subtype can be expected even in case 
the actual rate of participants with gallbladder cancer is below the assumed rate of 25%. A 
subgroup of 25% of the overall sample size of 141 participants would results in 35 participants.
Risk of observing a high ORR in a subgroup by chance if true ORR is low (“H0”)
With a sample size of 30 participants and assuming a true ORR of 10%, the probability to observe 
at least 5 (16.7%) responders is 17.5%.
Risk of observing a low ORR in a subgroup by chance if true ORR is 18% (“H1”) 
With a sample size of 30 participants and assuming a true ORR of 18% (same as assumed for 
overall population), the probability to observe no more than 4 (13.3%) responders is 35.1%.
BTC subtype analyses are not powered for a formal statistical test, e.g., 30 participants would have 
15.8% power to reject the null hypothesis of ORR ≤10%, using the same assumption of ORR of 
18% and alpha = 0.025 (1-sided).
Justification of the Assumption of a Confirmed ORR of 18%
M7824, as a monotherapy, has demonstrated promising clinical efficacy signal in 2L BTC. As of 
20 March 2018, 30 participants with pretreated BTC received M7824 for a median duration of 
8.9 weeks (range: 2 to 57.6 weeks); 5 participants remained on treatment. Seven participants had 
a confirmed OR (ORR, 23.3% by Investigator read and 20% by IRC, including 1 confirmation of 
response after data cutoff). Therefore, it is reasonable to assume that the confirmed ORR of M7824 
in 2L BTC is 18% or higher. 
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Justification of the Assumption of a Benchmark ORR of 10% to Define the Study Sample 
Size
The benchmark for the ORR for 2L treatments is based on an update of a systematic review 
published in 2014 (Lamarca 2014) from available literature conducted in August 2018. Based on 
this updated review, which included 2L BTC studies reporting ORR results for chemotherapy
alone or in association with an approved systemic anticancer therapy restricted to studies with 
> 20 participants (to avoid imprecise ORR estimates reported in smaller samples), 32 studies were 
identified reporting outcomes for 2137 participants globally.
The ORR estimate derived from these studies based on a regression model with a random effect 
was 7.2% with a 95% CI ranging from 5.5% to 9.2%. Using the upper limit of this CI we assumed 
the benchmark ORR to be 10%.
9.3
Populations for Analyses
The analyses populations are specified below. The final decision to exclude participants from any 
analysis population will be made during a data review meeting prior to database lock.
For purposes of analysis, the analysis populations are defined in Table 9.
Table 9
Analysis Populations
Screening (SCR) 
All participants, who provided informed consent, regardless of the participant’s 
study intervention status in the study.
Safety (SAF)/
Intention-to-treat (ITT)
All participants, who were administered at least 1 infusion of M7824. 
The primary analysis (PA) population for all analyses of efficacy, safety, and 
health-related quality of life is the Safety population.
Pharmacokinetic (PK)
All participants who complete at least 1 infusion of M7824, and who provide at least 
1 sample with a measurable concentration of M7824.
Immunogenicity 
Analysis Set (IMM)
All participants who were administered at least 1 infusion of M7824 and have at 
least one valid antidrug antibody (ADA) result. All ADA analyses will be based on 
this analysis set.
9.4
Statistical Analyses
9.4.1
Efficacy Analyses
9.4.1.1
Analysis of Primary Endpoint
The primary endpoint is confirmed OR according to RECIST 1.1, as determined by an IRC. For 
an OR of PR or CR, confirmation of the response according to RECIST 1.1 will be required no 
sooner than 4 weeks after the initial documentation of CR or PR. Confirmation of PR can be 
confirmed at an assessment later than the next assessment after the initial documentation of PR. 
The response at each scheduled tumor assessment and the OR will be listed for each participant. 
The number and proportion of OR (defined as CR + PR) will be tabulated. The ORR will be 
determined as the proportion of participants with a confirmed OR of PR or CR. The 95% CI for 
the ORR will be calculated using the Clopper-Pearson method. The test statistic of the exact 
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binomial test (1 sample) against the null hypothesis for the ORR will be calculated to determine 
whether the null hypothesis of an ORR ≤10% can be rejected.
Analysis of efficacy variables will also be performed on subgroup of interest, including but not 
restricted to 
! PD-L1 expression 
! MSI status
Further details will be specified in the integrated analysis plan (IAP).
9.4.1.2
Analysis of Secondary and 
 Endpoints
9.4.1.2.1
Analysis of Secondary Endpoints 
PFS according to RECIST 1.1, is defined as the time from first administration of study intervention
until date of the first documentation of PD or death due to any cause in the absence of documented 
PD, whichever occurs first.
PFS data will be censored on the date of the last adequate tumor assessment for participants who 
do not have an event (PD or death), for participants who start new anticancer treatment prior to an 
event, or for participants with an event after two or more missing tumor assessments. Participants 
who do not have a baseline tumor assessment or who do not have any postbaseline tumor 
assessments will be censored on the date of first administration of study intervention unless death 
occurred on or before the time of the second planned tumor assessment, in which case the death 
will be considered an event. 
Sensitivity analyses of PFS will be done including but not limited to:
! Alternative censoring rules including an analysis which counts death and progression according 
to RECIST 1.1 as PFS event regardless of the start of a new anticancer therapy and ignoring the 
number of missing evaluable tumor assessments before progression or death
! PFS as assessed by the Investigator
Details will be defined in the IAP.
DOR is defined, for participants with a confirmed OR, as the time from first documentation of OR
(CR or PR) to the date of first documentation of objective PD or death due to any cause whichever 
occurs first. The censoring rules for DOR are as described above for PFS.
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A durable response is defined as an OR (CR or PR) according to RECIST 1.1, determined by an 
IRC, with a duration of at least 6 months. Participants for whom the DOR is censored will be 
treated as failures (successes) in the analysis of durable response if the censored DOR is below (at 
least) 6 months. The DRR is defined as the percentage of participants with durable response. The 
95% CI for the DRR will be calculated using the Clopper-Pearson method.
Overall survival (OS) is defined as the time from first administration of study intervention to the 
date of death due to any cause. Participants last known to be alive will be censored at date of last 
contact.
The Kaplan-Meier method will be used to estimate parameters for DOR, PFS, and OS. In 
particular, the PFS rate at 6 and 12 months will be estimated with corresponding 2-sided 95% CIs, 
and the survival rate at 6 and 12 months will be estimated with corresponding 2-sided 95% CIs. 
The CIs for the median will be calculated according to Brookmeyer and Crowley (Brookmeyer 
and Crowley 1982) and the CIs for the survival function estimates at the time points defined above 
will be derived using the log-log transformation according to Kalbfleisch and Prentice (Kalbfleisch 
and Prentice 1980). The estimate of the standard error will be computed using Greenwood’s 
formula. The DOR, PFS, and OS will also be presented in participant listings.
The association between PD-L1 expression and efficacy endpoints – primarily ORR and 
DOR/DRR – will be analyzed. 
 
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9.4.2
Safety Analyses
The on-treatment period is defined as the time from the first study intervention administration to 
the last study intervention administration date + 30 days or the earliest date of subsequent 
anticancer drug therapy minus 1 day, whichever occurs first, unless otherwise stated.
Safety endpoints include AEs, clinical laboratory assessments, vital signs, physical examination, 
ECG parameters, and ECOG PS as described in Section 8.2.
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Adverse Events
All AEs will be coded according to the MedDRA. Severity of AEs will be graded using the 
NCI-CTCAE v5.0 toxicity grading scale. 
The incidence of treatment-emergent adverse events (TEAEs), regardless of attribution, and 
TEAEs defined as possibly related to M7824 will be summarized by MedDRA preferred term and 
system organ class (SOC) and described in terms of intensity and relationship to M7824. TEAEs 
are those events with onset dates occurring during the on-treatment period or if the worsening of 
an event is during the on-treatment period. Any AEs with an onset or worsening date after the 
on-treatment period will be reported separately.
The incidence of SAEs and AESIs will be summarized by preferred term and SOC.
Descriptive statistics will be examined for indications of dose-related ADRs.
Laboratory Variables 
Laboratory results will be classified by grade according to NCI-CTCAE v5.0. The worst on-study 
grades after the first study intervention will be summarized. Shifts in toxicity grading from first 
treatment to highest grade will be displayed. Results for variables that are not part of NCI-CTCAE 
v5.0 will be presented as below, within, or above normal limits. Only participants with postbaseline 
laboratory values will be included in these analyses. 
Physical Examination (Including Vital Signs and 12-Lead ECGs)
Physical examination findings, including vital signs (body temperature, respiratory rate, heart rate, 
and blood pressure) and 12-lead ECGs, as indicated in the Schedule of Activities (Table 1) will be 
presented. 
Further details will be provided in the IAP based on current safety experience applying the latest 
MedDRA version.
All safety analyses will be performed on the Safety Analysis population.
9.4.3
Other Analyses
Analysis of efficacy variables may be performed on subgroups of interest as needed. The detailed 
subgroups will be outlined in the IAP. 
Serum concentrations of M7824 will be determined by a validated method at the times listed in 
the Schedule of Activities (Section 1.3; Table 2). 
! Details on the PK, immunogenicity, and 
 will be in the IAP that 
will be finalized before database lock. The PopPK analysis and exposure-response may be 
performed using combined data from several M7824 clinical studies and will be specified in a 
separate IAP. The PopPK, exposure-response and biomarker analyses will be presented 
separately from the main CSR.
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Estimation of Individual PK Parameters
! PK parameters will be calculated by the PK/PD Data Processing Group of QPD, Merck, 
Darmstadt, Germany, or by a CRO selected by the Sponsor.
! The statistical software SAS® (Statistical Analysis System, SAS-Institute, Cary NC, USA, 
windows version 9.4 or higher) may be used to produce tables, listings, and figures and in the 
calculation of PK parameters, if appropriate.
PK analyses (CEOI and Ctrough) will be specified in the IAP finalized before database lock.
ADA/Immunogenicity
Samples for ADA assessments will be collected as per the Schedule of Activities. 
Immunogenicity testing strategy will be implemented and conducted in line with:
! Immunogenicity 
Assessment 
of 
Biotechnology-Derived 
Therapeutic 
Proteins 
(EMEA/CHMP/BMWP/14327/2006) 
! Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use 
(EMA/CHMP/BMWP/86289/2010) 
! FDA Guidance for Industry: Assay Development for Immunogenicity Testing of Therapeutic 
Proteins (refer to FDA; December 2009, draft).
A validated method to detect ADAs in the presence of drug in human serum will be applied. The 
ADA titers of positive samples will be determined. Positive samples may be further evaluated for 
neutralizing capability. Individual participants will be categorized across all valid ADA results as 
ever-positive versus never-positive. ADA ever-positive participants will be further categorized as 
pre-existing, including treatment boosted, versus treatment emergent. ADA treatment-emergent 
participants will be further subdivided into transient positive and persistent positive.
Individual participants may be categorized across all valid neutralizing antibody results as 
ever-positive versus never-positive. Neutralizing antibody ever-positive participants may be 
further categorized as pre-existing versus treatment-emergent. Neutralizing antibody 
treatment-emergent participants may be further subdivided into transient positive and persistent 
positive.
Listings of drug concentration, TEAEs, and efficacy measures may be prepared for ADA 
ever-positive participants.
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9.4.4
Sequence of Analyses
There will be 2 data cutoff time points in this study:
! An 
per BTC subtype will be performed once 
15 participants of each subtype have reached at least one postbaseline tumor assessment. Each 
subtype will be analyzed separately once criteria are met.
! The PA will be conducted 9 months after the accrual of the last of 141 planned participants.
! Second analysis for DRR and DOR will be conducted 15 months after the accrual of the last of 
141 planned participants. The analysis will comprise a full evaluation of all efficacy and safety 
endpoints.
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10
References
Azuma A, Kudoh S. High prevalence of drug-induced pneumonia in Japan. JMAJ. 
2007;50:405-11.
Blazeby JM, Currie E, Zee BC, et al. EORTC Quality of Life Group. Development of a 
questionnaire module to supplement the EORTC QLQ-C30 to assess quality of life in patients with 
hepatocellular carcinoma, the EORTC QLQ-HCC18. Eur J Cancer. 2004 Nov;40(16):2439-44.
 
. Management of Immune-Related Adverse Events 
in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical 
Oncology Clinical Practice Guideline. J Oncol Pract. 2018 Apr;14(4):247-249. 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics.
1982;38:29-41.
Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade 
dysimmune toxicities: A collaborative position paper. Ann Oncol. 2016;27(4):559-74.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47.
Food and Drug Administration [Internet]. Development resources. Drug Development and Drug 
Interactions: Table of substrates, inhibitors and inducers. 2017 [cited 2018 July 16]. Available 
from:
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteracti
onsLabeling/ucm093664.htm
Friend E, Yadegarfar G, Byrne C, et al. Development of a questionnaire (EORTC module) to 
measure quality of life in patients with cholangiocarcinoma and gallbladder cancer, the EORTC 
QLQ-BIL21. Br J Cancer. 2011;104:587–92.
Goudie DR, D’Alessandro M, Merriman B, et al. Multiple self-healing squamous epithelioma is 
caused by a disease-specific spectrum of mutations in TGFBR1. Nat Genet. 2011;43(4):365-9. 
Hezel AF, Zhu AX. Systemic therapy for biliary tract cancers. Oncologist. 2008;13(4):415-23.
Jarnagin WR, Ruo L, Little SA, et al. Patterns of initial disease recurrence after resection of 
gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic 
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Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. New York: Wiley: 1980.
Kaupp-Roberts SD, Yadegarfar G, Friend E, et al. Validation of the EORTC QLQ-BIL21 
questionnaire for measuring quality of life in patients with cholangiocarcinoma and cancer of the 
gallbladder. Br J Cancer. 2016;115(9):1032-8.
Kubo K, Azuma A, Kanazawa M, et al. Consensus statement for the diagnosis and treatment of 
drug-induced lung injuries. Respir Investig. 2013;51(4):260-77.
Lamarca A, Hubner RA, David Ryder W, et al. Second-line chemotherapy in advanced biliary 
cancer: a systematic review. Ann Oncol. 2014;25(12):2328-38.
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Lan Y, Zhang D, Xu C, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional 
fusion 
protein 
simultaneously 
targeting 
PD-L1 
and 
TGF-β. 
Sci 
Transl 
Med.
2018;10(424):pii eaan5488. 
Morris JC, Tan AR, Olencki TE, et al. Phase I study of GC1008 (fresolimumab): a human anti-
transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant 
melanoma or renal cell carcinoma. PLoS One. 2014;9(3):e90353.
Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet.
2015;47(9):1003-10.
National Comprehensive Cancer Network® guidelines. Hepatobiliary cancers. Version 2.2018. 
Available at: https://www.nccn.org/patients/guidelines/hepatobiliary/4/.
Noone AM, Howlader N, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2015, National 
Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2015/, based on November 2017 
SEER data submission, posted to the SEER web site, April 2018.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 2018;68(1):7-30.
Spigel DR, McLeod M, Hussein MA, et al. Randomized results of fixed-duration (1-yr) vs 
continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). Ann 
Oncol. 2017;28(suppl 5):v460-v496.
Takada T. Time to stand up. Are Japanese prone to diffuse alveolar damage? Austin J Pulm Respir 
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Results from the multicohort, phase 2 KEYNOTE-158 study. Ann Oncol. 2018;29(Suppl_8): 
viii205-viii270.
Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract 
cancer. N Engl J Med. 2010;362(14):1273-81.
Valle JW, Borbath I, Khan SA, et al. Biliary cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment, and follow-up. Ann Oncol. 2016;27(suppl 5):v28-v37.
Vansteenkiste J. Nivolumab for NSCLC in Japanese patients: similar benefits, but beware of 
pneumonitis. ESMO Open. 2017; 2(Suppl 1): e000119.
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Appendices
Appendix 1
Abbreviations
1L
First-line
2L
Second-line
ADA
Antidrug antibody
ADR
Adverse drug reactions
AE
Adverse events
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
BTC
Biliary tract cancer
CCA
Cholangiocarcinoma
CI
Confidence Interval
CCr
Creatinine clearance
CNS
Central nervous system
CR
Complete response
CRO
Contract Research Organization
cSCC
Cutaneous squamous cell carcinoma
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
Ctrough
Trough concentration
DNA
Deoxyribonucleic acid
DOR
Duration of response
DRR
Durable response rate
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
eCRF
Electronic Case Report Form
FSH
Follicle-stimulating hormone
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GCP
Good Clinical Practices
HBV
Hepatitis B virus
HCC-18
Hepatobiliary Cancer 18 item module
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HRT
Hormone replacement therapy
IAP
Integrated analysis plan
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
ILD
Interstitial lung disease
INR
International normalized ratio
ITT
Intention-to-treat
irAE
Immune-related adverse event
IRB
Institutional Review Board
IRC
Independent Review Committee
IRR
Infusion-related reaction
KA
Keratoacanthoma
MedDRA
Medical Dictionary for Regulatory Activities 
MRI
Magnetic resonance imaging
NCI
National Cancer Institute
NSAID
Nonsteroidal anti-inflammatory drugs
OR
Objective response
ORR
Objective response rate
OS
Overall survival
PA
Primary analysis
PD
Progression of disease
PD-1
Programmed death-1
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PD-L1
Programmed death ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
PopPK
Population pharmacokinetics
PR
Partial response
PS
Performance status
PT
Prothrombin time
RECIST 1.1
Response Evaluation Criteria in Solid Tumors 1.1
RNA
Ribonucleic acid
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SOC
System organ class
SP-A
Surfactant protein A
SP-D
Surfactant protein D
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
TGF-β
Transforming growth factor-beta
TTP
Thrombotic thrombocytopenic purpura
ULN
Upper limit of normal
VAS
Visual Analog Scale
WOCBP
Woman of childbearing potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the participant or 
his/her legally-authorized representative (where allowed by local laws and regulations) and answer 
all questions on the study.
Participants must be informed that their participation is voluntary.
Participants or their legally-authorized representative (where allowed by local laws and 
regulations) will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; the Japanese ministerial ordinance on GCP; local regulations; ICH guidelines; 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable; and 
the IRB/IEC or study center.
The medical record will include a statement that written informed consent was obtained before the 
participant was enrolled in the study and the date the written consent was obtained. The authorized 
person obtaining the informed consent must also sign the ICF.
If the ICF is updated during their participation in the study, participants must be reconsented to the 
most current, approved version.
Participants who are rescreened are required to sign a new ICF.
Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed consent. 
All participant records or datasets transferred to the Sponsor will contain the identifier only; 
participant names or any identifiable information will not be transferred.
The Sponsor will inform participants that their personal study-related data will be used per local 
data protection and privacy laws. The level of disclosure will also be explained to the participant
and pregnant partners (if applicable), who will be required to give consent for their data to be used, 
as specified in the informed consent.
The participant will be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate IRB/IEC 
members, and by regulatory authority inspectors. All such persons will strictly maintain 
participants’ confidentiality.
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Study Administrative
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the CSR.
The study will appear in the following clinical studies registries: ClinicalTrials.gov and EudraCT.
This study requires a significant logistic and administrative structure for its efficient execution. 
Details of structures and associated procedures will be defined in a separate Operations Manual.
This will be prepared under the supervision of the Clinical Trial Leader in close collaboration with 
the responsible units at the Sponsor.
The Sponsor will coordinate the study and will provide the support for a Contract Research 
Organization (CRO) for some activities of the study. Sponsor Global Clinical Operations will 
perform oversight of the activities performed by the CRO.
The Clinical Trial Supplies department of the Sponsor will supply the study medication of M7824, 
which will be distributed to the sites by Fisher Clinical Services.
Participant enrollment will be managed by an interactive voice response system or an interactive 
web response system.
Safety laboratory assessments will be performed locally by investigational sites. Pharmacokinetic 
(PK), 
, and 
 assessments will be performed under 
the responsibility and/or supervision of the Sponsor. 
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany, or its designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs) and 
serious adverse events (SAEs).
Quality assurance of the study conduct will be performed by the Development Quality Assurance 
Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics will supervise the statistical analyses (with the exception 
of the PK data analyses that will be outsourced to a CRO).
Details of structures and associated procedures will be defined in a separate Operations Manual.
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Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
! Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
! Applicable ICH GCP Guidelines
! The Japanese ministerial ordinance on GCP 
! Applicable laws and regulations.
The Investigator will submit the protocol, protocol amendments (if applicable), ICF, Investigator 
Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and the IRB/IEC 
will review and approve them before the study is initiated.
The Sponsor initiates the study at a site after obtaining written approval from the Head of the study 
site, based on favorable opinion/approval from the concerned IRB.
Any protocol amendments (i.e., changes to the protocol) will be documented in writing and require 
IRB/IEC approval before implementation of changes, except for changes necessary to eliminate 
an immediate hazard to study participants. When applicable, amendments will be submitted to the 
appropriate Health Authorities.
The Investigator will be responsible for the following:
! Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.
! Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures
! Providing oversight of the study conduct at the site and adherence to requirements of 21 CFR, 
ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations.
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
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Emergency Medical Support
The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as participating 
in a clinical study. Also, these give health care providers access to any information about this 
participation that may be needed to determine the course of medical treatment for the participant. 
The information on the Emergency Medical Support card may include the process for emergency 
unblinding (if applicable).
The first point of contact for all emergencies will be the clinical study Investigator caring for the 
participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer any 
questions. Any subsequent action (e.g., unblinding) will follow the standard process established 
for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical emergency.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the participants, except for AEs caused by an intentional and/or significant 
deviation on the part of the Investigator, the study site, and/or the participant. The Sponsor takes 
out insurance to fulfill the responsibility.
Clinical Study Report
After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator.
Publication
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter studies 
only in their entirety and not as individual site data. In this case, a Coordinating Investigator will 
be designated by agreement.
Authorship will be determined by agreement and in line with International Committee of Medical 
Journal Editors authorship requirements.
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Dissemination of Clinical Study Data
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 and will be submitted in 
accordance with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff who had 
been made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study.
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study intervention and therefore may be 
disclosed as required to other clinical Investigators, to the United States Food and Drug 
Administration, and to other government agencies. The Investigator also understands that, to allow 
for the use of the information derived from the clinical study, the Investigator has the obligation 
to provide the Sponsor with complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement.
Data Quality Assurance
All participant study data will be recorded on printed or electronic eCRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically or electronically 
signing the eCRF. Details for managing eCRFs are in the Operations Manual.
For 
 data (e.g., 
and pain assessments), 
 will be used.
The Investigator will maintain accurate documentation (source data) that supports the information 
in the eCRF.
The Investigator will permit study-related monitoring, quality assurance audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to the study file and source data.
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are in the Monitoring Plan or contracts.
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The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. Details will be outlined in Data 
Management documents and procedures.
Study monitors will perform ongoing source data verification to confirm that data in the eCRF are 
accurate, complete, and verifiable; that the safety and rights of participants are being protected; 
and that the study is being conducted per the currently approved protocol and any other study 
agreements, ICH GCP, the Japanese ministerial ordinance on GCP, and all applicable regulatory 
requirements.
The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
retention period without the Sponsor’s written approval. No records may be transferred to another 
location or party without the Sponsor’s written notification.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
The Investigator will keep a paper or electronic file (medical file and original medical records) at 
the site for each study participant. The file will identify each participant, contain the following 
demographic and medical information for the participant, and will be as complete as possible:
! Participant’s full name, date of birth, sex, height, and weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identifier (i.e., the Sponsor’s study number) and participant’s study number.
! Dates of entry into the study (i.e., signature date on the informed consent) and each visit to the 
site
! Any medical examinations and clinical findings predefined in the protocol
! All AEs
! Date that the participant left the study, including any reason for early withdrawal from the study 
or study intervention, if applicable.
All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory results). 
Each document will have the participant number and the procedure date; ideally, printed by the 
instrument used for the procedure. As necessary, medical evaluation of these records will be 
performed, documented, signed and dated by the Investigator. 
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Data recorded on printed or electronic eCRFs that are transcribed from source documents will be 
consistent with the source documents or the discrepancies will be explained. The Investigator may 
need to request previous medical records or transfer records, depending on the study. Also, current 
medical records will be available.
The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will be signed and dated by the Investigator and kept in the study file.
Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator or in Japan: 
a record retainer designated by the Head of the study site ensures that no destruction of medical 
records is performed without the Sponsor’s written approval.
Definition of what constitutes source data is found in the eCRF guidelines.
Study and Site Start and Closure
First Act of Recruitment
! The study start date is the date when the clinical study will be open for recruitment.
! The first act of recruitment is the first date that the first ICF is signed and will be the study start 
date.
Study Closure and Site Termination
! The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason. 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 site closure visit has 
been completed.
! The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough 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:
! 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 development of the Sponsor’s compound.
! If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator will promptly inform the participants and assure appropriate participant 
therapy and/or follow-up.
The whole study may be discontinued prematurely in the event of any of the following:
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! New information leading to unfavorable risk-benefit judgment of the study intervention, for 
example, due to:
! evidence of inefficacy of the study intervention,
! occurrence of significant previously unknown adverse reactions or unexpectedly high 
intensity or incidence of known adverse reactions, or
! other unfavorable safety findings.
(Note: Evidence of inefficacy may arise from this study or from other studies; unfavorable safety 
findings may arise from clinical or nonclinical examinations, for example, toxicology.)
! Sponsor’s decision that continuation of the study is unjustifiable for medical or ethical reasons.
! Poor enrollment of participants making completion of the study within an acceptable time frame 
unlikely.
! Discontinuation of development of the Sponsor’s study intervention.
Health Authorities and IECs/IRBs will be informed about the discontinuation of the study in 
accordance with applicable regulations (Head of study site will also be informed in Japan).
The whole study may be terminated or suspended upon request of Health Authorities.
Survival Follow-up will continue until each participant was followed up for at least 3 years after 
the End-of-Treatment.
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Appendix 3
Contraception
Contraceptive use by males or females will be consistent with local regulations on contraception 
methods for those participating in clinical studies. 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, consider additional evaluation. 
A WOCBP is not: 
1. Premenarchal 
2. A premenopausal female with 1 of the following: 
!
Documented hysterectomy 
!
Documented bilateral salpingectomy 
!
Documented bilateral oophorectomy.
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview. 
For a female with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry. 
3. A postmenopausal female 
! A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. 
! A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in a female not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, more 
than 1 FSH measurement is required in the postmenopausal range. 
A female on HRT and whose menopausal status is in doubt will be required to use one of the non-
estrogen hormonal highly effective contraception methods if she wishes to continue her HRT 
during the study. Otherwise, she must discontinue HRT to allow confirmation of postmenopausal 
status before study enrolment.
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CONTRACEPTIVES ALLOWED DURING THE STUDY
Highly Effective Methods That Have Low User Dependency 
! Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation*
! Intrauterine device (IUD) 
! Intrauterine hormone-releasing system (IUS) 
! Bilateral tubal occlusion 
! Vasectomized partner: a highly effective contraceptive method provided that the 
partner is the sole sexual partner of a WOCBP and the absence of sperm has been 
confirmed. Otherwise, use an additional highly effective method of contraception. The 
spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 
! Oral 
! Intravaginal*
! Transdermal*
! Injectable*
Progestogen-only hormone contraception associated with inhibition of ovulation 
! Oral 
! Injectable*
! Sexual abstinence: a highly effective method only if defined as refraining from 
intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study. 
Notes: 
Contraceptive use by men or women is consistent with local regulations on the use of 
contraceptive methods for clinical study participants. 
Highly effective methods are those with a failure rate of < 1% per year when used 
consistently and correctly.
Typical use failure rates differ from those when used consistently and correctly. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not 
acceptable methods of contraception for this study. Male condom and female condom 
cannot be used together (due to risk of failure with friction). 
* Not approved in Japan
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, 
regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, regardless if it is considered related to the medicinal 
product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the NCI-CTCAE, v5.0 (publication date: 27 November 2017), a 
descriptive terminology that can be used for AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment.
The 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening 
! Grade 5 or Death.
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (e.g., sudden death, 
unexplained death), the death per se might then be reported as an SAE.
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Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other non-study interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the study 
intervention include, but may not be limited to, temporal relationship between the AE and the study 
intervention, known side effects of study intervention, medical history, concomitant medication, 
course of the underlying disease, and study procedures.
Unrelated:
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
study 
intervention.
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(e.g., anemia or increased ALT) must be reported as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening. Life-threatening refers to an event in which the participant is at risk of death 
at the time of the event, not an event that hypothetically might have caused death if it was more 
severe.
! Requires inpatient hospitalization or prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be medically important (e.g., new cancer). Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered as 
SAEs when, based upon appropriate medical judgment, they may jeopardize the participant or 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs.
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Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (i.e.,
undesirable effects of any administered treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
AE/SAEs Observed in Association With Disease Progression
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the participant’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the AE reporting period, as defined in Section 8.3.2.
Adverse Events of Special Interest
Infusion-related reactions including hypersensitivity, immune-related AEs, TGF-β inhibition 
mediated skin reactions, anemia, and bleeding AEs are all considered as AESI for M7824.
Other Adverse Events to be Reported Following a Specialized Procedure 
Not applicable.
Recording and Follow-up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified, and the appropriate seriousness criteria 
documented.
Specific guidance is in the eCRF Completion and Monitoring Conventions provided by the 
Sponsor.
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Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the electronic SAE Report Form in the Electronic Data Capture 
(EDC) system.
Reporting of SAEs using a paper report form is required as a back-up method only for an EDC 
system failure. Names, addresses, and telephone and fax numbers will be included on the paper 
form. All information from the paper form must be transcribed into the electronic form as soon as 
the system becomes available.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an electronic SAE Report Form must be completed immediately thereafter.
Relevant pages from the eCRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report). 
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the drug safety department may contact the Investigator directly to obtain further 
information or to discuss the event.
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Appendix 5
Clinical Laboratory Tests
The required laboratory safety tests for the full chemistry and hematology panel is summarized in 
Table A. See Section 1.3 for details of which panel to run at each visit.
Table A
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Plateletsa
Mean Corpuscular Volume
(MCV)
White blood cell 
(WBC) Count with 
Differentiala:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Mean corpuscular hemoglobin 
concentration (MCHC)
Hemoglobina
Mean corpuscular hemoglobin 
(MCH)
Hematocrit
Activated partial thromboplastin
time (aPTT)b
Red blood cell counta
Prothrombin timeb
Absolute lymphocyte counta
International normalized ratio 
(INR)b
Absolute neutrophil counta
Biochemistry
Blood Urea Nitrogen
Potassium
Aspartate aminotransferasea
Bilirubin (total, 
indirect/direct)a
Creatininea
Sodium
Alanine aminotransferasea
Total Protein
Glucose
Calcium
Alkaline phosphatase
Lipase
Chloride
Albumin
C-reactive protein
Amylase
Full Urinalysis
Dipstick plus microscopic evaluation. Dipstick, including physical appearance, bilirubin, blood, 
color, glucose, ketones, leukocyte esterase, nitrite, pH, protein, specific gravity, urobilinogen, 
as locally available
Routine 
Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones, by dipstick
!
Microscopic examination (if blood or protein is abnormal).
Other Tests
!
FSH and estradiol (as needed if not a WOCBP only)
!
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test
!
Free T4 and TSH
!
Hepatitis Screeningc: Hepatitis B surface antigen; Hepatitis B core antibody and Hepatitis C 
antibody
!
KL-6, SP-A and SP-Dd
!
Tumor marker: CA 19.9
a Results must be reviewed by the Investigator within 48 hours prior to dosing.
b Coagulation parameters must be collected at Baseline, Day 1, every 4 weeks thereafter, End-of-Treatment Visit, 
and 28 Days Safety Follow-up Visit (See Schedule of Assessment [Table 1]).
c If hepatitis B surface antigen positive and hepatitis B core antibody positive, then reflex to quantitative HBV DNA 
(PCR); if hepatitis B core antibody positive alone, then reflex to quantitative hepatitis B DNA (PCR); if hepatitis C 
antibody positive, then reflex to quantitative hepatitis C RNA (PCR).
d Only applicable for Japanese sites.
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Appendix 6
Management of irAEs
This appendix provides recommendations to the Investigators for the management of irAEs. The 
contents are based on the NCCN irAE management guidelines (in Accordance with the Joint 
American Society of Clinical Oncology Clinical Practice Guidelines and National Comprehensive 
Cancer Network, Brahmer JR, 2018) and FDA recommendations to require permanent treatment 
discontinuation for Grade 4 irAEs (unless otherwise indicated in the tables below). Differences 
with ASCO/NCCN irAE management guidelines as recommended by the FDA are shown in bold 
and underlined text in the tables below. Critical instructions include the requirement that treatment 
must be permanently discontinued for the following Grade 4 irAE toxicities: Rash/inflammatory 
dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic syndrome, aplastic anemia, 
immune thrombocytopenia, acquired TTP, and in certain circumstances, lymphopenia.
The management of immune-related adverse events (irAEs) in patients treated with immune 
checkpoint inhibitors is presented in the following tables:
Table A1
Management of Skin irAEs in Patients Treated With ICPis.............103
Table A2
Management of GI irAEs in Patients Treated With ICPis................108
Table A3
Management of Lung irAEs in Patients Treated With ICPis ...........112
Table A4
Management of Endocrine irAEs in Patients Treated With ICPis ...113
Table A5
Management of Musculoskeletal irAEs in Patients Treated With 
ICPis .................................................................................................118
Table A6
Management of Renal irAEs in Patients Treated With ICPis...........122
Table A7
Management of Nervous System irAEs in Patients Treated With 
ICPis .................................................................................................124
Table A8
Management of Hematologic irAEs in Patients Treated With 
ICPis .................................................................................................129
Table A9
Management of Cardiovascular irAEs in Patients Treated With 
ICPis .................................................................................................136
Table A10
Management of Ocular irAEs in Patients Treated With ICPis.........138
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Table A1
Management of Skin irAEs in Patients Treated With ICPis
1.0 Skin Toxicities
1.1 Rash/inﬂammatory dermatitis
Deﬁnition: Erythema multiforme minor (a targetoid reaction in the skin and mucous membranes usually 
triggered by infections, such as herpes simplex viruses, but can be associated with an immune-related drug 
eruption and if progresses to erythema multiforme major, it and can be a harbinger of SCAR, such as SJS), 
lichenoid (resembling the ﬂat-topped, polygonal, and sometimes scaly or hypertrophic lesions of lichen-planus), 
eczematous (inﬂammatory dermatitis characterized by pruritic, erythematous, scaly, or crusted papules or 
plaques on the skin, which is vulnerable to superinfection, psoriasiform [resembling the well-demarcated, 
erythematous, and scaly papules and plaques of psoriasis], morbilliform [a nonpustular, nonbullous measles-
like exanthematous rash of the skin often referred to as “maculopapular” and without systemic symptoms or 
laboratory 
abnormalities, 
excluding 
occasional 
isolated 
peripheral 
eosinophilia], 
palmoplantar 
erythrodysesthesia [hand-foot syndrome; redness, numbness, burning, itching, and superﬁcial desquamation 
of the palms and soles], neutrophilic dermatoses [e.g., Sweet syndrome], and others)
Diagnostic work-up
Pertinent history and physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease or unrelated primary skin disorder
If needed, a biologic checkup, including a blood cell count and liver and kidney tests
Directed serologic studies if an autoimmune condition is suspected, such as lupus or dermatomyositis: a 
screening 
antinuclear 
antibody 
test, 
SS-A/Anti-Ro, 
SS-B/Anti-La 
if 
predominantly 
photodistributed/photosensitivity, antihistone, double-stranded DNA, and other relevant serologies. Consider 
expanding serologic studies or diagnostic work-up if other autoimmune conditions are considered based on 
signs, symptoms 
Skin biopsy
Consider clinical monitoring with use of serial clinical photography
Review full list of patient medications to rule out other drug-induced cause for photosensitivity
Grading
Management
Grading according to CTCAE is a challenge for skin. 
Instead, severity may be based on BSA, tolerability, 
morbidity, and duration.
G1: Symptoms do not affect the quality of life or 
controlled with topical regimen and/or oral antipruritic
Continue ICPi
Treat with topical emollients and/or mild-moderate 
potency topical corticosteroids
Counsel patients to avoid skin irritants and sun 
exposure
G2: Inﬂammatory reaction that affects quality of life 
and requires intervention based on diagnosis
Consider holding ICPi and monitor weekly for 
improvement. If not resolved, interrupt treatment until 
skin AE has reverted to Grade 1
Consider initiating prednisone (or equivalent) at 
dosing 1 mg/kg, tapering over at least 4 weeks
In addition, treat with topical emollients, oral 
antihistamines, and medium- to high-potency topical 
corticosteroids
G3: As G2 but with failure to respond to indicated 
interventions for a G2 dermatitis
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Treat with topical emollients, oral antihistamines, and 
high-potency topical corticosteroids
Initiate (methyl)prednisolone (or equivalent) 1-2 
mg/kg, tapering over at least 4 weeks
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1.0 Skin Toxicities
G4: All severe rashes unmanageable with prior 
interventions and intolerable
Permanently discontinue ICPi
Systemic corticosteroids: IV (methyl)prednisolone (or 
equivalent) dosed at 1-2 mg/kg with slow tapering 
when the toxicity resolves
Monitor closely for progression to severe cutaneous 
adverse reaction
Should admit patient immediately with direct 
oncology involvement and with an urgent consult by 
dermatology
1.2 Bullous dermatoses
Deﬁnition: Including bullous pemphigoid or other autoimmune bullous dermatoses, bullous drug reaction
Diagnostic work-up
Physical examination
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease
If needed, a biologic checkup, including a blood cell count, liver, and kidney tests; consider serum antibody 
tests to rule out bullous pemphigoid or, under the guidance of dermatology, sending patient serum for indirect 
immunoﬂuorescent testing to rule out other autoimmune blistering diseases
Referral to dermatology for blisters that are not explained by infectious or transient other causes (e.g., herpes 
simplex, herpes zoster, bullous impetigo, bullous insect bite, friction or pressure blister)
Consider skin biopsy (both hematoxylin and eosin evaluation of lesional skin and direct immunoﬂuorescence 
evaluation of perilesional skin)
Grading
Management
G1: Asymptomatic, blisters covering < 10% BSA and 
no associated erythema
If blisters are < 10% BSA, asymptomatic, and 
noninﬂammatory (such as the case with friction 
blisters or pressure blisters), cessation of ICPi is not 
necessary, and only observation and/or local wound 
care is warranted
When symptomatic bullae or erosions, which are 
deroofed vesicles or bullae, are observed on the skin 
or mucosal surfaces, the cutaneous irAE is by 
deﬁnition considered at least G2
See G2 management recommendations
G2: Blistering that affects quality of life and requires 
intervention based on diagnosis not meeting criteria 
for grade > 2
Blisters covering 10% to 30% BSA
Hold ICPi therapy and consult with dermatology for 
work-up and to determine appropriateness of 
resuming
Attention given to general local wound care, which 
includes plain petrolatum ointment and bandages or 
plain petrolatum ointment gauze and bandage over 
any open erosions, which are left over on the skin 
after the blister has popped or if the roof of the blister 
easily sloughs off
Counsel patients to avoid skin irritants and 
overexposure to sun, wear protective clothing, use 
sunscreens
Work-up for autoimmune bullous disease as above
Initiate class 1 high-potency topical corticosteroid 
(e.g., clobetasol, betamethasone or equivalent) and 
reassess every 3 days for progression or 
improvement
Low threshold to initiate treatment with prednisone 
(or equivalent) at 0.5-1 mg/kg dosing and taper over 
at least 4 weeks
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1.0 Skin Toxicities
Monitor patients with G2 irAEs closely for 
progression to involvement of greater BSA and/or 
mucous membrane involvement. Consider following 
patients closely using serial photography
Primer on monitoring for complicated cutaneous 
adverse drug reactions:
Review of systems: Skin pain (like a sunburn), 
fevers, malaise, myalgias, arthralgias, abdominal 
pain, ocular discomfort or photophobia, sores or 
discomfort in the nares, sores or discomfort in the 
oropharynx, odynophagia, hoarseness, dysuria, 
sores or discomfort in the vaginal area for women or 
involving the meatus of the penis for men, sores in 
the perianal area, or pain with bowel movements
Physical examination: Include vital signs and a full 
skin examination speciﬁcally evaluating all skin 
surfaces and mucous membranes (eyes, nares, 
oropharynx, genitals, and perianal area). Assess for 
lymphadenopathy, facial or distal extremity swelling 
(may be signs of DIHS/DRESS). Assess for pustules 
or blisters or erosions in addition to areas of “dusky 
erythema,” which may feel painful to palpation. To 
assess for a positive Nikolsky sign, place a gloved 
ﬁnger tangentially over erythematous skin and apply 
friction parallel to the skin surface. Nikolsky sign is 
positive if this results in detached or sloughing 
epidermis demonstrating poor attachment of the 
epidermis to the dermis, which is the case in some 
autoimmune disorders (e.g., pemphigus) and 
SJS/TEN
G3: Skin sloughing covering > 30% BSA with 
associated pain and limiting self-care ADL
Hold ICPi therapy and consult with dermatology to 
determine appropriateness of resuming
Administer IV (methyl)prednisolone (or equivalent) 1-
2 mg/kg, tapering over at least 4 weeks
If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab, as an 
alternative approach to treating the irAE
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other 
infection risk factors, such as neutropenia, etc.
G4: Blisters covering > 30% BSA with associated 
ﬂuid or electrolyte abnormalities
Permanently discontinue ICPi.
Admit patient immediately and place under 
supervision of a dermatologist.
Administer IV (methyl)prednisolone (or equivalent) 1-
2 mg/kg with tapering over at least 4 weeks when the 
toxicity resolves.
If bullous pemphigoid is diagnosed, it may be 
possible to avoid long-term use of systemic 
corticosteroids and treat with rituximab as an 
alternative approach to treating the irAE
Seek infectious disease consultation if patient might 
have secondary cellulitis or if patient has other 
infection risk factors, such as neutropenia, etc.
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1.0 Skin Toxicities
1.3 SCARs, including SJS, TEN, acute generalized exanthematous pustulosis, and DRESS/DIHS
Deﬁnition: Severe changes in either structure or functions of skin, the appendages or the mucous membranes 
due to a drug
Diagnostic work-up
Total body skin examination with attention to examining all mucous membranes as well as complete review of 
systems
Rule out any other etiology of the skin problem, such as an infection, an effect of another drug, or a skin 
condition linked to another systemic disease
A biologic checkup, including a CBC with differential test, and liver and kidney function tests, including 
urinalysis, in addition to the blood work; if the patient is febrile, blood cultures should be considered as well
Skin biopsies to assess for full-thickness epidermal necrosis, as is seen in SJS/TEN, as well as other possible 
etiologies like paraneoplastic pemphigus or other autoimmune blistering dermatoses or other drug reactions, 
such as acute generalized exanthematous pustulosis
Consider following patients closely using serial clinical photography
If mucous membrane involvement or blistering is observed on the skin, consider early admission to a burn 
center for further monitoring and management. Primer on monitoring for complicated cutaneous adverse drug 
reactions:
Review of systems: Skin pain (like a sunburn), fevers, malaise, myalgias, arthralgias, abdominal pain, ocular 
discomfort or photophobia, sores or discomfort in the nares, sores or discomfort in the oropharynx, 
odynophagia, hoarseness, dysuria, sores or discomfort in the vaginal area for women or involving the meatus 
of the penis for men, sores in the perianal area, or pain with bowel movements
Physical examination: Include vital signs and a full skin examination speciﬁcally evaluating all skin surfaces 
and mucous membranes (eyes, nares, oropharynx, genitals, and perianal area). Assess for lymphadenopathy, 
facial or distal extremity swelling (may be signs of DIHS/DRESS). Assess for pustules or blisters or erosions 
in addition to areas of “dusky erythema,” which may feel painful to palpation. To assess for a positive Nikolsky 
sign, place a gloved ﬁnger tangentially over erythematous skin and apply friction parallel to the skin surface. 
Nikolsky sign is positive if this results in detached or sloughing epidermis demonstrating poor attachment of 
the epidermis to the dermis, which is the case in some autoimmune disorders (e.g., pemphigus) and SJS/TEN
Grading
Management
All Grades
In cases of suspected SJS or any mucous 
membrane involvement, discontinue ICPi treatment 
and monitor closely for improvement, regardless of 
grade
G1: NA
For SCARs, there is no G1 category; if lower BSA is 
involved with bullae or erosions, there should remain 
a high concern that this reaction will progress to G3 
or G4
G2: Morbilliform (“maculopapular”) exanthem 
covering 10%-30% BSA with systemic symptoms, 
lymphadenopathy, or facial swelling
Hold ICPi and monitor patients closely every 3 days 
with G2 irAEs for progression to involvement of 
greater BSA and/or mucous membrane involvement
Consider following patients closely using serial 
photography
Initiate therapy with topical emollients, oral 
antihistamines, and medium- to high-strength topical 
corticosteroids
Consider initiation of prednisone (or equivalent) 0.5-1 
mg/kg tapered over at least 4 weeks
G3: Skin sloughing covering < 10% BSA with 
mucosal involvement associated signs (e.g., 
erythema, purpura, epidermal detachment, mucous 
membrane detachment)
Hold ICPi therapy and consult with dermatology
Treat skin with topical emollients and other 
petrolatum emollients, oral antihistamines, and high-
strength topical corticosteroids; dimethicone may
also be offered as an alternative to petrolatum
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1.0 Skin Toxicities
Administer IV (methyl)prednisolone (or equivalent) 
0.5-1 mg/kg and convert to oral corticosteroids on 
response, wean over at least 4 weeks
Admit to burn and/or consult wound services with 
attention to supportive care, including ﬂuid and 
electrolyte balance, minimizing insensible water 
losses, and preventing infection
Given the immune mechanism of action of these 
medicines, use of immune suppression is warranted 
and should be offered
For mucous membrane involvement of SJS or TEN, 
appropriate consulting services should be offered to 
guide management in preventing sequelae from 
scarring (e.g., ophthalmology; ear, nose, and throat; 
urology; gynecology; etc, as appropriate)
G4: Skin erythema and blistering/sloughing covering 
≥10% to > 30% BSA with associated signs (e.g., 
erythema, purpura, epidermal detachment, mucous 
membrane detachment) and/or systemic symptoms 
and concerning associated blood work abnormalities 
(e.g., liver function test elevations in the setting of 
DRESS/DIHS)
Permanently discontinue ICPi
Admit patient immediately to a burn unit or ICU with 
consulted dermatology and wound care services
Consider further consultations based on 
management of mucosal surfaces
(e.g., ophthalmology; urology; gynecology; ear, nose, 
and throat surgery; etc). Initiate IV 
(methyl)prednisolone (or equivalent) 1-2 mg/kg, 
tapering when toxicity resolves to normal
IVIG or cyclosporine may also be considered in 
severe or corticosteroid-unresponsive cases
Consider pain/palliative consultation and/or 
admission in patients presenting with DRESS 
manifestations
Additional considerations: The usual prohibition of corticosteroids for SJS is not relevant here, as the 
underlying mechanism is a T-cell immunodirected toxicity
Adequate suppression is necessary with corticosteroids or other agents and may be prolonged in cases of 
DRESS/DIHS
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate
ADL=activities of daily living,
AE=Adverse event,
BSA=
body surface area,
CBC=complete blood count, 
CTCAE=Common Terminology Criteria for Adverse Events,
DIHS=drug-induced hypersensitivity syndrome,
DRESS=drug reaction with eosinophilia and systemic symptoms, G=grade, ICPi=immune checkpoint inhibitor,
ICU=intensive care unit, irAE=immune-related adverse event, IV=intravenous, IVIG=intravenous immunoglobulin,
NA=not applicable, SCAR=severe cutaneous adverse reactions, SJS=Stevens-Johnson syndrome, SS-A/B= Sjogren's 
syndrome A/B, TEN=toxic epidermal necrolysis.
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Table A2
Management of GI irAEs in Patients Treated With ICPis
2.0 GI Toxicities
2.1 Colitis
Deﬁnition: A disorder characterized by inﬂammation of the colon
Diagnostic work-up
G2
Work-up of blood (CBC, comprehensive metabolic panel, TSH, ESR, CRP), stool (culture, Clostridium difficile, 
parasite, CMV or other viral etiology, ova and parasite) should be performed
Consider testing for lactoferrin (for patient stratiﬁcation to determine who needs more urgent endoscopy) and 
calprotectin (to follow-up on disease activity)
Screening laboratories (HIV, hepatitis A and B, and blood QuantiFERON for TB) to prepare patients to start 
inﬂiximab should be routinely done in patients at high risk for those infections and appropriately selected 
patients based on infectious disease expert’s evaluation
Imaging (e.g., CT scan of abdomen and pelvis and GI endoscopy with biopsy) should be considered as there 
is evidence showing that the presence of ulceration in the colon can predict a corticosteroid-refractory course, 
which may require early inﬂiximab
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring can be considered when clinically indicated and when planning to resume 
therapy
G3-4
All the work-up listed for G2 (blood, stool, imaging, and scope with biopsy) should be completed immediately
Consider repeating endoscopy for patients who do not respond to immunosuppressive agents; repeating 
endoscopy for disease monitoring should only be considered when clinically indicated and when planning to 
resume ICPi
Grading (based on CTCAE for diarrhea, as most 
often used clinically)
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Abdominal pain, nausea, cramping, blood or mucus 
in stool or changes in bowel habits Fever, abdominal 
distention, obstipation, constipation
For G2 or higher, consider permanently discontinuing 
CTLA-4 agents and may restart PD-1, PD-L1 agents 
if patient can recover to G1 or less; concurrent 
immunosuppressant maintenance therapy should be 
considered only if clinically indicated in individual 
cases
G1: Increase of fewer than four stools per day over 
baseline; mild increase in ostomy output compared 
with baseline
Continue ICPi; alternatively, ICPi may be held 
temporarily and resumed if toxicity does not exceed
G1
Monitor for dehydration and recommend dietary 
changes Facilitate expedited phone contact with 
patient/caregiver May obtain gastroenterology 
consult for prolonged G1 cases
G2: Increase of four to six stools per day over 
baseline; moderate increase in ostomy output 
compared with baseline
Should hold ICPi temporarily until patient’s symptoms 
recover to G1; can consider permanently
discontinuing CTLA-4 agents and may restart PD-1, 
PD-L1 agents if patient can recover to G1 or less
Concurrent immunosuppressant maintenance 
therapy (< 10 mg prednisone equivalent dose) may 
be offered only if clinically indicated in individual 
cases
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2.0 GI Toxicities
May also include supportive care with medications 
such as Imodium if infection has been ruled out
Should consult with gastroenterology for G2 or higher
Administer corticosteroids, unless diarrhea is 
transient, starting with initial dose of 1 mg/kg/day 
prednisone or equivalent
When symptoms improve to G1 or less, taper 
corticosteroids over at least 4-6 weeks before 
resuming treatment, although resuming treatment 
while on low-dose corticosteroid may also be an 
option after an evaluation of the risks and beneﬁts
EGD/colonoscopy, endoscopy evaluation should be 
highly recommended for cases grade ≥2 to stratify 
patients for early treatment with inﬂiximab based on 
the endoscopic ﬁndings and to determine the safety 
of resuming PD-1, PD-L1 therapy
Stool inﬂammatory markers can be considered 
(lactoferrin and calprotectin) in cases of G2 or higher 
to differentiate functional v inﬂammatory diarrhea, 
and use calprotectin to monitor treatment response if 
provider prefers
Repeat colonoscopy is optional for cases of G2 or 
higher for disease activity monitoring to achieve 
complete remission, especially if there is a plan to 
resume ICPi
G3: Increase of seven or more stools per day over 
baseline, incontinence, hospitalization indicated, 
severe increase in ostomy output compared with 
baseline, limiting self-care ADL
Should consider permanently discontinuing CTLA-4 
agents and may restart PD-1, PD-L1 agents if patient 
can recover to G1 or less.
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Consider hospitalization or outpatient facility for 
patients with dehydration or electrolyte imbalance
If symptoms persist ≥3-5 days or recur after 
improvement, consider administering IV 
corticosteroid or noncorticosteroid (e.g., inﬂiximab)
Consider colonoscopy in cases where patients have 
been on immunosuppression and may be at risk for 
opportunistic infections as an independent cause for 
diarrhea (i.e., CMV colitis) and for those who are 
anti-TNF or corticosteroid refractory
G4: Life-threatening consequences; urgent 
intervention indicated
Permanently discontinue treatment
Should admit patient when clinically indicated; 
patients managed as outpatients should be very 
closely monitored
Administer 1-2 mg/kg/d methylprednisolone or 
equivalent until symptoms improve to G1, and then 
start taper over 4-6 weeks
Consider early inﬂiximab 5-10 mg/kg if symptoms 
refractory to corticosteroid within 2-3 days Consider 
lower GI endoscopy if symptoms are refractory 
despite treatment or there is concern of new 
infections
Additional considerations
The use of vedolizumab (not approved in Japan) may be considered in patients refractory to inﬂiximab and/or 
contraindicated to TNF-α blocker. The decision should be made on an individual basis from gastroenterology 
and oncology evaluation. This is based on case series showing promising results
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2.0 GI Toxicities
Patients with hepatitis and irAE colitis are rare, and management should include permanently discontinuing 
ICPi and offering other immunosuppressant agents that work systemically for both conditions
Currently, enteritis alone as the cause of diarrhea is uncommon and requires small bowel biopsy as the 
evaluation tool. It may be managed similar as colitis, including corticosteroid and/or inﬂiximab, etc.
2.2 Hepatitis
Deﬁnition: A disorder characterized by a viral pathologic process involving the liver parenchyma
Diagnostic work-up
Monitor patient for abnormal liver blood tests: AST, ALT, and bilirubin prior to each infusion and/or weekly if 
G1 liver function test elevations. No treatment is recommended for G1 liver function test abnormality
For G2 or higher:
Work-up for other causes of elevated liver enzymes should be tested, viral hepatitis, alcohol history, iron 
study, thromboembolic event, liver ultrasound, cross-sectional imaging for potential liver metastasis from 
primary malignancy. If suspicion for primary autoimmune hepatitis is high, can consider ANAs, antismooth 
muscle antibodies, antineutrophil cytoplasmic antibodies. If patients with elevated alkaline phosphatase 
alone, g-glutamyl transferase should be tested. For isolated elevation of transaminases, consider checking 
CK for other etiologies
Grading
Management
All patients
Counsel all patients to be aware of and inform their 
health care provider immediately if they experience:
Yellowing of skin or whites of the eyes Severe 
nausea or vomiting
Pain on the right side of the abdomen Drowsiness
Dark urine (tea colored)
Bleeding or bruising more easily than normal Feeling 
less hungry than usual
G1: Asymptomatic (AST or ALT > ULN to 3.0 x ULN 
and/or total bilirubin > ULN to 1.5 x ULN)
Continue ICPi with close monitoring; consider 
alternate etiologies
Monitor laboratories one to two times weekly
Manage with supportive care for symptom control
G2: Asymptomatic (AST or ALT > 3.0 to ≤5 x ULN 
and/or total bilirubin > 1.5 to ≤3 x ULN)
Hold ICPi temporarily and resume if recover to G1 or 
less on prednisone ≤10 mg/d
For grade 2 hepatic toxicity with symptoms, may 
administer corticosteroid 0.5-1 mg/kg/d prednisone or 
equivalent if the abnormal elevation persists with 
signiﬁcant clinical symptoms in 3-5 days Increase 
frequency of monitoring to every 3 days
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-mediated 
hepatitis given the potential risk of idiosyncratic liver 
failure (Note: No clear evidence shows the liver 
toxicity from inﬂiximab from other studies)
In follow-up, may resume ICPi treatment followed by 
taper only when symptoms improve to G1 or less and 
corticosteroid ≤10 mg/d; taper over at least 1 month
Patients should be advised to stop unnecessary 
medications and any known hepatotoxic drugs
G3: Symptomatic liver dysfunction, ﬁbrosis by 
biopsy, compensated cirrhosis, reactivation of 
chronic hepatitis (AST or ALT 5-20 x ULN and/or 
total bilirubin 3-10 x 3 ULN)
Permanently discontinue ICPi
Immediately start corticosteroid 1-2 mg/kg 
methylprednisolone or equivalent
If corticosteroid refractory or no improvement after 
3 days, consider mycophenolate mofetil or 
azathioprine (if using azathioprine should test for
thiopurine methyltransferase deﬁciency)
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2.0 GI Toxicities
Laboratories at daily or every other day; consider 
inpatient monitoring for patients with AST/ALT 
> 8 x ULN and/or elevated TB 3 x ULN
Increase frequency of monitoring to every 1-2 days
Inﬂiximab might not be the most appropriate 
treatment option in the situation of immune-mediated 
hepatitis given the potential risk of liver failure (Note: 
No clear evidence shows that the liver toxicity from 
inﬂiximab from other studies); alternatives include 
non–TNF-α agents as systemic 
immunosuppressants. If no improvement is achieved 
with corticosteroids or for patients on combination 
therapy with a novel agent, with standard 
chemotherapy, or with targeted therapy, refer to 
hepatologist for further pathologic evaluation of 
hepatitis
Corticosteroid taper can be attempted around 
4-6 weeks; re-escalate if needed; optimal duration 
unclear
G4: Decompensated liver function (e.g., ascites, 
coagulopathy, encephalopathy, coma; AST or ALT 
> 20 x ULN and/or total bilirubin > 10 x ULN)
Permanently discontinue ICPi
Administer 2 mg/kg/d methylprednisolone 
equivalents
If corticosteroid refractory or no improvement after 
3 days, consider mycophenolate mofetil
Monitor laboratories daily; consider inpatient 
monitoring
Avoid the use of inﬂiximab in the situation of immune-
mediated hepatitis
Hepatology consult if no improvement was achieved 
with corticosteroid
Corticosteroid taper can be attempted around 4- 6 
weeks when symptoms improve to G1 or less; re-
escalate if needed; optimal duration unclear
Consider transfer to tertiary care facility if necessary
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations is moderate.
ADL=activities of daily living, ALT=alanine aminotransferase, ANA=antinuclear antibody, AST= aspartate 
aminotransferase, CK=creatine kinase, CMV=cytomegalovirus, CRP=C-reactive protein, CT=computed tomography,
CTCAE=Common Terminology Criteria for Adverse Events, CTLA-4=cytotoxic T-cell lymphocyte-4,
EGD=esophagogastroduodenoscopy, ESR=erythrocyte sedimentation rate, G=grade; ICPi=immune checkpoint 
inhibitor, irAE=immune-related adverse event, IV=intravenous, PD-1=programmed death 1, PD-L1=programmed 
death ligand 1, TB=tuberculosis, TNF=tumor necrosis factor, TSH=thyroid-stimulating hormone, ULN=upper limit of 
normal.
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Table A3
Management of Lung irAEs in Patients Treated With ICPis
3.0 Lung Toxicities
3.1 Pneumonitis
Deﬁnition: Focal or diffuse inﬂammation of the lung parenchyma (typically identiﬁed on CT imaging)
No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis
Diagnostic work-up
Should include the following: CXR, CT, pulse oximetry
For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and sensitivity, 
blood culture and sensitivity, urine culture and sensitivity
Grading
Management
G1: Asymptomatic, conﬁned to one lobe of the lung 
or < 25% of lung parenchyma, clinical or diagnostic 
observations only
Continue ICPi 
If clinically indicated, monitor participants weekly 
or more frequently as needed with history, 
physical examination and pulse oximetry; may 
also offer CXR. May offer one repeat CT scan in 3-4 
weeks; in patients who have had baseline testing, 
may offer a repeat spirometry/DLCO in 3-4 weeks 
If symptoms appear and/or changes in the 
physical exam are noted, treat as G2
G2: Symptomatic, involves more than one lobe of 
the lung or 25%-50% of lung parenchyma, medical 
intervention indicated, limiting instrumental ADL
Hold ICPi until resolution to G1 or less
Prednisone 1-2 mg/kg/d and taper by 5-10 mg/wk 
over 4-6 weeks Consider bronchoscopy with BAL
Consider empirical antibiotics
Monitor every 3 days with history and physical 
examination and pulse oximetry, consider CXR; no 
clinical improvement after 48-72 hours of prednisone, 
treat as G3
G3: Severe symptoms, hospitalization required, 
involves all lung lobes or 50% of lung parenchyma, 
limiting self-care
ADL, oxygen indicated
G4: Life-threatening respiratory compromise, urgent 
intervention indicated (intubation)
Permanently discontinue ICPi
Empirical antibiotics; (methyl)prednisolone IV 
1- 2 mg/kg/d; no improvement after 48 hours, may 
add inﬂiximab 5 mg/kg or mycophenolate mofetil IV 
1 g twice a day or IVIG for 5 days or 
cyclophosphamide; taper corticosteroids over 
4-6 weeks
Pulmonary and infectious disease consults if 
necessary
Bronchoscopy with BAL ± transbronchial biopsy
Patients should be hospitalized for further 
management
Additional considerations
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged 
corticosteroid use (> 12 weeks), according to institutional guidelines
Consider calcium and vitamin D supplementation with prolonged corticosteroid use
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, and 
physicians should proceed according to institutional guidelines
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
ADL=activities of daily living, BAL=bronchoalveolar lavage, CT=computed tomography, CXR=chest x-ray,
DLCO=diffusing capacity of lung for carbon monoxide, G= grade, GI=gastrointestinal, ICPi= immune checkpoint 
inhibitor, irAE=immune-related adverse event, IV=intravenous, IVIG=intravenous immunoglobulin, PPI=proton pump 
inhibitor.
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Table A4
Management of Endocrine irAEs in Patients Treated With ICPis
4.0 Endocrine Toxicity
Counsel patients to inform their health care provider immediately if they experience any changes in their health 
since their last visit, especially any of the following:
Headaches that will not go away or unusual headache 
patterns
Vision changes
Rapid heartbeat
Increased sweating
Extreme tiredness or weakness
Muscle aches
Weight gain or weight loss
Dizziness or fainting
Feeling more hungry or thirsty than usual
Hair loss
Changes in mood or behavior, such as decreased sex 
drive, irritability, or forgetfulness Feeling cold
Constipation
Voice gets deeper
Urinating more often than usual
Nausea or vomiting
Abdominal pain
4.1 Thyroid
4.1.1 Primary hypothyroidism
Deﬁnition: Elevated TSH, normal or low FT4
Diagnostic work-up
TSH and FT4 every 4-6 weeks as part of routine clinical monitoring on therapy or for case detection in 
symptomatic patients
Grading
Management
G1: TSH < 10 mIU/L and asymptomatic
G2: Moderate symptoms; able to perform ADL; TSH 
persistently > 10 mIU/L
Should continue ICPi with close follow-up and 
monitoring of TSH, FT4 May hold ICPi until symptoms 
resolve to baseline
Consider endocrine consultation
Prescribe thyroid hormone supplementation in 
symptomatic patients with any degree of TSH elevation 
or in asymptomatic patients with TSH levels that persist 
> 10 mIU/L (measured 4 weeks apart)
Monitor TSH every 6-8 weeks while titrating hormone 
replacement to normal TSH FT4 can be used in the 
short term (2 weeks) to ensure adequacy of therapy in 
those with frank hypothyroidism where the FT4 was 
initially low
Once adequately treated, should monitor thyroid 
function (at least TSH) every 6 weeks while on active 
ICPi therapy or as needed for symptoms to ensure 
appropriate replacement; repeat testing annually or as 
indicated by symptoms once stable
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate supplementation
Endocrine consultation
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4.0 Endocrine Toxicity
May admit for IV therapy if signs of myxedema 
(bradycardia, hypothermia) Thyroid supplementation 
and reassessment as in G2
Additional considerations
For patients without risk factors, full replacement can be estimated with an ideal body weight–based dose of 
approximately 1.6 μg/kg/d
For elderly or fragile patients with multiple comorbidities, consider titrating up from low dose, starting at 25- 50 mg
Extreme elevations of TSH can be seen in the recovery phase of thyroiditis and can be watched in asymptomatic 
patients to determine whether there is recovery to normal within 3-4 weeks
Under guidance of endocrinology, consider tapering hormone replacement and retesting in patients with a history 
of thyroiditis (initial thyrotoxic phase)
Adrenal dysfunction, if present, must always be replaced before thyroid hormone therapy is initiated 
4.1.2 Hyperthyroidism
Deﬁnition: Suppressed TSH and high normal or elevated FT4 and/or triiodothyronine
Diagnostic work-up
Monitor TSH, FT4 every 4-6 weeks from the start of therapy or as needed for case detection in symptomatic 
patients
Consider TSH receptor antibodies if there are clinical features and suspicion of Grave disease (e.g., 
ophthalmopathy)
Close monitoring of thyroid function every 2-3 weeks after diagnosis to catch transition to hypothyroidism in 
patients with thyroiditis and hyperthyroidism
Grading
Management
G1: Asymptomatic or mild symptoms
Can continue ICPi with close follow-up and monitoring 
of TSH, FT4 every 2-3 weeks until it is clear whether 
there will be persistent hyperthyroidism (see below) or 
hypothyroidism (see 4.1.1)
Consider holding ICPi until symptoms return to baseline
Consider endocrine consultation
b-Blocker (e.g., atenolol, propranolol) for symptomatic 
relief
Hydration and supportive care
Corticosteroids are not usually required to shorten 
duration
For persistent hyperthyroidism (> 6 weeks) or clinical 
suspicion, work-up for Graves disease (TSI or TRAb) 
and consider thionamide (methimazole or PTU) Refer 
to endocrinology for Graves disease
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until symptoms resolve to baseline with 
appropriate therapy
Endocrine consultation
b-Blocker (e.g., atenolol, propranolol) for symptomatic 
relief
For severe symptoms or concern for thyroid storm, 
hospitalize patient and initiate prednisone 1- 2 mg/kg/d 
or equivalent tapered over 1-2 weeks; consider also 
use of SSKI or thionamide (methimazole or PTU).
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4.0 Endocrine Toxicity
Additional considerations
Thyroiditis is transient and resolves in a couple of weeks to primary hypothyroidism or normal. Hypothyroidism can 
be treated as above. Graves disease is generally persistent and is due to increased thyroid hormone production 
that can be treated with antithyroid medical therapy. Physical examination ﬁndings of ophthalmopathy or thyroid 
bruit are diagnostic of Graves and should prompt early endocrine referral.
4.2 Adrenal – primary adrenal insufﬁciency
Deﬁnition: Adrenal gland failure leading to low morning cortisol, high morning ACTH, as well as hyponatremia and 
hyperkalemia with orthostasis and volume depletion due to loss of aldosterone
Diagnostic work-up for patients in whom adrenal 
insufﬁciency is suspected:
Evaluate ACTH (AM), cortisol level (AM)
Basic metabolic panel (Na, K, CO2, glucose)
Consider ACTH stimulation test for indeterminate 
results
If primary adrenal insufﬁciency (high ACTH, low 
cortisol) is found biochemically:
Evaluate for precipitating cause of crisis such as 
infection Perform an adrenal CT for 
metastasis/hemorrhage
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Replacement therapy with prednisone (5-10 mg daily) 
or hydrocortisone (10-20 mg orally every morning, 5-10 
mg orally in early afternoon)
May require ﬂudrocortisone (0.1 mg/d) for 
mineralocorticoid replacement in primary adrenal 
insufﬁciency
Titrate dose up or down as symptoms dictate
G2: Moderate symptoms, able to perform ADL
Consider holding ICPi until patient is stabilized on 
replacement hormone
Endocrine consultation
Initiate outpatient treatment at two to three times 
maintenance
(if prednisone, 20 mg daily; if hydrocortisone, 20- 30 mg 
in the morning, and 10-20 mg in the afternoon) to 
manage acute symptoms.
Taper stress-dose corticosteroids down to maintenance 
doses over 5-10 days
Maintenance therapy as in G1.
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormone
Endocrine consultation
See in clinic or, for after hours, make an emergency 
department referral for normal saline (at least 2 L) and 
IV stress-dose corticosteroids on presentation
(hydrocortisone 100 mg or dexamethasone 4 mg [if the 
diagnosis is not clear and stimulation testing will be 
needed])
Taper stress-dose corticosteroids down to maintenance 
doses over 7-14 days after discharge
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4.0 Endocrine Toxicity
Maintenance therapy as in G1
Additional considerations
Primary and secondary adrenal insufﬁciency can be distinguished by the relationship between ACTH and cortisol. 
If the ACTH is low with low cortisol, then management is as per 4.3.
Patients on corticosteroids for management of other conditions will have low morning cortisol as a result of 
iatrogenic, secondary adrenal insufﬁciency. ACTH will also be low in these patients. A diagnosis of adrenal 
insufﬁciency is challenging to make in these situations (see next section on hypophysitis).
Emergent therapy for someone with suspected adrenal insufﬁciency is best done with dexamethasone as a 
stimulation test can still be performed. If the diagnosis is already conﬁrmed, can use hydrocortisone 100 mg.
All patients need education on stress dosing and a medical alert bracelet for adrenal insufﬁciency to trigger stress-
dose corticosteroids by EMS.
Endocrine consultation prior to surgery or any procedure for stress-dose planning.
4.3 Pituitary - hypophysitis
Deﬁnition: Inﬂammation of the pituitary with varying effects on hormone function. Most commonly presenting with 
central adrenal insufﬁciency. May also have central hypothyroidism, diabetes insipidus, and hypogonadism. 
Diagnostic work-up
Diagnosis: Low ACTH with a low cortisol. Low or normal TSH with a low FT4. Hypernatremia and volume depletion 
with diabetes insipidus. Low testosterone or estradiol with low LH and FSH.
Testing:
Evaluate ACTH, cortisol (AM), TSH, FT4, electrolytes
Consider evaluating LH, FSH, and testosterone levels in males or estrogen in premenopausal females with fatigue, 
loss of libido, and mood changes Consider MRI of the brain with or without contrast with pituitary/sellar cuts in 
patients with multiple endocrine abnormalities ± new severe headaches or complaints of vision changes
Grading
Management
G1: Asymptomatic or mild symptoms
Consider holding ICPi until patient is stabilized on 
replacement hormones
Endocrine consultation
Hormonal supplementation as in G1
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
Hold ICPi until patient is stabilized on replacement 
hormones
Endocrine consultation
Hormonal supplementation as in G1
Consider initial pulse dose therapy with prednisone 1-2 
mg/kg oral daily (or equivalent) tapered over at least 1-
2 weeks
Additional considerations
Be aware of the need to start corticosteroids ﬁrst when planning hormone replacement therapy for multiple 
deﬁciencies
All patients need instruction on doubling doses for illness (stress dosing) and a medical alert bracelet for adrenal 
insufﬁciency to trigger stress-dose corticosteroids by EMS
Corticosteroid use can cause isolated central adrenal insufﬁciency
Work-up cannot be done with a simple AM cortisol in a patient on corticosteroids for other conditions
Laboratory conﬁrmation of adrenal insufﬁciency should not be attempted until treatment with corticosteroids for 
other disease is ready to be discontinued for long-term exposure, consult endocrinology for recovery and weaning 
protocol using hydrocortisone.
4.4 Diabetes
Deﬁnition: T2DM is a combination of insulin resistance and insufﬁciency that may require oral or insulin therapy. It 
may be new onset or exacerbated during therapy for nonimmunologic reasons, such as corticosteroid exposure.
Autoimmune T1DM results from islet cell destruction and is often acute onset, with ketosis and an insulin 
requirement
Diagnostic work-up
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4.0 Endocrine Toxicity
Monitor patients for hyperglycemia or other signs and symptoms of new or worsening DM, including measuring 
glucose at baseline and with each treatment cycle during induction for 12 weeks, then every 3-6 weeks thereafter. 
To guide the work-up in new-onset hyperglycemia, clinicians should consider a patient’s medical background, 
exposure history, and risk factors for each subtype of DM.
Laboratory evaluation in suspected T1DM should include testing for ketosis in urine and an assessment of the 
anion gap on a metabolic panel. Anti-glutamic acid decarboxylase, anti-islet cell, or anti-insulin antibodies are 
highly speciﬁc for autoimmune diabetes. Insulin and C-peptide levels can also assist in the diagnosis.
Grading
Management
G1: Asymptomatic or mild symptoms; fasting glucose 
value > ULN (160 mg/dL); fasting glucose value > ULN 
(8.9 mmol/L); no evidence of ketosis or laboratory 
evidence of T1DM
Can continue ICPi with close clinical follow-up and 
laboratory evaluation
May initiate oral therapy for those with new-onset T2DM
Screen for T1DM if appropriate, for example, acute 
onset with prior normal values or clinical concern for 
ketosis
G2: Moderate symptoms, able to perform ADL, fasting 
glucose value > 160-250 mg/dL; fasting glucose value
> 8.9- 13.9 mmol/L, ketosis or evidence of T1DM at any 
glucose level
May hold ICPi until glucose control is obtained
Titrate oral therapy or add insulin for worsening control 
in T2DM Should administer insulin for T1DM (or as 
default therapy if there is confusion about type)
Urgent endocrine consultation for any patient with 
T1DM; in the absence of endocrinology, internal 
medicine may sufﬁce
Consider admission for T1DM if early outpatient 
evaluation is not available or signs of ketoacidosis are 
present
G3-4: Severe symptoms, medically signiﬁcant or life-
threatening consequences, unable to perform ADL
G3: > 250-500 mg/dL (> 13.9-27.8 mmol/L)
G4: > 500 mg/dL (> 27.8 mmol/L)
Hold ICPi until glucose control is obtained on therapy 
with reduction of toxicity to G1 or less
Urgent endocrine consultation for all patients
Initiate insulin therapy for all patients
Admit for inpatient management: Concerns for 
developing DKA, Symptomatic patients regardless of 
diabetes type, New-onset T1DM unable to see 
endocrinology
Additional considerations
Insulin therapy can be used as the default in any case with hyperglycemia
Long-acting therapy alone is not usually sufﬁcient for T1DM, where half of daily requirements are usually given in 
divided doses as prandial coverage and half as long acting.
Insulin doses will be lower in T1DM because of preserved sensitivity (total daily requirement can be estimated at 
0.3-0.4 units/kg/d).
In T2DM, sliding-scale coverage with meals over a few days provides data to estimate a patient’s daily 
requirements and can be used to more rapidly titrate basal needs.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
ACTH=adrenocorticotropic hormone, ADL=activities of daily living, CT=computed tomography, DKA=diabetic 
ketoacidosis, DM=diabetes mellitus, EMS=emergency medical services, FSH=follicle-stimulating hormone, FT4=free 
thyroxine, G=grade, ICPi=immune checkpoint inhibitor, irAE=immune-related adverse event, LH=luteinizing hormone,
MRI=magnetic resonance imaging, PTU=propylthiouracil, SSKI=potassium iodide, T1DM=type 1 diabetes mellitus,
T2DM=type 2 diabetes mellitus, TRAb=thyroid-stimulating hormone receptor antibody, TSH=thyroid-stimulating 
hormone, TSI=thyroid-stimulating immunoglobulin, ULN=upper limit of normal.
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Table A5
Management of Musculoskeletal irAEs in Patients Treated With ICPis
5.0 Musculoskeletal Toxicities
5.1 Inﬂammatory arthritis
Deﬁnition: A disorder characterized by inﬂammation of the joints
Clinical symptoms: Joint pain accompanied by joint swelling; inﬂammatory symptoms, such as stiffness after 
inactivity or in the morning, lasting > 30 minutes to 1 hour; improvement of symptoms with NSAIDs or 
corticosteroids but not with opioids or other pain medications may also be suggestive of inﬂammatory arthritis.
Diagnostic work-up
G1
Complete rheumatologic history and examination of all peripheral joints for tenderness, swelling, and range of 
motion; examination of the spine Consider plain x-ray/imaging to exclude metastases and evaluate joint damage 
(erosions), if appropriate
Consider autoimmune blood panel including ANA, RF, and anti-CCP, and anti-inﬂammatory markers (ESR and 
CRP) if symptoms persist; if symptoms are suggestive of reactive arthritis or affect the spine, consider HLA B27 
testing
G2
Complete history and examination as above; laboratory tests as above
Consider US ± MRI of affected joints if clinically indicated (e.g., persistent arthritis unresponsive to treatment, 
suspicion for differential diagnoses such as metastatic lesions or septic arthritis)
Consider early referral to a rheumatologist, if there is joint swelling (synovitis) or if symptoms of arthralgia persist 
> 4 weeks
G3-4
As for G2
Seek rheumatologist advice and review
Monitoring: Patients with inﬂammatory arthritis should be monitored with serial rheumatologic examinations, 
including inﬂammatory markers, every 4-6 weeks after treatment is instituted.
Grading
Management
All Grades
Clinicians should follow reports of new joint pain to 
determine whether inﬂammatory arthritis is present; 
question whether symptom new since receiving ICPi
G1: Mild pain with inﬂammation, erythema, or joint 
swelling
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs
G2: Moderate pain associated with signs of 
inﬂammation, erythema, or joint swelling, limiting 
instrumental ADL
Hold ICPi and resume upon symptom control and on 
prednisone ≤10 mg/d 
Escalate analgesia and consider higher doses of 
NSAIDS as needed
If inadequately controlled, initiate prednisone or 
prednisolone 10-20 mg/d or equivalent for 4-6 weeks
If improvement, slow taper according to response 
during the next 4-6 weeks; if no improvement after initial 
4-6 weeks, treat as G3
If unable to lower corticosteroid dose to < 10 mg/d after 
3 months, consider DMARD
Consider intra-articular corticosteroid injections for large 
joints
Referral to rheumatology
G3-4: Severe pain associated with signs of 
inﬂammation, erythema, or joint swelling; irreversible 
joint damage; disabling; limiting self-care ADL
For G3: Hold ICPi temporarily and may resume in 
consultation with rheumatology, if recover to G1 or less
For G4: permanently discontinue ICPi
Initiate oral prednisone 0.5-1 mg/kg
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5.0 Musculoskeletal Toxicities
If failure of improvement after 4 weeks or worsening in 
meantime, consider synthetic or biologic DMARD
Synthetic: methotrexate, leﬂunomide
Biologic: consider anticytokine therapy such as TNF-α
or IL-6 receptor inhibitors. (Note: As caution, IL-6 
inhibition can cause intestinal perforation; while this is 
extremely rare, it should not be used in patients with 
colitis.) Test for viral hepatitis B, C, and latent/active 
tuberculosis test prior to DMARD treatment
Referral to rheumatology.
Additional considerations
Early recognition is critical to avoid erosive joint damage.
Corticosteroids can be used as part of initial therapy in inﬂammatory arthritis, but due to likely prolonged treatment 
requirements, physicians should consider starting corticosteroid-sparing agents earlier than one would with other 
irAEs
Oligoarthritis can be treated early on with intra-articular corticosteroids; consider early referral.
Consider PCP prophylaxis for patients treated with high dose of corticosteroids for 12 weeks, as per local 
guidelines.
5.2 Myositis
Deﬁnition: A disorder characterized by muscle inﬂammation with weakness and elevated muscle enzymes (CK). 
Muscle pain can be present in severe cases. Can be life-threatening if respiratory muscles or myocardium are 
involved
Diagnostic work-up
Complete rheumatologic and neurologic history regarding differential diagnosis; rheumatologic and neurologic 
examination, including muscle strength; and examination of the skin for ﬁndings suggestive of dermatomyositis. 
Muscle weakness is more typical of myositis than pain. Consider pre-existing conditions that can cause similar 
symptoms.
Blood testing to evaluate muscle inﬂammation
CK, transaminases (AST, ALT), LDH, and aldolase can also be elevated
Troponin to evaluate myocardial involvement and other cardiac testing, such as echocardiogram, as needed
Inﬂammatory markers (ESR and CRP)
Consider EMG, imaging (MRI), and/or biopsy on an individual basis when diagnosis is uncertain and overlap with 
neurologic syndromes, such as myasthenia gravis, is suspected
Consider paraneoplastic autoantibody testing for myositis and neurologic conditions, such as myasthenia gravis 
Monitoring: CK, ESR, CRP
G1: Complete examination and laboratory work-up as above
G2: Complete history and examination as above; autoimmune myositis blood panel; EMG, MRI of affected joints
Early referral to a rheumatologist or neurologist
G3-4: As for G2
Urgent referral to a rheumatologist or neurologist
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5.0 Musculoskeletal Toxicities
Grading
Management
G1: Mild weakness with or without pain
Continue ICPi
If CK is elevated and patient has muscle weakness, 
may offer oral corticosteroids, and treat as G2
Offer analgesia with acetaminophen or NSAIDs if there
are no contraindications
G2: Moderate weakness with or without pain, limiting 
age-appropriate instrumental ADL
Hold ICPi temporarily and may resume upon symptom 
control, if CK is normal and prednisone dose, 10 mg; if 
worsens, treat as per G3
NSAIDs as needed
Referral to rheumatologist or neurologist
If CK is elevated three times or more, initiate 
prednisone or equivalent at 0.5-1 mg/kg
May require permanent discontinuation of ICPi in most 
patients with G2 symptoms and objective ﬁndings 
(elevated enzymes, abnormal EMG, abnormal muscle 
MRI or biopsy)
G3-4: Severe weakness with or without pain, limiting 
self-care ADL
For G3: Hold ICPi until G1 or less and permanently 
discontinue if any evidence of myocardial involvement
For G4: permanently discontinue ICPi
Consider hospitalization for severe weakness
Referral to rheumatologist or neurologist
Initiate prednisone 1 mg/kg or equivalent. Consider 1-2 
mg/kg of methylprednisolone IV or higher-dose bolus if 
severe compromise (weakness severely limiting 
mobility, cardiac, respiratory, dysphagia)
Consider plasmapheresis
Consider IVIG therapy
Consider other immunosuppressant therapy, such as 
methotrexate, azathioprine, or mycophenolate mofetil, if 
symptoms and CK levels do not improve or worsen 
after 4-6 weeks; rituximab is used in primary myositis 
but caution is advised given its long biologic duration
In case of management with rituximab, ICPi 
treatment should be discontinued
Additional considerations: Caution is advised with rechallenging
5.3 Polymyalgia-like syndrome
Deﬁnition: Characterized by marked pain and stiffness in proximal upper and/or lower extremities and no signs of 
true muscle inﬂammation such as CK elevation or EMG ﬁndings of myositis. No true muscle weakness, difﬁculty in 
active motion related to pain
Diagnostic work-up
G1
Complete rheumatologic history regarding differential diagnosis and examination of all joints and skin
Check for symptoms of temporal arteritis, such as headache or visual disturbances; refer to ophthalmologist if 
present, and consider temporal artery biopsy ANA, RF, anti-CCP
CK to evaluate differential diagnosis of myositis
Inﬂammatory markers (ESR, CRP)
Monitoring: ESR, CRP
G2: Complete history and examination as above; autoimmune tests as required for differential diagnosis; early 
referral to a rheumatologist
G3-4: As for G2; see rheumatologist advice and review
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5.0 Musculoskeletal Toxicities
Grading
Management
G1: Mild stiffness and pain
Continue ICPi
Initiate analgesia with acetaminophen and/or NSAIDs if 
there are no contraindications
G2: Moderate stiffness and pain, limiting age-
appropriate instrumental ADL
Consider holding ICPi and resuming upon symptom 
control, prednisolone < 10 mg; if worsens, treat as per 
G3
Initiate prednisone 20 mg/d or equivalent; if symptoms 
improve, start to taper dose after 3-4 weeks
If no improvement or need for higher dosages after 
4 weeks, escalate to G3 Consider referral to 
rheumatology
G3-4: Severe stiffness and pain, limiting self-care ADL
For G3: Hold ICPi and may resume, in consultation with 
rheumatology, if recover to G1 or less; however, note 
that cases of toxicity returning upon rechallenge have 
been 
reported. 
ICPi 
should 
be 
permanently 
discontinued in such cases
For G4: permanently discontinue ICPi
Referral to rheumatology
Should initiate prednisone 20 mg/d or equivalent. If no 
improvement or need for higher dosages for prolonged 
time, may offer a corticosteroid-sparing agent such as 
methotrexate or IL-6 inhibition with tocilizumab
(Note: As caution, IL-6 inhibition can cause intestinal 
perforation; while this is extremely rare, it should not be 
used in patients with colitis or GI metastases). Consider 
admission for pain control
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
ADL=activities of daily living, ANA=antinuclear antibodies, CCP=citrullinated protein antibody, CK= creatine kinase,
CRP=C-reactive protein, DMARD=disease-modifying antirheumatic drug, EMG=electromyography, ESR=erythrocyte 
sedimentation rate,
ICPi=immune checkpoint inhibitor, IL=interleukin,
irAE=immune-related adverse event,
IV=intravenous,
IVIG=intravenous immunoglobulin,
LDH=lactate dehydrogenase,
NSAID=nonsteroidal anti-
inﬂammatory drug, PCP=Pneumocystis pneumonia, RF=rheumatoid factor, TNF=tumor necrosis factor.
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Table A6
Management of Renal irAEs in Patients Treated With ICPis
6.0 Renal Toxicities
Nephritis and renal dysfunction: diagnosis and monitoring
For any suspected immune-mediated adverse reactions, exclude other causes
Monitor patients for elevated serum creatinine prior to every dose
Routine urinalysis is not necessary, other than to rule out UTIs, etc; nephrology may consider further
If no potential alternative cause of AKI identiﬁed, then one should forego biopsy and proceed directly with 
immunosuppressive therapy Swift treatment of autoimmune component important
6.1 Nephritis
Deﬁnition: Inﬂammation of the kidney affecting the structure
Grading
Management
G1: Creatinine level increase 
> ULN - 1.5 x ULN 
Consider temporarily holding ICPi, pending 
consideration of potential alternative etiologies 
(recent IV contrast, medications, ﬂuid status) and 
baseline renal function. A change that is still 
< 1.5 ULN could be meaningful
G2: Creatinine 
> 1.5 - 3.0 x baseline; > 1.5 - 3.0 x ULN 
Hold ICPi 
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc); if other etiologies ruled 
out, administer 0.5-1 mg/kg/d prednisone equivalents
If worsening or no improvement: 1 to 2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
If improved to G1 or less, taper corticosteroids over 4-
6 weeks If no recurrence of chronic renal insufﬁciency, 
discuss resumption of ICPi with patient after taking 
into account the risks and beneﬁts.
G3: Creatinine 
> 3.0 x baseline; > 3.0 - 6.0 x ULN
Permanently discontinue ICPi
G4: Life-threatening consequences; dialysis 
indicated
> 6.0 x ULN
Permanently discontinue ICPi
Consult nephrology
Evaluate for other causes (recent IV contrast, 
medications, ﬂuid status, etc)
Administer corticosteroids (initial dose of 1-2 mg/kg/d 
prednisone or equivalent)
Additional considerations
Monitor creatinine weekly
Reﬂex kidney biopsy should be discouraged until corticosteroid treatment has been attempted
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6.0 Renal Toxicities
6.2 Symptomatic nephritis: follow-up
Grading
Management
G1
Improved to baseline, resume routine creatinine 
monitoring
G2
If improved to G1, taper corticosteroids over at least 
3 weeks before resuming treatment with routine 
creatinine monitoring If elevations persist > 7 days or 
worsen and no other cause found, treat as G3
G3
If improved to G1, taper corticosteroids over at least 
4 weeks 
If elevations persist 3-5 days or worsen, consider 
additional immunosuppression (e.g., mycophenolate)
G4
If improved to G1, taper corticosteroids over at least 
4 weeks
If elevations persist 2-3 days or worsen, consider 
additional immunosuppression (e.g., mycophenolate)
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
AKI=acute kidney injury, G=grade, ICPi=immune checkpoint inhibitor, irAE=immune-related adverse event,
IV=intravenous, ULN=upper limit of normal, UTI=urinary tract infection.
Document No. 
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Table A7
Management of Nervous System irAEs in Patients Treated With ICPis
7.0 Nervous System Toxicities
7.1 Myasthenia gravis
Deﬁnition: Fatigable or ﬂuctuating muscle weakness, generally more proximal than distal. Frequently has 
ocular and/or bulbar involvement (ptosis, extraocular movement abnormalities resulting in double vision, 
dysphagia, dysarthria, facial muscle weakness). May have neck and/or respiratory muscle weakness. Note: 
May occur with myositis and/or myocarditis. Respiratory symptoms may require evaluation to rule out 
pneumonitis, myocarditis. Miller Fisher variant of Guillain-Barré syndrome (ophthalmoparesis) and the 
oculobulbar myositis (ptosis, ophthalmoparesis, dysphagia, neck and respiratory weakness) with ICPi may 
have overlapping symptoms.
Diagnostic work-up
AChR and anti-striated muscle antibodies in blood; if AChR antibodies are negative, consider muscle speciﬁc 
kinase and lipoprotein-related 4 antibodies in blood Pulmonary function assessment with NIF and VC
CPK, aldolase, ESR, CRP for possible concurrent myositis
Consider MRI of brain and/or spine, depending on symptoms to rule out CNS involvement by disease or 
alternate diagnosis
If respiratory insufﬁciency or elevated CPK, troponin T, perform cardiac examination with ECG and TTE for 
possible concomitant myocarditis
Neurologic consultation
Electrodiagnostic studies, including neuromuscular junction testing with repetitive stimulation and/or jitter 
studies, NCS to exclude neuropathy, and needle EMG to evaluate for myositis
Grading
Management
All grades
All grades warrant work-up and intervention given 
potential for progressive myasthenia gravis to lead to 
respiratory compromise
No G1
G2: Some symptoms interfering with ADL MGFA 
severity class 1 (ocular symptoms and ﬁndings only) 
and MGFA severity class 2 (mild generalized 
weakness)
Hold ICPi and may resume in G2 patients (MGFA 
1 and 2) only if symptoms resolve 
Should consult neurology
Pyridostigmine starting at 30 mg orally three times a 
day and gradually increase to maximum of 120 mg 
orally four times a day as tolerated and based on 
symptoms Administer corticosteroids (prednisone, 
1-1.5 mg/kg orally daily) if symptoms G2; wean based 
on symptom improvement
G3-4: Limiting self-care and aids warranted, 
weakness limiting walking, ANY dysphagia, facial 
weakness, respiratory muscle weakness, or rapidly 
progressive symptoms, or MGFA severity class 3-4 
moderate to severe generalized weakness to 
myasthenic crisis
Permanently discontinue ICPi
Admit patient, may need ICU-level monitoring
Neurology consult
Continue corticosteroids and initiate IVIG 2 g/kg IV 
over 5 days (0.4 g/kg/d) or plasmapheresis for 5 days
Frequent pulmonary function assessment
Daily neurologic review
Additional considerations
Avoid medications that can worsen myasthenia: β-blockers, IV magnesium, ﬂuoroquinolones, 
aminoglycosides, and macrolides Initially a 5-day course of plasmapheresis or a 2 g/kg course of IVIG over 
5 days
1-2 mg/kg methylprednisolone daily, wean based on symptom improvement
Pyridostigmine, wean based on improvement
ICPi-associated myasthenia gravis may be monophasic, and additional corticosteroid-sparing agents may not 
be required
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7.0 Nervous System Toxicities
7.2 Guillain-Barré syndrome
Deﬁnition: Progressive, most often symmetrical muscle weakness with absent or reduced deep tendon 
reﬂexes. Often starts with sensory symptoms/neuropathic pain localized to lower back and thighs. May 
involve extremities (typically ascending weakness but not always), facial, respiratory, and bulbar and 
oculomotor nerves. May have dysregulation of autonomic nerves.
Diagnostic work-up
Neurologic consultation
MRI of spine with or without contrast (rule out compressive lesion and evaluate for nerve root 
enhancement/thickening)
Lumbar puncture: CSF typically has elevated protein and often elevated WBCs; even though this is not 
typically seen in classic Guillain-Barré syndrome, cytology should be sent with any CSF sample from a 
patient with cancer.
Serum antibody tests for Guillain-Barré syndrome variants (GQ1b for Miller Fisher variant a/w ataxia and 
ophthalmoplegia) Electrodiagnostic studies to evaluate polyneuropathy
Pulmonary function testing (NIF/VC)
Frequent neurochecks
Grading
Management
All grades
Warrant work-up and intervention given potential for 
progressive Guillain-Barré syndrome to lead to 
respiratory compromise
Note: There is no G1 toxicity
G1: Mild, none
NA
G2: Moderate, some interference with ADL, 
symptoms concerning to patient
Discontinue ICPi
G3-4: Severe, limiting self-care and aids warranted, 
weakness, limiting walking, ANY dysphagia, facial 
weakness, respiratory muscle weakness, or rapidly 
progressive symptoms
Permanently discontinue ICPi.
Admission to inpatient unit with capability of rapid 
transfer to ICU-level monitoring Start IVIG (0.4 g/kg/d 
for 5 days for a total dose of 2 g/kg) or 
plasmapheresis. Corticosteroids are usually not 
recommended for idiopathic Guillain-Barré syndrome; 
however, in ICPi-related forms, a trial is reasonable 
(methylprednisolone 2-4 mg/kg/d), followed by slow 
corticosteroid taper
Pulse corticosteroid dosing (methylprednisolone 1 g/d 
for 5 days) may also be considered for G3-4 along 
with IVIG or plasmapheresis
Frequent neurochecks and pulmonary function 
monitoring
Monitor for concurrent autonomic dysfunction
Nonopioid management of neuropathic pain
Treatment of constipation/ileus
Additional considerations
Slow prednisone taper after corticosteroid pulse plus IVIG or plasmapheresis May require repeat IVIG 
courses
Caution with rechallenging for severe cases
7.3 Peripheral neuropathy
Deﬁnition: Can present as asymmetric or symmetric sensory, motor, or sensory motor deﬁcit. Focal 
mononeuropathies, including cranial neuropathies (e.g., facial neuropathies/Bell palsy) may be present. 
Numbness and paresthesias may be painful or painless. Hypo- or areﬂexia or sensory ataxia may be 
present.
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7.0 Nervous System Toxicities
Diagnostic work-up
G1
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein 
electrophoresis, and other vasculitis and autoimmune screen Neurologic consultation
Consider MRI of spine with or without contrast
G2: in addition to above
MRI spine advised/MRI of brain if cranial nerve Consider EMG/NCS
Consider neurology consultation
G3-4: go to Guillain-Barré syndrome algorithm
Grading
Management
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate
Low threshold to hold ICPi and monitor symptoms for 
a week If to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (i.e., pain but no 
weakness or gait limitation)
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg 
(if progressing from mild)
Neurontin, pregabalin, or duloxetine for pain
G3-4: Severe, limiting self-care and aids warranted, 
weakness limiting walking or respiratory problems 
(i.e., leg weakness, foot drop, rapidly ascending 
sensory changes) Severe may be Guillain-Barré
syndrome and should be managed as such
Permanently discontinue ICPi
Admit patient
Neurologic consultation
Initiate IV methylprednisolone 2-4 mg/kg and proceed 
as per Guillain-Barré syndrome management
7.4 Autonomic neuropathy
Deﬁnition: Nerves that control involuntary bodily functions are damaged. This may affect blood pressure, 
temperature control, digestion, bladder function, and sexual function. A case of severe enteric neuropathy 
with ICPi has been reported. Can present with GI difﬁculties such as new severe constipation, nausea, 
urinary problems, sexual difﬁculties, sweating abnormalities, sluggish pupil reaction, and orthostatic 
hypertension.
Diagnostic work-up
An evaluation by neurologist or relevant specialist, depending on organ system, with testing that may include
Screening for other causes of autonomic dysfunction: diabetic screen, adrenal insufﬁciency, HIV, 
paraproteinemia, amyloidosis, botulism; consider chronic diseases such as Parkinson and other autoimmune 
screening
AM orthostatic vitals
Consider electrodiagnostic studies to evaluate for concurrent polyneuropathy
Consider paraneoplastic Lambert-Eaton myasthenic syndrome, antineutrophil cytoplasmic antibodies, and 
ganglionic AChR antibody testing
Grading
Management
G1: Mild, no interference with function and 
symptoms not concerning to patient
Low threshold to hold ICPi and monitor symptoms for 
a week; if to continue, monitor very closely for any 
symptom progression
G2: Moderate, some interference with ADL, 
symptoms concerning to patient
Hold ICPi and resume once return to G1
Initial observation OR initiate prednisone 0.5-1 mg/kg 
(if progressing from mild)
Neurologic consultation
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7.0 Nervous System Toxicities
G3-4: Severe, limiting self-care and aids warranted
Permanently discontinue ICPi
Admit patient
Initiate methylprednisolone 1 g daily for 3 days 
followed by oral corticosteroid taper Neurologic 
consultation
7.5 Aseptic meningitis
Deﬁnition: may present with headache, photophobia, and neck stiffness; often afebrile but may be febrile. 
There may be nausea/vomiting. Mental status should be normal (distinguishes from encephalitis).
Diagnostic work-up
MRI of brain with or without contrast + pituitary protocol
AM cortisol, ACTH to rule out adrenal insufﬁciency
Consider lumbar puncture: measure opening pressure; check cell count and protein glucose; and perform 
Gram stain, culture, PCR for HSV, and other viral PCRs depending on suspicion, cytology
May see elevated WBC count with normal glucose, normal culture, and Gram stain; may see reactive 
lymphocytes or histiocytes on cytology
Grading
Management
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate.
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (i.e., pain but no 
weakness or gait limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts.
Consider empirical antiviral (IV acyclovir) and 
antibacterial therapy until CSF results. Once bacterial 
and viral infection are negative, may closely monitor 
off corticosteroids or consider oral prednisone 0.5-
1 mg/kg or IV methylprednisolone 1 mg/kg if 
moderate/severe symptoms
7.6 Encephalitis
Deﬁnition: As for aseptic meningitis, need to exclude infectious causes, especially viral (i.e., HSV).
Confusion, altered behavior, headaches, seizures, short-term memory loss, depressed level of 
consciousness, focal weakness, speech abnormality 
Diagnostic work-up
Neurologic consultation
MRI of brain with or without contrast may reveal T2/ﬂuid-attenuated inversion recovery changes typical of 
what is seen in autoimmune encephalopathies or limbic encephalitis or may be normal
Lumbar puncture: check cell count and protein glucose and perform Gram stain, culture, PCR for HSV and 
other viral PCRs depending on suspicion, cytology, oligoclonal bands, autoimmune encephalopathy, and 
paraneoplastic panels.
May see elevated WBC count with lymphocytic predominance and/or elevated protein
EEG to evaluate for subclinical seizures
Blood: metabolic, CBC, ESR, CRP, ANCA (if suspect vasculitic process), thyroid panel including TPO and 
thyroglobulin Rule out concurrent anemia/thrombocytopenia, which can present with severe headaches and 
confusion
Grading
Management
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate.
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (i.e., pain but no 
weakness or gait limitation)
G3-4: Severe, limiting self-care and aids warranted
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts
As above for aseptic meningitis suggest concurrent 
IV acyclovir until PCR results obtained and negative
Trial of methylprednisolone 1-2 mg/kg
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7.0 Nervous System Toxicities
If severe or progressing symptoms or oligoclonal 
bands present, consider pulse corticosteroids 
methylprednisolone 1 g IV daily for 3-5 days plus 
IVIG 2 g/kg over 5 days If positive for autoimmune 
encephalopathy antibody and limited or no 
improvement, consider rituximab or plasmapheresis 
in consultation with neurology.
7.7 Transverse myelitis
Deﬁnition: Acute or subacute weakness or sensory changes bilateral, often with increased deep tendon 
reﬂexes
Diagnostic work-up
Neurologic consultation
MRI of spine (with thin axial cuts through the region of suspected abnormality) and MRI of brain
Lumbar puncture: cell count, protein, glucose, oligoclonal bands, viral PCRs, cytology, onconeural antibodies 
Blood: B12, HIV, RPR, ANA, Ro/La, TSH, aquaporin-4 IgG
Evaluation for urinary retention, constipation
Grading
Management
G1: Mild, no interference with function and 
symptoms not concerning to patient. Note: Any 
cranial nerve problem should be managed as 
moderate.
G2: Moderate, some interference with ADL, 
symptoms concerning to patient (i.e., pain but no 
weakness or gait limitation)
G3-4: Severe, limiting self-care and aids warranted
Permanently discontinue ICPi
Methylprednisolone 2 mg/kg
Strongly consider higher doses of 1 g/d for 3-5 days 
Strongly consider IVIG
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
AChR=acetylcholine receptor, ACTH=adrenocorticotropic hormone, ADL=activities of daily living,
ANCA=antineutrophil cytoplasmic antibodies, CNS=central nervous system, CPK=creatine phosphokinase, CRP=C-
reactive protein, CSF=cerebrospinal fluid, ECG=electrocardiogram, EMG=electromyography, ESR=erythrocyte 
sedimentation rate, HIV=human immune deficiency, HSV=herpes simplex virus, ICPi=immune checkpoint inhibitor,
ICU=intensive care unit, IgG=immunoglobulin G, IV=intravenous, IVIG=intravenous immunoglobulin, irAE=immune-
related adverse event, MGFA=Myasthenia Gravis Foundation of America, MRI=magnetic resonance imaging, NA=not 
applicable, NCS=nerve conduction study, NIF=negative inspiratory force, PCR=polymerase chain reaction,
RPR=rapid plasma reagin, TPO=thyroid peroxidase, TSH=thyroid-stimulating hormone, TTE=transthoracic 
echocardiogram, VC=vital capacity.
Document No. 
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Table A8
Management of Hematologic irAEs in Patients Treated With ICPis
8.0 Hematologic Toxicities
8.1 Autoimmune hemolytic anemia
Deﬁnition: A condition in which RBCs are destroyed and removed from the blood stream before their normal 
lifespan is over. Symptoms include weakness, paleness, jaundice, dark-colored urine, fever, inability to do 
physical activity, and heart murmur.
Diagnostic work-up
History and physical examination (with special consideration of history of new drugs and insect, spider, or 
snake bites)
Blood chemistry, CBC with evidence of anemia, macrocytosis, evidence of hemolysis on peripheral smear; 
LDH, haptoglobin, bilirubin, reticulocyte count, free Hgb DIC panel, which could include PT, INR, infectious 
causes
Autoimmune serology
Paroxysmal nocturnal hemoglobinuria screening
Direct and indirect bilirubin; LDH; direct agglutinin test; and if no obvious cause, bone marrow analysis, 
cytogenetic analysis to evaluate for myelodysplastic syndromes
Evaluation for viral/bacterial (mycoplasma, etc) causes of hemolysis studies
Protein electrophoresis, cryoglobulin analysis
Work-up for bone marrow failure syndrome if refractory, including B12, folate, copper, parvovirus, FE, 
thyroid, infection
Glucose-6-phosphate dehydrogenase
Evaluation of common drug causes (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillin, 
NSAIDs, quinine/quinidine, ﬂudarabine, ciproﬂoxacin, lorazepam, diclofenac, etc).
Assessment of methemoglobinemia
Grading
Management
G1: Hgb < LLN to 10.0 g/dL; < LLN to 6.2 mmol/L; 
< LLN to 100 g/L
Continue ICPi with close clinical follow-up and 
laboratory evaluation
G2: Hgb < 10.0 to 8.0 g/dL; < 6.2 - 4.9 mmol/L; 
< 100 to 80 g/L
Hold ICPi and strongly consider permanent 
discontinuation
Administer 0.5-1 mg/kg/d prednisone equivalents
G3: Hgb < 8.0 g/dL; < 4.9 mmol/L; < 80 g/L; 
transfusion indicated
Permanently discontinue ICPi
Should use clinical judgment and consider admitting 
the patient
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms/speed of development)
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue
ICPi treatment
Consider RBC transfusion per existing guidelines; do 
not transfuse more than the minimum number of RBC 
units necessary to relieve symptoms of anemia or to 
return a patient to a safe Hgb range (7-8 g/dL in 
stable, noncardiac inpatients)
Should offer patients supplementation with folic acid 
1 mg once daily
G4: Life-threatening consequences, urgent 
intervention indicated
Permanently discontinue ICPi
Admit patient
Hematology consult
IV prednisone corticosteroids 1-2 mg/kg/d
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8.0 Hematologic Toxicities
If no improvement or if worsening while on 
corticosteroids or severe symptoms on presentation, 
initiate other immunosuppressive drugs, such as 
rituximab, IVIG, cyclosporin A, and mycophenolate 
mofetil
RBC transfusion per existing guidelines; discuss with 
blood bank team prior to transfusions that a patient 
with possible ICPi serious AE is in house.
Additional considerations: Monitor Hgb levels on a weekly basis until the corticosteroid tapering process is 
complete; thereafter, less-frequent testing is needed
8.2 Acquired TTP
Deﬁnition: A disorder characterized by the presence of microangiopathic hemolytic anemia, 
thrombocytopenic purpura, fever, renal abnormalities, and neurologic abnormalities, such as seizures, 
hemiplegia, and visual disturbances. It is an acute or subacute condition. 
Diagnostic work-up
History with speciﬁc questions related to drug exposure (e.g., chemotherapy, sirolimus, tacrolimus, opana ER 
antibiotics, quinine) physical examination, peripheral smear
ADAMTS13 activity level and inhibitor titer
LDH, haptoglobin, reticulocyte count, bilirubin, urinalysis to rule out other causes
PT, activated PTT, ﬁbrinogen
Blood group and antibody screen, direct antiglobulin test, CMV serology
Consider CT/MRI brain, echocardiogram, ECG
Viral studies
Note: This disorder is usually associated with a severe drop in platelets and hemolysis/anemia precipitously
Grading
Management
All grades
The ﬁrst step in the management of TTP is a high 
index of suspicion for the diagnosis and timely 
recognition; hematology consult should immediately 
be called, as delay in identiﬁcation is associated with 
increased mortality/morbidity.
Initially, the patient should be stabilized, and any 
critical organ dysfunction stabilized
G1: Evidence of RBC destruction (schistocytosis) 
without anemia, renal insufﬁciency, or 
thrombocytopenia clinically
G2: Evidence of RBC destruction (schistocytosis) 
without clinical consequence with G2 anemia and 
thrombocytopenia
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts, noting 
that there are currently no data to recommend 
restarting ICPi therapy Hematology consult
Administer 0.5-1 mg/kg/d prednisone
G3: Laboratory ﬁndings with clinical consequences 
(G3 thrombocytopenia, anemia, renal insufﬁciency 
> 2)
G4: Life-threatening consequences (e.g., CNS 
hemorrhage or thrombosis/embolism or renal 
failure)
For G3: Hold ICPi and discuss resumption with patient 
only after taking into account the risks and beneﬁts, 
noting that there are currently no data to recommend 
restarting ICPi therapy
For G4: permanently discontinue ICPi
Hematology consult
In conjunction with hematology, initiate PEX according 
to existing guidelines with further PEX dependent on 
clinical progress
Administer methylprednisolone 1 g IV daily for 3 days, 
with the ﬁrst dose typically administered immediately 
after the ﬁrst PEX
May offer rituximab
In case of management with rituximab, ICPi 
treatment will be discontinued.
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8.0 Hematologic Toxicities
8.3 Hemolytic uremic syndrome
Deﬁnition: A disorder characterized by a form of thrombotic microangiopathy with renal failure, hemolytic 
anemia, and severe thrombocytopenia. Signs and symptoms of hemolytic uremic syndrome can include:
Bloody diarrhea
Decreased urination or blood in the urine
Abdominal pain, vomiting, and occasionally fever
Pallor
Small, unexplained bruises or bleeding from the nose and mouth 
Fatigue and irritability
Confusion or seizures
High blood pressure
Swelling of the face, hands, feet, or entire body
Diagnostic work-up
History and physical examination (special consideration for new history of high-risk drugs, hypertension, or 
cardiac causes), CBC with indices
Blood smear morphology. Note that the presence of schistocytes on smear is critical for diagnosis.
Serum creatinine
ADAMTS13 (to rule out TTP)
Homocysteine/methylmalonic acid
Complement testing C3, C4, CH50 (complement inhibitory antibodies for suspected familial)
Evaluate reticulocyte count and mean corpuscular volume
Evaluation of infectious cause, including screening for EBV, CMV, HHV6
Evaluation for nutritional causes of macrocytosis (B12 and folate)
Pancreatic enzymes
Evaluation for diarrheal causes, shiga toxin, Escherichia coli O157, etc
Direct antibody test (Coombs test), haptoglobin, LDH, and other etiologies of anemia
Evaluation for common drugs causing hemolysis (tacrolimus, cyclosporine, sirolimus, etc)
Evaluation for concurrent confusion
Grading
Management
G1-2: Evidence of RBC destruction (schistocytosis) 
without clinical consequences of anemia, 
thrombocytopenia grade 2
G3: Laboratory ﬁndings with clinical consequences 
(e.g., renal insufﬁciency, petechiae)
G4: Life-threatening consequences (e.g., CNS 
thrombosis/ embolism or renal failure)
For G1 and G2: Continue ICPi with close clinical 
follow-up and laboratory evaluation
Supportive care 
For G3 and G4: Permanently discontinue ICPi
Begin therapy with eculizumab therapy 900 mg 
weekly for four doses, 1,200 mg week 5, then 
1,200 mg q2w
Red blood transfusion according to existing guidelines
8.4 Aplastic anemia
Deﬁnition: Condition in which the body stops producing enough new blood cells 
Diagnostic work-up
History and physical examination (close attention to medications, exposure to radiation, toxins, recent viral 
infections), CBC, smear, reticulocyte count
Viral studies, including CMV, HHV6, EBV, parvovirus
Nutritional assessments including B12, folate, iron, copper, ceruloplasmin, vitamin D
Serum LDH, renal function
Work-up for infectious causes
Identify marrow hypo/aplasia
Bone marrow biopsy and aspirate analysis
Peripheral blood analysis, including neutrophil count, proportion of GPI-negative cells by ﬂow for PNH
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8.0 Hematologic Toxicities
Flow cytometry to evaluate loss of GPI-anchored proteins
Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and 
ﬁltered
Grading
Management
G1: Non-severe, < 0.5 polymorphonuclear cells x 
109/L hypocellular marrow, with marrow cellularity 
< 25%, peripheral platelet count > 20,000, 
reticulocyte count < 20,000
Hold ICPi and provide growth factor support and close 
clinical follow-up, and laboratory evaluation 
Supportive transfusions as per local guidelines
G2: Severe, hypocellular marrow < 25% and two of 
the following: ANC < 500, peripheral platelet 
< 20,000, and reticulocyte < 20,000
Hold ICPi and provide growth factor support and close 
clinical laboratory evaluations daily
Administer ATG + cyclosporine; HLA typing and 
evaluation for bone marrow transplantation if patient is 
candidate; all blood products should be irradiated and 
ﬁltered
Supportive care with granulocyte colony-stimulating 
factor may be added in addition
G3-4: Very severe, ANC > 200, platelet count 
> 20,000, reticulocyte count > 20,000, plus 
hypocellular marrow > 25%
For G3: Hold ICPi and monitor weekly for 
improvement; if not resolved, discontinue treatment 
until AE has reverted to G1
For G4: permanently discontinue ICPi
Hematology consult, growth factor support
Horse ATG plus cyclosporine
If no response, repeat immunosuppression with rabbit 
ATG plus cyclosporine, cyclophosphamide
For refractory patients, consider eltrombopag plus 
supportive care
8.5 Lymphopenia
Deﬁnition: An abnormally low level of lymphocytes in PB; for adults, counts of < 1,500/mm3 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy such as ﬂudarabine, 
ATG, corticosteroids, cytotoxic chemotherapy, radiation exposure, etc, as well as history of autoimmune 
disease, family history of autoimmune disease), Evaluation of nutritional state as cause
Spleen size
CBC with differential, peripheral smear and reticulocyte counts
CXR for evaluation of presence of thymoma
Bacterial cultures and evaluation for infection (fungal, viral, bacterial speciﬁcally CMV/HIV)
Grading
Management
G1-2: 500-1,000 PB lymphocyte count
G3: 250-499 PB lymphocyte count
G4: < 250 PB lymphocyte count
Continue ICPi for G1 to G2
For G3 single laboratory values out of normal 
range without any clinical correlates, hold 
treatment until resolution to G1
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For G4, for single laboratory values out of normal 
range without any clinical correlates, permanent 
treatment discontinuation is not required.  
Treatment should be held until the etiology is 
determined. Permanent treatment discontinuation 
will only be required, if lymphopenia is considered 
of immune related in nature, no clear alternative 
explanation exists for the event, and Grade 4 
lymphopenia does not resolve within 14 days. If 
the event is not considered immune related and 
resolves to G ≤1 restarting treatment may be 
considered.
Check CBC weekly for monitoring, initiation of CMV 
screening Consider holding ICPi
Initiate Mycobacterium avium complex prophylaxis 
and Pneumocystis jirovecii prophylaxis, CMV 
screening. HIV/hepatitis screening if not already done
May consider EBV testing if evidence of 
lymphadenopathy/hepatitis, fevers, hemolysis 
consistent with lymphoproliferative disease.
8.6 Immune thrombocytopenia
Deﬁnition: An autoimmune disorder characterized by immunologic destruction of otherwise normal platelets 
Diagnostic work-up
History and physical examination (special attention for lymphocyte-depleting therapy, such as ﬂudarabine, 
ATG, corticosteroids, cytotoxic therapy), Family history of autoimmunity or personal history of autoimmune 
disease
History of viral illness
CBC
Peripheral blood smear, reticulocyte count
Bone marrow evaluation only if abnormalities in the above test results and further investigation is necessary 
for a diagnosis
Patients with newly diagnosed immune thrombocytopenia should undergo testing for HIV, hepatitis C virus, 
hepatitis B virus, and Helicobacter Pylori Direct antigen test should be checked to rule out concurrent Evan 
syndrome
Nutritional evaluation
Bone marrow evaluation if other cell lines affected and concern for aplastic anemia
Grading
Management
G1: Platelet count < 100/μL
G2: Platelet count < 75/μL
Continue ICPi with close clinical follow-up and 
laboratory evaluation
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
Administer prednisone 1 mg/kg/d (dosage range, 
0.5-2 mg/kg/d) orally for 2-4 weeks after which time 
this medication should be tapered over 4-6 weeks to 
the lowest effective dose IVIG may be used in 
conjunction with corticosteroids if a more-rapid 
increase in platelet count is required.
G3: Platelet count < 50/μL
Hold ICPi but monitor for improvement; if not resolved, 
interrupt treatment until AE has reverted to G1
G4: Platelet count < 25/μL
Permanently discontinue ICPi.
Hematology consult
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms)
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8.0 Hematologic Toxicities
If worsening or no improvement, 1-2 mg/kg/d 
prednisone equivalents and permanently discontinue 
treatment
IVIG used with corticosteroids when a more-rapid 
increase in platelet count is required
If IVIG is used, the dose should initially be 1 g/kg as a 
one-time dose. This dosage may be repeated if 
necessary
If previous treatment with corticosteroids and/or IVIG 
unsuccessful, subsequent treatment may include 
rituximab, thrombopoietin receptor agonists, or more-
potent immunosuppression (From American Society 
of Hematology guideline on immune 
thrombocytopenia; consult for further details)
8.7 Acquired hemophilia
Deﬁnition: Disorder caused by the development of autoantibodies (inhibitors) directed against plasma 
coagulation factors 
Diagnostic work-up
Full blood count to assess platelet number, ﬁbrinogen, PT, PTT, INR; the typical ﬁnding in patients with 
acquired hemophilia A is a prolonged activated PTT with a normal PT
MRI, CT, and ultrasonography may be indicated to localize, quantify, and serially monitor the location and 
response of bleeding. Medication review to assess for alternative causes
Determination of Bethesda unit level of inhibitor
Grading
Management
G1: Mild, 5%-40% of normal factor activity in blood, 
0.05-0.4 IU/mL of whole blood
Hold ICPi and discuss resumption with patient only 
after taking into account the risks and beneﬁts
Administer 0.5-1 mg/kg/d prednisone
Transfusion support as required
Treatment of bleeding disorders with hematology 
consult
G2: Moderate, 1%-5% of normal factor activity in 
blood, 0.01- 0.05 IU/mL of whole blood
Hematology consult
Administration of factor replacement (choice based on 
Bethesda unit of titer)
Administer 1 mg/kg/d prednisone, ± rituximab (dose, 
375 mg/m2 weekly for 4 weeks) and/or 
cyclophosphamide (dose, 1-2 mg/kg/d); choice of 
rituximab v cyclophosphamide is patient speciﬁc and 
should be done with assistance of hematology 
consult; prednisone, rituximab, and cyclophosphamide 
should be given for at least 5 weeks
Factors should be provided to increase level during 
bleeding episodes, with choice of factor based on 
presence or absence of inhibitor
G3-4: Severe, < 1% of normal factor activity in 
blood, < 0.01 IU/mL of whole blood
Permanently discontinue ICPi
Admit patient
Hematology consult
Administration of factor replacement, choice based on 
Bethesda unit level of inhibitor Bypassing agents may 
be used (factor VII, factor VIII inhibitor bypass 
activity); caution should be taken in the elderly and 
those with coronary artery disease
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8.0 Hematologic Toxicities
Prednisone 1-2 mg/kg/d (oral or IV depending on 
symptoms), ± rituximab (dose, 375 mg/m2 weekly for 4 
weeks) and/or cyclophosphamide (dose, 
1--2 mg/kg/d).
Transfusion support as required for bleeding
If worsening or no improvement add cyclosporine or 
immunosuppression/immunoadsorption
Additional considerations: The American Heart Association requires specialist clinical and laboratory 
expertise. Consult and/or transfer to a specialist center is often appropriate. If consultation with or transfer to 
a hemophilia center is not immediately possible, then investigation and treatment should be initiated while a 
liaison is being established.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
AE=adverse event, ANC=absolute neutrophil count, ANCA=antineutrophil cytoplasmic antibodies; ATG=antithymocyte 
globulin,
CMV=cytomegalovirus,
CT=computed 
tomography,
DIC=disseminated 
intravascular 
coagulation,
EBV=Epstein-Barr virus, G=grade, GPI=glycosylphosphatidylinositol, Hgb=hemoglobin, HHV6=human herpesvirus 6,
ICPi=immune checkpoint inhibitor,
INR=international normalized ratio,
irAE=immune-related adverse event,
IV=intravenous,
IVIG=intravenous immunoglobulin,
LDH=lactate dehydrogenase,
LLN=lower limit of normal,
MRI=magnetic resonance imaging, NSAID=nonsteroidal anti-inﬂammatory drug, PB=peripheral blood, PEX=plasma 
ex-change, PNH=paroxysmal nocturnal hemoglobinuria, PT=prothrombin time, PTT=partial thromboplastin time,
Q2W=every 2 weeks, RBC=red blood cell, TTP= thrombotic thrombocytopenic purpura.
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Table A9
Management of Cardiovascular irAEs in Patients Treated With ICPis
9.0 Cardiovascular Toxicities
9.1 Myocarditis, pericarditis, arrhythmias, impaired ventricular function with heart failure and 
vasculitis
Deﬁnition: Signs and symptoms may include chest pain, arrhythmia, palpitations, peripheral edema, 
progressive or acute dyspnea, pleural effusion, fatigue
Diagnostic work-up
At baseline
ECG
Consider troponin, especially in patient treated with combination immune therapies Upon signs/symptoms 
(consider cardiology consult)
ECG
Troponin
BNP Echocardiogram CXR
Additional testing to be guided by cardiology and may include
Stress test
Cardiac catherization 
Cardiac MRI
Grading
Management
G1: Abnormal cardiac biomarker testing, including 
abnormal ECG
G2: Abnormal screening tests with mild symptoms
G3: Moderately abnormal testing or symptoms with 
mild activity
G4: Moderate to severe decompensation, IV 
medication or intervention required, life-threatening 
conditions
All grades warrant work-up and intervention given 
potential for cardiac compromise
Consider the following:
For G1: Hold ICPi
For G2, G3, and G4: Permanently discontinue ICPi
For G1-G4: High-dose corticosteroids (1-2 mg/kg of 
prednisone) initiated rapidly (oral or IV depending on 
symptoms)
Admit patient, cardiology consultation
Immediate transfer to a coronary care unit for 
patients with elevated troponin or conduction 
abnormalities
In patients without an immediate response to high-
dose corticosteroids, consider early institution of 
cardiac transplant rejection doses of corticosteroids 
(methylprednisolone 1 g every day) and the addition 
of either mycophenolate, inﬂiximab, or antithymocyte 
globulin
Qualifying statement: Treatment recommendations are based on anecdotal evidence and the life-threatening 
nature of cardiovascular complications. The appropriateness of rechallenging remains unknown. Note that 
inﬂiximab has been associated with heart failure and is contraindicated at high doses in patients with 
moderate-severe heart failure.
9.2 Venous thromboembolism
Deﬁnition: A disorder characterized by occlusion of a vessel by a thrombus that has migrated from a distal 
site via the blood stream. Clinical signs and symptoms are variable and may include pain, swelling, increased 
skin vein visibility, erythema, and cyanosis accompanied by unexplained fever for DVT and dyspnea, pleuritic 
pain, cough, wheezing, or hemoptysis for PE
Diagnostic work-up
Evaluation of signs and symptoms of PE or DVT may include 
Clinical prediction rule to stratify patients with suspected venous thromboembolism Venous ultrasound for 
suspected DVT
CTPA for suspected PE
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9.0 Cardiovascular Toxicities
Can also consider D-dimer for low-risk patients based on risk stratiﬁcation by clinical prediction rule for 
DVT/PE when CT or Doppler are not available or appropriate Ventilation/perfusion scan is also an option 
when CTPA is not appropriate
Consider other testing, including ECG, CXR, BNP and troponin levels, and arterial blood gas
Grading
Management
G1: Venous thrombosis (e.g., superﬁcial thrombosis)
Continue ICPi
Warm compress
Clinical surveillance
G2: Venous thrombosis (e.g., uncomplicated DVT), 
medical intervention indicated
G3: Thrombosis (e.g., uncomplicated PE [venous], 
nonembolic cardiac mural [arterial] thrombus), 
medical intervention indicated
Hold ICPi until AE reverts back to G1 or less. If 
reverts to G2, use benefit-risk assessment for ICPi 
continuation
Consider consult from cardiology or other relevant 
specialties
LMWH is suggested over VKA, dabigatran, 
rivaroxaban apixaban, or edoxaban for initial and 
long-term treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long 
term
G4: Life-threatening (e.g., PE, cerebrovascular 
event, arterial insufﬁciency), hemodynamic or 
neurologic instability, urgent intervention indicated
Permanently discontinue ICPi
Admit patient and management according to CHEST, 
ACC, and/or AHA guidelines and with guidance from 
cardiology
Respiratory and hemodynamic support
LMWH is suggested over VKA, dabigatran, 
rivaroxaban, apixaban, or edoxaban for initial and 
long-term treatment
IV heparin is an acceptable alternative for initial use, 
and oral anticoagulants are acceptable for the long 
term
Further clinical management as indicated based on 
symptoms
Additional considerations
While it may be impossible to determine the etiology of thromboembolic disease in patients with advanced 
cancer and the role, if any, that ICPi treatment plays, it is reasonable to remove the potential inciting agents 
given the severity and life-threatening potential of G4 complications. Clinicians are to use clinical judgment 
and take into account the risks and beneﬁts when deciding whether to discontinue ICPi treatment.
Anticoagulant therapy duration should continue for a minimum of 9-12 months to indeﬁnitely in the setting of 
active cancer unless patient is asymptomatic, doing well, or in remission.
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
BNP=brain natriuretic peptide, CT=computed tomography, CTPA=computed tomography pulmonary angiography,
CXR=chest x-ray, DVT=deep vein thrombosis, ICPi=immune checkpoint inhibitor, irAE=immune-related adverse 
event, IV=intravenous, LMWH=low-molecular-weight heparin, MRI=magnetic resonance imaging, PE=pulmonary 
embolism, VKA=vitamin K agonist.
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Table A10
Management of Ocular irAEs in Patients Treated With ICPis
10.0 Ocular Toxicities
Counsel all patients to inform their health care provider immediately if they experience any of the following 
ocular symptoms
Blurred vision
Change in color vision Photophobia
Distortion
Scotomas
Visual ﬁeld changes Double vision Tenderness
Pain with eye movement Eyelid swelling Proptosis
Evaluation, under the guidance of ophthalmology
Check vision in each eye separately
Color vision
Red reﬂex
Pupil size, shape, and reactivity
Fundoscopic examination
Inspection of anterior part of eye with penlight
Prior conditions
Exclude patients with history of active uveitis
History of recurrent uveitis requiring systemic immunosuppression or continuous local therapy
Additional considerations
Ocular irAEs are many times seen in the context of other organ irAEs
High level of clinical suspicion as symptoms may not always be associated with severity Best to treat after 
ophthalmologist eye examination
10.1 Uveitis/iritis
Deﬁnition: Inﬂammation of the middle layer of the eye Diagnostic work-up: as per above
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Medical intervention required, anterior uveitis
Hold ICPi temporarily until after ophthalmology 
consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
May resume ICPi treatment once off systemic 
corticosteroids, which are purely indicated for ocular 
adverse effects or once corticosteroids for other 
concurrent systemic irAEs are reduced to ≤10 mg; 
continued topical/ocular corticosteroids are permitted 
when resuming therapy to manage and minimize 
local toxicity Re-treat after return to G1 or less
G3: Posterior or panuveitis
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and 
intravitreal/periocular/topical corticosteroids
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10.0 Ocular Toxicities
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral
Systemic corticosteroids (IV prednisone 1-2 mg/kg or 
methylprednisolone 0.8-1.6 mg/kg) and 
intravitreal/periocular/topical corticosteroids per 
ophthalmologist opinion
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe and 
refractory to standard treatment
10.2 Episcleritis
Deﬁnition: Inﬂammatory condition affecting the episcleral tissue between the conjunctiva and the sclera that 
occurs in the absence of an infection Diagnostic work-up: As per 10.0
Grading
Management
G1: Asymptomatic
Continue ICPi
Refer to ophthalmology within 1 week
Artiﬁcial tears
G2: Vision 20/40 or better
Hold ICPi therapy temporarily until after 
ophthalmology consult
Urgent ophthalmology referral
Topical corticosteroids, cycloplegic agents, systemic 
corticosteroids
G3: Symptomatic and vision worse than 20/40
Permanently discontinue ICPi
Urgent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids 
with cycloplegic agents
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral.
Systemic corticosteroids and topical corticosteroids 
with cycloplegic agents
Additional considerations: Consider use of inﬂiximab or other TNF-α blockers in cases that are severe and 
refractory to standard treatment.
10.3 Blepharitis
Deﬁnition: Inﬂammation of the eyelid that affects the eyelashes or tear production Diagnostic work-up: As per 
10.0
Grading
Management
No formal grading system
Warm compresses and lubrication drops
Continue therapy unless persistent and serious
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate.
ICPi=immune checkpoint inhibitor, irAE=immune-related adverse event, IV=intravenous, TNF=tumor necrosis factor.
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Appendix 8
Protocol Amendment History
The information for the current amendment is on the title page. 
Note: changes incorporated into protocol version 4.1 CHN are not included in the current 
document.
Protocol Version 4.1-CHN (21 October 2020)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The key change to the protocol is to align the China-specific protocol with the changes made in 
Version 4.0 (global protocol amendment; 20 October 2020) which were to update the definitions 
for end of study and Survival Follow-up period, as described in the table below.
Section # and Name
Description of Change
Brief Rationale
Title Page
Appendix 9 Sponsor 
Signature Page
Appendix 10 Coordinating 
Investigator Signature 
Page
Appendix 11 Principal 
Investigator Signature 
Page
Added the ClinicalTrials.gov number
For transparency and easy tracking
Title Page
6.1 Study Intervention
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
8 Study Assessments and 
Procedures
8.2.3 Clinical Safety 
Laboratory Assessments
8.5 Pharmacokinetics
8.10 Immunogenicity 
Assessments
9.4.3 Other Analyses
Appendix 2 Study 
Governance
Added additional text or modified the 
previous text
To update wording to be consistent with 
current Sponsor protocol template
Title page
Updated Medical Monitor Name and 
Contact Information 
Administrative change
1.1 Synopsis
8.2.4 Review Committees
Removed Contract Research 
Organization from Review 
Committees
To correct an error (Contract Research 
Organization is not a review committee)
1.1 Synopsis
1.3 Table 1 Schedule of 
Activities
4.1 Overall Design
Updated Survival Follow-up period 
and end of study definition
Provide sufficient survival follow up data 
collection for participants with long-term 
benefit
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Section # and Name
Description of Change
Brief Rationale
4.4 End of Study Definition
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Appendix 2 Study 
Governance
1.3 Table 1 Schedule of 
Activities
Updated T4 and TSH Assessments & 
Procedures
To specify in Table 1 that Free T4 should 
be measured
Throughout the document
Minor editorial, typographic, 
grammatical or administrative 
changes
Minor text revisions are made for clarity, 
readability, consistency of language 
across the development program, and 
compliance with current Sponsor 
guidelines
Protocol Version 4.0 (20 October 2020)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The key changes to the protocol are to update the definitions for end of study and Survival 
Follow-up period.
Section # and Name
Description of Change
Brief Rationale
Title Page
Appendix 9 Sponsor 
Signature Page
Appendix 10 Coordinating 
Investigator Signature 
Page
Appendix 11 Principal 
Investigator Signature 
Page
Added the ClinicalTrials.gov number
For transparency and easy tracking
Title Page
6.1 Study Intervention
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
8 Study Assessments and 
Procedures
8.2.3 Clinical Safety 
Laboratory Assessments
8.5 Pharmacokinetics
8.10 Immunogenicity 
Assessments
9.4.3 Other Analyses
Appendix 2 Study 
Governance
Added additional text or modified the 
previous text
To update wording to be consistent with 
current Sponsor protocol template
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Section # and Name
Description of Change
Brief Rationale
Title page
Updated Medical Monitor Name and 
Contact Information 
Administrative change
1.1 Synopsis
8.2.4 Review Committees
Removed Contract Research 
Organization from Review 
Committees
To correct an error (Contract Research 
Organization is not a review committee)
1.1 Synopsis
1.3 Table 1 Schedule of 
Activities
4.1 Overall Design
4.4 End of Study Definition
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Appendix 2 Study 
Governance
Updated Survival Follow-up period 
and end of study definition
Provide sufficient survival follow up data 
collection for participants with long-term 
benefit
1.3 Table 1 Schedule of 
Activities
Updated T4 and TSH Assessments & 
Procedures
To specify in Table 1 that Free T4 should 
be measured
Throughout the document
Minor editorial, typographic, 
grammatical or administrative 
changes
Minor text revisions are made for clarity, 
readability, consistency of language 
across the development program, and 
compliance with current Sponsor 
guidelines
Protocol Version 3.1-CHN (14 March 2020)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The key change to the protocol is the addition of a China extension cohort to the study.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis (Overall 
Design, Number of 
Participants), 4.1 Overall 
Design, 5 Study 
Population
Details of the addition of a China 
extension cohort, into which participants 
will continue to be enrolled once global 
enrollment has been closed, were 
added.
The China extension cohort was added 
to satisfy a China regulatory request. 
4.4 End of Study Definition
Text was added to accommodate the 
China extension cohort in the definition 
of end of study.
To describe the definition of the end of 
study for the China extension cohort. 
1.3 Schedule of Activities, 
7.2 Participant 
Discontinuation/Withdrawal 
from the Study, 
Appendix 2 Study 
Governance
Text was added defining the survival 
follow-up for participants enrolled in 
China.
To describe the extent of survival 
follow-up for participants in the China 
extension cohort.
9.2 Sample Size 
Determination
A justification for the sample size of the 
China extension cohort was added.
To explain the size decided for the 
China extension cohort.
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Section # and Name
Description of Change
Brief Rationale
9.3 Populations for 
Analyses
Text was added stating that the 
Chinese participants enrolled in the 
China extension cohort after global 
enrollment is closed will not be included 
in the analysis sets specified in Table 9, 
and that China participants (including 
those enrolled both in global study and 
extension cohort) will be analyzed 
separately.
Per regulatory requirements. 
1.1 Synopsis (Statistical 
Analyses), 9.4.4 Sequence 
of Analyses
The details of when the separate 
analyses of China participants will be 
performed were added. 
To describe when the separate 
analyses of China participants will be 
performed. 
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Protocol Version 3.0 (10 October 2019)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The key changes of the protocol are:
! To clarify exclusion criteria of the study population and the management of immune-related 
adverse event and bleeding events during study intervention.
Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Clarified the exclusion criterion #13
To exclude participants with history of 
bleeding diathesis or recent major bleeding 
events
6.6.1 Adverse Drug 
Reactions Requiring 
Treatment Modification
6.9.5.1 Management of 
Bleeding Events
Added text to describe management of
bleeding events
To provide guidelines for the management 
of bleeding events and indications for when
participants should have study intervention
held or discontinued
6.9.2 Immune-Related 
Adverse Events
Added text regarding Grade 4 events 
requiring permanent treatment 
discontinuation
For consistency with current risk 
information.
Appendix 6 
Management of irAEs
Revised the recommendations for 
immune related adverse events (irAE) 
management
To update irAE management guidelines. 
Instructions include the requirement that 
treatment must be permanently 
discontinued for certain Grade 4 irAE 
toxicities. 
Throughout the 
document
Minor editorial, typographic, 
grammatical or, administrative changes.
Minor text revisions are made for clarity, 
readability, consistency of language across 
the development program, and compliance 
with current Sponsor guidelines.
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Protocol Version 2.0 (26 August 2019)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The key changes of the protocol are:
! To clarify eligibility criteria of the study population
! To modify non-serious adverse event of special interest (AESI) reporting
! To include separate consent forms for treatment after initial and confirmed progressive disease
! To revise the laboratory assessments
! To include 
 per biliary tract cancer (BTC) subtype.
Section # and Name
Description of Change
Brief Rationale
Title Page
Updated the Sponsor name in Japan
To be consistent with current information
Title Page
Appendix 9
Updated the Medical Responsible 
name and contact information
To be consistent with current information
1.1 Synopsis
1.2 Schema
4.1 Overall Designs
and throughout the 
document as applicable
Sections updated
!
To clarify that treatment up to 
24 months will be applicable only for 
participants with confirmed complete 
response and that treatment beyond 
24 months, it may be permissible after 
discussion with the Medical Monitor and 
the Sponsor Medical Responsible.
!
To correct an error about when tumor 
response evaluation will be performed.
Section 1.3
Table 1: Schedule of 
Activities
Removed mention of an abbreviated 
checklist for Day 1 for confirmation of 
eligibility
Abbreviated checklist will not be used to 
confirm the participant eligibility
Updated note regarding tumor archival 
(deleted the following sentence: 
If no archival material is available and 
only 1 lesion is amenable for biopsy 
and it is the only target lesion, the 
Medical Monitor should be consulted for 
participant eligibility)
To remove the information about 
participant eligibility based on a discussion 
with Medical Monitor.
Section 1.3
Table 1 Schedule of 
Activities
and
throughout the 
document as applicable
Updated note for premedication and 
M7824 administration
!
To specify ‘related’ for the Grade 2 
infusion reactions
!
To remove the specific time window for 
premedication 
Document No. 
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Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
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Section # and Name
Description of Change
Brief Rationale
Updated note for laboratory 
assessment (hematology, serum 
chemistry and coagulation parameters)
!
To clarify which laboratory tests must 
be reviewed before dosing and for 
consistency with Appendix 5.
!
To specify time points for the 
assessment of coagulation parameters.
!
To remove the information about 
participant eligibility based on a 
discussion with Medical Monitor.
Updated note for β-HCG pregnancy test
For clarity and consistency
Updated note for PRO assessments
Clarify the timing and the procedure of 
PRO questionnaires
Updated note for patient interview
To clarify the countries who will follow this 
procedure in protocol
Updated the tumor evaluation/staging 
assessment and notes
!
Clarify the timing of tumor evaluation 
with confirm CR or PR
!
Tumor assessment should continue in 
any case until confirmed PD, regardless 
of subsequent anticancer therapy
Section 1.3
Table 2: M7824 
Pharmacokinetic, 
Immunogenicity 
Sampling
and
throughout the 
document as applicable
Clarified the protocol deviation for PK 
blood sample when the time of 
collection is not recorded
To add clarity on protocol deviation 
definition regarding PK sampling
2. Introduction and
throughout the 
document as applicable
Bintrafusp alfa was included as the 
international nonproprietary name for 
M7824
For consistency across the development 
program
3 Objectives and 
Endpoints
4.2 Scientific Rationale 
for Study Design
Addition of the following text:
In this study participants who benefit 
from treatment will stay on treatment 
with frequent safety monitoring visits 
until unacceptable toxicity or loss of 
clinical benefit. Participants with 
confirmed CR will continue treatment 
for up to 24 months since confirmation 
of CR. In the M7824 program, 
participants have been exposed to 
M7824 beyond 12 months and the 
treatment was well tolerated. In Study 
MS200647-0008, some participants 
with objective responses had long 
lasting reduction in tumor size beyond 
12 months under ongoing treatment. 
Treatment up to 24 months was also 
used with other checkpoint inhibitors 
published in 2L BTC (Ueno 2018). In 
addition, recent data showed 
continuous treatment beyond 12 
months of nivolumab significantly 
A scientific rationale for treatment up to 24 
months was provided based on the 
published literature.
Document No. 
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Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
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Section # and Name
Description of Change
Brief Rationale
improved progression-free survival 
(PFS) in non-small cell lung cancer 
compared to 12-month treatment 
duration (Spigel 2017).
4.3 Justification for 
dose
Reduced the section content and 
referred to the information provided in 
the Investigator’s Brochure
To summarize the key information while 
providing source for detailed information, if 
needed
4.4 End of Study 
Definition
Added the following information:
“The Sponsor may terminate the study 
at any time once access to study 
intervention for participants still 
benefitting is provided via a rollover 
study, expanded access, marketed 
product or another mechanism of 
access as appropriate.”
To provide further clarification about end of 
study definition
5.1 Inclusion Criteria
and
throughout the 
document as applicable
Updated inclusion criterion 3
To clarify that no time window is needed for
availability of tumor archival material or 
fresh biopsies
Updated inclusion criterion 4
To clarify eligibility criteria for 2L 
participants
Updated inclusion criterion 9 to delete 
“transfusion” (inclusion criterion 8 in the 
current protocol) 
Transfusion is standard of care procedure 
in cancer patients
Updated inclusion criterion 10 (inclusion 
criterion 9 in the current protocol)
To clarify inclusion criteria for subjects with 
biliary obstruction
Updated inclusion criterion 16 (inclusion 
criterion 15 in the current protocol)
For consistency across the development 
program
5.1 Inclusion Criteria
5.2 Exclusion Criteria
Removed inclusion criterion 8 regarding 
curative cancer and added it as the 
exclusion criterion 5 with updated 
language
For clarity in the protocol
5.2 Exclusion Criteria
and
throughout the 
document as applicable
Updated exclusion criterion 7 (exclusion 
criterion 8 in the current protocol)
To revise this criterion to cover only 
specific disease situations
Added exclusion criterion 16
To clarify eligibility criteria for 2L 
participants 
Updated exclusion criterion 25 
(inclusion criterion 27 in the current 
protocol)
To add stenting/ percutaneous transhepatic 
biliary drainage procedures as an 
exception of exclusion criteria
5.4 Screen Failure
Section updated to avoid waiver and to 
provide clarification about rescreening.
To allow rescreening instead of extending 
the Screening window and to provide 
specific information about rescreening to 
the sites.
6.5.3
Prohibited Medicines
Section updated to:
!
exclude information already 
mentioned in the exclusion criteria
!
include prohibited procedures
!
For clarity and to avoid repetition
!
To indicate that procedures as 
radio/chemo-embolization are 
prohibited since they can confound the 
efficacy results.
6.6.1 Adverse Drug 
Reactions Requiring 
Treatment Modification
Updated the definition and 
management of adverse drug reaction 
For consistency across the development 
program
6.9 Management of 
Adverse Events of 
Special Interest
Updated non-serious AESI reporting
To discontinue expedited reporting of 
non-serious AESI
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Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
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Section # and Name
Description of Change
Brief Rationale
and
throughout the 
document as applicable
6.9.1 Infusion-related 
Reactions Including 
Immediate 
Hypersensitivity
Addition of the following text: 
If IRR is observed at the first or second 
infusion, premedication should be used 
for subsequent infusions at the 
discretion of the Investigator.
To clarify as some sites had concerns that 
premedication is prohibited.
6.9.3.
Skin Adverse Events
Updated the skin adverse events and 
the management of potential TGF-β 
mediated skin adverse events
For consistency across the development 
program and to provide guidelines on the 
management of potential TGF-β mediated 
skin adverse events
6.9.4 Treatment-related 
Anemia
Appendix 4
Section updated to add information for 
new anemia events.
For consistency across the development 
program
6.9.5.3 Mild to 
moderate mucosal 
bleeding events
Included low grade mucosal bleeding 
events as additional potential risks
To be aligned with newly identified potential 
risk as per current Investigator’s Brochure 
(Version 5)
7.1 Discontinuation of 
Study Intervention
!
Inclusion of occurrence of exclusion 
criteria as a reason for participant 
withdrawn.
!
Deletion that nonpermitted 
concomitant drug can be approved 
by Sponsor and Medical 
Responsible
To clarify study discontinuation
7.1.2 Rechallenge
Section updated
To specify the rechallenge only after 
treatment discontinuation for PD. All other 
cases (discontinuation due to AEs, should 
be covered in the dose modifications 
section).
7.1.2.1 Treatment 
Beyond Initial 
Progression
7.1.2.2 Treatment 
Beyond Confirmed 
Progression
Updated criteria and treatment 
discontinuation information.
To include a separate informed consent if a 
participant wants to continue to receive 
treatment after disease progression as per 
the United States FDA request.
7.1.2.3 Continuation of 
Study Intervention After 
Local Treatment of 
Disease Progression
Included radiotherapy
To broaden the treatment options
8.1.1 Tumor Response
Added a note that measurable disease 
at Baseline will be made by IRC
For clarity
8.2.1 Physical 
Examinations and Vital 
Signs
Removed the following information: 
Three readings of blood pressure and 
pulse will be taken. The first reading 
should be rejected. The second and 
third readings should be averaged to 
give the measurement to be recorded in 
the CRF.
To correct the text to be aligned with 
standard vital signs measurement
8.3.1 Time Period and 
Frequency for 
Collecting Adverse 
Event and Serious 
Updated the timing for collecting 
Adverse Event and Serious Adverse 
Event Information
For consistency across the development 
program
Document No. 
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MS200647_0047
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Section # and Name
Description of Change
Brief Rationale
Adverse Event 
Information
8.3.3 Follow-up of 
Adverse Events and 
Serious Adverse 
Events
8.5 Pharmacokinetics
9.4.3 Other Analyses
Section updated to delete detailed 
information about PK that will be 
included in the IAP
Information will be described in the IAP as 
indicated in Section 9.4.3
9.3 Population for 
Analyses
Changes the analysis population from 
“Antidrug Antibody” to Immunogenicity 
Analysis Set” 
For consistency across the development 
program
9.4.4 Sequence of 
Analyses
!
Deletion of the following text:
Additional Interim Analyses
Interim analyses at time points that are 
not specified in the protocol may be 
performed for internal planning 
purposes
Text related to the interim analyses was 
removed based on VHP feedback
Appendix 5
Appendix 5 (Liver Safety: Suggested 
Actions and Follow-up Assessments) 
was deleted
For consistency across the development 
program
Appendix 5 (previous 
Appendix 6)
!
Deletion of bicarbonate 
!
Addition of amylase 
!
Incorrect cross-reference to footnote 
‘a’ removed from the term ‘Lipase’
!
Specified which laboratory tests
must be reviewed before dosing.
To revise the laboratory assessments
Throughout the 
document
Minor editorial, typographic, 
grammatical or administrative changes.
Minor text revisions are made for clarity, 
readability, consistency of language across 
the development program, and compliance 
with current Sponsor guidelines.
Document No. 
Object No.
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Protocol Version 1.3 (31 May 2019)
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study.
Overall Rationale for the Amendment
This protocol is being amended based on Chinese authorities request.
Section # and 
Name
Description of Change
Brief Rationale
Title Page
Appendix 11
Update the Medical Responsible name 
and contact information
To be consistent with current information
1.3
Table 1: 
Schedule of 
Activities
and throughout 
the document 
as applicable
Update laboratory assessment 
(coagulation)
To specify time points for the assessment of 
coagulation parameters
Update the tumor evaluation/staging 
assessment and notes
Clarify the timing of tumor evaluation with confirm 
CR or PR
5.1 Inclusion 
Criteria
Update inclusion criterion 4
To clarify eligibility criteria for second-line (2L)
participants
5.2 Exclusion 
Criteria
Add exclusion criterion 15
To clarify eligibility criteria for 2L participants
Appendix 6
Incorrect cross-reference to footnote ‘a’
removed from the term ‘Lipase’
To revise the laboratory assessments
Throughout the 
document
Minor editorial, typographic, grammatical 
or administrative changes.
Minor text revisions are made for clarity, 
readability, consistency of language across the 
development program, and compliance with 
current Sponsor guidelines.
Document No. 
Object No.
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MS200647_0047
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Protocol Version 1.2 (01 February 2019)
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The protocol is being amended based on a United States Food and Drug Administration request.
Section # and 
Name
Description of Change
Brief Rationale
Title Page; 
Appendix 11
Medical responsible amended to Motonobu 
Osada
To update medical responsible person.
7.1.2.1Treatment 
Beyond Initial 
Progression
Addition of the following text:
!
Participants must sign a separate 
informed consent to ensure that they are 
aware of being treated beyond initial 
progression.
To include a separate informed consent if a 
participant wants to continue to receive 
treatment after disease progression as per 
the USA FDA’s request.
7.1.2.2Treatment 
Beyond 
Confirmed 
Progression
Addition of following text: 
To qualify for treatment beyond confirmed 
progression:
!
Participants must sign a separate 
informed consent to ensure that they are 
aware of being treated beyond confirmed 
progression.
!
Investigators must document clinical 
judgment to justify the continuation of 
study drug rather than other possible 
alternative treatments.
Treatment should be discontinued 
permanently in case of any overall, 
meaningful and unequivocal further increase 
in tumor burden after confirmation of PD. As 
a general guidance, a meaningful increase, 
for example, may represent an approximately 
10% increase in tumor burden, considering 
the totality of all existing target lesions, 
non-target lesion burden, existing new 
lesions, and any further new lesions. Note: 
This 10% increase is provided as a general 
guide to be interpreted considering the 
clinical condition of the participant and any 
other considerations which the Investigator 
feels relevant, such as the availability of 
alternative treatments. In unclear situations, 
the Investigator should consult with the 
Medical Monitor, and the wellbeing of the 
individual participant should be the key 
consideration in determining the continuation 
of study drug after confirmed progression.
To include a separate informed consent if a 
participant wants to continue to receive 
treatment after disease progression as per 
the USA FDA’s request.
Document No. 
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Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
153/156
Protocol Version 1.1 (15 January 2019)
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The protocol is being amended based on VHP request.
Section # and 
Name
Description of Change
Brief Rationale
4.2 Scientific 
Rationale for 
Study Design
Addition of the following text:
Treatment in this study is limited to 
24 months. Only participants who benefit 
from treatment (either stable disease, 
PR, or CR) will stay on treatment with 
frequent safety monitoring visits. In the 
M7824 program, participants have been 
exposed to M7824 beyond 12 months 
and the treatment was tolerated. In 
study MS200647_0008, some 
participants with objective responses 
had long lasting tumor shrinkages 
beyond 12 months under ongoing 
treatment. Treatment up to 24 months 
was also used with other checkpoint 
inhibitors published in 2L BTC (Ueno 
2018). In addition, recent data showed 
continuous treatment beyond 12 months 
of nivolumab significantly improved 
progression-free survival (PFS) in 
non-small cell lung cancer (NSCLC) 
compared to 12-month treatment 
duration (Spigel 2017).
A scientific rationale for treatment up to 24 months 
was provided based on the published literature.
6.5.3 Prohibited 
Medicines
Addition of the following text:
Concomitant local or regional treatment 
(radio/chemo-embolization) are not 
permitted.
To provide direction to sites that 
radio/chemo-embolization are not allowed as they 
can confound the efficacy results of M7824 
monotherapy.
9.4.4 Sequence 
of Analyses
Deletion of the following text:
Additional Analyses
Interim analyses at time points that are 
not specified in the protocol may be 
performed for internal planning 
purposes.
Text related to the interim analyses was removed 
based on VHP feedback.
Document No. 
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Appendix 11
Principal Investigator Signature Page
Study Title:
A Phase II, Multicenter, Open-label Study to Investigate 
the Clinical Efficacy of M7824 Monotherapy in 
Participants With Locally Advanced or Metastatic Biliary 
Tract Cancer Who Fail or are Intolerant to First-line 
Platinum-Based Chemotherapy
Regulatory Agency Identifying 
Numbers:
IND: 
EudraCT: 2018-003707-19
ClinicalTrials.gov: NCT03833661
Clinical Study Protocol Version:
22 June 2021/Version 5.0
Site Number:
I am responsible for the conduct of the study at this site, and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, International Council for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
Document No. 
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SAP_001.pdf: 
Bintrafusp alfa (M7824) 
                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
                                                            Version 2
1/79
Integrated Analysis Plan
Clinical Study Protocol 
Identification No.
MS200647_0047
Title:
A Phase II, Multicenter, Open-label Study to Investigate the 
Clinical Efficacy of M7824 Monotherapy in Participants With 
Locally Advanced or Metastatic Biliary Tract Cancer Who Fail or 
are Intolerant to First-line Platinum-Based Chemotherapy
Study Phase
Phase II
Investigational Medicinal 
Product(s)
Bintrafusp Alfa (M7824)
Clinical Study Protocol 
Version
10 October 2019/Version 3.0
Integrated Analysis Plan 
Author
Coordinating Authors
, 
, 
Integrated Analysis Plan
Date and Version
26 August 2020, Version 2
Integrated Analysis Plan 
Reviewers
Function
, Merck Healthcare
, Merck Healthcare
, 
, 
, Merck 
Healthcare 
, Merck Healthcare
, 
, 
, EMD Serono
, Merck Healthcare
 Merck Healthcare
 EMD Serono
, 
, 
, 
, EMD Serono
, Merck Healthcare
, EMD Serono
, EMD Serono
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2020 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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Bintrafusp alfa (M7824) 
                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
                                                            Version 2
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Approval Page
Integrated Analysis Plan: MS200647_0047
A Phase II, Multicenter, Open-label Study to Investigate the Clinical Efficacy of M7824
Monotherapy in Participants With Locally Advanced or Metastatic Biliary Tract Cancer Who Fail 
or are Intolerant to First-line Platinum-Based Chemotherapy
Approval of the IAP by all Merck Data Analysis Responsible has to be documented within CARA 
via eSignature. With the approval within CARA, the Merck responsible for each of the analysis 
also takes responsibility that all reviewers’ comments are addressed adequately.
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Bintrafusp alfa (M7824) 
                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
                                                            Version 2
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1
Table of Contents
     Approval Page .................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................6
3
Modification History ..........................................................................10
4
Purpose of the Integrated Analysis Plan.............................................11
5
Objectives and Endpoints ...................................................................12
6
Overview of Planned Analyses...........................................................13
6.1
Primary and Second Analysis.............................................................13
7
Changes to the Planned Analyses in the Clinical Study Protocol ......14
7.1
COVID-19 Impact ..............................................................................14
8
Protocol Deviations and Analysis Populations...................................15
8.1
Definition of Protocol Deviations.......................................................15
8.2
Definition of Analysis Populations and Subgroups............................16
9
General Specifications for Data Analyses ..........................................19
10
Study Participants ...............................................................................26
10.1
Disposition of Participants and Discontinuations...............................26
10.2
Protocol Deviations ............................................................................28
11
Demographics and Other Baseline Characteristics.............................28
11.1
Demographics.....................................................................................28
11.2
Medical History ..................................................................................29
11.3
Other Baseline Characteristics............................................................29
11.3.1
Disease History...................................................................................29
11.3.2
Vital signs at Baseline ........................................................................30
11.3.3
ECOG Performance Status at Baseline...............................................30
11.3.4
Skin status history...............................................................................31
11.3.5
Tumor Biopsy.....................................................................................31
11.3.6
PD-L1 test...........................................................................................31
12
Previous or Concomitant Medications/Procedures.............................31
12.1
Previous and concomitant medications ..............................................32
12.2
Premedications for bintrafusp alfa......................................................32
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12.3
Concurrent procedures........................................................................33
12.4
Previous anticancer treatments and procedures..................................33
12.5
Anticancer Treatment after Discontinuation ......................................34
13
Study intervention Compliance and Exposure ...................................35
14
Efficacy Analyses ...............................................................................37
14.1
Best Overall Response according to RECIST 1.1 as adjudicated 
by IRC (Primary endpoint).................................................................37
14.1.1
Subgroup analysis for BOR................................................................41
14.2
Best Overall Response according to RECIST 1.1 as assessed by 
Investigator (Secondary endpoint)......................................................41
14.4
Progression-Free Survival (Secondary Endpoint) ..............................44
14.4.1
Sensitivity analysis for PFS................................................................47
14.4.2
Subgroup analysis for PFS..................................................................48
14.5
Duration of Response (Secondary Endpoint) .....................................48
14.5.1
Subgroup analysis for DOR................................................................49
14.6
Durable Response (Secondary Endpoint)...........................................50
14.6.1
Subgroup analysis for DRR................................................................50
14.7
Delayed Response...............................................................................50
14.8
Overall survival ..................................................................................51
14.8.1
Subgroup analysis for OS...................................................................53
14.9
Follow-up time (PFS) .........................................................................53
14.10
Follow-up time (OS)...........................................................................53
15
Safety Analyses ..................................................................................53
15.1
Adverse Events...................................................................................53
15.1.1
All Adverse Events.............................................................................55
15.1.2
Adverse Events Leading to Study Intervention Discontinuation .......58
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events...................................................................................58
15.2.1
Deaths .................................................................................................58
15.2.2
Serious Adverse Events......................................................................59
15.2.3
Bleeding Events..................................................................................59
15.2.4
Adverse Events of Special Interest.....................................................59
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15.3
Clinical Laboratory Evaluation...........................................................63
15.4
Vital Signs ..........................................................................................67
15.5
Other Safety or Tolerability Evaluations............................................68
16
Analyses of Other Endpoints..............................................................69
16.1
Pharmacokinetics................................................................................69
16.1.1
Missing/non-quantifiable PK Data Handling .....................................69
16.1.2
Descriptive PK Analysis.....................................................................70
16.3
Patient-Reported Outcome..................................................................72
16.4
Immunogenicity..................................................................................72
16.4.1
Antidrug Antibody..............................................................................72
16.4.2
Neutralizing Anti-drug Antibody .......................................................75
17
References...........................................................................................78
18
Appendices .........................................................................................79
18.1.1
Appendix 1: Definition of important protocol deviations ..................79
18.1.2
Appendix 2: Rules for identification of previous or concomitant 
medications/procedures ......................................................................79
18.1.3
Appendix 3: Definition of NCI-CTCAE grading...............................79
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
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2
List of Abbreviations and Definition of Terms
Abbreviation
Definition
2L
Second-line
ADA
Antidrug antibody
ADaM
Analysis Data Model
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine aminotransferase
ALP
Alkaline Phosphatase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
BMI
Body Mass Index
BOR
Best overall response
BTC
Biliary Tract Cancer
cBOR
Confirmed best overall response
CEOI
The concentration observed immediately at the end of infusion
CI
Confidence Interval
COVID-19
Coronavirus disease 2019
CR
Complete Response
CSR
Clinical Study Report
Ctrough
The concentration observed immediately before next dosing 
(corresponding to pre-dose or trough concentration for multiple 
dosing)
CV%
Coefficient of Variation (%)
DBP
Diastolic Blood Pressure
DCR
Disease control rate
DI
Dose Intensity
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
ECG 
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
eCRF
Electronic Case Report Form
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eDISH
Evaluation of Drug-Induced Serious Hepatotoxicity
GeoCV%
Geometric Coefficient of Variation (%)
GeoMean
Geometric mean
HBV
Hepatitis B Virus
HCV
Hepatitis C virus
HGB
Hemoglobin
HLT
High level term
IAP
Integrated Analysis Plan
IC
Immune Cells
ICH
International Council for Harmonization
IDMC 
Independent Data Monitoring Committee
irAE
Immune-Related Adverse Event
IRC
Independent Review Committee
IRR
Infusion-Related Reaction
ITT
Intent-to-Treat
LLN
Lower Limit of Normal
LLOQ
lower limit of quantification
logStD
StD of log-transformed data
Max
Maximum
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean Corpuscular Volume
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Mean
Arithmetic mean
Med
Median
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MSS
Microsatellite stable
NC
Not calculated
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for 
Adverse Events
nd
Not determined
ND
No Disease
OR
Objective Response
ORR
Objective Response Rate
OS
Overall Survival
PA
Primary Analysis
PD
Progressive Disease
PFS 
Progression-Free Survival
PK
Pharmacokinetic(s)
PR
Partial Response
PT
Prothrombin Time/Preferred Term
Q1
First Quartile
Q3
Third Quartile
RBC
Red Blood Cell
RDI
Relative Dose Intensity
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
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SBP
Systolic Blood Pressure
SCR
Screening (analysis population)
SD
Stable Disease
SDTM
Study Data Tabulation Model
SI
International System of Units
SOC
System Organ Class
StD 
Standard Deviation
T4
Thyroxine
TBILI
Total Bilirubin
TC
Tumor Cells
TEAE
Treatment-Emergent Adverse Event
TGF-β
Transforming Growth Factor-Beta
TMTB
Total measured tumor burden
TNM
Tumor, Lymph Nodes, Metastasis
TSH
Thyroid-stimulating hormone
ULN
Upper Limit of Normal
VAS
Visual analog scale
WBC
White Blood Cells
WHO
World Health Organization
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
MS200647_0047
                                                            Version 2
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3
Modification History
Unique 
Identifier 
for IAP 
Version
Date of IAP 
Version
Author
Changes from the Previous Version
1
05JUL2019
Not Applicable
2
26AUG2020
Updated to be in line with updated protocols, including 
addition of
 per 
biliary tract cancer (BTC) subtype, Section 6.2.
Replaced ‘M7824’ with ‘bintrafusp alfa’ in IAP specific text.
Section 7.1 added (COVID-19 impact), with analysis details 
added in sections 10.1, 10.2 and 15.1.1.
Section 8.2: Added genetic profiling at baseline and nAb 
status subgroups.
Section 9: The on-treatment period definition was updated 
to include the treatment reinitiation period. Added 
categorization of participants for COVID-19 impact 
assessment.
Section 12.4: Added “Number of previous lines of therapy 
for metastatic/locally advanced disease” to the previous 
systemic anticancer drug therapy summary.
Section 13: Updated to include the treatment re-initiation 
period if a participant re-initiates treatment.
Section 14.1: Updated definition of PD for unconfirmed best 
overall response from “PD = at least one PD assessment 
(and does not meet criteria of CR, PR, SD or Non-CR/Non-
PD)” to “PD = progression ≤16 weeks after first date of 
study intervention (and does not meet criteria of CR, PR, 
SD or Non-CR/Non-PD)”;
Sections 14.1.1, 14.4.2, 14.8.1: Added listings by ADA and 
nAb status.
Section 14.3: Added the following to the definition of PD 
“PD is also to be confirmed if the participant:
-
dies within 12 weeks after the initial observation of 
PD, or
-
discontinues treatment due to disease progression 
prior to or within 12 weeks after the assessment of 
PD.”
Section 15.2.4.3: Added the narrow and broad definitions 
for potential TGF-β-mediated skin adverse events.
Section 15.5: Added listing description for non-protocol 
Related Hospital Visits.
Section 161.2: Added PK summaries by ADA and nAb 
subgroups.
Section 16.3: Referenced the 
 SAP.
Section 16.4.1: Added definitions for start of 
immunogenicity response and duration of immunogenicity 
response and analyses by race.
Section 16.4.2 added (neutralizing anti-drug antibody).
Section 16.5.3: Added pooled derivation details since data 
from multiple sources.
).
Added Protocol Deviation and Definition of NCI-CTCAE 
Grading appendices.
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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4
Purpose of the Integrated Analysis Plan
The purpose of this integrated analysis plan (IAP) is to document technical and detailed 
specifications for primary, second and BTC subtype analyses of data collected for protocol 
MS200647_0047. Independent Data Monitoring Committee (IDMC) analysis will be developed 
in a separate statistical analysis plan (SAP).
Results of the analyses described in this IAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this IAP may be included in regulatory 
submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective IAP will be clearly identified 
in the CSR. 
The IAP is based upon Section 9 (Statistical Considerations) of the study protocol and is prepared 
in compliance with International Council for Harmonization (ICH) Guideline E9. It describes 
analyses planned in the protocol.
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5
Objectives and Endpoints
Table 1
Study Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
IAP section
Primary
To evaluate clinical efficacy of 
M7824 based on ORR
!
Confirmed objective response (OR) according to 
Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) assessed by an 
Independent Review Committee (IRC)
14.1
Secondary
To evaluate clinical efficacy of 
M7824 based on duration of 
response (DOR)
!
DOR assessed from complete response (CR) or 
partial response (PR) until progression of disease 
(PD), death, or last tumor assessment assessed by 
an IRC
14.5
To evaluate clinical efficacy of 
M7824 based on durable 
response rate (DRR)
!
Durable response of at least 6 months according to 
RECIST 1.1 assessed by IRC
14.6
To evaluate clinical safety of 
M7824
!
Occurrence of treatment-emergent adverse events 
(TEAEs) and treatment-related AEs, including 
adverse events of special interest (AESIs)
15.1, 15.2
To evaluate clinical efficacy 
based on progression-free 
survival (PFS)
!
PFS according to RECIST 1.1 assessed by IRC
14.4
To evaluate ORR, DOR, DRR, 
and PFS by Investigator read
!
OR, DOR, DRR, and PFS according to RECIST 1.1 
assessed by Investigator read
14.2, 14.4, 14.5, 
14.6
To evaluate clinical efficacy 
based on overall survival
!
OS
14.8
To characterize the 
pharmacokinetic (PK) profile of 
M7824
!
The concentration observed immediately at the end 
of infusion (CEOI) of M7824
!
The concentration observed immediately before 
next dosing (corresponding to pre-dose or trough 
concentration [Ctrough] for multiple dosing) of M7824
16.1
To characterize the 
immunogenicity of M7824
!
Immunogenicity of M7824 as measured by antidrug 
antibody (ADA) assay, from Screening through 12 
weeks (± 2 weeks) after last treatment
16.4
To evaluate clinical efficacy of 
M7824 based on ORR, DOR and 
DRR according to programmed 
death ligand 1 (PD-L1) 
expression and microsatellite 
instability (MSI) status 
retrospectively
!
Confirmed OR according to RECIST 1.1 assessed 
by an IRC according to PD-L1 expression and MSI 
status
!
DOR and durable response of at least 6 months 
according to RECIST 1.1 assessed by an IRC 
according to PD-L1 expression and MSI status
14.1.1, 14.5.1, 
14.6.1
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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Objectives
Endpoints (Outcome Measures)
IAP section
* Items noted above with an * symbol are not collected in sites in China.
6
Overview of Planned Analyses
This IAP addresses the primary and second analyses for the global study as well as BTC subtype 
efficacy analysis. Additional statistical analysis plans for Independent Data Monitoring Committee 
(IDMC) will be developed separately.
All statistical analyses will be performed using cleaned eCRF data as well as external data 
including tumor assessment measured by the Independent Review Committee (IRC). All data used 
in the analysis will be included up to a data cut-off point.
6.1
Primary and Second Analysis
Table 2 displays an overview of the primary and secondary analyses to be provided for this study.
Table 2
Overview of Analyses
Analysis
Data cut-off point
Endpoints
Primary analysis (PA) at 9 
Months
9 months after the first dose of the 
last of 141 planned participants
Full evaluation of all efficacy and 
safety endpoints. Plus, assessment 
of impact of COVID-19.
Second analysis at 15 Months
15 months after the first dose of the 
last of 141 planned participants
Full evaluation of all efficacy and 
safety endpoints
The timing of conduct of the primary and secondary analyses will be triggered by the data cut-off 
points displayed in Table 2 above and will evaluate all criteria described in this IAP.
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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                                                            Version 2
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7
Changes to the Planned Analyses in the Clinical Study 
Protocol
The statistical methods as described in the protocol were adopted. There are no changes to the 
planned analyses. 
7.1
COVID-19 Impact
No changes to the planned analysis of the efficacy endpoints will be performed due to the impact 
of COVID-19 outbreak. 
Instead, additional outputs (summary tables, listings and figures) will be generated to assess 
potential impacts of COVID-19 to this study including: 
! number of participants in pre/during COVID-19 study period,
! number of COVID-19 related protocol deviations,
! number of participants in pre/during COVID-19 study period with AEs,
! listing of participants with any missed treatment administrations, tumor assessments or 
missed visits due to COVID-19, and
! listing of AEs related to COVID-19.
Details of the categorization of participants for COVID-19 impact assessment is provided in 
Section 9 and details of the analyses is provided in Sections 10.1, 10.2, and 15.1.1.
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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                                                            Version 2
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8
Protocol Deviations and Analysis Populations
8.1
Definition of Protocol Deviations
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 
Important protocol deviations will be defined in a specific document (see Appendix 1). They 
could include, but are not limited to:
! Participants that are dosed on the study despite not satisfying the inclusion criteria
! Participants that develop withdrawal criteria whilst on the study but are not withdrawn
! Participants that receive an incorrect dose of study intervention
! Participants that receive an excluded concomitant medication
! Deviation from Good Clinical Practice
Important protocol deviations will be identified and confirmed prior to or at Data Review Meeting 
and will include:
! Deviations from the inclusion and exclusion criteria
! Deviations post-inclusion
All important protocol deviations will be documented in Study Data Tabulation Model (SDTM) 
datasets whether identified through site monitoring, medical review or data-management
programming.
Further considerations for PK analysis:
Examples of protocol deviations or important events for PK analysis and PK result interpretation
may include, but may not be limited to, the following:
! Dose delayed outside the allowed window
! Actual dosing time not recorded
! Dose change or missed dose
! Pre-dose sample collected after the actual start of infusion
! End-of-infusion sample collected before the actual end of infusion
! Sample processing errors that may lead to inaccurate bioanalytical results
For the above protocol deviations or important events for PK, the relevant PK data will be excluded 
from summaries based on the PK analysis set.
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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Refer to Section 16.1 for more details of protocol deviations and handling relevant to PK.
8.2
Definition of Analysis Populations and Subgroups
Screening Analysis Set (SCR)
All participants who signed the informed consent.
Intention-to-Treat Set (ITT)/Safety Analysis Set (SAF)
The Intention-To-Treat analysis set as well as the Safety Analysis Set include all participants who 
received at least 1 dose of bintrafusp alfa. 
The ITT analysis set will be used for all analyses of demographics and baseline characteristics, 
efficacy,
and 
. The SAF analysis set will be used for 
all exposure and safety analyses.  
Pharmacokinetic Analysis Set (PK)
All participants who completed at least 1 dose of bintrafusp alfa, and who provided at least 1 
sample with a measurable concentration of bintrafusp alfa, without important protocol deviations 
or events deemed to affect PK evaluation.
All PK analyses will be based on this analysis set. Refer to Section 16.1 for protocol deviations 
and handling relevant to PK.
Pharmacokinetic ADA Analysis Set (PKADA)
A subpopulation of the PK Analysis Set restricted to subjects who have in addition at least one 
valid result of ADA at any time point.
Pharmacokinetic nAb Analysis Set (PKNAB)
A subpopulation of the PK Analysis Set restricted to subjects who have in addition at least one 
valid result of neutralizing anti-drug antibodies (nAb) at any time point.
Immunogenicity analysis set (IMM)
All participants who received at least 1 dose of bintrafusp alfa and have at least one valid ADA 
result. 
All immunogenicity analyses will be based on this analysis set.
Table 3 displays the use of the analysis sets in the different analyses:
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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                                                            Version 2
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Table 3
Overview of the Analysis Set Used in the Analyses
Analyses
SCR
SAF
ITT
PK
PKADA
PKNAB
IMM
Disposition

Demographics 

Baseline Assessments

Previous and Concomitant 
Therapies

Compliance and Exposure

Efficacy

Safety and Tolerability

Pharmacokinetics



Immunogenicity

Additional Subgroup Analysis Sets
Analysis of primary, key secondary efficacy and safety endpoints may be performed on subgroups
of interest as specified in this IAP Section 14 and Section 15.1 respectively. Since the study is not 
powered for any subgroup analysis, all the subgroup analyses are 
 in nature.
The following major subgroups will be used for analysis:
! BTC subtype
o
Intrahepatic cholangiocarcinoma
o
Extrahepatic cholangiocarcinoma
o
Gallbladder cancer
!
Age group
o
Age < 65 years
o
Age ≥ 65 years
!
ECOG PS at baseline
o
ECOG PS 0
o
ECOG PS 1
!
Sex
o
Male
o
Female
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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!
Race
o
White
o
Black or African American
o
Asian
o
American Indian or Alaska Native
o
Native Hawaiian or other Pacific Islander
o
More than one race
o
Not collected at the site
o
Other
!
Geographic Region
o
Asia
o
US
o
Europe
!
Time since completion of 1L platinum-based treatment
o
<6 months
o
≥6 months
!
Disease status at initial diagnosis (based on TNM classification)
o
Locally advanced (M0)
o
Metastatic disease (M1)
o
Unknown (MX)
! PD-L1 expression on tumor cells (TC) and on immune cells (IC) at baseline 
o
<1%, ≥1%; <5%, ≥5%; <25%, ≥25%; <50%, ≥50% for TC
o
<1%, ≥1%; <5%, ≥5%; <25%, ≥25%; <50%, ≥50% for IC
o
<1%, 1-<50%, ≥50% for TC
o
<1%, 1-<50%, ≥50% for IC
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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                                                            Version 2
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!
ADA status
o
Ever positive
o
Never positive
!
nAb status
o
Ever positive (for either assay TGF-β or PD-L1)
o
Never positive
For Extrahepatic cholangiocarcinoma participants, following subgroups may also be used for 
analysis: 
! Extrahepatic cholangiocarcinoma subtype
o
Perihilar cholangiocarcinoma
o
Distal cholangiocarcinoma
For ADA and nAb status subgroups, the subgroup analyses will be performed if there are at least 
3 ever positive participants.
For all other subgroup variables with more than two categories, any subgroup category with less 
than 7 participants (approximately 5% of the population) will not be reported in the analysis.
9
General Specifications for Data Analyses
Refer to Section 16.1 for PK data handling/analysis details.
Data handling after cut-off date:
Data after cut-off will not undergo the cleaning process, and will be cut at SDTM level, i.e. before 
the process of ADAM creation. Data after cut-off will not be displayed in any listings or used for 
summary statistics, e.g. laboratory values of samples taken after data cut-off, AE with onset date 
after data cut-off, etc.
Stop dates will not be affected by this rule, e.g. a stop date of an AEs, with start date prior to the 
cut-off, but stop date after the date of cut-off, will be used for analysis as reported. 
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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                                                            Version 2
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Pooling of centers:
Because of the high number of participating centers and the anticipated small number of 
participants treated in each center, data will be pooled across centers, and the factor center will not 
be considered in subgroup analysis. 
Significance level:
The overall significance level is 2.5% one-sided. Statistical tests will be described in Section 14. 
If confidence intervals are to be calculated, these will be two-sided with a confidence probability 
of 95%, unless otherwise specified in this IAP.
Presentation of continuous and qualitative variables:
Continuous (non-PK) variables will be summarized using descriptive statistics i.e.:
! Number of participants (N), number of participants with missing values 
! Mean, standard deviation
! Median, 25th Percentile - 75th Percentile (Q1-Q3), 
! Minimum, and maximum,
If there are no missing values, the number of participants with missing values should be set to 0.
Pharmacokinetic variables (concentrations and parameters) will be summarized as described in 
Section 16.1.2.
Qualitative variables will be summarized by counts and percentages. 
Unless otherwise stated, the calculation of proportions will be based on the number of participants 
of the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category. 
In case the analysis refers only to certain visits, percentages will be based on the number of 
participants still present in the study at that visit, unless otherwise specified. 
Definition of baseline: 
The last available/non-missing measurement prior to the first study intervention will serve as the 
baseline measurement for safety and efficacy analyses.
If an assessment is planned to be performed prior to the first study intervention in the protocol and 
the assessment is performed on the same day as the first study intervention, it will be assumed that 
it was performed prior to study intervention, if assessment time is not collected or is missing. If 
assessment time is collected, the observed time as well as time of first dose will be used to 
determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will be used 
in the determination of baseline. However, if time is missing, an unscheduled assessment on Study 
Day 1 will be considered to have been obtained after study intervention.
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                     Phase II M7824 Monotherapy in 2L Biliary Tract Cancer
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Definition of change from baseline
Change from baseline = timepoint value – baseline value
Percent Change from Baseline = 100 * (timepoint value – baseline value) / baseline value
Definition of on-treatment period: 
On-treatment period is defined as the time from the first study intervention to the last study
intervention date + 30 days OR the earliest date of subsequent anticancer therapy minus 1 day, 
whichever occurs first, unless otherwise stated. For participants with treatment ongoing at cut-off 
date, all data from the first study intervention up to the cut-off date will be considered under the 
on-treatment period.
For immune-related AEs as listed in Section 15.2.4.2, an expanded on-treatment period will be 
used as a default for any analysis:
Time from the first study intervention to the last study intervention date + 90 days, death OR to 
the earliest date of subsequent anticancer therapy minus 1 day, whichever occurs first, unless 
otherwise stated.
Any systemic anticancer therapy, any anticancer surgery and any anticancer radiotherapy as 
documented in the ”Anti-cancer treatment after discontinuation” CRF page will be considered as 
subsequent anticancer therapy.
The on-treatment period will include the initial treatment period as well as the reinitiation of 
treatment period, as applicable. Whether a participant reinitiates treatment (following the rules as 
outlined in the protocol) or not, the on-treatment period is defined as the time from the first study 
intervention administration to the last study intervention administration date + 30 days or the 
earliest date of subsequent anticancer drug (anticancer therapy, anticancer surgery and anticancer 
radiotherapy) therapy minus 1 day, whichever occurs first, unless otherwise stated. 
Unscheduled assessments:
As per database definition, the safety unscheduled assessments are always linked to a scheduled 
timepoint (each unscheduled assessment is linked to the previous scheduled timepoint). Safety 
data retrieved from an unscheduled timepoint (vital signs, electrocardiogram [ECG] and laboratory 
data) will be analyzed according to the following scenario:
! For shift table, they will be taken into account in the definition of the worst assessment 
during study
! For description at each timepoint post-baseline, the first available result (in chronological 
order) per timepoint will be taken into account in the analysis in case of multiple values
! For description at baseline, the last available result before first study intervention will be 
taken into account in the analysis in case of multiple values
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For immunogenicity analysis, unscheduled visits will also be taken into account in the analysis
following the same rules as detailed above.
For PK analysis, unscheduled samples will not be linked to a scheduled timepoint and will be 
excluded from summaries.
Definition of duration:
Duration will be calculated by the difference between start and stop date + 1 if not otherwise 
specified. For example, duration of response (days) = date of PD/death/censoring – date of 
response + 1.
The time since an event (e.g. time since initial cancer diagnosis) will be calculated as reference 
date minus date of event. In general, the reference date will be the date of first study intervention.
The time to an event will be calculated by the difference between the time of event and the 
reference date + 1 if not otherwise specified. For example, survival time (days) = date of death -
date of first study intervention + 1.
Common calculations: 
For quantitative measurements, change from baseline will be calculated as:
! Test Value at timepoint X – Baseline Value
Conversion factors:
The following conversion factors will be used to convert days into months or years: 
! 1 month = 30.4375 days
! 1 year = 365.25 days
Handling of missing data:
Unless otherwise specified in this IAP, missing data will not be replaced. 
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd” for “not 
determined. For example, if n=1, the measure of variability [e.g. standard deviation (StD)] cannot 
be computed and should be presented as “nd”.
Handling of incomplete dates:
!
Missing data handling rules for age calculation
Incomplete dates (date of informed consent, date of birth) for the calculation of age will be 
imputed as follows: 
o
In case of missing day for at least one date, but month and year available for both dates: 
the day of informed consent and the day of birth will be set to 1.
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o
In case of missing month for at least one date, but year available for both dates, the day 
and the month of informed consent and the day and month of birth will be set to 1.
o
In all other cases, the incomplete dates will not be imputed. 
!
Missing data handling rules for disease history
Incomplete dates for disease history (date of initial diagnosis date, date of documented, locally 
advanced, inoperable or metastatic disease diagnosis, date of response or progression in prior 
treatment) will be imputed as follows: 
o
If the day is missing, it will be imputed to the 1st day of the month.
o
If both day and month are missing, the month and day will be imputed as January 1st 
o
If the date is completely missing, no imputation will be performed.
!
Missing data handling rules for adverse events
Incomplete AE-related dates will be imputed as follows: 
o
In case the onset date is missing completely or missing partially but the onset month 
and year, or the onset year are equal to the start of study treatment, then the onset date 
will be imputed by the minimum of start of study treatment and AE resolution date (if 
not missing). 
o
In all other cases, the missing onset day or missing onset month will be imputed by 1.
o
Incomplete stop dates will be imputed by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of participant’s death. In the latter 
case, the date of death will be used to impute the incomplete stop date.
o
In all other cases, the incomplete stop date will not be imputed.
!
Missing data handling rules for previous and concomitant medications
Incomplete dates for previous and concomitant medications will be imputed as follows: 
For start date of medication
o
If the day is missing, it will be imputed to the 1st day of the month. 
o
If both day and month are missing, the month and day will be imputed as January 1st. 
o
If the date is completely missing, no imputation will be performed. 
For end date medication: 
o
If the day is missing, it will be imputed to the last day of the month. 
o
If both day and month are missing, the month and day will be imputed as December 
31st
o
If the date is completely missing, no imputation will be performed.
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Note: In case the imputation results in a date later than the date of participant’s death, then the 
date of death will be used to impute the incomplete stop date.
!
Missing data handling rules for subsequent anticancer therapy
Incomplete dates for start date of subsequent anticancer therapy (drug therapy, radiotherapy, 
surgery) will be imputed as follows and will be used for determining censoring dates for 
efficacy analyses and in the derivation of the end of on-treatment period:
o
If only day is missing, it will be imputed as the last day of the month unless the end 
date of subsequent anticancer therapy is before that date. In that case, the incomplete 
anticancer therapy start date will be imputed as the end date of the anticancer therapy.
o
Otherwise it will not be imputed.
Incomplete subsequent anticancer therapy stop dates will not be imputed. 
!
Missing data handling rules for death date
For the purpose of survival analyses, partially missing death dates will be imputed as follows:
o
If only the day is missing, the death date will be imputed to the maximum of the (non-
imputed) day after the date of last known alive date and the 15th day of the month
o
Otherwise it will not be imputed
!
Handling rules for tumor assessments
o
If there are multiple scan dates associated with an evaluation, the earliest of the scan 
dates associated with the evaluation will be used as the date of assessment
Partial dates, which are not to be imputed according to the IAP, will be presented in the format 
like “_____YYYY”. If values are imputed according to the IAP, imputed values will be presented 
in participant data listings and imputed information will be flagged. 
Treatment day
Day 1 is the day of start of study intervention, the day before is Day -1 (no Day 0 is defined).
Study day/Study intervention day is defined relative to Day 1.
Preferred term for analysis of WHO-DD coded data
For data coded according to WHO Drug B3 (e.g., concomitant medications), summaries will be 
done on the preferred term level where the preferred term is corresponding to codes ending in 
01001. With this approach, variations of salt forms of active ingredients will be analyzed under 
the same term, e.g. diphenhydramine and diphenhydramine hydrochloride will be analyzed as the 
same preferred term diphenhydramine. 
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Re-screened participants:
Re-screened participants will be only counted once in the screening analysis set, considering the 
latest screening (screening with latest informed consent). 
Data collected after re-initiated treatment:
Data collected after re-initiation of treatment will be included in the summary statistics. A data 
listing will include AE data for all reinitiated participants.
Categorization of participants for COVID-19 impact assessment
For the assessment of COVID-19 impact on this study, participants will be categorized as being 
affected by COVID-19 (either due to infection or due to circumstances of social distancing 
affecting the capabilities of sites/hospitals etc.) based on the COVID-19 study period defined as:
! The start of COVID-19 study period will be defined by country as the minimum of the date 
of the first death from COVID-19 occurred in each country according to the published data 
by European Centre for Disease Prevention and Control on 26th June 2020 and 11 March 
2020 (WHO-start of world-wide pandemic).
! Post-pandemic could be defined as date (1) vaccination is released, (2) WHO declares 
COVID-19 pandemic over, (3) region-specific calls are made to end social distancing 
measures with no relevant rise in cases thereafter. As study treatment for the last participant 
started on 3rd January 2020, no participant will be grouped into the post COVID-19 study 
period for this study and no post-pandemic date will be defined.
Participants will be categorized into subgroups according to the methods shown in Table 4
depending on the purpose of analysis.
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Table 4
Types of categorization for COVID-19 assessment
Type of categorization
Subgroup
Definition
Categorization for 
assessment on efficacy 
Pre
Participant started treatment prior to and had progressive disease or 
died or withdrew from tumor assessments prior to COVID-19 study 
period
During
Participant started treatment prior to or during COVID-19 study 
period and had any tumor assessments during the COVID-19 study 
period
Post*
Participant started treatment post the COVID-19 study period
Categorization for 
assessment on safety
without time window
Pre
Participant started treatment prior to COVID-19 study period
During*
Participant started treatment during the COVID-19 study period
Post*
Participant started treatment post the COVID-19 study period
Categorization for 
assessment on safety with 
time window
Pre
Participant started treatment 3 months prior to COVID-19 study 
period
During
Participant started treatment on or after the date 3 months prior to 
COVID-19 study period
Post*
Participant started treatment post the COVID-19 study period
* No participants will be categorized into the ‘post COVID-19 study period’ or the ’during COVID-19 study period for 
safety without time window’ for this study.
Software:
All statistical analyses will be performed using statistical software SAS® (Statistical Analysis 
System, SAS-Institute, Cary NC, USA, Windows Version 9.4 or higher) in the SAS Grid 
environment. 
The computer program Phoenix® WinNonlin® Version 8.0, or higher (Certara, L.P., Princeton, 
New Jersey, USA) could be used for PK data.
10
Study Participants
The subsections in this section include specifications for reporting participant disposition and 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
10.1
Disposition of Participants and Discontinuations
Descriptive statistics will be used to summarize participant disposition based on the electronic case 
report form (eCRF) data.
The following information will be reported:
! Total number of participants screened (i.e. participants who gave informed consent)
! Number of participants who discontinued from the study prior to study intervention overall 
and grouped by the main reason (e.g. the failed specific inclusion or exclusion criteria, 
adverse event, lost to follow-up, death, progressive disease, withdrawal of consent and other)
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! Number of re-screened participants
!
Number of participants who received at least one dose of study intervention (ITT/SAF 
analysis set)
! Number of participants with treatment ongoing at the data cutoff date
! Number of participants off study treatment, grouped by main reason (treatment completed 
as per protocol, progressive disease, death, adverse event, lost to follow-up, protocol non-
compliance, withdrew consent, other)
! Number of participants who re-initiated the study treatment and number of participants who 
discontinued the study intervention after re-initiation
! Number of participants with treatment ongoing
! Number of participants who completed/discontinued the study participation, with the 
associated main primary reason (study completed according to protocol, adverse event, lost 
to follow-up, protocol non-compliance, death, withdrew consent, other)
Percentages will be calculated based on the number of participants in the ITT/SAF population, 
except for the number of screened and re-screened participants where no percentage will be 
provided.
In addition, the number of participants in each analysis set defined in Section 8.2 will be 
summarized, overall and by region (Europe, North America, Asia), country within region and 
center.  
The listing of participant disposition will include all participants (i.e. including screening failures, 
but not re-screened participants [at their screen failure time] which will be listed in a specific 
listing). The listing will include the following information: participant identifier, date of informed
consent, included in the study (if not reason for exclusion), first/last study intervention date, date
and reason off-treatment, date and reason off-study, population flags. When the reason such as 
reason off-treatment will be categorized as “Other, specify” or “Withdrew consent from treatment, 
specify”, the verbatim text as entered in the eCRF will be presented in the listing.
In addition, a listing of participants for which bintrafusp alfa has been reinitiated will be provided 
with the following information: participant identifier, date of first study intervention, date of last 
study intervention, reason for treatment termination, first and last re-initiation bintrafusp alfa
administration date and status at end of treatment re-initiation including reason for treatment 
discontinuation, as applicable.
If any re-screened participants are observed, they will be presented in a specific listing which will 
include: participant identifier (identifier at inclusion in the study), date of informed consent at 
inclusion, date of first study treatment, initial participant identifier (identifier at screen failure), 
date of informed consent at screen failure, date and reason of screen failure. Note in case 
participants have been screened several times, all screening attempts will be listed.
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In addition, for the assessment of COVID-19 impact on this study, number of participants in 
subgroup of pre/during/post COVID-19 study period according to each categorization method 
described in Table 4 (Section 9) will be provided.
10.2
Protocol Deviations
Analysis Set: ITT
The following summary tables and listings of important protocol deviations will be provided:
! Frequency table per reason of important protocol deviations
! Listing of important protocol deviations which will include participant identifier, category 
of the deviation (e.g. inclusion/exclusion), and a description of the deviation.
Potential impact of COVID-19 pandemic in MS200647-0047 will be evaluated by an analysis of 
protocol deviations. The number of participants with important protocol deviations overall as well 
as all protocol deviations due to COVID-19 will be tabulated. A subject listing of participants with 
any missed treatment administrations, missed tumor assessments, and missed visits due to COVID-
19 will also be provided.
11
Demographics and Other Baseline Characteristics
Analysis Set: ITT
11.1
Demographics
Demographic characteristics will be summarized using the following information:
! Sex: male, female
! Ethnicity: Hispanic or Latino, not Hispanic or Latino; Japanese, not Japanese
! Race: 
o
For participants reporting one race only: White, Black or African American, Asian, 
American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Not 
collected at the site, Other.
o
For participants reporting several races, all combinations will be reported under ‘More 
than one race” category. 
! Age (years): summary statistics 
! Age categories: 
o
< 65 years, ≥ 65 years
o
65-74 years, 75-84 years, ≥ 85 years
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! Geographic Region: North America, Europe, Asia
Specifications for computation:
o
Age [years]: (date of given informed consent - date of birth + 1) / 365.25
The integer part of the calculated age will be used for reporting purposes.
o
Investigator site codes will be used for the determination of the participant’s geographic 
region.
Demographic characteristics including participant identifier, sex, race (including all reported races 
in case of “multiple” races, and details in case of “other” race), ethnicity, geographic region, age 
(years) will be presented in a listing.
11.2
Medical History
Relevant past and ongoing medical conditions at baseline will be summarized from the “Medical 
History Details” eCRF page, using the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA), preferred term (PT) as event category and MedDRA system 
organ class (SOC) body term as Body System category. 
Medical history will be displayed in frequency tables, ordered by primary SOC and PT in 
alphabetical order. Each participant will be counted only once within each PT or SOC.
Listing of medical history including participant identifier, age, sex, race, preferred term, reported 
medical history term, start/end dates, related study condition, ongoing at screening and toxicity 
grade (when medical history is ongoing) will be presented.
11.3
Other Baseline Characteristics
11.3.1
Disease History
Information on disease characteristics collected on the “Disease History” eCRF page will be 
summarized as follows:
! Biliary Tract Cancer (BTC) subtype classification: Intrahepatic cholangiocarcinoma, 
Extrahepatic cholangiocarcinoma (perihilar vs distal cholangiocarcinoma) and Gallbladder 
cancer
! Tumor histology: Adenocarcinoma
well differentiated, Adenocarcinoma
moderate 
differentiated, Adenocarcinoma poorly differentiated, Adenocarcinoma unknown, Other
! Time since initial cancer diagnosis (months)
! Time since documented, locally advanced or metastatic disease (months)
! Time since last progression of disease prior to study entry (months)
! TNM classification at initial diagnosis and at study entry: each T, N, M category will be 
described (TX, T0, N1, etc.)
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11.3.2
Vital signs at Baseline
The following vital signs at baseline will be collected from the “Vital signs” eCRF page and will 
be summarized:
! Height (cm)
! Weight at baseline (kg)
! Body Mass Index (BMI) (kg/m2)
Specifications for computation:
o
BMI (kg/m2) = weight(kg)/[height(m)]2
Heigth, weight and BMI will be listed in the demographics listing (see Section 11.1).
11.3.3
ECOG Performance Status at Baseline
The ECOG Performance Status will be described from the data collected on the “ECOG 
Performance Status” eCRF page. It will be described at baseline by the frequency and percentage 
of participants in each category: 
0: Fully active, able to carry on all pre-disease performance without restriction.
1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light housework, office work.
2: Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about 
more than 50% of waking hours.
3: Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.
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5: Dead.
11.3.4
Skin status history
Skin status history is collected on the “Skin Status History” eCRF page and will be summarized 
by the frequency and percentage of participants having the following history of:
! Frequent sunburn (Yes, No, Unknown)
! Easy sunburn (Yes, No, Unknown)
! Skin cancer (Yes, No, Unknown)
! Significant UV exposure (Yes, No, Unknown)
! Photosensitivity due to skin disorder (Yes, No, Unknown)
! Photosensitivity due to medication (Yes, No, Unknown)
! Family history of skin cancer in first degree relative (i.e. parents, siblings and/or children) 
(Yes, No, Unknown)
! Number of participants having history of the skin conditions above (No condition, 1 
condition, 2 conditions, 3 or more conditions)
A listing of skin status history will be provided.
11.3.5
Tumor Biopsy
Tumor Biopsy is collected on the “Tumor Biopsy” eCRF page, a listing of tumor biopsy will be 
provided including: participant identifier, age, sex, race, visit, collection date, sample type (fresh 
biopsy or archival tissue sample), sample identifier, sample type for tumor block and for tumor 
tissue the number of slides collected.
11.3.6
PD-L1 test
PD-L1 expression on tumor cells or on immune cells as collected at screening will be descripted 
using the following categories:
! <1%, ≥1%; <5%, ≥5%; <25%, ≥25%; <50%, ≥50% for TC
! <1%, 1-50, ≥50% for TC
! <1%, ≥1%; <5%, ≥5%; <25%, ≥25%; <50%, ≥50% for IC
! <1%, 1-50, ≥50% for IC
Listing will also be provided and include: participant identifier, age, sex, race, unique sample 
identifier, visit, collection date and PD-L1 expression.
12
Previous or Concomitant Medications/Procedures
Analysis set: ITT
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12.1
Previous and concomitant medications
Previous medications are medications, other than study medications, which started before first 
study intervention. In case the date values will not allow to unequivocally allocate a medication to 
previous medication, the medication will be considered as previous medication.
Concomitant medications are medications, other than study medications, which are taken by 
participants any time on-treatment (on or after the first day of study intervention for each 
participant) or within 30 days after last dose of study drug OR the earliest date of subsequent 
anticancer drug therapies minus 1 day, whichever occurs first. In case the date values will not 
allow to unequivocally allocate a medication to concomitant medication, the medication will be 
considered as concomitant medication. All medications starting the same day as study drug will 
be considered as concomitant. Medications starting the 30th days after the last dose of study 
treatment will also be considered as concomitant.
Specific rules will be used to define if a medication/procedure is considered as a previous, 
concomitant or both previous and concomitant medication/procedure as detailed in Appendix 2. 
Concomitant and previous medications are reported on the “Concomitant Medications Details”
eCRF page.
Summaries of previous and concomitant medications will present the number and percentage of 
participants by drug class and preferred term according to the WHO-Drug B3 dictionary. Drug 
class will be derived as ATC classification Level 2, and the preferred term will be taken as the 
preferred drug name. If multiple ATCs are assigned to a drug, all ATCs for that drug will be 
reported. 
A participant will be counted only once within a given drug class and within a given drug name, 
even if he/she received the same medication at different times. 
Previous and concomitant medications will be presented in listing and include: participant
identifier, age, sex, race, preferred term, medication name as provided by the Investigator, start 
date, end date, dose, dose units, frequency, route, reason for the medication. 
12.2
Premedications for bintrafusp alfa
Premedications are medications administered per protocol on the same day as, but prior to, the 
study intervention to mitigate potential infusion-related reactions. 
As per protocol, the first 15 participants will not receive premedications (except if requested by 
Investigator) before first and second bintrafusp alfa infusions to establish whether mandatory use 
of premedication is required. If two or more Grade 2 infusion reactions are seen during the first 2 
infusions for the first 15 participants (without medication), IDMC will determine if mandatory 
premedication is needed. Study enrollment will continue in parallel to this review and sites will be 
notified accordingly if premedication becomes required. If IDMC determines mandatory 
premedication is justified, premedication prior to each dose of bintrafusp alfa will be mandatory 
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for the first 2 infusions. After 2 infusions, premedication will be optional and at the discretion of 
the Investigator. 
The number of participants receiving premedication will be summarized for each treatment visit 
based on “Premedication details” eCRF page. If the IDMC determines that mandatory 
premedication is required, then the table will be split into two columns, participants enrolled 
before vs after the review of the first 15 participants.
Percentages will be calculated on the number of participants who actually received an infusion at 
the associated visit.  
Listing will also be provided including: participant identifier, age, sex, race, medication name,
visit, date/time of study intervention, dose, dose units, and route.
12.3
Concurrent procedures
Concurrent procedures are reported according to the “Concomitant Procedures Details” eCRF 
page.
Concurrent procedures will be presented in a listing which will include participant identifier, age, 
sex, race, name of procedure (as provided by the Investigator), start date, end date, indication,
reason for procedure and type of specimen collected. A flag will be displayed to identify each 
procedure as prior to treatment and on-treatment.
12.4
Previous anticancer treatments and procedures
The previous anticancer treatments and procedures are collected under the “Prior Anti-Cancer 
Drug Therapies Details” and the “Prior Anti-Cancer Surgeries Details” eCRF pages. 
The number of participants in each of the following anticancer treatment categories will be 
tabulated:
! Participants with at least one type of previous anticancer treatment or procedure (i.e. drug 
therapy, radiotherapy or surgery)
! Participants with at least one previous anticancer drug therapy 
! Participants with at least one previous anticancer radiotherapy 
! Participants with at least one previous anticancer surgery
Following details for previous systemic anticancer drug therapy will also be summarized:
! Number of any previous anticancer therapy regimens: 0 / 1 / 2 / 3 / ≥ 4
! Number of previous lines of therapy for metastatic/locally advanced disease: 0 / 1 / 2 / 3 / ≥ 
4 (categories will be data dependent)
! Intent of therapy: Neoadjuvant / Adjuvant / Metastatic or Locally advanced
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! Best response of last treatment regimen: Complete Response (CR) / Partial Response (PR) / 
Stable Disease (SD) / Progressive Disease (PD) / Non-Complete Response/Non-Progressive 
Disease (non-CR/non-PD) / Not Assessable / Unknown / Not applicable.
! The time since completion of first-line (1L) of platinum-based treatment will also be 
summarized. Platinum-based treatment will be identified for participants who received at 
least one platinum-based drug (cisplatin, oxaliplatin or carboplatin) and at least one of the 
following drugs in the same regimen: gemcitabine, fluorouracil or capecitabine. The time 
since completion will be measured using the maximum stop date of any of platinum-based 
drug/gemcitabine/fluorouracil/capecitabine treatment (maximum start date will be used in 
case the stop date is not available).
! Number of participants per 1L regimen, e.g., cisplatin/gemcitabine, cisplatin/fluorouracil.
Previous anticancer drugs, previous anticancer radiotherapy, and previous anticancer surgery will 
be presented in separate listings:
! The previous anticancer drug listing will contain participant identifier, age, sex, race,
regimen ID, preferred term, medication name, start date, end date, intent of therapy, best 
response, date of progression.
! The previous anticancer radiotherapy listing will contain participant identifier, age, sex, race, 
start date, end date, was prior radiotherapy to bone for palliation only, location of 
radiotherapy, total dose, number of fractions.
! The previous anticancer surgery listing will contain participant identifier, age, sex, race, date 
of surgery, name and location of surgery, curative intent of surgery (Y/N), and outcome of 
surgery. 
12.5
Anticancer Treatment after Discontinuation
Anticancer treatment after discontinuation of study drug will be summarized according to the 
eCRF page "Anti-cancer Treatment After Discontinuation” for anticancer drug therapy, 
“Radiotherapy After Discontinuation” for anticancer radiotherapy and to “Surgery After 
Discontinuation” for anticancer surgery.
The number of participants in each of the following anticancer treatment categories will be 
tabulated:
! Participants with at least one subsequent anticancer treatment (i.e. drug therapy, radiotherapy 
or surgery)
! Participants with at least one subsequent anticancer drug therapy
! Participants with at least one subsequent anticancer radiotherapy
! Participants with at least one subsequent anticancer surgery
The type of subsequent anticancer drug therapy as provided in the e-CRF (i.e. Cytotoxic therapy/ 
Monoclonal antibodies therapy/ Small molecules/ Immunotherapy/ Other) will be described.
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In addition, the anticancer treatment after discontinuation of study treatment will be provided in 
two listings:
! For medication: participant identifier, age, sex, race, preferred term/medication name, 
medication type, regimen name, intent of therapy, start date and end date.
! For radiotherapy and surgery: participant identifier, age, sex, race, type of therapy, start date, 
end date, radiotherapy site or name of surgery/location, if radiotherapy total dose and number 
of fractions, if surgery outcome and was the surgery curative in intent (Y/N)
13
Study intervention Compliance and Exposure
Analysis set: SAF
Participants will be treated with bintrafusp alfa at a dose of 1200 mg once every 2 weeks, until 
confirmed progression of disease (PD), death, unacceptable toxicity, study withdrawal, or up to 24 
months. This dose will be administered as “flat” doses independent of the body weight.
All dosing calculations below and summaries will be based on “Study Treatment Administration 
Details” eCRFs page. Data collected during the treatment re-initiation phase will be included in 
the summary statistics and flagged in the listings.
For the analysis of exposure, a dose is regarded to be administered if the actual dose received is > 
0 mg.
Whether the participant re-initiates the treatment or not, the duration of treatment of bintrafusp
alfa  (in weeks) during the study is defined as: 
Duration of treatment = date of last dose -date of first dose +14
7

The cumulative dose of bintrafusp alfa per participant in a time period is the sum of the actual 
dose that the participants received within that period (i.e., total dose administered (mg)). 
The dose intensity of treatment (DI) (mg/cycle) of bintrafusp alfa per 2-week/cycle is defined as 
DI  treatment= 
Cumulative dose of treatment (mg)
Duration of 	
 alfa of treatment(in weeks)/2
The relative dose intensity (RDI) is defined as the actual dose intensity divided by the planned 
dose intensity per cycle and expressed in percentage:
RDI of treatment (%)=100× 
DI of treatment (mg/cycle)
planned dose level (mg/cycle) 
The following summary tables will be provided:
! Duration of therapy (weeks) 
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! Total number of infusions received 
! Cumulative dose (mg) 
! Dose intensity (mg/cycle) 
! Relative dose intensity (%) as continue variable, and categorized as
o
< 80%
o
80%-90%
o
>90%
Two listings will be presented: 
! A listing of study intervention which will provide: participant identifier, age, sex, race, visit, 
infusion start date and time, infusion end date and time, infusion rate (mL/hr), actual dose 
(mg), route, administration modification and reason for modification, change in 
administration detail, treatment delay (days). Data collected during the treatment re-
initiation phase will be flagged.
! An additional listing of treatment exposure and compliance which will include participant
identifier, age, sex, race, duration of therapy (weeks), total number of infusions received, 
cumulative dose of therapy (mg), dose intensity (mg/cycle), and relative dose intensity (%).
For data collected during the treatment re-initiation phase, only the duration of therapy as 
well as the number of infusions during the re-initiation phase will be summarized.
Dose Modification
Dose modification is not allowed per protocol. No summaries will be provided.
Therapy Delays
Delays of therapy will be derived for each infusion as the number of days since last infusion – 14:
Therapy Delays = start date of current infusion – start date of the previous infusion – 14
If the result is >0 day, then this will be classed as a delay. A participant may have more than one 
treatment delay throughout the course of treatment.
The following will be summarized in a table:
! Number of participants with at least one delay
! Number of participants with no delay
! Number of delays per participant (0 delay, 1 delay, 2 delays, 3 delays, ≥ 4 delays)
! Longest delay per participant (no delay, 1-2 days, 3-8 days, 9-15 days, ≥16 days) 
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Infusion Temporary Interruptions
Study drug infusion temporarily interrupted as recorded on the “Study Treatment Administration 
Details” page of the eCRF will be used for analysis. Number of participants with at least one study 
drug temporary interruption, reason for study drug temporary interruption (adverse event or other), 
as well as a categorization of the number of study drug temporary interruptions (1 / 2 / ≥3) will be 
summarized.
Infusion Rate Reductions
Infusion rate reductions as recorded on the “Study Treatment Administration Details” eCRF page
will be used for analysis. Number of participants with at least one infusion rate reduction, reason 
for infusion rate reductions (adverse event or other), as well as a categorization of the number of 
infusion rate reductions (1 / 2 / ≥3) will be summarized. 
14
Efficacy Analyses
Analysis Sets: ITT
14.1
Best Overall Response according to RECIST 1.1 as 
adjudicated by IRC (Primary endpoint)
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
Primary endpoint: confirmed Objective Response (OR)
Primary 
analysis
(ITT)
Confirmed Objective Response Rate 
(ORR) according to RECIST 1.1 as 
adjudicated by the IRC is defined as 
the number of participants having a 
confirmed 
objective 
response 
assessment of Complete Response 
(CR) or Partial Response (PR) (at 
least two determinations of CR/PR at 
least 4 weeks apart and before 
progression), out of the total number 
of participants.
ORR will be provided with a two-
sided 95% Confidence Interval 
(CI) using the Clopper-Pearson 
method (exact CI for a binomial 
proportion as computed by default 
by the FREQ procedure using the 
EXACT option).
Exact binomial test (1 sample) 
against the null hypothesis for the 
ORR 
will 
be 
calculated 
to 
determine 
whether 
the 
null 
hypothesis of an ORR ≤ 10% can 
be rejected.
Participants 
with 
missing post-baseline 
data are considered as 
having 
no 
objective
response
Best overall response (BOR)
Best overall response will be assessed based on the tumor response at different evaluation 
timepoints from the first study intervention until the first documented disease progression for 
RECIST criterion. Only tumor assessments performed before the start of any further anticancer
treatment will be considered in the assessment of BOR. Clinical deterioration will not be 
considered as documented disease progression.
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BOR can be defined as confirmed or unconfirmed, both definitions are provided below.
Confirmed best overall response (cBOR)
cBOR according to RECIST 1.1 as adjudicated by IRC will be assessed according to the following 
rules: 
! CR = at least two determinations of CR at least 4 weeks apart and before progression 
Note: It is reasonable to consider CR-NE-CR or CR-PR-CR as CR as long as the second CR 
is more than 28 days away from the first timepoint.
! PR = at least two determinations of PR at least 4 weeks apart and before progression (and 
not qualifying for a CR) 
Note: It is reasonable to consider PR-NE-PR or PR-SD-PR as PR as long as the second PR
is more than 28 days away from the first timepoint
! SD = at least one SD assessment (or better) ≥ 6 weeks after first date of study intervention
and before progression (and not qualifying for CR or PR)
! Non-CR/Non-PD= at least one Non-CR/Non-PD assessment ≥ 6 weeks after first date of 
study intervention and before progression with no measurable disease and does not meet 
criteria of CR
Note: As tumor lesions are evaluated by the IRC, it may happen that the independent 
reviewer disagrees with the Investigator and does not assess any tumors as “measurable” at 
screening. However, as per inclusion criteria, measurable disease must be confirmed by IRC 
at inclusion, so such case is not expected to occur. But in case of Non-CR/Non-PD, the 
overall response is rated as “non-CR/non-PD” (if no “CR” or “PD” are previously reported) 
by the IRC. Non-CR/Non-PD is specific to IRC assessment (it does not apply for Investigator 
assessment)
! PD = progression ≤16 weeks after first date of study intervention (and not qualifying for CR, 
PR or SD)
! ND = at least one ND assessment
Note: Overall response is rated as “No Disease” (ND) when the IRC is not able to identify 
any disease at baseline (target or non-target lesions). However, as per inclusion criteria, 
measurable disease must be confirmed by IRC at inclusion, so such case is not expected to 
occur. ND is specific to IRC assessment (it does not apply for Investigator assessment)
! NE = all assessments are NE or participant has a missing (or not evaluable) baseline tumor 
assessment and/or no (or not evaluable) tumor assessments on-treatment, or participant does 
not complete any of the following response above
Unconfirmed best Overall Response (uBOR)
uBOR according to RECIST 1.1 as adjudicated by IRC will be assessed according to the following 
rules: 
! CR = at least one determination of CR
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! PR = at least one determination of PR (and does not meet criteria of CR)
! SD = at least one SD assessment ≥ 6 weeks after start date and before progression (and does 
not meet criteria of CR or PR)
! Non-CR/Non-PD= at least one Non-CR/Non-PD assessment ≥ 6 weeks after start date and 
before progression with no measurable disease (and does not meet criteria of CR)
Note: As tumor lesions are evaluated by the IRC, it may happen that the independent 
reviewer disagrees with the Investigator and does not assess any tumors as “measurable” at 
screening. However, as per inclusion criteria, measurable disease must be confirmed by IRC 
at inclusion, so such case is not expected to occur. But in case of Non-CR/Non-PD, the 
overall response is rated as “non-CR/non-PD” (if no “CR” or “PD” are previously reported) 
by the IRC. Non-CR/Non-PD is specific to IRC assessment (it does not apply for Investigator 
assessment)
! PD = progression ≤16 weeks after first date of study intervention (and does not meet criteria 
of CR, PR, SD or Non-CR/Non-PD)
! ND = at least one ND assessment
Note: Overall response is rated as “No Disease” (ND) when the IRC is not able to identify 
any disease at baseline (target or non-target lesions). However, as per inclusion criteria, 
measurable disease must be confirmed by IRC at inclusion, so such case is not expected to 
occur. ND is specific to IRC assessment (it does not apply for Investigator assessment)
! NE = all assessments are NE or participant has a missing (or not evaluable) baseline tumor 
assessment and/or no (or not evaluable) tumor assessments on-treatment, or participant does 
not complete any of the following response above
Objective Response Rate (ORR)
The Objective Response Rate (ORR) is defined as the number of participants having an OR
assessment of Complete Response (CR) or Partial Response (PR), out of the total number of 
participants.
Confirmed ORR will be determined as the proportion of participants with a confirmed OR of PR 
or CR (having at least two determinations of CR/PR at least 4 weeks apart and before progression).
The confirmed ORR according to RECIST 1.1 as assessed by the IRC is the primary endpoint of 
the study.
Disease Control Rate (DCR)
Disease Control Rate (DCR) is defined as the proportion of participants with BOR according to 
evaluation criteria of CR, PR, or SD out of the total number of participants.
Separate tables will be provided for confirmed and unconfirmed BOR. Each one will provide the 
number and percentage of participants with cBOR (respectively uBOR) of CR, PR, SD, Non-
CR/Non-PD, PD, ND and NE as well as the ORR and the DCR. The ORR and DCR will be 
provided with a two-sided 95% CI using the Clopper-Pearson method (exact CI for a binomial 
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proportion as computed by default by the FREQ procedure using the EXACT option). Exact 
binomial test (1 sample) against the null hypothesis for the ORR will be calculated for confirmed 
BOR to determine whether the null hypothesis of an ORR ≤10% can be rejected.
The individual percentage of change in the sum of diameter since baseline will be displayed over 
time on a spider plot, together with the first occurrence of new lesion and the participant off 
treatment. The change in the sum of diameters between baseline and the best post-baseline 
assessment (i.e. minimum change since baseline) will be displayed on a waterfall graph. Note the 
sum of diameters includes all target lesions (longest diameter for non-nodal lesions and short axis 
for nodal target lesions)
The best percent change in sum of target lesion diameters will also be presented in a waterfall 
plot with confirmed BOR per IRC and investigator, PD-L1 in tumor cells and immune cells, 
, 
 and 
status.
For spider plots and waterfall plots, the percent change from baseline in the sum of diameters will 
be displayed for valid timepoint assessments, only. For the purpose of this analysis, a valid 
timepoint assessment is defined as a complete assessment of all target lesions reported at baseline. 
Further, split and coalesced lesions have to be taken into account appropriately to determine if a 
timepoint assessment is valid to derive the percent change from baseline in sum of diameters. All 
sum of diameters should be used, including the ones beyond first PD (for waterfall plot, the best 
post-baseline sum of diameters will be used even if occurring beyond PD). For waterfall plot, the 
percent change from baseline to 8-weeks assessment, as well as the percent change from baseline 
to the best post-baseline sum of diameters will be displayed for each participant.
Listing of tumor assessment will be provided with the following information: participant identifier, 
age, sex, race, date of start of subsequent anticancer therapy, date of death when death occurs,
unconfirmed and confirmed BOR, visit, date(s) of imaging, description of target lesions (size, site, 
type, method, response), non-target lesions (status, site, type, method, response), and new lesions 
(site, type, method), sum of lesion diameters, percent change in target lesions from baseline, 
percent change in target lesions from nadir and overall response of participant. Note that response 
of target and non-target lesions and change from nadir is not applicable at baseline.
In addition, a summary table of the reasons for non-evaluable confirmed BOR will be provided, 
the following reasons will be detailed:
! No baseline assessment (if applicable)
! No post-baseline assessments due to death within 8 weeks after the start of study treatment 
! No post-baseline assessments due to other reasons
! All post-baseline assessments have overall response ‘Non-evaluable’
! New anticancer therapy started before first evaluable post-baseline assessment 
! SD of insufficient duration (<6 weeks after the start of study treatment)
Note: Special cases where BOR is NE due to both early SD and late PD will be classified into 
this category
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! Non-CR/Non-PD of insufficient duration (<6 weeks after the start of study treatment) (if 
required by the data)
! No evaluable tumor assessment >16 weeks followed by PD (i.e. tumor assessment of PD 
was >16 weeks after start of study treatment and there was no evaluable tumor assessment 
in between) 
! No IRC review and Not determined categories may also be added if applicable
A listing of reasons for non-evaluable confirmed BOR will also be created including: participant
identifier, age, sex, race, date of first and last dose, date(s) of imaging, overall response and the 
reason for confirmed BOR non-evaluable.
14.1.1
Subgroup analysis for BOR
Confirmed BOR, ORR and DCR according to RECIST 1.1 as adjudicated by IRC will also be 
evaluated on all subgroups as defined in Section 8.2. This will be repeated for Japanese participants 
including only the ADA and nAb status subgroup.
For ADA and nAb subgroups a listing will present the tumor assessment and overall response per 
RECIST 1.1 as assessed by the IRC including:  participant ID, age, sex, race, ADA Status, nAb 
PD-L1 Assay Status, nAb TGF-β Assay Status, visit, date(s) of imaging, description of target 
lesions (size, site, status, type, method, response), non target lesions (status, site, method, 
response), and new lesions (site, status, method), sum of lesion diameters, percent change in target 
lesions at baseline, and overall response. Two listings will be created: for the ADA positive 
participants and for nAb positive in either away (PD-L1 and TGF-β) participants.
Participants with missing subgroup category will not be included in the related subgroup analysis.
Those subgroups analyses will be supported by forest plots.
14.2
Best Overall Response according to RECIST 1.1 as assessed 
by Investigator (Secondary endpoint)
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis 
Methods
Missing data 
handling
Secondary endpoint: confirmed Objective Response (OR)
Secondary  
analysis 
(ITT)
Confirmed Objective Response Rate 
(ORR) according to RECIST 1.1 as 
assessed by the Investigator is 
defined as the number of participants 
having 
a 
confirmed 
objective 
response assessment of Complete 
Response (CR) or Partial Response 
(PR) (at least two determinations of 
CR/PR at least 4 weeks apart and 
before progression), out of the total 
number of participants.
ORR will be provided with a 
two-sided 95% CI using the 
Clopper-Pearson 
method 
(exact CI for a binomial 
proportion as computed by 
default 
by 
the 
FREQ 
procedure using the EXACT 
option).
Participants 
with 
missing post-baseline 
data are considered as 
having a non-evaluable 
response
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Data collected in the eCRF for RECIST 1.1 response criteria as assessed by the Investigator 
(“Assessment of disease based on imaging (according to RECIST 1.1)” eCRF page) will be treated 
in the same way as data adjudicated by the IRC. Analyses described in Section 14.1 will be 
repeated based on Investigator assessment, i.e.:
! Number and percentage of participants with confirmed BOR of CR, PR, SD, PD and NE and 
corresponding listing
! ORR and DCR with their two-sided 95% CI
! Spider and Waterfall plots
! A summary table of the reasons for non-evaluable confirmed BOR and related listing, with 
the following reasons:
o
No baseline assessment (if applicable)
o
No post-baseline assessments due to death within 8 weeks after the start of study 
treatment
o
No post-baseline assessments due to other reasons
o
All post-baseline assessments have overall response ‘Non-evaluable’
o
New anticancer therapy started before first evaluable post-baseline assessment 
o
SD of insufficient duration (<6 weeks after the start of study treatment)
o
No evaluable tumor assessment >16 weeks followed by PD (i.e. tumor assessment of 
PD was >16 weeks after start of study treatment and there was no evaluable tumor 
assessment in between) 
o
Not determined category may also be added if applicable
All above analyses will be repeated for unconfirmed BOR.
In addition, a summary of the BOR (confirmed and unconfirmed) as adjudicated by IRC versus 
Investigator assessment will be provided included numbers of concordant and discordant 
assessment, and a listing of inconsistencies will be provided. 
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14.4
Progression-Free Survival (Secondary Endpoint)
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data handling
Secondary endpoint: Progression-Free Survival (PFS)
Secondary
analysis
(ITT)
Time 
from 
first 
administration 
of 
study treatment until 
the 
first 
documentation 
of 
progression 
of 
disease (PD) or death 
due to any cause, 
whichever occur first, 
per RECIST 1.1 as 
measured by the IRC.
Kaplan-Meier estimates (product-
limit estimates) will be presented 
together with a summary of 
associated 
statistics 
(median 
time, 3-, 6-, 9-, 12-, 24-month rate 
estimates) 
including 
the 
corresponding 
two-sided 
95% 
confidence 
intervals.
The 
confidence 
intervals 
for 
the 
median 
will 
be 
calculated 
according to Brookmeyer and 
Crowley (1982) and confidence 
intervals for the survival function 
estimates 
at 
above 
defined 
timepoints will be derived using 
the 
log-log 
transformation 
according 
to 
Kalbfleisch 
and 
Prentice (2011) (conftype=loglog 
default 
option
in 
SAS 
Proc 
LIFETEST). The estimate of the 
standard error will be computed 
using Greenwood's formula.
PFS will be censored at the date of last 
progression-free tumor assessment or 
date of first study treatment, whatever 
is later.
Censoring rules (details provided in 
body text):
-
No event (PD or death)
-
No baseline and/or post-baseline 
assessment
-
Start of new anticancer treatment
-
Event 
after 
two 
or 
more 
subsequent 
missing 
response 
assessments
Sensitivity 
analysis 1
(ITT)
PFS will be censored at the date of last 
tumor assessment with outcome CR, 
PR or SD or date of first study 
treatment, whatever is later.
Censoring rules (details provided in 
body text):
-
No event (PD or death)
-
No baseline and/or post-baseline 
assessment
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Sensitivity 
analysis 2
(ITT)
Time 
from 
first 
administration 
of 
study treatment until 
the 
first 
documentation 
of 
progression 
of 
disease (PD) or death 
due to any cause, 
whichever occur first, 
per RECIST 1.1 as 
measured
by 
the 
Investigator.
PFS will be censored at the date of last 
tumor assessment with outcome CR, 
PR or SD or date of first study 
treatment, whatever is later.
Censoring rules (details provided in 
body text):
-
No event (PD or death)
-
No baseline and/or post-baseline 
assessment
-
Start of new anticancer treatment
-
Event 
after 
two 
or 
more 
subsequent 
missing 
response 
assessments
Sensitivity Analysis 1: PFS counting all events (PD and death) regardless of the start of a new anticancer therapy and ignoring the 
number of missing evaluable tumor assessments before progression or death
Sensitivity Analysis 2: PFS as assessed by the Investigator
Progression-Free Survival (PFS) time is defined as the time from first administration of study
treatment until the first documentation of progression of disease (PD) or death due to any cause, 
whichever occur first.
PFS = (date of PD or death or censoring – date of first administration of study treatment + 1)/
30.4375 (months). 
The following censoring rules will also be applied for the PFS computation:
! Participants with no event (PD or death) will be censored on the date of the last adequate 
tumor assessment
! Participants who do not have a baseline tumor assessment or who do not have any evaluable
post-baseline tumor assessments will be censored at the date of first administration of study
treatment unless death occurred on or before the time of the second planned tumor 
assessment (i.e. 16 weeks) in which case the death will be considered an event.
! Participants who start new anticancer treatment prior to an event will be censored on the date 
of the last evaluable tumor assessment before anticancer therapy is given.
Note: any systemic anticancer therapy, any anticancer surgery and any anticancer
radiotherapy with exception of palliative bone radiotherapy will be considered as 
new/subsequent anticancer therapy and will lead to censoring.
! Participants with an event after two or more subsequent missing response assessments (i.e. 
no assessments in 112 days during the first 12 months of follow-up or 168 days after the first 
12 months of follow-up) will be censored on the date of the last evaluable tumor assessment.
The last tumor assessment date is defined as the last available and evaluable tumor assessment 
performed prior to the cut-off date (or prior to end of study, i.e. participants lost to follow-up or 
who withdraw consent) or prior to subsequent anticancer therapy. If no evaluable tumor 
assessment is available, this date will be the date of first administration of study treatment.
Censoring rules are also summarized in Table 5.
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Table 5
Censoring Rules for Primary and Sensitivity Analysis of PFS
Situation
Primary Analysis
Sensitivity Analysis 
1
Sensitivity Analysis 
2
No PD and no 
death
New anticancer 
therapy is not 
initiated
Censored at last tumor 
assessment*
Censored at last 
tumor assessment*
Censored at last 
tumor assessment*
New anticancer 
therapy is initiated
Censored at last tumor 
assessment* before 
new anticancer therapy
Censored at last 
tumor assessment*
Censored at last 
tumor assessment* 
before new 
anticancer therapy
No baseline 
assessment or 
no evaluable
post-baseline 
assessment
No death or death 
>16 weeks after 
start of study 
treatment
Censored at date of 
first administration of 
study treatment
Censored at date of 
first administration of 
study treatment
Censored at date of 
first administration of 
study treatment
Death ≤16 weeks 
after start of study 
treatment
Progressed at date of 
death
Progressed at date of 
death
Progressed at date of 
death
PD or death
After ≤1 subsequent 
missing response 
assessmenta
Progressed at date of 
document PD or death, 
whichever came first
Progressed at date of 
documented PD or 
death, whichever 
came first
Progressed at date of 
documented PD or 
death, whichever 
came first
After ≥2 subsequent 
missing response 
assessmenta
Censored at last tumor 
assessment* before 
missing assessments.
Progressed at date of 
documented PD or 
death, whichever 
came first
Censored at last 
tumor assessment* 
before missing 
assessments
Before started new 
anticancer therapy
Progressed at date of 
document PD or death, 
whichever came first
Progressed at date of 
documented PD or 
death, whichever 
came first
Progressed at date of 
document PD or 
death, whichever 
came first
After started new 
anticancer therapy
Censored at last tumor 
assessment* before 
new anticancer therapy
Progressed at date of 
documented PD or 
death, whichever 
came first
Censored at last 
tumor assessment* 
before new 
anticancer therapy
Sensitivity Analysis 1: PFS counting all events (PD and death) regardless of the start of a new anticancer therapy and 
ignoring the number of missing evaluable tumor assessments before progression or death
Sensitivity Analysis 2: PFS as assessed by the Investigator
* with outcome CR, PR or SD. If no adequate tumor assessment, censored at date of first administration of study 
treatment
a No assessments in 112 days during the first 12 months of follow-up or 168 days after the first 12 months of follow-up
PFS according to RECIST 1.1 as measured by the IRC will be described (secondary endpoints).
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The analysis of PFS will be performed with a Kaplan-Meier method (product-limit estimates) and 
a summary of associated statistics will be presented including corresponding two-sided 95% CIs. 
The CIs for the median will be calculated according to Brookmeyer and Crowley (1982) and CIs 
for the survival function estimates will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (1980) (CONFTYPE=loglog default option in SAS PROC LIFETEST).  
The estimate of standard error will be computed using Greenwood’s formula. 
Frequency (number and percentage) of participants with and without event and within each event 
type (PD or death) will be presented as well as the PFS median, min and max. Number of 
participants at risk, failed and PFS rates with their CI at 6, 12 and 24 months will also be provided.
Censoring reasons will also be described. Censoring reasons are as follows:
! Administrative censoring (ongoing in the study without an event)
! No baseline assessment
! No evaluable post-baseline assessment
! Start of new anticancer therapy
! Event after 2 or more missing or non-evaluable post-baseline assessments
! Withdrawal of consent
! Lost to follow-up
Lost to follow-up will include the following participants:
! Lost to follow-up status is collected on the eCRF treatment termination page or eCRF study 
termination page prior to the analysis cut-off
! Participants with the last alive date > 14 weeks prior to the analysis cut-off date (duration of 
14 weeks is based on the assessment schedule of every 3 months for survival follow-up 
interval + 2-weeks window)
PFS will also be presented graphically with Kaplan-Meier figures.
Separate listings will be provided for the different assessment methods with the following 
information: participant identifier, age, sex, race, date of first administration of study treatment, 
date of last tumor assessment, date of event/censoring, event/censoring reason, time to event. 
14.4.1
Sensitivity analysis for PFS
The two following sensitivity analyses will be conducted:
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1. PFS counting all events (PD and death) regardless of the start of a new anticancer therapy 
and ignoring the number of missing evaluable tumor assessments before progression or 
death
2. PFS as assessed by the Investigator (described above in Section 14.4)
Those sensitive analyses will be supported with Kaplan-Meir plots. Listing of progression-free 
survival by the Investigator will also be provided.
14.4.2
Subgroup analysis for PFS
PFS according to RECIST 1.1 as adjudicated by IRC will also be evaluated on all subgroups as 
defined in Section 8.2. This will be repeated for Japanese participants including only the ADA and 
nAb status subgroup.
For the ADA and nAb subgroups, participant listings will provide the following information: 
participant ID, age, sex, race, ADA status, nAb PD-L1 assay status, nAb TGF-β assay status, date 
of first administration, date of last tumor assessment, date of event/censoring, event/censoring 
reason, time to event. Two listings will be created: for the ADA positive participants and for nAb
positive in either assay (PD-L1 and TGF-β) participants.
Participants with missing subgroup category will not be included in the related subgroup analysis.
Those subgroups analyses will be supported by Kaplan-Meir and forest plots (based on PFS rates 
at 6-month and 12-month).
14.5
Duration of Response (Secondary Endpoint)
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
Secondary endpoint: Duration of Response (DOR)
Secondary
analysis
(ITT)
The duration of overall response is 
measured from the time from first
documentation of confirmed objective 
response (CR or PR) to the date of 
first 
documentation 
of
objective 
progression of disease (PD) or death 
due to any cause, whichever occurs 
first This definition applies only to 
participants 
who 
experienced 
confirmed objective response. It will 
be measured according to RECIST 
1.1 as measured by the IRC and the 
Investigator
Kaplan-Meier estimates (product-
limit estimates) will be presented 
together 
with 
a 
summary 
of 
associated statistics (median time, 
3-, 6-, 9-, 12-, 24-month rate 
estimates) 
including 
the 
corresponding 
two-sided 
95% 
confidence 
intervals.
The 
confidence intervals for the median 
will be calculated according to 
Brookmeyer and Crowley (1982) 
and confidence intervals for the 
survival function estimates at above 
defined timepoints will be derived 
using the log-log transformation 
according 
to 
Kalbfleisch 
and 
Prentice (2011) (conftype=loglog 
default 
option 
in 
SAS 
Proc 
LIFETEST). The estimate of the 
standard error will be computed 
using Greenwood's formula.
Same censoring rules 
as for PFS.
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Duration of response (DOR) is defined for participants with a confirmed objective response, as 
the time from first documentation of confirmed objective response (CR or PR) to the date of first 
documentation of objective progression of disease (PD) or death due to any cause whichever 
occurs first:
DOR = (date of PD or death or censoring – date of confirmed objective response + 1)/30.4375 
(months).
The censoring rules for DOR are as described above for PFS (primary definition in Table 5) in 
Section 14.4.
DOR of confirmed CR/PR according to RECIST 1.1 as measured by the IRC and the Investigator
will be described. Considering confirmed CR/PR involve having at least two objective responses, 
the date of occurrence of the first CR/PR will be used as date of objective response.
The analysis of DOR will be performed with a Kaplan-Meier method (product-limit estimates) and 
a summary of associated statistics will be presented including corresponding two-sided 95% CIs. 
The CIs for the median will be calculated according to Brookmeyer and Crowley (1982) and CIs 
for the survival function estimates will be derived using the log-log transformation according to 
Kalbfleisch and Prentice (1980) (CONFTYPE=loglog default option in SAS PROC LIFETEST). 
The estimate of standard error will be computed using Greenwood’s formula. 
DOR rates with their CI at 3, 6, 9, 12 and 24 months will be presented, as well as the number of 
participants at risk and failed.
The time to and duration of response per participant having a confirmed objective response 
(including delayed response, see Section 14.7 below) will be displayed in swimmer graphs. 
Kaplan-Meier figures will also be provided. 
Listings will be provided with the following information: participant identifier, age, sex, race, date 
of first study treatment administration, date of first response, date of last tumor assessment, 
censored (Y/N), date of event/censoring, event/censoring reason and duration of response.
14.5.1
Subgroup analysis for DOR
DOR according to RECIST 1.1 as adjudicated by IRC will also be evaluated on all subgroups as 
defined in Section 8.2. This will be repeated for Japanese participants including only the ADA and 
nAb status subgroup.
Participants with missing subgroup category will not be included in the related subgroup analysis.
Those subgroups analyses will be supported by forest plots (based on DOR rates at 6-month and 
12-month).
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14.6
Durable Response (Secondary Endpoint)
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data 
handling
Secondary endpoint: Durable Response Rate (DRR)
Secondary
analysis
(ITT)
Number of participants having a DOR 
of at least 6 months, out of the total 
number of participants
DRR will be provided with a two-
sided 95% CI using the Clopper-
Pearson method (exact CI for a 
binomial proportion as computed by 
default by the FREQ procedure 
using the EXACT option).
Participants with 
missing baseline 
and post-baseline 
tumor assessments 
will be defined as
non-evaluable, and 
considered as 
having no response.
Durable Response Rate (DRR) is defined as the number of participants having a DOR of at least 
6 months, out of the total number of participants.
The DRR will be provided with a two-sided 95% CI using the Clopper-Pearson method (exact CI 
for a binomial proportion as computed by default by the FREQ procedure using the EXACT 
option). 
DRR will be described according to RECIST 1.1 as measured by the IRC and the Investigator.
14.6.1
Subgroup analysis for DRR
DRR according to RECIST 1.1 as adjudicated by IRC will also be evaluated on all subgroups as 
defined in Section 8.2. This will be repeated for Japanese participants including only the ADA and 
nAb status subgroup.
Participants with missing subgroup category will not be included in the related subgroup analysis.
Those subgroups analyses will be supported by forest plots.
14.7
Delayed Response
Delayed response will be defined as a documented objective response [CR or PR] that occurred 
after the initial progression of disease. For those participants, the duration of delayed response 
(DOdR) will be defined as: 
DOdR = (date of end of objective response – date of objective response + 1)/30.4375 (months).
with end of response being the earliest date between PD occurring after response, death, start of 
new anticancer treatment or cut-off date.
Two listings for participants having a delayed response according to RECIST 1.1 as measured by 
IRC will be described will be provided:
!
For tumor assessment including: participant identifier, age, sex, race, date of first and last 
study intervention, date(s) of imaging, sum of lesion diameters, percent change in target 
lesions from baseline, and overall response.
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! For duration of response including: participant identifier, age, sex, race, date of first and last
study intervention, date/study day of first PD, date/study day of first response (CR or PR), 
ongoing response at cutoff date (Y/N), date/study day of end of response (with reason for 
end of response being PD, death, new anticancer treatment), duration of delayed response.
14.8
Overall survival
Analysis
(Analysis 
Population)
Derivation
Statistical Analysis Methods
Missing data handling
Secondary endpoint: Overall Response (OS)
Secondary
analysis 
(ITT)
Time from first 
administration of 
study treatment 
to the date of 
death due to any
cause
Kaplan-Meier estimates (product-limit 
estimates) will be presented together 
with 
a 
summary 
of 
associated 
statistics (median time, 3-, 6-, 9-, 12-, 
24-month rate estimates) including 
the corresponding two-sided 95% 
confidence intervals. The confidence 
intervals for the median will be 
calculated according to Brookmeyer 
and Crowley (1982) and confidence 
intervals for the survival function 
estimates at above defined timepoints 
will be derived using the log-log 
transformation 
according 
to 
Kalbfleisch 
and 
Prentice 
(2011) 
(conftype=loglog default option in 
SAS Proc LIFETEST). The estimate 
of the standard error will be computed 
using Greenwood's formula.
For alive participants,
OS will be 
censored at last date known to be alive
The following dates will be considered 
to determine the last date known to be 
alive (dates past the data cut-off will be 
ignored by the derivation; details 
provided in body text):
!
All participant assessment 
dates 
!
Start and end dates of 
anticancer therapies 
administered after study 
treatment discontinuation. 
!
AE start and end dates 
!
Last known alive date collected 
on the ‘Subject Status / Survival 
Follow-Up’ eCRF page (do not 
use follow up date)
!
Study drug start and end dates 
Date of discontinuation from the “Study 
Termination” eCRF page (do not use if 
reason for discontinuation is lost to 
follow-up or death)
Overall survival (OS) is defined as the time from first administration of study treatment to the 
date of death due to any cause:
OS = (date of event or censoring – date of the first dose + 1)/30.4375 (months). 
For participants alive at the time of data cut-off date or who are lost to follow up, OS will be 
censored at the last date known to be alive. The date of event / censoring is defined in Table 6.
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Table 6
Survival Event / Censoring
Survival Status
Date of event/censoring
Censoring
Participants alive or lost to follow-up before
or at cut-off date
Last date known to be alive
Yes
Participants who died before or at cut-off 
date
Date of death
No
The following complete dates will be considered to determine the last date known to be alive. Only 
the ones among them that are before or at data cut-off and which are not imputed shall be used in 
the derivation:
! All participant assessment dates (blood draws [laboratory, PK], vital signs, performance 
status, ECG, tumor assessments, quality of life assessments) 
! Start and end dates of anticancer
therapies administered after study treatment 
discontinuation. 
! AE start and end dates 
! Last known alive date in “Subject Status / Survival Follow-Up” eCRF page (do not use the 
follow up date)
! Study drug start and end dates (including reinitiation of treatment)
! Date of discontinuation from the “Study Termination” eCRF page (do not use if reason for 
discontinuation is lost to follow-up or death)
Only dates associated with actual examinations of the participant reported in the eCRF will be 
used in the derivation.  Dates associated with a technical operation unrelated to participant status 
such as the date a blood sample was processed will not be used. 
Data collected after re-initiated treatment will be considered in the derivation of the last known to 
be alive date.
The analysis of OS time will be performed with a Kaplan-Meier method with the same approach 
as for PFS described in Section 14.4. Kaplan-Meier estimates (product-limit estimates) will be 
presented together with a summary of associated statistics including corresponding two-sided 95% 
CIs. OS rates with their CI at 3, 6, 9,12 and 24 months will be presented, as well as the number of 
participants at risk and failed. Censoring reasons will also be described. Censoring reasons are as 
follows:
! Alive at cut-off date
! Withdrawal of consent
! Lost to follow-up
OS will also be presented graphically with Kaplan-Meier figures.
A participant listing will provide the following information: participant identifier, age, sex, race, 
date of first study intervention, date of event/censoring, event/censoring reason, time to event. 
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14.8.1
Subgroup analysis for OS
Overall survival will also be evaluated on all subgroups as defined in Section 8.2. This will be 
repeated for Japanese participants including only the ADA and nAb status subgroup.
For the ADA and nAb subgroups, participant listings will provide the following information: 
participant ID, age, sex, race, ADA status, nAb PD-L1 assay status, nAb TGF-β assay status, date 
of first administration, date of last tumor assessment, date of event/censoring, event/censoring 
reason, time to event. Two listings will be created: for the ADA positive participants and for nAb
positive in either assay (PD-L1 and TGF-β) participants.
Participants with missing subgroup category will not be included in the related subgroup analysis.
Those subgroups analyses will be supported by Kaplan-Meier and forest plots (based on OS rates 
at 6-month and 12-month).
14.9
Follow-up time (PFS)
Kaplan-Meier analysis will be performed to estimate median time of duration of follow-up for PFS 
as adjudicated by IRC using the reverse censoring indicator of the PFS analysis (see Section 14.4).
Kaplan-Meier survival curves will also be presented with median duration of follow-up an its two-
sided 95% CI. In particular, the follow-up rates at 3, 6, 9, 12 and 24 months will be estimated with 
their 95% CI. 
14.10
Follow-up time (OS)
Kaplan-Meier analysis will be performed to estimate median time of duration of follow-up for OS
using the reverse censoring indicator of the OS analysis (see Section 14.8).
Kaplan-Meier survival curves will also be presented with median duration of follow-up an its two-
sided 95% CI. In particular, the follow-up rates at 3, 6, 9, 12 and 24 months will be estimated with 
their 95% CI. 
15
Safety Analyses
Analysis set: SAF
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as adverse events, laboratory tests and vital signs.
15.1
Adverse Events
Treatment-emergent adverse events (TEAEs) are those events with onset dates occurring during 
the on-treatment period or if the worsening of an event is during the on-treatment period.
Changes in toxicity grade, seriousness or outcome of AEs are recorded as separate entries in the 
eCRF with associated end and start dates (start date equals end date of previous entry). Such entries 
reporting the same event in such immediately consecutive periods will be considered as one event 
in the analysis. These events will be kept as separate records in the database in order to maintain 
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the full detailed history of the events. The start date of the initial record in the sequence is taken 
as start date of the entire event, similarly the end date of the last event in the sequence is taken as 
end date of the entire event. The overall outcome of the adverse event is the outcome of the last 
event in the sequence. Duration of the AE and the TEAE flag will be adjusted accordingly in the 
analysis.
All analyses described in this section will be based on TEAEs if not otherwise specified. The AE 
listings will include all AEs. AEs outside the on-treatment period (prior or after) will be flagged 
in listings. AEs occurring during the re-initiation phase will be considered in the summary tables 
and will be flagged in listings.
Incomplete AE-related dates will be handled as stated in Section 9.
Related Adverse Events are those events with relationship to study treatment (as recorded on the 
“Adverse Events Details” eCRF page, Relationship with M7824= Related) reported by the
Investigator and those of unknown relationship (i.e. no answer to the question “Relationship with 
M7824”). 
Serious Adverse Events (SAE) are those events reported on the “Adverse Events Details” eCRF 
page, with the “Serious Adverse Event” field ticked “Yes”. 
Adverse Events Leading to Temporary Discontinuation are those events leading to temporary 
discontinuation of study treatment (answer to the question “Action(s) taken with M7824” = “Drug 
interrupted” on “Adverse Event Details” eCRF page).
Adverse Events leading to Permanent Treatment Discontinuation are those events leading to 
permanent discontinuation of study treatment (answer to the question “Action(s) taken with 
M7824” = “Drug withdrawn” on “Adverse Event Details” eCRF page).
Adverse Events leading to Death are those events leading to death (as recorded on the “Adverse 
Event Details” eCRF page, change in grade = “No” and outcome = “Fatal”, or Grade = “Grade 5 
or death related to AE” or Serious adverse event = “Yes” and seriousness criteria include “Results 
in death”).
Adverse Events of Special Interest (AESI): AESI are identified according to a pre-specified 
search list of MedDRA Preferred Terms (PTs). Categories of AESI include:
! Infusion-Related Reactions (IRRs)
! Immune-Related Adverse Events (irAEs)
! Skin AEs possibly related to TGF-β inhibition
! Anemia
Bleeding events are those events belonging to the MedDRA SMQ Haemorrhage terms (excluding 
laboratory terms).
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15.1.1
All Adverse Events
Adverse events will be summarized by worst severity (according to National Cancer Institute -
Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0) per participant,
using the latest version of MedDRA preferred term (PT) as event category and MedDRA primary 
system organ class (SOC) body term as Body System category.
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PTs and 
primary SOCs in alphabetical order. 
Each participant will be counted only once within each PT or SOC. If a participant experiences
more than one AE within a PT or SOC for the same recording period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity.
If an adverse event is reported for a given participant more than once during treatment, the worst 
severity and the worst relationship to study treatment will be tabulated. In case a participant had 
events with missing and non-missing grades, the maximum of the non-missing grades will be 
displayed.
A table presenting the overall summary of AEs will be presented including the frequency (number 
and percentage) of participants within each of the following categories:
! TEAEs 
! Related TEAEs 
! Serious TEAEs 
! Related Serious TEAEs 
! TEAEs NCI-CTCAE severity grade (∀3, ∀4) 
! Related TEAEs NCI-CTCAE severity grade (∀3, ∀4) 
! TEAEs leading to death 
! Related TEAEs leading to death
! AEs and related AE of special interest: 
o
Infusion-related reactions (IRRs)
o
Immune-related AEs (irAEs)
o
Potential TGF-β-mediated skin AEs
o
Anemia
! TEAE, bleeding events
! Related TEAEs bleeding events
Tables for TEAEs frequency corresponding to each category in the overview table above will be 
provided by:
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! MedDRA primary SOC (ordered alphabetically) and PT (ordered alphabetically), (except 
for AE of special interest)
TEAEs and related TEAEs by worst grade will also be summarized, and the most frequent PT (at 
least 5%) will be presenting graphically by worst grade and PT with bar chart figures.
Clinicaltrials.gov and EudraCT -requirements
Summary table for non-serious TEAEs excluding SAEs applying frequency threshold of 5% will 
be provided.
Listings of adverse events will contain the following information: participant identifier, age, sex, 
race, first and last date of study intervention, preferred term, reported term for the AE, start date, 
end date, duration of AE (in days), day relative to the first infusion, day relative to the most recent 
infusion prior to AE onset, relationship to study treatment, toxicity grade, action(s) taken, outcome, 
seriousness (Y/N), AESI infusion-related (Y/N), AESI immune-related (Y/N), potential TGF-β-
mediated skin AESI (Y/N), anemia AESI (Y/N). TEAEs and AEs occurring during the re-initiation 
period will be flagged. 
Following listings will be provided with the relevant information:
! Listing of all AE (whether treatment-emergent or not) (TEAEs will be flagged) (AE 
occurring during re-initiation phase will be flagged)
! Listing of TEAEs
! Listing of non-TEAE for AEs occurring after enrollment (date of first signature of informed 
consent/date of first signature of first informed consent) but prior to the first dose of study 
intervention.  
! Listing of AE with onset or worsening after the on-treatment period (AE occurring during 
re-initiation phase will be flagged) 
! Listing of AEs for participants who reinitiated the treatment
Evaluation of Potential Effect of ADA and nAb on bintrafusp alfa Safety
The following analyses frequency and percentage of AEs by ADA status (ever positive, never 
positive), and by nAb status (ever positive for either assay, never positive) will be performed:
!
TEAEs
!
TEAEs, grade ∀3
!
TEAEs leading to permanent treatment discontinuation 
!
TEAEs excluding IRRs leading to drug interruptions
!
Serious TEAEs
!
TEAEs leading to death
!
irAEs (see definition in Section 15.2.4.2)
!
IRRs (see definition in Section 15.2.4.1)
This will be repeated for Japanese participants.
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Listings of all AEs and all IRRs for ever-positive ADA participants (pre-existing, transient 
treatment-emergent, persistent-treatment emergent) will be prepared including participant 
identifier and showing the date(s) of the positive ADA result together with the AEs or IRRs. For 
the AEs and IRRs, start and stop date will be shown along with grade. Adverse events recorded 
during the period of 2-weeks prior to the positive ADA value till two weeks after the positive ADA 
value will be flagged. This will be repeated for ever-positive nAb participants in either assay (PD-
L1 and TGF-β). These analyses for ever positive ADA and ever positive nAb subjects in either 
assay will be repeated for Japanese participants.
Evaluation of COVID-19 effects on AEs
The direct effect of COVID-19 for AEs will be assessed via listings of COVID-19 related AEs.
The following listings will be generated using the ‘COVID-19 related terms MedDRA 23.0 update 
Spreadsheet’ (https://www.meddra.org/covid-19-related-terms-meddra-230-update-spreadsheet, 
last accessed on 28 May 2020) as available from Maintenance and Support Services Organization 
(MSSO), considering all ‘search terms for COVID-19-related’ =’Y’. The following information 
will be provided:
!
Subject ID, country. age, sex, race
!
Date of first, last treatment with study drug
!
COVID-19-associated AE start date (day), COVID-19 associated AE stop date (day)
!
AE preferred term, verbatim
!
Toxicity grade
!
Seriousness
!
Relationship to treatment
!
Action taken
!
Outcome
The indirect effect of COVID-19 for AEs will be assessed based on the difference in incidence rate 
between subgroups of pre and during COVID-19 period according to categorization method with time 
window:
!
For common TEAEs applying frequency threshold of 10% in either subgroup of pre/during 
COVID-19 period, butterfly plots displaying incidence rates of TEAEs NCI-CTCAE 
severity grade ≤2 and ≥3 will be provided.
!
For each AESIs defined in Section 15.2.4 occurred on 4 or more participants in any 
subgroup (Rule-of-4), forest plots displaying incidence rates, differences in incidence rates 
as well as the CI for the difference will be provided.
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15.1.2
Adverse 
Events 
Leading 
to 
Study 
Intervention 
Discontinuation
Frequency tables summarizing the following actions taken with study treatment will be presented 
by PT and primary SOC in alphabetical order:
! TEAEs leading to temporary drug interruption
! Related TEAEs leading to temporary drug interruption
! TEAEs leading to permanent treatment discontinuation
! Related TEAEs leading to permanent treatment discontinuation
! TEAEs leading to infusion rate reduction
! Related TEAEs leading to infusion rate reduction
In addition, the incidences for above items will be summarized in an overview table.
The listing of TEAEs leading to permanent treatment discontinuation will also be provided with 
the relevant information.
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
All deaths, deaths within 30 days after last dose of study treatment (in case of re-initiated 
participants, the last dose will be the last dose of the re-initiation phase), death within 60 days after 
first dose of study treatment (for all participants, the first dose will be the first dose of the first 
treatment phase) as well as the primary reason for death will be tabulated based on information 
from the “Death” eCRF pages.
The following summaries will be provided:
! Number of deaths (including deaths during re-initiation phase)
! Number of deaths within 30 days after last dose of study treatment 
! Number of deaths within 60 days after first dose of study treatment 
! Primary Reason for Death
o
Progressive disease and/or disease related condition
o
Event unrelated to study treatment 
o
Event related to study treatment
o
Unknown 
In addition, date and cause of death will be provided in an individual participant data listing 
together with following dosing information: participant identifier, age, sex, race, date of first/last
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study intervention, number of infusions, day relative to the first and the last infusion, autopsy 
(Y/N/U), AEs with fatal outcome (list preferred terms of AEs with outcome=Fatal, as well as 
Grade 5 or Serious resulting in death), flag for death within 30 days of last dose of study treatment 
and flag for death within 60 days of first dose of study treatment.
15.2.2
Serious Adverse Events
The number of participants with serious AEs (SAEs) will be described by SOC and PT:
! SAEs 
! Related SAEs 
Bar charts presenting SAEs and related SAEs of the most frequent PT (at least 5%) will be 
displayed by worst grade and PT.
Listing of SAEs will also be provided (see description of listing in Section 15.1.1).
15.2.3
Bleeding Events
Bleeding events of interest are the preferred terms belonging to the MedDRA SMQ Haemorrhage 
terms (excluding laboratory terms).
Bleeding events and study drug related bleeding events will be summarized in a frequency table 
presenting SOC and PT sorted by alphabetical order. The worst grade per participant, per SOC and 
per PT will be reported:
! Any grade (including missing grade)
! Grade 1
! Grade 2
! Grade 3
! Grade 4
! Grade 5
15.2.4
Adverse Events of Special Interest
15.2.4.1
Infusion-Related 
Reaction 
including 
Immediate 
Hypersensitivity
Infusion-Related Reactions (IRRs) are defined as adverse events with PTs according to a
pre-specified MedDRA search list, and are divided into two subcategories: “Reactions” and “signs 
and symptoms” based on criteria on the timely relationship as detailed below:
Reactions of IRR: should be considered when onset is on the day of infusion (during or after the 
infusion) or the day after the infusion (irrespective of resolution date) for any infusion-related 
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reaction, drug hypersensitivity, anaphylactic reaction, hypersensitivity and/or Type 1 
hypersensitivity.
Signs and symptoms of IRRs and hypersensitivity/allergic reactions: should be considered 
when onset is on the day of infusion (during or after the infusion) and resolved completely with 
the end date on the same day of the infusion or the day after for any of the following: pyrexia, 
chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain and urticaria. 
IRR, overall and by subcategories, will be summarized by the following variables:
! Number of participants with at least one IRR by the worst NCI-CTCAE toxicity grade (grade 
1/ grade 2/ grade 3/ grade 4/ grade 5/ missing grade)
! Number of participants with IRR leading to permanent treatment discontinuation
! Number of participants with IRR leading to infusion rate reduction
! Time related to first onset (infusion 1/ infusion 2/ infusion 3/ infusion 4 or later). The events 
should be assigned to the actual drug infusions that the participant received, not to the 
planned dates. An IRR is assigned to a drug infusion if its onset is at the same date (but not 
before dosing when time is recorded) or the following day of drug infusion.
When at least 10 participants will have received premedication for the first infusion and 
respectively at least 10 participants will have received the first study medication without 
premedication, results will also be split by premedication (Y/N) subgroups.
The frequency table of IRR AEs by worst grade, SOC, and PT will also be provided. 
The listing of IRRs will be provided with the relevant information (see description of listing in 
Section 15.1.1). One additional listing will display the study drug administration details together 
with the infusion-related adverse event including administration date (day) /time, reason for 
modification, type of modification, modification start time, use of pre-medication, IRR AE 
Preferred Term, IRR AE grade, IRR AE start day /stop day, IRR AE time related to infusion.
15.2.4.2
Immune-Related Adverse Events
Immune-related adverse events (irAEs) will be identified programmatically. AEs which satisfy all 
of the following criteria will be flagged as immune-related:
1) The AE preferred term matches a preferred term on the list of pre-selected MedDRA terms.
2) The AE onset or worsening occurs after the first study drug administration and no more than 90 
days after last dose.
3) On the “AE” eCRF page, the question “Were Corticosteroids, Immunosuppresants, or hormonal 
therapy (e.g. Thyroid) applied?” has the answer “Yes” selected.
4) On the “imAE SPECIFIC QUESTIONS” eCRF page, either:
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a. The question “Does any of the following provide a clear etiology for the event?” has the 
answer “No” selected, indicating that the AE is not attributable to underlying cancer 
disease/PD, prior or concomitant medications/procedures, nor another medical condition 
such as an infection or pre-existing disease.
OR 
b. The “imAE SPECIFIC QUESTIONS” eCRF page indicates that a biopsy was performed 
and the question “Is the histopathology/biopsy consistent with an immune-mediated 
event?” has the answer “Yes” selected.
In the case that criteria (1) through (3) are met, and entries for condition (4) are missing, the 
following rules will be applied: 
• If the answer to “Does any of the following provide a clear etiology for the event?” (4a) 
is missing, the event will be considered as irAE (irrespective of biopsy results). 
•
If the answer to “Is the histopathology/biopsy consistent with an immune-mediated 
event?” (4b) is missing, or if no biopsy was performed, and condition (4a) is not satisfied,
i.e. “Yes” is selected (i.e. at least one (clear) etiology of the event is provided) as the 
answer to the question “Does any of the following provide a clear etiology for the 
event?”, the event will be considered as a non-irAE.
All non-pre-treatment AE records will be flagged for an event if at least one non-pre-treatment 
record satisfies the criteria.
PTs will be compiled into categories: Immune-mediated rash, Immune-mediated colitis, Immune-
mediated pneumonitis, Immune-mediated hepatitis, Immune-mediated nephritis and renal 
dysfunction, Immune-mediated endocrinopathies (Adrenal insufficiency, Hypogonadism, 
Pituitary dysfunction, Type 1 Diabetes Mellitus, Thyroid disorders), Other immune-mediated
adverse events (myositis, myocarditis, pancreatitis, neurologic events, other).
Immune-related adverse events (irAEs) will be summarized by the following variables:
! Any irAEs
! irAEs by the worst grade
! irAEs leading to permanent treatment discontinuation
! Serious irAEs 
The frequency table of immune-related AEs by worst grade, category, subcategory (for Immune-
mediated endocrinopathies), sub-subcategory (for Immune-mediated endocrinopathies – thyroid 
disorders) and PT will also be provided. 
The listing of irAE will also be provided with the relevant information, including additional 
interventions for irAE (e.g. biopsies, surgical procedures, medical procedures) (see description of 
listing in Section 15.1.1).
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15.2.4.3
Potential TGF-β-mediated skin adverse events
To identify potential skin AEs possibly related to TGF-β inhibition, MedDRA PT queries will be 
used to search for skin AEs of interest in the clinical database. A listing containing these pre-
specified PT search terms will be generated. PTs will be compiled into categories: Narrow 
definition, and Broad definition:
Narrow definition:
!
Keratoacanthoma
!
Squamous cell carcinoma of skin
Broad definition has additional PTs:
!
Hyperkeratosis
!
Actinic keratosis
!
Basal cell carcinoma
!
Lip squamous cell carcinoma
!
Bowen´s disease
Further details (e.g. MedDRA PT queries) are regularly updated based on the current MedDRA 
version.
The overall summary of skin TEAE will include the following categories for narrow and broad 
definition:
! All skin TEAE
! All skin TEAE by worst grade
! Skin TEAE leading to permanent treatment discontinuation
! Serious skin TEAEs 
Tables for skin TEAEs frequency will be provided by MedDRA PTs (including both narrow and 
broad definition PTs).A listing of skin AEs will also be provided, containing participant identifier, 
age, sex, race, first and last date of study intervention, preferred term, reported term for the AE, 
start date, end date, duration of AE (in days), day relative to the first infusion, day relative to the 
most recent infusion prior to AE onset, relationship to study treatment, toxicity grade, action(s) 
taken, outcome, seriousness (Y/N). Plus, from the “TGFβ Mediated Skin Reaction” eCRF page, 
the number of lesions, confirmation of the diagnosis (Y/N) and lesion location.
15.2.4.4
Anemia
A listing of anemia will be provided with the relevant information (see description of listing in 
Section 15.1.1). 
The following high level terms (HLT) and PTs will be used to select the anemia AEs to be included 
in the listing:
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! Anaemias NEC (HLT)
! Anaemias haemolytic immune (HLT)
! Anaemias haemolytic NEC (HLT)
! Haemoglobin decreased (PT)
15.3
Clinical Laboratory Evaluation 
Baseline and on-treatment laboratory values (including corresponding normal ranges), converted 
in standard unit, will be used for summary statistics and shift tables.
Laboratory results will be classified according to the NCI-CTCAE criteria version 5.0 and as 
specified in Appendix 3. Additional laboratory results that are not part of NCI-CTCAE will be 
categorized as follows: below normal limits, within normal limits, and above normal limits 
(according to the original laboratory normal ranges).
Quantitative data will be summarized using descriptive statistics (mean, standard deviation, 
median, Q1, Q3, minimum, and maximum) of actual baseline values, on-treatment values and 
changes from baseline to each on-treatment visit over time. Refer to Section 9 to the consideration
of Unscheduled assessments. Qualitative data based on reference ranges will be described 
according to the categories (i.e. Abnormal, Normal).
Summary tables over time will present summary statistics for continuous and categorical variables 
by timepoint.
The following figures will be provided:
! Boxplots of the laboratory values by timepoint
! Boxplots of the change from baseline by timepoint
Boxplots for laboratory parameters where toxicity grades are defined based on the ratio of the 
parameter values and the upper limit of normal (ULN) will not be displayed using the unit of 
measurement but instead using the ratio of the measured value over ULN. This comprises alkaline 
phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Activated 
Partial Thromboplastin Time (aPTT), bilirubin, and creatinine.
Laboratory parameters with NCI-CTC grades available
Laboratory parameters with NCI-CTC grades available will be analyzed with their respective NCI-
CTC name and direction of abnormality. For parameters which are graded with both low and high 
values as potassium (hypokalemia/hyperkalemia), the toxicities will be summarized separately. 
Low direction toxicity (e.g. hypokalemia) grades at baseline and post-baseline will be set to 0 
when the variables are derived for summarizing high direction toxicity (e.g. hyperkalemia), and 
vice versa. 
The following summaries will be displayed:
! Number and percentage of participants by worst on-treatment grade (>=1, >=3, >=4)
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! Shift in toxicity grading from baseline to highest on-treatment toxicity grade
The definitions of the NCI-CTCAE toxicity grading version 5.0 for each parameter are provided 
in Appendix 3 of this IAP. 
Table 7
NCI-CTC Gradable parameters
Parameter 
Parameter 
code
Name in NCI-CTC
Direction of 
abnormality
Biochemistry
Alanine 
Aminotransferase
ALT
Alanine aminotransferase
increased
High
Albumin
ALB
Hypoalbuminemia
Low
Alkaline Phosphatase
ALP
Alkaline phosphatase increased
High
Amylase
AMYLASE
Serum amylase increased
High
Aspartate 
Aminotransferase
AST
Aspartate aminotransferase
increased
High
Bilirubin total
BILI
Blood bilirubin increased
High
Calciuma
CA
Hypercalcemia/Hypocalcemiaa
High/Low
Creatinine
CREAT
Creatinine increased
High
Glucose
GLUC
Hypoglycemia
Low
Lipase
LIPASET
Lipase increased
High
Potassium
K
Hyperkalemia/Hypokalemia
High/Low
Sodium
SODIUM
Hypernatremia/Hyponatremia
High/Low
Hematology
Absolute eosinophils
EOS
Eosinophilia
High
Absolute lymphocyte 
LYM
Lymphocyte count decreased/Lymphocyte count 
increased
High/Low
Absolute neutrophils 
NEUT
Neutrophil count decreased
Low
Hemoglobin
HGB
Anemia/Hemoglobin increased
Low/High
Leukocytes (WBC)
WBC
Leukocytosis/White blood cell decreased
High/Low
Platelets count
PLAT
Platelet count decreased
Low
Coagulation
Activated Partial 
Thromboplastin Timeb
APTT
Activated partial thromboplastin
time prolonged
High
Activated 
PTT/Standardb
APTTSTND
Activated partial thromboplastin
time prolonged
High
Prothrombin 
International 
Normalized Ratiob
INR
INR increased
High
a based on corrected calcium (see Appendix 3)
b reported on the “Coagulation” eCRF page
For WBC differential counts (neutrophil, lymphocyte counts), the absolute value will be used 
when reported.  When only percentages are available (this is mainly important for neutrophils and 
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lymphocytes, because the CTCAE grading is based on the absolute counts), the absolute value is 
derived as follows:
Derived differential absolute count = (WBC count) * (Differential %value / 100)
For calcium, CTCAE grading is based on corrected calcium. Corrected calcium is calculated from 
albumin and calcium as follows based on the International System of Units (SI):
Corrected calcium (mmol/L) = measured total calcium (mmol/L) + 0.02 (40 – serum albumin 
[g/L]).
Laboratory parameters with NCI-CTC grades not available
Table 8
Non-NCI-CTC Gradable Parameters
Parameter (LBTEST)
Biochemistry
Bilirubin direct
BILIDIR
Bilirubin Indirect
BILINDIR
Chloride
CL
C-Reactive Protein
CRP
Total Protein
PROT
Urea Nitrogen
BUN
Hematology
Absolute Basophils
BASO
Absolute Monocytes
MONO
Absolute Reticulocytes 
RETI
Basophils/Leukocytes
BASOLE
Eosinophils/Leukocytes
EOSLE
Erythrocytes (RBC)
RBC
Hematocrit
HCT
Lymphocytes/Leukocytes
LYMLE
Mean Corpuscular Hemoglobin
MCH
Mean Corpuscular HGB Concentration
MCHC
Mean Corpuscular Volume
MCV
Monocytes/Leukocytes
MONOLE
Neutrophils/Leukocytes
NEUTLE
Reticulocytes/Erythrocytes
RETIRBC
Coagulation
Prothrombin Time*
PT
Standard Prothrombin Time*
PTS
* reported on the “Coagulation” eCRF page
For all non-gradable parameters, the following summaries will be displayed:
! Number and percentage of participants by lowest on-treatment value (classified as normal, 
high, low)
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! Number and percentage of participants by highest on-treatment value (classified as normal, 
high, low)
! Shift from baseline to highest/lowest on-treatment value (classified as normal, high, low)
Separate listings of hematology, biochemistry and coagulation will be created. Each listing will 
include: participant identifier, age, sex, race, first dose date, last dose date, laboratory parameter 
(units), visit, date, International System of Units (SI) value, lower limit of normal (LLN), upper 
limit of normal (ULN), indicator of normal range (low, normal, high), toxicity grade according to 
NCI-CTCAE (when applicable) and highest/lowest on treatment value flag. Baseline and post-
baseline values after the on-treatment period will be flagged. These listings will be sorted by 
participant identifier, parameter and laboratory measurement date. 
Liver function tests
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin are used to 
assess possible drug induced liver toxicity. The ratios of test result over upper limit of normal 
(ULN) will be calculated and classified for these three parameters during the on-treatment period.
The number and percentage of participants within each of the following liver function categories 
during on-treatment period will be described:
! ALT <3×ULN, ALT ≥3×ULN, ALT ≥5×ULN, ALT ≥10×ULN, ALT ≥20×ULN
! AST <3×ULN, AST ≥3×ULN, AST ≥5×ULN, AST ≥10×ULN, AST ≥20×ULN
! (ALT and AST) <3×ULN, (ALT or AST) ≥3×ULN, (ALT or AST) ≥5×ULN, (ALT 
or AST) ≥10×ULN, (ALT or AST) ≥20×ULN
! Total Bilirubin (TBILI) < 2×ULN, TBILI ≥2×ULN
! Concurrent ALT ≥3×ULN and TBILI ≥2×ULN
! Concurrent AST ≥3×ULN and TBILI ≥2×ULN
! Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN
! Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP > 2×ULN
! Concurrent (ALT or AST) ≥3×ULN and TBILI ≥2×ULN and ALP ≤2×ULN or 
missing
Concurrent measurements are those occurring on the same date.
Categories will be cumulative, i.e., a participant with an elevation of AST ≥10×ULN will also 
appear in the categories ≥5×ULN and ≥3×ULN. 
A plot of peak ALT versus peak total bilirubin, both relative to the ULN will be provided. This 
eDISH plot (evaluation of drug-induced serious hepatotoxicity) will be divided into 4 quadrants 
by the lines through ALT ≥ 3×ULN and total bilirubin ≥2×ULN. The left lower quadrant is then 
considered normal or insignificant elevations in liver chemistries, the upper quadrants indicate 
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participants with possible Gilbert’s cholestasis; the right upper quadrant are the possible Hy’s Law 
participants; the right lower quadrant is possible Temple’s Corollary (participants with ALT≥ 3 x 
ULN but not satisfying Hy’s Law). Same plot will be provided for AST.
In addition, a listing of all total bilirubin, ALT, AST and ALP values for participants with a post-
baseline total bilirubin ≥2×ULN, ALT≥3×ULN or AST ≥3×ULN will be provided.
Urinalysis / urinalysis microscopic evaluation, hormonal tests, serum, serology, cancer 
antigen 19.9
All test results for urinalysis /urinalysis microscopic evaluation, hormonal tests, serum and 
serology parameters will also be listed in dedicated listings:
! Urinalysis parameters: 
o
Urinalysis full parameters: physical appearance, pH, specific gravity, protein, glucose,
ketones, nitrite, leukocyte esterase, blood, urobilinogen, bilirubin, color
o
Urinalysis microscopic parameters: erythrocytes (RBC), leukocytes (WBC), epithelial 
cells, bacteria, crystals, casts, mucus
!
Hormonal parameters: thyroxine free (Free T4), thyrotropin (Thyroid-Stimulating 
Hormone; TSH)
!
Serum parameters: Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), 
surfactant protein D (SP-D) (only for Japanese sites)
!
Cancer antigen 19.9
!
Serology parameters: hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis B DNA, 
hepatitis C RNA
Pregnancy test
Results for pregnancy and post-menopausal status as collected on the “Pregnancy Test” and ‘FSH 
and Estradiol’ eCRF pages will also be listed:
! Pregnancy parameters (serum or highly sensitive urine human chorionic gonadotropin 
(hCG))
! Post-menopausal status: FSH and estradiol parameters
15.4
Vital Signs 
Summary table over time will present summary statistics for vital signs variables by timepoint.
The following potentially clinically significant abnormalities will be summarized:
! ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg in systolic blood pressure
! ≥ 140 mmHg and increase from baseline ≥ 20 mmHg in systolic blood pressure
! ≤ 45 mmHg and decrease from baseline ≥ 20 mmHg in diastolic blood pressure
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! ≥ 90 mmHg and increase from baseline ≥ 20 mmHg in diastolic blood pressure
! ≤ 50 beats/min and decrease from baseline ≥ 20 beats/min in heart rate
! ≥ 100 beats/min and increase from baseline ≥ 20 beats/min in heart rate
! ≤ 20 breaths/min and decrease from baseline ≥ 5 breaths/min in respiratory rate
! ≥ 20 breaths/min and increase from baseline ≥ 5 breaths/min in respiratory rate
! ≥ 10% weight increase
! ≥ 10% weight decrease
A listing of vital signs will be provided including participant identifier, age, sex, race, vital sign 
parameter, visit, timepoint, date, time, value, unit and change from baseline. Baseline values and 
post-baseline values collected after the on-treatment period will be flagged. 
Oxygen Saturation
Results for oxygen saturation as collected on the “Oxygen Saturation” eCRF page will be listed.
15.5
Other Safety or Tolerability Evaluations
ECG
Single 12-lead ECGs will be obtained as outlined in the protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc Intervals. ECG 
parameters will be derived from the data collected on the “Electrocardiogram” eCRF page. Shift 
table for ECG interpretation value at baseline and value at end of treatment will be provided.
A listing of ECG values will be provided including participant identifier, age, sex, race, ECG 
parameter and unit, visit, ECG date, value, change from baseline. Baseline values and post-
baseline values collected after the on-treatment period will be flagged. Qualitative ECG results 
will also be provided in the listing. 
ECOG Performance Status
The ECOG Performance Status will be derived from the data collected on the “ECOG Performance 
Status” eCRF page. 
The ECOG shift from baseline to the highest score during the on-treatment period will be 
summarized. 
ECOG performance status will also be presented in a listing at each timepoint. 
Non-protocol Related Hospital Visits
Participant’s non-protocol related hospital visits will be listed from data collected on the “Non
Protocol Related Hospital Visit” eCRF page. The listing will include participant identifier, age, 
sex, race, total number of pre-planned ambulant (outpatient) hospital visits since the last study 
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visit, total number of unplanned ambulant (outpatient) hospital visits since the last study visit, total 
number of nights spent in the hospital for pre-planned overnight (inpatient) hospital visits since 
the last study visit and total number of nights spent in the hospital for unplanned overnight
(inpatient) hospital visits since the last study visit.
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
The analyses described in this section will be performed by the Clinical PK/PD group (CPK) of 
Translational Medicine, Merck Healthcare KGaA, Darmstadt, Germany, or by a Contract Research 
Organization selected by the Sponsor. Pharmacokinetic listings and individual data will be 
presented based on the Safety Analysis Set.  Summaries and statistical analyses will be based on 
the PK Analysis Set. Only subgroup sample size with a minimal 3 subjects will be displayed.
Pharmacokinetic concentrations/parameters refer to bintrafusp alfa concentrations/PK parameters.
16.1.1
Missing/non-quantifiable PK Data Handling
Concentrations below the lower limit of assay quantification
Pharmacokinetic concentrations below the lower limit of quantification (<LLOQ) will be set to
zero for calculating parameters and descriptive statistics.
Deviations, missing concentrations, and anomalous values
There will be no imputation of missing data. Concentrations will be set to missing in summary 
tables if the value is reported as no result. Pharmacokinetic concentrations which are erroneous 
due to a protocol deviation (as defined in the clinical study protocol), documented handling error, 
or analytical error (as documented in the bioanalytical report) may be excluded from the PK 
analysis if agreed upon prior to performing a statistical analysis. In this case the rationale for 
exclusion must be provided in the CSR.
Exclusions for concentration data (and CEOI/Ctrough) descriptive statistics 
-
Positive pre-dose values on day 1
-
Concentration observed at the end of infusion (CEOI) <LLOQ
-
In case of missed dose, exclude all concentrations until intended dosing is resumed
-
Concentration observed at the end of the dosing interval (Ctrough) values in case samples 
are taken at least 7 days late or early
Any 
other 
PK 
concentrations 
that 
appear 
implausible 
to 
the 
Pharmacokineticist/PK/Pharmacodynamic Data Analyst must not be excluded from the analysis. 
Any implausible data will be documented in the relevant listing/table.
If a PK parameter cannot be derived from a participant’s concentration data, the parameter will be 
coded as NC (not calculated). (Note that NC values will not be generated beyond the day that a 
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participant discontinues the treatment). For statistical analyses, PK parameters coded as NC will 
be set to missing.
If an individual participant has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this participant/value will be excluded from the descriptive 
statistics, and instead the result will be listed in a separate table.
16.1.2
Descriptive PK Analysis
Presentation of PK Concentration Data
A by-participant listing will present PK sample times, time deviations, and concentrations based 
on the Safety Analysis Set. Concentrations will be reported with the same precision as the source 
data.
Presentation of PK Parameter Data
The PK parameters listed below will be taken directly from the observed bintrafusp alfa
concentration-time data. 
Ctrough
The concentration observed immediately before next dosing (corresponding 
to pre-dose or trough concentration for multiple dosing).
CEOI
The concentration observed immediately at the end of infusion.
Individual PK parameters will be listed by nominal study day based on the Safety Analysis Set.
Individual PK parameters will be reported with the same precision as the source data.
Pharmacokinetic parameter data will be presented in tables and descriptively summarized by 
nominal study day using: number of non-missing observations (n), arithmetic mean (Mean), 
standard deviation (StD), coefficient of variation (CV%), minimum (Min), median (Med), 
maximum (Max), geometric mean (GeoMean), StD of log-transformed data (logStD), the 
geometric coefficient of variation (GeoCV%) and the 95% CI for the GeoMean (LCI 95% GM, 
UCI 95% GM). Summaries will be based on the Pharmacokinetic Analysis Set. Subgroup analysis 
is done with at least 3 subjects
Additional table(s) will summarize Ctrough and CEOI with further stratification by ADA subsets ever 
positive and never positive, based on the PKADA. Additional table(s) will summarize Ctrough and 
CEOI with further sub-stratification by nAb subsets ever positive and never positive, based on the 
PKNAB. For nAb subsets, summaries will be done for ever positive in either of 2 nAb assays
(PDL1 and TGFß receptor neutralization; PDL1+/TGFß+, PDL1+/TGFß−, PDL1−/TGFß+)
versus never positive (PDL1−/TGFß−). Additional table(s) will summarize Ctrough and CEOI with 
stratification by Japanese, non-Japanese Asian, all Asian and all non-Asian participants based on 
the PKAS. 
Additional table(s) will summarize Ctrough and CEOI with further sub-stratification by ADA subsets 
ever positive and never positive and, nested within, Japanese, non-Japanese Asian, all Asian and
all non-Asian participants based on the PKADA. Additional table(s) will summarize Ctrough of 
ADA ever positive subjects with further sub-stratification by ADA subgroups (e.g. Pre-existing, 
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Treatment boosted, Treatment emergent, Transient positive, Persistent positive), based on the 
PKADA. For nAb ever-positive subjects, serum bintrafusp alpha Ctrough will be descriptively 
summarized in additional table(s) for nAb status subgroups (positive in any of 2 nAb assays), based 
on the PKNAB. Additional table(s) will summarize Ctrough of ADA ever-positive subjects with 
further sub-stratification by ADA subgroups and, nested within, Japanese, non-Japanese Asian, all 
Asian, and all non-Asian participants, based on the PKADA. For nAb ever-positive subjects, serum 
bintrafusp alpha Ctrough will be descriptively summarized in additional table(s) for nAb status 
subgroups (positive in any of 2 nAb assays) and, nested within, Japanese, non-Japanese Asian, all 
Asian, and all non-Asian participants, based on the PKNAB. Additional table(s) will summarize 
Ctrough of ADA Treatment-emergent subjects and nAb Treatment-emergent subjects by PK day 
relative to seroconversion, for all subjects, Japanese, non-Japanese Asian, all Asian and non-Asian
participants based on the PKADA and PKNAB, respectively. Only subgroup sample size with a 
minimal 3 subjects will be displayed.
Pharmacokinetic parameters will be reported to 3 significant figures. In export datasets, as well as 
in the SDTM PP domain, PK parameters will be provided with full precision and will not be 
rounded. Descriptive statistics of PK parameter data will be calculated using full precision values 
and rounded for reporting purposes only.
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data:
! Mean, Min, Med, Max, GeoMean, 95% CI: 
3 significant digits
! StD, logStD: 
4 significant digits
! CV%, GeoCV%: 
1 decimal place
Individual PK Ctrough and CEOI values will be plotted versus actual study day on a linear scale, for 
all participants. Individual data will be presented based on the Safety Analysis Set.
Arithmetic mean (±SD), GeoMean (±logStD), and Med Ctrough and CEOI will be plotted versus 
nominal study day on a linear scale. Summaries will be based on the Pharmacokinetic Analysis 
Set.
Additional figure(s) will present Mean, GeoMean, and Med Ctrough and CEOI with with further 
stratification by ADA subsets ever positive and never positive, based on the PKADA, as long as 
both subsets consist of 3 or more participants. Additional figure(s) will present Mean, GeoMean, 
and Med Ctrough and CEOI with further sub-stratification by nAb subsets ever positive and never 
positive, based on the PKNAB, as long as both subsets consist of 3 or more participants. Additional 
figure(s) will present Mean, GeoMean, and Med Ctrough and CEOI with stratification by Japanese, 
non-Japanese Asian, all Asian and all non-Asian participants, based on the PKAS. Only subgroup 
sample size with a minimal 3 subjects will be displayed.
For ADA treatment-emergent subjects with at least one Ctrough measurement before and after ADA 
seroconversion, individual Ctrough will be plotted versus PK day relative to seroconversion (for 
readability, split further into groups of 10 subjects or fewer as needed), for all subjects, Japanese, 
non-Japanese Asian, all Asian, and all non-Asian participants, based on the SAF. Box plots will 
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be prepared for Ctrough versus PK day relative to seroconversion, for all subjects, Japanese, non-
Japanese Asian, all Asian, and all non-Asian participants, based on the PKADA.
For nAb treatment-emergent subjects with at least one Ctrough measurement before and after nAb 
seroconversion (earliest of 2 assays if positive in both), individual Ctrough will be plotted versus PK 
day relative to seroconversion (for readability, split further into groups of 10 subjects or fewer as 
needed), for all subjects, Japanese, non-Japanese Asian, all Asian, and all non-Asian participants, 
based on the SAF. Box plots will be prepared for Ctrough versus PK day relative to seroconversion, 
for all subjects, Japanese, non-Japanese Asian, Asian, and non-Asian, based on the PKNAB. 
16.4
Immunogenicity
Analysis Sets: Immunogenicity analysis set
16.4.1
Antidrug Antibody
The ADA results will be derived for each visit based on the algorithm in Table 9.
Table 9
Algorithm for the Derivation of ADA Results
Sample Screen Result
Confirmatory
Titer
ADA Result
Negative
NA
NA
Negative
NR
NA
NA
NR
Positive
Negative
NA
Negative
Positive
NR
NA
NR
Positive
Positive
Number
Number
Positive
Positive
NR
Positive-TNR
NR = no result, NA = not applicable, TNR = titer no result.
Note that samples collected during and after the on-treatment period (e.g. safety follow-up)
including the ones collected during the re-initiation period will be included in the analysis. 
Negative, number, or positive-TNR are valid results while number and positive-TNR are 
considered as positive. Participants will be characterized into different categories based on the 
criteria in Table 10.
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Table 10
Participants Characterized based on ADA Results
Category
Definition
Participant at Risk (Denominator for 
Incidence)
Never 
positive
No positive results at any time point
Number of participants with at least one valid 
result at any time point
Ever positive
At least one positive result at any time point, 
including baseline
Number of participants with at least one valid 
result at any time point
Pre-existing
A positive ADA result prior to treatment with 
bintrafusp alfa
Number of participants with valid baseline 
result
Treatment 
boosted
A positive ADA result prior to treatment with 
bintrafusp alfa and the titer ≥8*baseline titer at 
least one post-baseline value 
Number of participants with valid baseline 
result and at least one valid post-baseline 
result
Treatment 
emergent
Not positive prior to treatment with bintrafusp alfa
and with at least one positive post-baseline result
Number of participants with at least one valid 
post-baseline result and without positive 
baseline result (including missing, NR)
Transient 
positive
If treatment emergent participants have 
- a single positive evaluation
or
- duration between first and last positive result <16 
weeks 
and last assessment not positive
Number of participants with at least one valid 
post-baseline result and without positive 
baseline result (including missing, NR)
Persistent 
positive
If treatment emergent participants have duration 
between first and last positive result ≥16 weeks 
or a positive evaluation at the last assessment
Number of participants with at least one valid 
post-baseline result and without positive 
baseline result (including missing, NR)
Start of Immunogenicity Response
For participants with any positive ADA response, the date of the first assessment with positive 
ADA result will be considered as start date of ADA response. 
Time to onset (weeks) of ADA response will be calculated as:
(Date of first positive ADA assessment – start date of bintrafusp alfa treatment + 1) / 7
Note: If the first positive is prior to the start of treatment, the formula is revised to: 
(Date of first positive ADA assessment – start date of bintrafusp alfa treatment) / 7
Duration of Immunogenicity Response
Duration of ADA immunogenicity response (weeks) is defined as: 
(Date of last positive ADA assessment – date of first positive ADA assessment + 1) / 7
For participants with pre-existing positive, duration will be calculated from start date of bintrafusp 
alfa treatment rather than from date of first positive assessment. Participants still on treatment at 
the data cut-off and positive assessment at their last assessment before cut-off will be censored at 
the date of last assessment.
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The following analysis will be described:
! The frequency and percentage of each ADA category will be tabulated
! The ADA titer value by timepoint will be summarized
! The maximum observed ADA titer per participant will be tabulated. For each discrete titer 
value, percentages will be calculated using the total number of participants in each ADA 
status group as the denominator
! The time to first ADA positive response will be summarized
! The duration of ADA immunogenicity response will be summarized.
The ADA category, titer, maximum titer, time to first ADA positive response and duration of 
response analyses will also be performed by subgroup: 
!
Japanese, non Japanese Asian, all Asian, non-Asian.
The following further analyses will also be described:
! Evaluation of potential effect of ADA on bintrafusp alfa safety (see section 15.1.1)
! Evaluation of potential effect of ADA on bintrafusp alfa efficacy
o
for best overall response according to RECIST 1.1 as adjudicated by IRC (see 
section 14.1.1)
o
for progression-free survival according to RECIST 1.1 as adjudicated by IRC (see 
section 14.4.2)
o
for duration of confirmed response according to RECIST 1.1 as adjudicated by IRC
(see section 14.5.1)
o
for durable confirmed response according to RECIST 1.1 as adjudicated by IRC
(see section 14.6.1)
o
for overall survival (see section 14.8.1)
! Evaluation of potential effect of ADA on bintrafusp alfa Pharmacokinetic (see section 
16.1.2)
Potential effect of ADA on safety, efficacy and PK will be evaluated on ADA positive status (ever 
positive, never positive).
Listings of ADA results from ever positive participants will be provided with the following:
participant ID, age, sex, race, ADA categories status, visit, date of assessment and results of 
screening, confirmatory and titer values. A further listing will contain: participant ID, age, sex, 
race, date of first ADA positive result, responder per IRC/investigator, date of response and timing 
of response related to the date of first ADA positive result. Responders will be defined as 
participants meeting confirmed CR or PR and non-responders as all other participants.
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16.4.2
Neutralizing Anti-drug Antibody
Analysis Sets: Immunogenicity analysis set
Samples with a reportable ADA titer will also be tested in two nAb assays, PD-L1 and TGF-β. 
nAb results are positive or negative in a single assay and only derived when not performed because 
ADA was negative (see Table 11). Subjects will be characterized into different nAb categories for 
each assay based on the criteria in Table 12. Treatment boosted is not defined for nAb.
Table 11
Algorithm for the Derivation of nAb Results
ADA Confirmatory Result
nAb Result
Derived nAb Result
Negative
NA
Negative
NR
NA
NR
NA (screen NR)
NA
NA
NA (screen negative)
NA
Negative
Positive
NR
NR
Positive
Positive
Positive
Positive
Negative
Negative
ADA = antidrug antibody, NA = not applicable, nAb = neutralizing antibody, NR = no result.
Table 12
Participants Characterized based on nAb Results
Category
Definition
Subject at Risk (Denominator for Incidence)
Never 
positive
No nAb positive results at any time point
Number of subjects with at least one valid ADA 
result at any time point
Ever 
positive
At least one nAb positive result at any time point
Number of subjects with at least one valid ADA 
result at any time point
Pre-existing
A positive nAb
result prior to treatment with 
bintrafusp alfa
Number of subjects with valid ADA baseline 
result
Treatment 
emergent
Not nAb positive prior to treatment with bintrafusp 
alfa and with at least one nAb positive post-baseline 
result
Number of subjects with at least one valid ADA
post-baseline result and without nAb positive 
baseline results (including missing, NR)
Transient 
positive
If treatment emergent subjects have (a single nAb
positive evaluation, or duration between first and 
last nAb positive result <16 weeks) and last ADA 
assessment not nAb positive.
Number of subjects with at least one valid ADA 
post-baseline result and without nAb positive 
baseline results (including missing, NR)
Persistent 
positive
If treatment emergent subjects have duration 
between first and last nAb positive result ≥16 weeks 
or a nAb positive evaluation at the last ADA 
assessment
Number of subjects with at least one valid ADA 
post-baseline result and without nAb positive 
baseline results (including missing, NR)
ADA = antidrug antibody, nAb = neutralizing antibody, NR = no result.
The following analysis will be described (the titer summaries will be provided if the titer data is 
available):
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! The frequency and percentage of each nAb category will be tabulated for each assay 
individually and combined (either assay).
! The nAb titer value by timepoint will be summarized, per assay
! The maximum observed nAb titer per participant per assay will be tabulated. For each 
discrete titer value, percentages will be calculated using the total number of participants in 
each nAb status group as the denominator
! The time to first nAb positive response will be summarized, per assay
! The duration of nAb response will be summarized, per assay.
See Section 16.4.1 for the derivation of time to first positive response and duration of response.
The nAb category, titer, maximum titer, time to first nAb positive response and duration of 
response analyses will also be performed by subgroup: 
!
Japanese, non Japanese Asian, all Asian, non-Asian.
A listing of nAb results from ever positive participants (in either assay) will be provided with the 
following: participant ID, age, sex, race, nAb categories status, visit, date of assessment and results 
of screening and titer values. A further listing will contain: participant ID, age, sex, race, date of 
first nAb positive result, responder per IRC/investigator, date of response and timing of response 
related to the date of first nAb positive result. Responders will be defined as participants meeting 
confirmed CR or PR and non-responders as all other participants.
The following further analyses will also be described as follows:
! Evaluation of potential effect of nAb on bintrafusp alfa safety (see section 15.1.1)
! Evaluation of potential effect of nAb on bintrafusp alfa efficacy
o
for best overall response according to RECIST 1.1 as adjudicated by IRC (see 
section 14.1.1)
o
for progression-free survival according to RECIST 1.1 as adjudicated by IRC (see 
section 14.4.2)
o
for duration of confirmed response according to RECIST 1.1 as adjudicated by IRC
(see section 14.5.1)
o
for durable confirmed response according to RECIST 1.1 as adjudicated by IRC
(see section 14.6.1)
o
for overall survival (see section 14.8.1)
! Evaluation of potential effect of nAb on bintrafusp alfa Pharmacokinetic (see section 16.1.2)
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Potential effect of nAb on safety, efficacy and PK will be evaluated on nAb positive status (ever 
positive in either assay, never positive).
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17
References
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-47.
European Centre for Disease Prevention and Control. Data on COVID-19 geographic distribution 
by country. https://www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-
distribution-covid-19-cases-worldwide, accessed and downloaded on 26 June 2020.
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18
Appendices
18.1.1
Appendix 1: Definition of important protocol deviations 
See document: ctp-ms200647-0047-iap-v1-appendix-1.docx
18.1.2
Appendix 2: Rules for identification of previous or 
concomitant medications/procedures 
See document: ctp-ms200647-0047-iap-v1-appendix-2.docx
18.1.3
Appendix 3: Definition of NCI-CTCAE grading
See document: CTC V5.0 guidance.xlsx
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ELECTRONIC SIGNATURES
Document: ctp-ms200647-0047-iap-v2
Signed By
Event Name
Meaning of Signature
Server Date
(dd-MMM-yyyy
HH:mm ‘GMT’Z)
Task Completed (Approval
eSign): Approved
Technical Approval
Task Completed (Approval
eSign): Approved
Technical Approval
Task Completed (Approval
eSign): Approved
Business Approval
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PPD
PPD
PPD
PPD
PPD
PPD