A Phase II, Multicenter, Open Label Study of Bintrafusp Alfa (M7824) Monotherapy in Participants With Advanced, Unresectable Cervical Cancer With Disease Progression During or After Platinum-Containing Chemotherapy
Phase: PHASE2
Conditions: Uterine Cervical Neoplasms
Sponsor: EMD Serono Research & Development Institute, Inc.



Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647_0017
in Platinum-Experienced Cervical Cancer
C O N F I D E N T I A L
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Sponsor Name and Legal Registered 
Address:
Affiliates of Merck KGaA, Darmstadt, Germany
For all countries, except the US, Canada, and 
Japan:
Merck Healthcare KGaA, Darmstadt, Germany
an affiliate of Merck KGaA, Darmstadt, Germany
Frankfurter Str. 250
Darmstadt, Germany
In the US and Canada:
EMD Serono Research & Development Institute, 
Inc.
an affiliate of Merck KGaA, Darmstadt, Germany
45A Middlesex Turnpike
Billerica, MA, 01821, USA
Local Sponsor for Sites in Japan:
Merck Biopharma Co., Ltd.: Japan
an affiliate of Merck KGaA, Darmstadt, Germany
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
Regulatory 
Agency 
Identifying 
Numbers:
, EudraCT: 2019-003583-40
Protocol Version:
22 June 2021/Version 3.0
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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647_0017
in Platinum-Experienced Cervical Cancer
C O N F I D E N T I A L
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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
30-Aug-2019
1.0
Original Protocol including 
FDA Feedback
18-Oct-2019
2.0
Global Amendment 1.0
23-Jun-2020
3.0
Global Amendment 2.0
22-Jun-2021
Protocol Version 3.0 (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. In addition, the primary 
analysis time point has been moved from 8 months to 12 months after the accrual of the last global
participant.
Section # and Name
Description of Change
Brief Rationale
Title Page
Removed “Medical Responsible” field
Removed “Amendment number”,
“Replaces Version” and “Approval 
Date” rows 
To be consistent with current Sponsor 
protocol template (Version 15)
2.3 Benefit/Risk 
Assessment
Text updated to address risk 
reclassification
The risk reclassification was based on in-
depth analysis of a pooled safety dataset 
of N = 765 participants who received 
bintrafusp alfa monotherapy at 1200 mg 
Q2W.
5. Study Population
Appendix 2
Edits related to informed consent 
procedure
To be consistent with current Sponsor 
protocol template (Version 15)
6.9 Management of 
Adverse Events of 
Special Interest
Appendix 4
Risk reclassification has been done 
and the list of events has been 
updated accordingly
6.9.1 Infusion-related 
Reactions Including 
Immediate 
Hypersensitivity
Infusion-related reactions are 
reclassified from “important identified 
risk” to “identified risk” for bintrafusp 
alfa
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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
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Section # and Name
Description of Change
Brief Rationale
6.9.3. TGF-β Inhibition 
Mediated Skin Reactions
Skin Adverse Events have been 
renamed as TGF-β Inhibition 
Mediated Skin Reactions
The risk reclassification was based on in-
depth analysis of a pooled safety dataset 
of N = 765 participants who received 
bintrafusp alfa monotherapy at 1200 mg 
Q2W as reflected in Investigator’s 
Brochure, v7.0.
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 bintrafusp alfa
6.9.5 Bleeding Events
Bleeding events are reclassified from 
“potential risk” to “important identified 
risk” for bintrafusp alfa
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)
8.1.2 Patient-reported 
Outcomes
Information added that PRO 
responses should not be reviewed or 
used to inform care decisions
To update protocol in accordance with 
administrative letter sent to sites
Update to PGIC responses
To update protocol in accordance with 
administrative letter sent to sites, which 
was to address an error in the responses
9.4.4 Sequence of 
Analyses
The primary analysis timing has been 
updated from 8 to 12 months after the 
accrual of the last planned global
participant
To have 12 months of follow up for all 
participancts and allowing a longer follow 
up of potential late responders.
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.
- Confidential -
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 
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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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647_0017
in Platinum-Experienced Cervical Cancer
C O N F I D E N T I A L
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................5
Table of In-Text Tables .......................................................................................................9
Table of In-Text Figures......................................................................................................9
1
Protocol Summary ..............................................................................10
1.1
Synopsis..............................................................................................10
1.2
Schema................................................................................................13
1.3
Schedule of Activities.........................................................................14
2
Introduction.........................................................................................24
2.1
Study Rationale...................................................................................24
2.2
Background.........................................................................................25
2.3
Benefit/Risk Assessment ....................................................................27
3
Objectives and Endpoints ...................................................................28
4
Study Design.......................................................................................29
4.1
Overall Design....................................................................................29
4.2
Scientific Rationale for Study Design ................................................30
4.3
Justification for Dose..........................................................................32
4.4
End of Study Definition......................................................................32
5
Study Population.................................................................................32
5.1
Inclusion Criteria ................................................................................33
5.2
Exclusion Criteria...............................................................................36
5.3
Lifestyle Considerations .....................................................................38
5.4
Screen Failures....................................................................................38
6
Study Intervention(s) ..........................................................................39
6.1
Study Intervention(s) Administration.................................................39
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................39
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................40
6.3.1
Study Intervention Assignment ..........................................................40
6.3.2
Blinding ..............................................................................................40
6.4
Study Intervention Compliance..........................................................41
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6.5
Concomitant Therapy .........................................................................41
6.5.1
Permitted Medicines...........................................................................41
6.5.2
Prohibited Medicines..........................................................................42
6.5.3
Other Interventions.............................................................................43
6.6
Dose Selection and Modification........................................................43
6.7
Study Intervention after the End of the Study ....................................43
6.8
Special Precautions.............................................................................43
6.9
Management of Adverse Events of Special Interest...........................46
6.9.1
Infusion-related Reactions Including Immediate Hypersensitivity....46
6.9.3
TGF-β Inhibition Mediated Skin Reactions .......................................50
6.9.4
Anemia................................................................................................51
6.9.5
Bleeding Events..................................................................................53
6.9.5.1
Mucosal/Non-Tumor Bleeding...........................................................53
6.9.5.2
Tumor Bleeding..................................................................................53
6.9.6
Other Potential Risks..........................................................................53
6.9.6.1
Impaired Wound Healing ...................................................................53
6.9.6.2
Embryofetal Toxicity..........................................................................53
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................54
7.1
Discontinuation of Study Intervention................................................54
7.1.1
Temporary Discontinuation................................................................55
7.1.2
Rechallenge.........................................................................................55
7.1.2.1
Reinitiation .........................................................................................55
7.1.3
Treatment Beyond Progression...........................................................56
7.1.3.1
Treatment Beyond Initial Progression................................................56
7.1.3.2
Treatment Beyond Confirmed Progression ........................................56
7.1.3.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression............................................................................56
7.2
Participant Discontinuation/Withdrawal from the Study ...................57
7.3
Lost to Follow-Up...............................................................................57
8
Study Assessments and Procedures....................................................59
8.1
Efficacy Assessments and Procedures................................................59
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8.2
Safety Assessments and Procedures ...................................................64
8.2.1
Physical Examinations........................................................................64
8.2.2
Vital Signs ..........................................................................................65
8.2.3
Electrocardiograms.............................................................................65
8.2.4
Clinical Safety Laboratory Assessments ............................................65
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....................................................66
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...66
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............66
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....67
8.3.5
Pregnancy ...........................................................................................68
8.4
Treatment of Overdose .......................................................................68
8.7
Pharmacogenetics ...............................................................................70
8.9
Health Economics...............................................................................73
8.10
Immunogenicity Assessments ............................................................73
9
Statistical Considerations....................................................................73
9.1
Statistical Hypotheses.........................................................................73
9.3
Populations for Analyses ....................................................................75
9.4
Statistical Analyses.............................................................................76
9.4.1
Efficacy Analyses ...............................................................................76
9.4.2
Safety Analyses ..................................................................................78
9.4.3
Other Analyses....................................................................................79
9.4.4
Sequence of Analyses.........................................................................80
10
References...........................................................................................81
11
Appendices .........................................................................................83
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Bintrafusp alfa (M7824)
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MS200647_0017
in Platinum-Experienced Cervical Cancer
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Appendix 1
Abbreviations......................................................................................84
Appendix 2
Study Governance...............................................................................88
Appendix 3
Contraception......................................................................................95
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................97
Appendix 5
The Recommendations for irAE Management................................101
Appendix 6
Clinical Laboratory Tests .................................................................139
Appendix 7
Prohibited Traditional Chinese Medicines .......................................140
Appendix 9
Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 .....................................................................................................142
Appendix 10 
Protocol Amendment History...........................................................151
Appendix 11
Sponsor Signature Page....................................................................154
Appendix 12
Coordinating Investigator Signature Page........................................155
Appendix 13
Principal Investigator Signature Page...............................................156
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Phase II Bintrafusp alfa Monotherapy
MS200647_0017
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Table of In-Text Tables
Table 1
Schedule of Assessments....................................................................14
Table 2
Bintrafusp alfa Pharmacokinetic, Immunogenicity Sampling............23
Table 3
Study Objectives and Endpoints.........................................................28
Table 4
Study Intervention ..............................................................................39
Table 5
Treatment Modification of Bintrafusp alfa for Symptoms of 
Infusion-related Reactions Including Immediate Hypersensitivity....47
Table 6
Evaluation Guidance of Suspected Anemia Adverse Events .............52
Table 7
Pharmacokinetic Parameters...............................................................69
Table 9
Confidence Intervals for Different Objective Response Rates at 
the Interim Analysis............................................................................74
Table 10
Confidence Intervals for Different Objective Response Rates at 
the Primary Analysis...........................................................................74
Table 11
Analysis Populations ..........................................................................76
Table 12
Statistical Analysis Methods for Efficacy Analysis ...........................77
Table 13
Safety Endpoints and Statistical Analysis Methods ...........................78
Table of In-Text Figures
Figure 1
Study Design Diagram........................................................................13
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Bintrafusp alfa (M7824)
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MS200647_0017
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1
Protocol Summary
1.1
Synopsis
Protocol Title:
A Phase II, Multicenter, Open Label Study of Bintrafusp alfa (M7824) Monotherapy in 
Participants with Advanced, Unresectable Cervical Cancer with Disease Progression During or 
After Platinum-containing Chemotherapy
Short Title:
Phase II Bintrafusp alfa Monotherapy in Platinum-Experienced Cervical Cancer
Rationale: 
Globally, cervical cancer is one of the most common and lethal gynecologic cancers. 
Advanced/metastatic disease is typically treated with chemotherapy, often with poor response rates
and short durations of response (DOR). Improved treatment options are needed for patients with 
advanced cervical cancer. For patients with advanced, unresectable and/or metastatic cervical 
cancer with disease progression during or after platinum-based chemotherapy there is no 
established consensus for second-line treatment options due to low response rates that are typically 
short-lived with variable toxicities. The majority of studies of systemic anticancer treatments 
(including chemotherapy and targeted agents) in platinum-experienced cervical cancer patients 
have resulted in meager clinical response with reported objective response rates (ORR) ranging 
from 3% to 10%.  
Pembrolizumab is the first checkpoint inhibitor that received accelerated approval from the Food 
and Drug Administration (FDA) in 2018 for use as monotherapy for the treatment of patients with 
recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose 
tumors express programmed death-ligand 1 (PD-L1) (Combined Positive Score (CPS) ≥ 1) as 
determined by an FDA-approved test. While the overall response rates with pembrolizumab 
(12.2% to 14.3%) are comparable to other treatment options for platinum-experienced cervical 
cancer patients, the durability of responses with pembrolizumab are noteworthy and have 
presented immunotherapy as a promising treatment for this disease. Notably, the limited response 
rates leave significant room for improvement.  
A novel agent such as bintrafusp alfa, which targets the tumor microenvironment where it blocks 
both the cell intrinsic PD-L1/programmed death-1 (PD-1) interaction and the immunosuppressive 
transforming growth factor-β (TGF-β), is hypothesized to be more effective than agents that target 
only a single pathway.
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Bintrafusp alfa (M7824)
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MS200647_0017
in Platinum-Experienced Cervical Cancer
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Objectives and Endpoints:
Objectives
Endpoints
Primary
!
To evaluate clinical efficacy of bintrafusp alfa
based on ORR
!
Confirmed objective response according to 
RECIST 1.1 assessed by an IRC
Secondary
!
To evaluate clinical efficacy of bintrafusp alfa
based on DOR
!
DOR according to RECIST 1.1 assessed by an IRC
!
To evaluate clinical efficacy of bintrafusp alfa
based on DRR
!
Durable response of at least 6 months according to 
RECIST 1.1 assessed by an IRC
!
To evaluate clinical safety of bintrafusp alfa
!
Occurrence of TEAEs and treatment-related AEs 
including AEs of special interest
!
To evaluate clinical efficacy based on PFS
!
PFS according to RECIST 1.1 assessed by an IRC
!
To evaluate ORR, DOR, DRR and PFS by 
Investigator read
!
Confirmed objective response, DOR, DRR, and PFS 
according to RECIST 1.1 assessed by Investigator 
!
To evaluate clinical efficacy based on OS
!
OS
!
To characterize the PK profile of bintrafusp alfa
!
The concentration observed immediately at the end 
of infusion (CEOI) of bintrafusp alfa
!
The concentration observed immediately before next 
dosing (corresponding to pre-dose or trough 
concentration [Ctrough] for multiple dosing) of 
bintrafusp alfa
!
To characterize the immunogenicity of bintrafusp 
alfa
!
Immunogenicity of bintrafusp alfa as measured by 
ADA assay from Screening through Safety Follow-up
visit (up to 28 days after last treatment)
!
To evaluate clinical efficacy of bintrafusp alfa 
according to PD-L1 expression
!
Efficacy endpoints by PD-L1 expression in tumor
ADA=antidrug antibody, AE=adverse event, DOR=duration of response, DRR=durable response rate, 
IRC=Independent Review Committee, NCI-CTCAE v5.0=National Cancer Institute-Common Terminology Criteria 
for Adverse Events v5.0, OS =overall survival, PD-L1=programmed death-ligand 1, ORR=objective response 
rates, PFS=progression-free survival, PK=pharmacokinetic,  RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors Version 1.1, TEAE=Treatment-emergent adverse event.
Overall Design: This Phase II, multicenter, international, single-arm study is to evaluate 
bintrafusp alfa monotherapy in participants with advanced unresectable and/or metastatic cervical 
cancer with disease progression during or after platinum-based chemotherapy.
The study plans to enroll approximately 135 eligible participants from multiple study sites 
globally. The study is intended to enroll at least 15% of participants from China. After reaching 
the completion of the global study enrollment, if the number of participants enrolled in China does 
not meet the 15% target, enrollment may continue in China to meet local requirement until the 
target (at least 15%) participants from China is met.
Participants will receive an intravenous (IV) infusion of bintrafusp alfa at a dose of 1200 mg over 
1 hour (-10 minutes/+ 20 minutes, i.e., over 50 to 80 minutes) once every 2 weeks.
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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647-0017
in Platinum-Experienced Cervical Cancer
C O N F I D E N T I A L
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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647_0017
in Platinum-Experienced Cervical Cancer
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2
Introduction
Bintrafusp alfa (M7824) is a first-in-class, intravenously (IV) administered bifunctional fusion 
protein that combines an anti-programmed 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. Bintrafusp alfa is the recommended international 
nonproprietary name for M7824.
Complete information on the chemistry, pharmacology, efficacy, and safety of bintrafusp alfa is 
in the Investigator’s Brochure (IB).
2.1
Study Rationale
This is a Phase II, multicenter, international, single-arm, open label study to evaluate bintrafusp 
alfa monotherapy in participants with advanced unresectable cervical cancer with disease 
progression during or after prior platinum-based chemotherapy. 
The majority of studies of systemic anticancer treatments (including chemotherapy and targeted 
agents) in platinum-experienced cervical cancer patients have resulted in meager clinical response 
with a reported objective response rates (ORR) ranging from 3% to 10% (Monk 2009). A literature 
review of studies including almost 2000 patients (see Section 2.2) similarly resulted in a median 
ORR across studies of 10% and weighted average median progression-free survival (PFS) and 
overall survival (OS) of only 3.3 and 8.3 months, respectively.
Pembrolizumab is the first checkpoint inhibitor that received accelerated approval from the Food 
and Drug Administration (FDA) in 2018 for use as a monotherapy for the treatment of patients 
with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy 
whose tumors express PD-L1 (Combined Positive Score [CPS] ≥ 1) as determined by an 
FDA-approved test. While the overall response rates with pembrolizumab (12.2% to 14.3%) are 
comparable to other treatment options for platinum-experienced cervical cancer patients, the 
durability of responses for pembrolizumab are noteworthy and have presented immunotherapy as 
a promising treatment for this disease (see Section 2.2). Notably, the limited response rates leave 
room for improvement.  
A novel agent such as bintrafusp alfa, which targets the tumor microenvironment where it blocks 
both the cell intrinsic PD-L1/programmed death-1 (PD-1) interaction and the immunosuppressive 
TGF-β, is hypothesized to be more effective than agents that target only a single pathway (see 
Section 2.2).
The promising clinical activity of bintrafusp alfa observed in cervical cancer patients of the Phase I 
Study EMR200647-001 (see Section 2.2) and its manageable safety profile in close to 
700 participants with various cancer types (refer to IB) support further investigation of bintrafusp 
alfa in participants with advanced, unresectable cervical cancer with disease progression during or 
after prior platinum-containing chemotherapy; see Section 4.2 for more details.
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MS200647_0017
in Platinum-Experienced Cervical Cancer
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2.2
Background
Globally, cervical cancer is one of the most common and lethal gynecologic cancers. 
Advanced/metastatic disease is typically treated with chemotherapy, often with poor response rates
and durations of response (DOR).
Improved treatment options are needed for patients with advanced cervical cancer:
! Currently, platinum-containing chemotherapy regimen with or without bevacizumab is the 
standard first-line therapy for patients with metastatic cervical cancer. In patients with 
locoregionally advanced cervical cancer, concurrent platinum-containing chemotherapy in 
combination with radiation therapy is recommended (Monk 2007).
! Despite a large series of tested treatment options for patients following standard of care first-line 
treatment, there is no established consensus for second-line treatment. Treatment options are 
limited due to low response rates that are typically short-lived and associated with variable 
toxicities (McLachlan 2017; Monk 2007).
A literature review of clinical studies reporting efficacy outcomes for systemic anticancer 
treatments in platinum-experienced patients with locally advanced or metastatic cervical cancer 
led to the identification of 59 relevant publications reporting results on 1,943 patients with
platinum-experienced cervical cancer. The majority of studies reported meager response rates with 
a median reported ORR of 10%. A random-effect model to account for heterogeneity between 
studies estimated the ORR across all selected publications at 15% (95% CI: 12.4%, 18.2%). In 
addition to this limited response the weighted average median OS and PFS times were 8.3 and 
3.3 months respectively. 
In addition to the low response rates, responses were short in duration when they were reported 
(15 studies): median DORs ranged from 1.6 to 13.9 months (13.9 months duration was reported in 
a study of temsirolimus with a single partial responder among 33 patients evaluable for response), 
and 12 studies (80%) reported median durations of responses of 6.2 months or less (Tinker 2013). 
Nivolumab was the first PD-1 inhibitor with reported efficacy data in cervical cancer. In 
Checkmate-358, 19 patients with recurrent and/or metastatic cervical cancer were treated, and an 
ORR of 26.3% (95% CI: 9.1, 51.2) was observed (Hollebecque 2017). Neither DOR, nor 
proportion of treated cervical cancer patients naïve to systemic chemotherapy were reported.
Pembrolizumab is the first checkpoint inhibitor that received approval (accelerated) from the FDA
in 2018 for use as monotherapy treatment of patients with recurrent or metastatic cervical cancer
with disease progression on or after chemotherapy whose tumors express PD-L1. This approval 
was based on the interim results from the Phase II KEYNOTE-158 study (Chung 2019):
! Among the 98 patients with previously treated advanced cervical cancer, the ORR was 12.2% 
(95% CI: 6.5%, 20.4%), median PFS was 2.1 months (95% CI: 2.0, 2.2 months), and median 
OS was 9.4 months (95% CI: 7.7, 13.1 months).
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Bintrafusp alfa (M7824)
Phase II Bintrafusp alfa Monotherapy
MS200647_0017
in Platinum-Experienced Cervical Cancer
C O N F I D E N T I A L
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! Among the 77 patients with PD-L1 positive (CPS ≥1), chemotherapy refractory cervical cancer, 
the ORR was 14.3% (95% CI: 7.4, 24.1). At the time of the publication, median DOR was not 
reached (range 4.1 to 18.6+ months), and median OS was 11 months (95% CI: 9.1, 14.1).
! In KEYNOTE-158, no responses were observed among the PD-L1 negative patients (CPS < 1, 
n=15), and 3 patients experienced best overall response as stable disease. 
While the overall response rates with pembrolizumab are only comparable to other treatment 
options for cervical cancer patients (12.2% to 14.3%), the durability of responses are noteworthy
and have presented immunotherapy as a promising treatment for this disease.
Recently, molecular characterization of cervical cancer by The Cancer Genome Atlas identified 
both PD-L1 and TGF-β signaling as frequently dysregulated in this disease (The Cancer Genome 
Atlas Research Network 2017, Roszik 2018). TGF-β is historically known to be expressed in a 
majority of cervical cancer tissues, and its expression correlates with the extent of tumor stroma 
infiltrate (Hazelbag 2002). Furthermore, the role of TGF-β in cervical cancer pathogenesis is 
supported by data including 1) TGF-β1 upregulation by human papilloma virus (HPV) oncoprotein 
E6 and E7 (Peralta-Zaragoza 2006), and 2) the correlation of poor prognosis in cervical cancer and 
the expression of plasminogen activator inhibitor-1, a molecule strongly and dose-dependently 
induced by TGF-β (Hazelbag 2004).
Bintrafusp alfa has shown promising clinical activity with durable responses in patients with 
chemotherapy refractory cervical cancer in Phase I study EMR200647-001. In the Phase I study, 
a total of 25 patients with recurrent or persistent cervical cancer following standard of care 
treatment were treated for advanced disease. The median treatment duration was 9.6 (range 2.0 to 
72.0) weeks. The results are summarized:
! ORR of 24.0% (95% CI: 9.4, 45.1) with 6 confirmed responses per Response Evaluation 
Criteria in Solid Tumors Version 1.1 (RECIST 1.1); 5/6 responses were ongoing at data cutoff 
(median DOR not reached; range 2.3+ to 24.9+ months). 
! One additional participant developed a partial response (PR) after initial confirmed disease 
progression, bringing the total clinical response rate to 28.0% (95% CI: 12.1, 49.4). This 
additional participant’s PR was ongoing for 8.7 months at data cutoff, with 73.3% disease 
shrinkage after initial progressive disease (PD). 
! No clear relationship between PD-L1 protein expression and clinical response was observed. 
One patient with negative tumor PD-L1 expression (via 73-10 assay) had a confirmed PR.
Based on the biological rationale and promising clinical activity of bintrafusp alfa in cervical 
cancer and manageable safety profile in close to 700 participants with various cancer types (refer 
to IB), this study is designed to further investigate bintrafusp alfa in participants with advanced, 
unresectable, cervical cancer with disease progression during or after platinum-containing 
chemotherapy.
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2.3
Benefit/Risk Assessment
At the time of study initiation, bintrafusp alfa demonstrated promising clinical efficacy in a cohort 
of participants with second-line (2L)+ cervical cancer in the Phase I study EMR200647-001, with 
a confirmed ORR of 24.0% and total clinical response rate of 28.0% (95% CI: 12.1, 49.4). The 
median DOR had not been reached by data cutoff - 5 of 6 responses were ongoing, with 1 ongoing 
response already lasting for > 2 years. These results demonstrate encouraging clinical efficacy of 
bintrafusp alfa in cervical cancer with favorable response rate and durability compared to historical 
benchmarks. 
Platinum-containing chemotherapy regimen with or without bevacizumab is the standard first-line 
therapy for patients with metastatic cervical cancer. For patients with advanced unresectable and/or 
metastatic cervical cancer with disease progression during or after platinum-based chemotherapy 
there is no established consensus for second-line treatment options due to low response rates, 
typically short-lived and variable toxicities (Bookman 2000; Muderspach 2001; Schilder 2005; 
Alberts 2012). Based upon the poor clinical prognosis new treatment options for this patient 
population are needed, and these patients are included in the eligibility for this study (further 
rationale included in Section 4.2).
The identified and potential risks with bintrafusp alfa monotherapy were overall manageable and 
no new safety signals emerged in the Phase I studies (EMR200647-001, MS200647-0008)
compared with therapies targeting PD-L1 or TGF-β. 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. The overall incidence and severity for irAEs is found to be 
consistent across bintrafusp alfa studies and similar to the known safety profile of approved anti-
PD-L1 agents (Brahmer 2018).
Infusion-related reactions (IRRs) are classified as identified risk for the treatment with bintrafusp 
alfa. Infusion-related reactions observed with bintrafusp alfa were similar to those seen with 
monoclonal antibodies. At the time of study initiation, the overall bintrafusp alfa related IRRs were
observed to be < 5%, of low-grade (Grade 1/2) severity and not requiring permanent treatment 
discontinuation.
Dermatologic AEs related to TGF-β-inhibition (including keratoacanthomas [KA] and cutaneous 
squamous cell cancers) are an important identified risk with bintrafusp alfa not seen with other 
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). At the time of study 
initiation, in the Phase I studies, treatment-emergent TGF-β inhibition mediated skin reactions 
were observed in approximately 11% of participants, and were well-managed with simple excision 
(or spontaneous resolution) and did not require any participant to discontinue treatment (refer to 
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IB). The risk of these lesions with bintrafusp alfa was considered manageable, especially in the 
context of encouraging clinical activity in several tumor types.
3
Objectives and Endpoints
Table 3
Study Objectives and Endpoints
Objectives
Endpoints
Primary
!
To evaluate clinical efficacy of bintrafusp alfa
based on ORR
!
Confirmed objective response according to 
RECIST 1.1 assessed by an IRC
Secondary
!
To evaluate clinical efficacy of bintrafusp alfa
based on DOR
!
DOR according to RECIST 1.1 assessed by an IRC
!
To evaluate clinical efficacy of bintrafusp alfa
based on DRR
!
Durable response of at least 6 months according to 
RECIST 1.1 assessed by an IRC
!
To evaluate clinical safety of bintrafusp alfa
!
Occurrence of TEAEs and treatment-related AEs 
including AEs of special interest
!
To evaluate clinical efficacy based on PFS
!
PFS according to RECIST 1.1 assessed by an IRC
!
To evaluate ORR, DOR, DRR, and PFS by 
Investigator read
!
Confirmed objective response, DOR, DRR, and PFS 
according to RECIST 1.1 assessed by Investigator 
!
To evaluate clinical efficacy based on OS
!
OS
!
To characterize the PK profile of bintrafusp alfa
!
The concentration observed immediately at the end 
of infusion (CEOI) of bintrafusp alfa
!
The concentration observed immediately before next 
dosing (corresponding to pre-dose or trough 
concentration [Ctrough] for multiple dosing) of 
bintrafusp alfa
!
To characterize the immunogenicity of bintrafusp 
alfa
!
Immunogenicity of bintrafusp alfa as measured by 
ADA assay from Screening through Safety Follow-up
visit (up to 28 days after last treatment)
!
To evaluate clinical efficacy of bintrafusp alfa 
according to PD-L1 expression
!
Efficacy endpoints by PD-L1 expression in tumor
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Single-Arm Design
This is a single-arm study for patients who have progressed on prior platinum-containing therapy.
Available treatments for this patient population have shown limited activity with low response 
rates and short DOR with most studies reporting median PFS results < 6 months (Monk 2009).  
The primary objective of this study is the confirmed overall response rate assessed by Independent 
Review Committee (IRC) according to RECIST 1.1, and the key secondary endpoints include 
DOR, PFS and OS.
Data from a similar patient population with cervical cancer in the Phase I study EMR200647-001 
demonstrated that bintrafusp alfa is an active drug with encouraging and durable (> 6 months) 
clinical responses for these patients. Therefore, this single-arm Phase II study will allow an 
adequate and more robust assessment of clinical activity in platinum-experienced cervical cancer. 
Prior Platinum-Based Therapy
Platinum-containing chemotherapy regimen with or without bevacizumab is the standard first-line 
therapy for patients with metastatic cervical cancer. For patients with advanced unresectable and/or 
metastatic cervical cancer with disease progression during or after platinum-based chemotherapy 
there is no established consensus for second-line treatment options due to low response rates that 
are typically short-lived with variable toxicities (Marth 2017). To be documented with the 
informed consent, all patients enrolled in the study must have all available treatment options 
discussed with them during the Screening period.
Inclusion of Human Immunodeficiency Virus Positive Patients
In the typical pathogenesis of cervical neoplasia, standard Screening and early treatment are
effective for detecting and treating pre-cancerous lesions as well as early cancerous growth. Given 
the natural history of the disease with a long developmental timeline, patients who develop 
metastatic disease are frequently those who had prolonged periods with limited access to standard 
medical care. In addition, these patients are also at higher risk for comorbid illnesses, including 
human immunodeficiency virus (HIV) infection.  
Research has suggested that HIV+ cancer patients are more likely to die due to their cancer than 
HIV-related complications. In addition, though with limited data, PD-1/PD-L1 inhibitors used in 
cancer patients with HIV were shown to be safe and with noted activity (Spano 2019). This is 
consistent with an analysis of literature reports, including PD-1/PD-L1 inhibitors as well as 
cytotoxic T-cell lymphocyte-associated antigen-4 (CTLA-4) blocking agents, from 73 patients 
showing a manageable safety profile consistent with the agents; activity in multiple tumor types. 
In addition, 93% of patients with undetectable viral loads maintained undetectable levels during 
treatment (Cook 2019).
The inclusion criteria in this study incorporate recommendations from recent FDA Guidance on
Cancer Clinical Trial Eligibility Criteria (March 2019) that specifies patients with stable, 
well-controlled HIV should be included in clinical studies. Human immunodeficiency virus testing 
is not mandatory for study inclusion; a known history of HIV infection should be reported for 
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verification of HIV-specific inclusion criteria and appropriate safety monitoring. Any patient 
undergoing HIV testing for the purpose of this study must be appropriately consented as per local 
regulations.
4.3
Justification for Dose
The recommended Phase II dose (RP2D) for bintrafusp alfa is 1200 mg administered as an IV 
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. 
Refer to the IB for the completed and detailed data and analysis for dose justification. 
4.4
End of Study Definition
A participant has completed the study if 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 67% of all study participants and 67% of the
participants from China have died (in case of additional China enrollment after global enrollment 
completion) whichever occurs last. However, the study ends when each participant was followed 
up for at least 3 years after the first dose if it occurs earlier. 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 criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study; thereby, ensuring 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 assessments 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.
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b.
Adequate hepatic function defined by a total bilirubin level ≤ the upper limit of normal 
(ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 
≤1.5 × ULN. For participants with liver involvement in their tumor, AST ≤ 5.0 × ULN, 
ALT ≤ 5.0 × ULN, and bilirubin ≤3.0 × ULN are acceptable.
c.
Adequate renal function defined by creatinine ≤ 1.5 × ULN or calculated creatinine 
clearance (CrCL) ≥ 30 mL/min for participant with creatinine > 1.5× ULN (glomerular 
filtration rate can also be used).
Note: CrCL should be calculated per institutional standard. If no local guideline is 
available, CrCL should be calculated using the Cockcroft-Gault Method:
CrCL = ([140-age] × weight [kg] × [0.85 for females only]) / (72 × creatinine).
d.
Adequate coagulation function defined as international normalized ratio (INR) or 
prothrombin time (PT) ≤ 1.5× ULN unless the participant is receiving anticoagulant 
therapy and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless the 
participant is receiving anticoagulant therapy.
8. Participants with known HIV infections are in general eligible if the following criteria are 
met (FDA Guidance on Cancer Clinical Trial Eligibility, March 2019):
a.
If clinically indicated patients must be stable on antiretroviral therapy (ART) for at least 
4 weeks and agree to adhere to ART. If not clinically indicated, consult study Medical 
Monitor.
b.
Participants with HIV infection should have no evidence of documented multi-drug 
resistance that would prevent effective ART.
c.
Have an HIV viral load of < 400 copies/mL at Screening.
d.
Have CD4+ T-cell (CD4+) counts ≥ 350 cells/μL.
e.
For patients with a history of an AIDS-defining opportunistic infection within the last 
12 months, patients may be eligible only after consultation and agreement with the study 
Medical Monitor.  
f.
If prophylactic antimicrobial drugs are indicated, patient may still be considered eligible 
upon agreement with the study Medical Monitor.   
9. Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are in 
general eligible if the following criteria are met (FDA Guidance on Cancer Clinical Trial 
Eligibility, March 2019):
a.
Patients with serologic evidence of chronic HBV infection must have an HBV viral load 
below the limit of quantification. If medically indicated, participants infected with HBV 
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 according to appropriate labeling guidance.
b.
Patients with a history of HCV infection should have completed curative antiviral 
treatment and require HCV viral load below the limit of quantification.
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c.
Patients on concurrent HCV treatment should have HCV below the limit of 
quantification.
Sex
10. A female is eligible if she is not pregnant or breastfeeding, and at least one of the following 
conditions applies:
!
Not a Woman of childbearing potential (WOCBP)
OR
! If a WOCBP, uses 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: 
! Before the first dose of the study intervention(s), 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.
! During the intervention period
! After the study intervention period (i.e., after the last dose of study intervention is 
administered) for at least 2 months.
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 
8.2.4.
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
11. Capable of giving signed informed consent, as indicated in Appendix 2, 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. Participants with active 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 4 weeks, and are not using steroids 
for at least 7 days prior to the start of study treatment. Note: Lesions in the CNS at baseline 
must be assessed as non-target lesions only.
2. Has interstitial lung disease OR has had a history of pneumonitis that has required oral or 
IV steroids
3. 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).
4. Previous malignant disease (other than the target malignancy to be investigated in this study) 
within the last 3 years, except:
a. Participants with a history of superficial/noninvasive bladder cancer, or basal or 
squamous cell carcinoma in situ previously treated with curative intent are NOT 
excluded. 
b. Endoscopically resected early gastrointestinal (GI) cancers limited to mucosal layer 
(esophageal, gastric, and colorectal) that are without recurrence in > 1 year are allowed. 
c. Participants with other localized malignancies (e.g., noninvasive breast cancer [ductal 
carcinoma in situ]) treated with curative intent should be discussed with the Medical 
Monitor. Further biopsy/evaluations may be required prior to allowing enrollment if there 
are any concerns of a non-cervical cancer recurrence.
Any questions regarding these criteria should be discussed with Medical Monitor.
5. Significant acute or chronic infections including but not limited to: 
a. Participants with active tuberculosis (history of exposure or history of positive 
tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
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b. Active bacterial or fungal infection requiring systemic therapy (except as indicated, 
discuss alternative scenarios with the Medical Monitor).
6. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent, except:
a. Participants with diabetes Type 1, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid 
disease not requiring immunosuppressive treatment are eligible.
b. 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.
c. 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.
7. Known severe hypersensitivity (Grade ≥ 3 National Cancer Institute-Common Terminology 
Criteria for Adverse Events v5.0 [NCI-CTCAE v5.0]) to investigational product (bintrafusp 
alfa) or any components in its formulation, any history of anaphylaxis, or recent, within 
5 months, history of uncontrollable asthma.
8. Persisting Grade > 1 NCI-CTCAE v5.0 toxicity (except alopecia and vitiligo) related to 
prior therapy; however, sensory neuropathy Grade ≤ 2 is acceptable.
9. Clinically significant cardiovascular/cerebrovascular disease including: 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. Participants with history of bleeding 
diathesis or recent major bleeding events considered by the Investigator as high risk for 
investigational drug treatment are also excluded.
10. Severe and/or clinically relevant acute or chronic diseases which, in the opinion of the 
Investigator, might impair the participant’s tolerance for the study or ability to consistently 
participate in study procedures.
Prior/Concomitant Therapy
11. Has received prior cancer treatment with any other immunotherapy or checkpoint inhibitors, 
such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or any other immune-modulating 
mAb (e.g. any other antibody or drug specifically targeting T-cell co-stimulation, 
checkpoint pathways or immune-suppressive pathways [e.g. TGF-β]).
12. Concurrent treatment with prohibited drugs (see Section 6.5.2).
13. 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. 
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14. Has received or will receive a live vaccine within 30 days prior to the first administration 
of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. 
Prior/Concurrent Clinical Study Experience
15. Participants, who received chemotherapy, radiation therapy (with the exception of palliative 
radiotherapy delivered in a normal organ-sparing technique), or biological therapy (e.g.,
antibodies) within 4 weeks, or who have been treated with small molecule therapeutics or 
investigational agents within 4 weeks prior to starting bintrafusp alfa or who have not 
recovered from the side effects of such therapy (except for alopecia or potentially 
neuropathy).
Other Exclusions
16. Major surgery within 28 days before the start of study intervention (diagnostic biopsy, for 
example, is not considered major surgery).
17. Pregnancy or breast feeding. 
18. Known active alcohol or drug abuse.
5.3
Lifestyle Considerations
Not applicable.
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.
For participants who have abnormal laboratory value at Screening that may correct or are using a 
prohibited concomitant medication that will be discontinued, or undergoing a prohibited procedure 
that will be completed, the Screening period may be extended up to 2 weeks upon discussion with 
the Medical Monitor as long as all Screening parameters will have been collected within 28 days 
from first study intervention. In other situations when a participant has been screen-failed, the site 
should contact the Medical Monitor to discuss whether the participant may be rescreened.
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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.
6.1
Study Intervention(s) Administration
Table 4
Study Intervention
Study Intervention Name:
Bintrafusp alfa (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
Packaging and Labeling:
Each vial will be packaged and labeled per all 
applicable regulatory requirements and Good 
Manufacturing Practice Guidelines.
6.2
Study Intervention(s) Preparation, Handling, 
, 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(s), 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(s) and only authorized 
site staff may supply it. All study intervention(s) 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(s) 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.
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! The dose(s) each participant used during the study.
! The disposition (including return, if applicable) of any unused study intervention(s).
! Dates, quantities, batch numbers, vial numbers, expiry dates, formulations, and the 
participant numbers.
! The Investigator site will maintain records, which adequately document that participants were 
provided the doses specified in this protocol, and that all study intervention(s) provided were 
fully reconciled.
! Unused study intervention(s) 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 re-dispensed to a 
different participant.
! A Study Monitor will periodically collect the study intervention(s) accountability forms.
! Destruction of used and unused study intervention(s) 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(s) is 
provided in the Operations Manual.
Bintrafusp alfa should be stored in a refrigerator 
 until use. Bintrafusp alfa must not 
be frozen and should be stored in the original packaging.
Additional instructions for the preparation, handling, storage, and disposal of bintrafusp alfa 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.
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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 (eCRFs). The Investigator will make sure that the 
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 form 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
Permitted Medicines
The only permitted medications are the following:
1. Any medications (other than prohibited in Section 6.5.2) that are considered necessary for 
the participants’ welfare and will not interfere with the study intervention may be given at 
the Investigator’s discretion.
2. Other drugs to be used for non-steroid premedication (antihistamine and acetaminophen)
for
the treatment of anaphylactic reactions, IRRs, and severe hypersensitivity 
reactions/flu-like symptoms and irAEs (see Section 6.9).
3. Blood transfusions and erythroid growth factors are permitted as clinically indicated.
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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6.5.2
Prohibited Medicines
The following treatments must not be administered during the 28-day Screening period and for the 
duration of study intervention. 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).
! Immunotherapy, immunosuppressive drugs (e.g., chemotherapy or systemic corticosteroids), or 
other experimental pharmaceutical products are prohibited. Exceptions are allowed for 
short-term treatment of allergic reactions or for the treatment of irAEs, specifically:
!
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 prohibited.
! Other systemic anticancer therapy.
! Live vaccines are prohibited. Administration of inactivated vaccines is allowed (e.g., 
inactivated influenza vaccines).
! Any traditional Chinese medication used as anticancer treatment (regardless of the type of 
cancer) is prohibited. Traditional Chinese medication for indications other than anticancer 
treatment, such as supportive care, may be administered at the discretion of the Investigator. 
List of prohibited Chinese medications is provided in the Appendix 7.
! Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to 
potentially interfere with major organ function (e.g., hypericin). 
Medications other than those specifically excluded in this study (see above) may be administered 
for the management of symptoms associated with the administration of bintrafusp alfa as required. 
These might include analgesics, anti-nausea medications, antihistamines, diuretics, antianxiety 
medications, and medication for pain management, including narcotic agents.
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6.5.3
Other Interventions
Permitted Procedures
! Palliative organ-sparing radiotherapy may be administered only for specific clinical indications 
during the study. The assessment of PD will be made according to RECIST 1.1 and not based 
on the necessity for palliative radiotherapy.
Prohibited Procedures
! Major surgery 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 re-treatment. Any 
diagnostic biopsies collected for clinical reasons during the study should be documented as a 
concomitant procedure including the outcome of available pathology reports.
6.6
Dose Selection and Modification
Participants will receive an IV infusion of bintrafusp alfa at a dose of 1200 mg over 1 hour 
once every 2 weeks as detailed in the SoA
(see Table 1).
Dose modification of bintrafusp alfa is not allowed.
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
Any treatment-emergent adverse event (TEAE) that is assessed as potentially related to bintrafusp 
alfa, may require permanent or transient discontinuation of bintrafusp alfa treatment. 
Single laboratory values out of the normal range that do not have any clinical correlation do not 
necessarily need treatment interruption. Questions or concerns with regard to management and/or 
follow-up of TEAEs 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 in their respective sections as 
indicated below. Permanent study intervention discontinuation may be recommended, so the 
relevant section must be reviewed:
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! For suspected irAEs, general management by NCI-CTCAE v5.0 toxicity grading is listed in 
Section 6.9.2. Recommended guidance and management for specific irAEs as per published 
guidelines is provided in Appendix 5. 
! Infusion-related reaction (IRR) and hypersensitivity reaction guidance are presented in 
Section 6.9.1.
! Anemia guidance is presented in Section 6.9.4.
! Potential TGF-β-mediated skin AEs guidance and management are provided in Section 6.9.3. 
! For guidance and management of bleeding events, see Section 6.9.5.
General guidance:
! In any case, if ≥ 2 doses are missed due to AE, the Medical Monitor should be consulted
! Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day
within 12 weeks is an indication for permanent treatment discontinuation (except for use of
steroids as hormone substitution)
! Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with hormone 
replacement therapy) that do not recover to Grade 0 to 1 within 12 weeks after last dose of study 
intervention is an indication for permanent treatment discontinuation.
In general, the following applies for TEAEs related to bintrafusp alfa that are not covered by the 
recommendations for irAE management in Appendix 5:
Grade 4 treatment-related TEAEs
Any Grade 4 treatment-related TEAEs require permanent treatment discontinuation, except:
!
Endocrinopathies that have been controlled by hormone replacement 
!
Isolated laboratory values out of normal range that do not have any clinical correlation. 
Discuss with Medical Monitor regarding work-up, management, and treatment 
continuation versus hold versus discontinuation for isolated Grade 4 laboratory 
abnormalities
!
If alternative explanation is identified for Grade 4 non-tumor bleeding.
See Appendix 5 for guidance on specific Grade 4 irAEs, as most require permanent treatment 
discontinuation.
Grade 3 treatment-related TEAE
1. Participants with any severe or Grade 3 treatment-related adverse reactions that recur 
should be permanently discontinued. Exceptions may be considered for the following after 
discussion with Medical Monitor:
! Transient Grade 3 flu-like symptoms or fever that is controlled with medical 
management
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! Transient Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves to 
≤Grade 1 or baseline
! 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
! Increases in ECOG PS ≥3 that resolves to ≤2 by Day 1 of the next infusion (i.e., 
infusions should not be given if the ECOG PS is ≥3 on the day of treatment and should 
be delayed until ECOG PS ≤2)
! Keratoacanthoma (KA) and cutaneous squamous cell carcinoma (cSCC)
! Grade 3 non-tumor bleeding requiring intervention or hospitalization if alternative 
explanation can be identified (such as concomitant use of antithrombotic agents, 
traumatic event, etc.).
2. See Appendix 5 for guidance on specific Grade 3 irAEs as many require permanent 
treatment discontinuation, including pneumonitis and nephritis.
! AST or ALT > 5 times ULN or total bilirubin greater than 3 times ULN must be 
permanently discontinued, except for participants with liver metastases (for example) 
who begin treatment with Grade 2 AST or ALT. These participants should be 
discontinued if AST or ALT increases by ≥50% relative to baseline and lasts for at 
least 1 week.
3. Persistent Grade 3 adverse reactions (excluding endocrinopathies controlled with hormone 
replacement therapy) that do not recover to Grade 0 to 1 within 12 weeks after dose of 
treatment.
Grade 2 treatment-related TEAE
1. If a Grade 2 treatment-related TEAE resolves to Grade ≤ 1 by the day before the next 
infusion, study intervention may be continued.
2. If a Grade 2 treatment-related TEAE 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 (refer to Appendix 5). Toxicity grading is assigned 
based on NCI-CTCAE v5.0. 
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6.9
Management of Adverse Events of Special Interest
Adverse events of special interest (AESI) are serious or nonserious AEs specific to the known 
mechanism of action of the study intervention that are of clinical interest.
For this study, AESIs include the following:
! Infusion-related reactions including immediate hypersensitivity
! Immune-related AEs
! TGF-β inhibition mediated skin reactions
! Anemia
! Bleeding AEs
6.9.1
Infusion-related 
Reactions 
Including 
Immediate 
Hypersensitivity
Infusion-related reactions including immediate hypersensitivity, are defined in this section. 
Infusion-related reactions are AESIs and identified risks for bintrafusp alfa.
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:
!
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 IRR 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
Premedication prior to bintrafusp alfa administration for the first 2 infusions is optional and at the 
discretion of the Investigator. If an Investigator chooses to administer premedications, 
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) 
approximately 30 to 60 minutes prior to each dose of bintrafusp alfa is recommended. 
If Grade ≥ 2 infusion reaction(s) are seen during the first 2 infusions, premedication should be 
continued/implemented for future infusions.
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An assessment for possible IRR should be triggered based upon the development of specific 
symptoms within 24 hours of an infusion. 
Management of symptoms should follow the guidelines shown in Error! Reference source not 
found..
Table 5
Treatment Modification of
Bintrafusp alfa
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 reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology 
Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
Once the bintrafusp alfa 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, bintrafusp alfa 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 5 (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 the above provided recommended 
optional premedication regimen, for selected participants. However, prophylactic steroids are not 
permitted. At the next dose, if the participant has a second IRR Grade ≥2 on the slower infusion 
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rate, with the addition of further medication to premedication, the infusion should be stopped, and 
the Investigator may consider withdrawal of this participant from the study.
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 
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 IV 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 IV infusion.
6.9.2
Immune-related Adverse Events
Immune-related AEs are specific to immunotherapies and vary by organ system. Immune-related 
AEs are considered AESIs. 
In general, the spectrum of irAEs is similar for bintrafusp alfa compared with other checkpoint 
inhibitors. 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 
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preventing progression into severe forms of toxicity that otherwise may become life-threatening 
and difficult to manage or warrant permanent discontinuation from the study.
The following irAEs are important identified risks for bintrafusp alfa:
! Immune-related hepatitis
! Immune-related pneumonitis
! 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
! Other immune-related events (myositis, myocarditis, encephalitis)
The following irAEs are important potential risks for bintrafusp alfa:
! 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. 
Recommended guidance and management for specific irAEs as per published guidelines as 
provided in Appendix 5. These recommendations are in accordance with the joint American 
Society of Clinical Oncology (ASCO) Clinical Practice Guidelines (Brahmer 2018) and National 
Comprehensive Cancer Network (NCCN 2018) guidelines.
Treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In general, 
management by NCI-CTCAE v5.0 grading 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 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. 
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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.
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, acquired thrombotic thrombocytopenic 
purpura, inflammatory arthritis, myositis, and polymyalgia-like syndrome. 
For Grade 4 immune-related lymphopenia, permanent treatment discontinuation 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 treatment 
discontinuation is not required when the AE is manifest by a single laboratory value out of normal 
range without any clinical correlates. In this case, treatment should be held until the etiology is 
determined. If the event is not considered immune related and resolves to Grade ≤1 restarting 
treatment may be considered.
! For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, monitor 
participants weekly or more frequently as needed with history, physical examination, and pulse 
oximetry. If symptoms appear and/or changes in the physical examination are noted, treat as 
Grade 2.
! For myositis: in case of management with rituximab, treatment should be discontinued.
For organ/system specific management guidelines, see the guideline tables in Appendix 5.
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 AESI for bintrafusp alfa.
Skin assessments are performed at Screening period and every 6 weeks for all participants per SoA
(see Table 1). Baseline skin assessments include a detailed medical history of genetic or iatrogenic 
skin conditions, skin type, significant UV exposure/sun damage of skin, geographical location, and 
occupational or environmental exposure to radiation or chemicals.  
Skin AEs appear to be related to both mechanisms of bintrafusp alfa; anti-PD-L1 and anti-TGF-β:
1. Immune-related skin AEs possibly mediated by PD-L1 inhibition (e.g. rash or maculo-papular 
rash, distributed typically on trunk and uniformly on limbs). Just as immune-related AEs to 
other organs (see Section 6.9.2), immune related AEs affecting the skin are important identified 
risks for bintrafusp alfa and AESI.
Immune-related skin AEs should be managed according to the recommended guidance and 
management for specific irAEs as per published guidelines (refer to Appendix 5). Treatment 
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typically include use of emollients, non-sedating antihistamines for pruritus, targeted use of 
potent topical steroids to most inflamed lesions; oral corticosteroids in highly symptomatic case.
2. Skin AEs, possibly due to TGF-β inhibition, including hyperkeratosis, KA and/or cSCC, are 
important identified risks and AESI for bintrafusp alfa. The distribution of lesions tends to be 
in sun-exposed areas. These AEs are AESIs for bintrafusp alfa.
Management guidelines for potential TGF-β inhibition mediated skin reactions are:
1. Discontinuation or interruption is not required in most cases. Continuation of treatment should 
be evaluated by the Investigator. 
2. Emollients may continue to be used.
3. Diagnostic and treatment plan should be developed in collaboration between Investigator and 
dermatologist. In general, treatment of TGF-β inhibition mediated skin lesions 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.
4. Treatment and follow-up for KA and cSCC will depend on number and localization of lesions. 
! For single lesions: Full excision may be recommended. 
! In case of multiple lesions or location not suitable for full excision, 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
5. Close clinical follow-up for re-evaluation, resolution, or potential recurrence should be 
implemented.
6. Spontaneous resolution of KA lesions without surgical intervention has been observed, 
typically occurring within weeks after discontinuing bintrafusp alfa.
7. 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 bintrafusp alfa. Notably, there 
are many reasons for anemia in patients with advanced cancer, therefore 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, 
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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:
1. Participants must enter the study with Hgb values at least 9 g/dL; routine blood test parameters 
are required in the SoA (see Table 1)
2. All relevant hematologic testing for anemias should be done prior to a blood transfusion, if 
clinically feasible.
3. 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 as clinically indicated.
Guidance for evaluation of suspected anemias is provided in Table 6.
Table 6
Evaluation Guidance of Suspected Anemia Adverse Events
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, PTT, 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, CBC=complete blood count, CT=computed tomography, FAST=Focused assessment 
with sonography for trauma, Hgb=hemoglobin, INR=international normalized ratio, LDH=lactate dehydrogenase, 
LFT=liver function test, MCV=mean corpuscular volume, MRI=magnetic resonance imaging, PT=prothrombin time, 
PTT=partial thromboplastin time, TIBC=total iron binding capacity, TSH=thyroid-stimulating hormone.
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6.9.5
Bleeding Events
Bleeding events are AESIs and considered an important identified risk for bintrafusp alfa (refer to 
the IB).
6.9.5.1
Mucosal/Non-Tumor Bleeding
Participants treated with bintrafusp alfa were commonly reported with mild to moderate mucosal 
AEs such as epistaxis, hemoptysis, gingival bleeding and hematuria. In general, these reactions 
resolve without discontinuation of treatment. 
For Grade 2 non-tumor bleeding, see Section 6.8 for general management of Grade 2 
treatment-related TEAEs.
For Grade 3 non-tumor bleeding, study treatment 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 
treatment should be held until the event recovers to Grade ≤1.
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 bintrafusp alfa were reported in lower frequencies, with Grade ≥3 
hemorrhages including tumor bleeding. For Grade ≥ 2 tumor bleeding, study treatment 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 bintrafusp alfa, 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 bintrafusp alfa. 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 bintrafusp alfa. An appropriate 
contraception warning is provided as part of the inclusion criteria. Pregnant and breastfeeding 
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women are not allowed in the bintrafusp alfa 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 bintrafusp alfa, guidance for prevention, monitoring, and medical management of 
potential risks, as well as guidance on study intervention interruption or discontinuation.
7
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Participants may be discontinued from study intervention for any of the following reasons, one 
reinitiating course of treatment may be allowed (see Section 7.1.2.1).
! A participant may discontinue 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 discontinued at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons (See Section 6.8 and 6.9 for TEAEs and 
AESIs that require treatment discontinuation).
! 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 at least stable, and if in the opinion 
of the Investigator, the participant will benefit from continued treatment (See Section 7.1.3).
! Unacceptable toxicity.
! Some TEAEs and AESIs require withdrawal from treatment. See Section 6.8 and 6.9 for 
additional details.
! Drug must not be given to a known pregnant participant (refer to Appendix 3).
! Use of a prohibited concomitant drug, as defined in Section 6.5.2, where the predefined 
consequence is withdrawal from the study intervention.
The SoA specifies the data to collect at study intervention discontinuation and follow-up and any 
additional evaluations that need to be completed.
In case of discontinuation from the study intervention:
! The day of End-of-Treatment will correspond to the day of withdrawal (or within 7 days).  
! An attempt should be made to perform all assessments scheduled for the End-of-Treatment visit 
if possible. If not possible, the most clinically relevant assessments and appropriate eCRFs for 
the End-of-Treatment visit should be prioritized as feasible. 
! Participants will be asked to continue Safety and Survival Follow-up, which includes the 
collection of data on survival, patient-reported outcome (PRO) questionnaires, and subsequent 
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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.
7.1.1
Temporary Discontinuation
See Sections 6.8 and 6.9 for guidance on temporary discontinuation from study intervention.
7.1.2
Rechallenge
7.1.2.1
Reinitiation
One reinitiating course of treatment at the same dose and schedule and treatment duration up to 
24 months is allowed at the discretion of the Investigator and agreement of the Medical 
Responsible for: 
! Participants who are experiencing SD, a PR, or CR at the time of discontinuation, and then 
subsequently develop disease progression after stopping therapy, but prior to the End of the 
Study.
OR
! Participants who are discontinued due to an AE that is subsequently well managed or resolved 
after stopping therapy, but prior to the End of the Study.
The participant should reinitiate treatment at the treatment phase visit where they left off according 
to the SoA (see Table 1). Participants who reinitiate treatment should stay on study and should be 
treated and monitored according the SoA for the rest 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 
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 rebaseline scan must be performed prior to reinitiation of study treatment. 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 work-up 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.
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7.1.3
Treatment Beyond Progression
7.1.3.1
Treatment Beyond Initial Progression
Participants will receive bintrafusp alfa as outlined in the SoA until disease progression. Bintrafusp 
alfa may continue past the initial determination of disease progression according to RECIST 1.1 
as long as the following criteria are met:
! Treatment with bintrafusp alfa is ongoing
! No new unacceptable treatment or disease-related toxicity
! Tolerance of study interventions
! At least stable ECOG PS
! Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).
A radiographic assessment should be performed within 4 to 6 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the participant is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with bintrafusp alfa.
7.1.3.2
Treatment Beyond Confirmed Progression
After confirmed PD, if the Investigator feels that the participant continues to achieve clinical 
benefit by continuing treatment, the participant should remain on the study and continue to receive 
monitoring according to the SoA. The decision to continue treatment beyond confirmed PD should 
be discussed with the Medical Monitor and documented in the study records.
Participants who continue beyond progression will be evaluated for further tumor response as per 
the protocol schedule. Treatment should be discontinued permanently upon documentation of 
further, unequivocal, disease progression unless there are no alternative therapeutic options and 
the benefit-risk assessment is favorable in consultation between the Investigator and the Medical 
Monitor. In case of continuation of treatment beyond PD, treatment will be discontinued once any 
other criteria for withdrawal are met.
7.1.3.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression
If disease progression is due to brain metastasis, participants may continue study interventions 
after the local treatment of the brain lesions provided that the above criteria are met in addition to 
the following:
! Tumor assessment showing disease progression has been performed and was documented 
according to RECIST 1.1 prior to the procedure.
! Brain metastases have been treated locally and are clinically stable for at least 2 weeks prior to 
reinitiation of study interventions. 
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! 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 under 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 surgically removed, participants may continue study interventions after the 
local treatment of such a lesion provided that:
! Tumor assessment showing disease progression has been performed and was documented 
according to RECIST 1.1. prior to the procedure.
! It has been at least 2 weeks and the participant has fully recovered from the surgery.
! Benefit-risk assessment to continue study intervention is favorable under 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.
! At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the SoA. The SoA 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.
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if 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 
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necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) where applicable locally and 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, she will be considered to have withdrawn from 
the study.
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8
Study Assessments and Procedures
! Study assessments and procedures and their timing are summarized in the SoA.
! 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 SoA, 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.
! 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 SoA.
! A maximum of 119 mL of blood will be collected in any 1-month (first month) period from 
each participant in the study, including all sample types.
8.1
Efficacy Assessments and Procedures
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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, 
electrocardiograms (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 SoA (Table 1). Periodic evaluations of 
the study data will be conducted by the study team 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 (LFT) is elevated in an HBV- or HCV-positive participant, HBV 
deoxyribonucleic acid (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.
8.2.1
Physical Examinations
! Vital signs, physical examinations, and ECOG PS will be conducted at Screening and at 
subsequent visits as indicated in the SoA (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. 
! 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. 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.
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8.2.2
Vital Signs
! Height (at Screening visit only) and weight will be measured and recorded.
! Vital signs including body temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed and recorded in the eCRF.
! Vital signs will be measured in a seated or semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse and respiratory rate.
! 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).
! Blood oxygen saturation will be measured with a pulse oximeter and recorded in the eCRF.
8.2.3
Electrocardiograms
Single 12-lead ECGs will be obtained as outlined in the SoA (Table 1) using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 6 at 
the time points listed in the SoA (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.
The Sponsor must receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study must be forwarded to the Sponsor or 
designated organization.
The Investigator must 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. 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 SoA (Table 1), including at the end of relevant systemic exposure 
of the study intervention. 
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HIV testing is not mandatory. History of HIV infection will be collected, if known, as part of the 
medical history. If a test 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.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are in Appendix 4.
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 nonserious 
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. 
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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).
Monitoring of Specific Adverse Events
If monitoring is warranted for certain treatment-related TEAEs for safety issues, the treating 
physician or Investigator is requested to follow the participant during the post-treatment long-term 
follow-up phase until the end of study period or the participant is “lost to follow-up” and report 
the management and outcome of AEs to the Sponsor. 
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 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. National regulations regarding Safety Report notifications to 
Investigators will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IRB/IEC 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 IRB/IEC of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
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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 pregnancies in female 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.
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 AE 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 bintrafusp alfa greater than 2 times (i.e., > 2400 mg) of 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 bintrafusp alfa 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. 
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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 bintrafusp alfa. Collection times are specified in the SoA. 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 bintrafusp alfa in serum will be performed using a validated immunoassay 
assay method. Concentrations will be used to evaluate the PK of bintrafusp alfa. 
! Remaining samples collected for analyses of bintrafusp alfa concentration may also be used to 
evaluate immunogenicity and safety or efficacy aspects related to concerns arising during or 
after the study. 
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.
Pharmacokinetic (PK) and antidrug antibody (ADA) samples will be collected according to the 
bintrafusp alfa PK, Immunogenicity Sampling (Table 2). Pharmacokinetic and 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.
The PK parameters will be summarized using descriptive statistics (Table 7). Individual as well as 
mean concentration-time plots will be depicted.
The following PK parameters will be calculated, when appropriate.
Table 7
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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9.3
Populations for Analyses
The analyses populations are specified below. The final decision to exclude participants from any 
analysis population will be made and documented during a data review meeting prior to database 
lock.
The analysis will be performed on approximately 135 patients globally. China participants 
(whether enrolled before or after the completion of the global enrollment) may be analyzed 
separately per local regulatory requirements, and follow the same definition as Section 4.1.
For purposes of analysis, the analysis populations are defined in Table 11.
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Table 11
Analysis Populations
Screening (SCR)
All participants, who provided informed consent, regardless of the participant’s study 
intervention status in the study.
Safety (SAF)/
Full Analysis Set 
(FAS)
All participants, who were administered at least 1 infusion of bintrafusp alfa.
The primary analysis population for efficacy and 
 analyses is the Full Analysis 
Set. The primary analysis population for all analyses of safety and health-related quality of 
life is the Safety population.
Pharmacokinetic 
(PK)
All participants who complete at least 1 infusion of bintrafusp alfa, and who provide at least 
1 sample with a measurable concentration of bintrafusp alfa.
Immunogenicity
Analysis Set (IMM)
All participants who were administered at least 1 infusion of bintrafusp alfa and have at
least one valid ADA result. All ADA analyses will be based on this analysis set.
9.4
Statistical Analyses
Full details of all planned analyses will be described in the study integrated analysis plan (IAP). 
Major modifications of planned analyses will be reflected in a protocol amendment or in the CSR.
In general, continuous variables will be summarized using number (n), mean, median, standard 
deviation, minimum, and maximum. Categorical variables will be summarized using frequency 
counts and percentages. Proportions are calculated based on the number of participants in the 
analysis set of interest, unless otherwise specified in the IAP. 
Data collected after reinitiation of treatment will be summarized according to the specifications in 
the IAP.
9.4.1
Efficacy Analyses
Analysis of efficacy variables will also be performed on subgroup of interest as listed in Table 3, 
including but not restricted to PD-L1 expression.
Statistical analysis methods for primary and key secondary efficacy endpoints are summarized in
Table 12. Further details will be specified in the IAP.
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Table 12
Statistical Analysis Methods for Efficacy Analysis
Endpoint
Statistical Analysis Methods
Primary
Confirmed objective 
response according to 
RECIST 1.1 assessed by 
IRC
The ORR will be determined as the proportion of participants with a confirmed
objective response 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.
The response at each scheduled tumor assessment and the overall response will be 
listed for each participant. The number and proportion of overall response (defined as
CR + PR) will be tabulated
The 95% CI for the ORR will be calculated using the Clopper-Pearson method.
Key Secondary
DOR assessed by an 
IRC
DOR is defined as the time from first documentation of a confirmed objective 
response (CR or PR) according to RECIST 1.1 to the date of first documentation of 
objective response of disease progression (PD) or death due to any cause, whichever 
occurs first. The censoring rules for DOR are as described below for PFS.
Kaplan-Meier estimates will be provided;
Median DOR and the 95% confidence interval for the median will be calculated 
according to Brookmeyer and Crowley (Brookmeyer 1982);
Swimmer plots will be provided.
Durable response 
assessed by an IRC
A durable response is defined as an objective response (CR or PR) according to 
RECIST 1.1, determined by 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 and 12 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.
PFS according to 
RECIST 1.1 assessed by 
an IRC
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 2 or more 
missing tumor assessments. Participants who do not have a baseline tumor 
assessment or who do not have any post-baseline 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.
Kaplan-Meier estimates will be provided;
Median PFS and the 95% confidence interval for the median will be calculated 
according to Brookmeyer and Crowley (Brookmeyer 1982)
Overall survival 
Overall survival 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.
Kaplan-Meier estimates will be provided;
Median OS and the 95% confidence interval for the median will be calculated 
according to Brookmeyer and Crowley (Brookmeyer 1982)
Confirmed Objective 
response, DOR, DRR, 
and PFS according to 
RECIST 1.1 assessed by 
Investigator
Definition and analyses to be performed on the efficacy endpoints as assessed by 
Investigator will be similar to the endpoints as assessed by IRC, see above
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Endpoint
Statistical Analysis Methods
CR= complete response, DOR= duration of response, DRR= durable response rate, IRC= Independent Review 
Committee, ORR= objective response rates, PFS= progression-free survival, PR= partial response, RECIST 
1.1= Response Evaluation Criteria in Solid Tumors Version 1.1.
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, AESIs, clinical laboratory assessments, vital signs, physical 
examination, and ECOG PS as described in Section 8.2.
The definitions, procedures for recording, evaluating, follow-up, and reporting of AEs are 
described in Appendix 4.
Treatment-emergent adverse events 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. The incidence 
of TEAEs, regardless of attribution, and TEAEs defined as possibly related to bintrafusp alfa will 
be summarized by MedDRA preferred term and System Organ Class (SOC) and described in terms 
of intensity and relationship to bintrafusp alfa. Any AEs with an onset or worsening date after the 
on-treatment period will be reported separately.
See Table 13 for analysis methods. The specifics for analysis will be defined in the IAP and 
finalized before database lock.
Table 13
Safety Endpoints and Statistical Analysis Methods
Endpoint
Statistical Analysis Methods
Primary
Not applicable
Secondary
Occurrence of TEAEs 
and treatment-related 
AEs
The Safety Analysis Set will include all participants who receive at least one dose of 
study intervention and will be based on all safety analysis reporting outcomes like 
AEs, clinically relevant bioscience (AESIs) and laboratory tests outcomes.
The safety endpoints will be tabulated using descriptive statistics.
!
Participants will be analyzed according to the actual treatment they receive.
!
The safety endpoints will be analyzed using descriptive statistics.
!
The incidence of TEAEs, SAEs, treatment-related AEs, and AESIs, irAEs will be 
summarized by Preferred Term and System Organ Class for each treatment arm,
and described in terms of severity and relationship to treatment.
!
The worst on-treatment grades for chemistry and hematology laboratory results 
will be summarized.
!
Shifts in toxicity grading from Baseline to highest grade during the on-treatment 
period will be displayed. 
!
For laboratory tests without an NCI-CTCAE grade definition results will be 
presented categorically (e.g., below, within, or above normal limits). 
Further details of safety analyses (including AEs, clinical laboratory assessments, 
vital signs, physical examination, ECG parameters, and ECOG PS) will be provided in 
the IAP.
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Endpoint
Statistical Analysis Methods
AE=adverse event; AESI=adverse event of special interest; ECG=electrocardiogram; IAP=Integrated Analysis 
Plan; irAE=immune-related adverse event; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria 
for Adverse Events; SAE=serious adverse event; TEAE=treatment-emergent adverse event.
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 bintrafusp alfa will be determined by a validated method at the times 
listed in the SoA (see Table 1).
! Details on the PK, immunogenicity, 
 will be 
specified in the IAP finalized before database lock. The PopPK analysis and exposure-response 
may be performed using combined data from several bintrafusp alfa clinical studies and will be 
specified in a separate IAP. PopPK, exposure response and 
 analyses will be 
presented separately from the main CSR. 
! Details on the 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 SoA. 
The immunogenicity testing strategy is in accordance with current regulatory guidance documents 
and industry best practices.
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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10
References
Alberts DS, Blessing JA, Landrum LM, et al. Phase II trial of nab-paclitaxel in the treatment of 
recurrent or persistent advanced cervix cancer: A gynecologic oncology group study. Gynecol 
Oncol. 2012 Dec;127(3):451-5.
Bookman MA, Blessing JA, Hanjani P, et al. Topotecan in squamous cell carcinoma of the cervix: 
A Phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000 Jun;77(3):446-9.
Brahmer JR, Lacchetti C, Schneider BJ, et al. 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. 
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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.
Chung HC, Ros W, Delord JP, at al. Efficacy and Safety of Pembrolizumab in Previously Treated 
Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019 
Jun 10;37(17):1470-1478. doi: 10.1200/JCO.18.01265. Epub 2019 Apr 3.
Cook MR, Kim C1. Safety and Efficacy of Immune Checkpoint Inhibitor Therapy in Patients With 
HIV Infection and Advanced-Stage Cancer: A Systematic Review. JAMA Oncol. 2019 Jul 
1;5(7):1049-1054. 
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.
FDA Guidance on Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, 
or Hepatitis C Virus Infections, Mar 2019.
Greimel ER, Kuljanic Vlasic K, Waldenstrom AC, et al. The European Organization for Research 
and Treatment of Cancer (EORTC) Quality-of-Life questionnaire cervical cancer module: EORTC 
QLQ-CX24. Cancer. 2006 Oct 15;107(8):1812-22.
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.
Hazelbag S, Gorter A, Kenter GG, et al. Transforming growth factor-beta1 induces tumor stroma 
and reduces tumor infiltrate in cervical cancer. Hum Pathol 2002;33(12):1193-9.
Hazelbag S, Kenter GG, Gorter A, et al. Prognostic relevance of TGF-beta1 and PAI-1 in cervical 
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Hollebecque A. An open-label, multicohort, Phase I/II study of nivolumab in patients with virus-
associated tumors (CheckMate 358): Efficacy and safety in recurrent or metastatic (R/M) cervical, 
vaginal, and vulvar cancers. ASCO 2017. Abstract 5504.  
Marth C, Landoni F, Mahner S, McCormack M, Gonzalez-Martin A, Colombo N; ESMO 
Guidelines Committee. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, 
treatment and follow-up. Ann Oncol. 2017 Jul 1;28(suppl_4):iv72-iv83. 
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McLachlan J, Boussios S, Okines A, et al. The Impact of Systemic Therapy Beyond First-line 
Treatment for Advanced Cervical Cancer. Clin Oncol (R Coll Radiol). 2017 Mar;29(3):153-160. 
doi: 10.1016/j.clon.2016.10.002. Epub 2016 Nov 9.
Monk BJ, Tewari KS, Koh WJ. Multimodality therapy for locally advanced cervical carcinoma: 
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Monk BJ, Sill MW, Burger RA, et al. Phase II trial of bevacizumab in the treatment of persistent 
or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin 
Oncol. 2009 Mar 1;27(7):1069-74. 
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 
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Muderspach LI, Blessing JA, Levenback C, Moore JL Jr. A Phase II study of topotecan in patients 
with squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecol 
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from human papillomavirus type 16 induce activation of human transforming growth factor beta1 
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Roszik J, Ring KL, Wani KM, et al. Gene Expression Analysis Identifies Novel Targets for 
Cervical Cancer Therapy. Front Immunol. 2018 Sep 19;9:2102. 
Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with 
non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group.
Gynecol Oncol. 2005 Jan;96(1):103-7.
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with an efficacy signal from the series in real life experience. AIDS. 2019 Sep 1;33(11):F13-F19. 
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Appendices
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Appendix 1
Abbreviations
2L
second-line
ADA
antidrug antibody
ADA
antidrug antibody            
AEs
adverse events            
AESIs
adverse events of special interest
ALT
alanine aminotransferase            
ANC
absolute neutrophil count           
anti-PD-L1
anti-programmed death-ligand 1            
ART
antiretroviral therapy            
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase            
CBC
complete blood count           
CEOI
concentration observed immediately at the end of infusion            
CI
confidence interval
CNS
central nervous system           
CPS
Combined Positive Score           
CR
complete response            
CrCL
creatinine clearance            
CROs
contract research organizations           
CSR
Clinical Study Report
cSCC
cutaneous squamous cell carcinoma          
CT
computed tomography            
CTLA-4
cytotoxic T-cell lymphocyte-associated antigen-4
Ctrough
concentration 
observed 
immediately 
before 
next 
dosing 
(corresponding to pre-dose or trough concentration for multiple 
dosing)
D
day             
DNA
deoxyribonucleic acid            
DOR
duration of response           
DRR
durable response rate           
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ECG
electrocardiogram             
ECOG
Eastern Cooperative Oncology Group          
eCRF
electronic case report forms          
EORTC
European Organisation for Research and Treatment of Cancer      
EQ    
EuroQol        
EQ-5D-5L
EuroQol 5-dimension
FAS
Full Analysis Set
FDA
Food and Drug Administration            
FT4
free thyroxine            
GCP
Good Clinical Practice           
GI
gastrointestinal             
HBV
hepatitis B virus           
HCV
hepatitis C virus           
Hgb
hemoglobin             
HIV
human immunodeficiency virus             
HPV
human papilloma virus           
IAP
integrated analysis plan           
IB
Investigator’s Brochure            
ICF
informed consent form           
ICH
International Council for Harmonisation          
IEC
Independent Ethics Committee           
INR
international normalized ratio
ir
immune-related             
irAEs
immune-related adverse events           
IRB
Independent Review Board
IRC
Independent Review Committee           
IRR
infusion-related reactions            
IV
intravenous             
KA
keratoacanthoma             
LDH
lactate dehydrogenase            
LFT
liver function test           
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MedDRA
Medical Dictionary for Regulatory Activities         
  
N
number of participants          
NCCN
National Comprehensive Cancer Network           
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for 
Adverse Events      
NSAID
nonsteroidal anti-inflammatory drug           
ORR
objective response rates           
OS
overall survival            
PAI-1
plasminogen activator inhibitor-1            
PD
progressive disease
PD-1
programmed death-1
PD-L1
programmed death-ligand 1           
PFS
progression-free survival            
 
  
PK
pharmacokinetic             
PopPK
population pharmacokinetic            
PR
partial response            
PS
performance status            
PT
prothrombin time            
PTT
partial thromboplastin time           
QLQ-C30
Quality-of-Life-Core 30 questionnaire
QLQ-CX24
Quality-of-Life Questionnaire Cervical Cancer module            
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1      
RNA
ribonucleic acid
RP2D
recommended Phase II dose          
SAE
serious adverse event           
SD
stable disease
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SoA
summary of activities            
SUSARs
suspected unexpected serious adverse reactions         
TEAEs
treatment-emergent adverse event            
TGF-β
transforming growth factor-β           
           
TSH
thyroid-stimulating hormone           
TTP
thrombotic thrombocytopenic purpura           
ULN
upper limit of normal          
V
visit             
VAS
visual analog scale           
W
week             
W1D1
Week 1 Day 1          
W3
week 3            
WOCBP
woman of childbearing potential             
β-HCG
β-human chorionic gonadotropin           
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with enough, 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 will be re-consented 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 must 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, who will be required to give consent for their data to be used, as specified in the 
informed consent.
! The participant must 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 Investigator Site File.
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 
bintrafusp alfa, 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), 
 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 Integrated Project 
Management Plan.
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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 Good Clinical Practice (GCP) Guidelines
! The Japanese ministerial ordinance on GCP 
! Applicable laws and regulations.
The Investigator must 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.
For sites in Japan, 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.
Review Committees
The following committees will be involved in the study: IRC
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 for the determination of the best overall response (objective response) 
and date of disease progression for each participant. In addition, the IRC will review radiographic 
imaging findings for each patient to confirm presence of measurable disease per RECIST 1.1 prior 
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to inclusion in the study. The full membership, mandate, and processes of the IRC will be detailed 
in the IRC charter.
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
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. Insurance coverage will be provided for each country 
participating in the study. Insurance conditions shall meet good local standards, as applicable.
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.
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Authorship will be determined by agreement and in line with International Committee of Medical 
Journal Editors authorship requirements.
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 USA 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 PRO data (e.g., quality of life and pain assessments), ePRO will be used. Paper collection can 
be used only when electronic collection is not readily available. Phone interview of PRO data 
collection will also be utilized at 12-week  Safety Follow-up visit. 
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, 
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responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are in the Monitoring Plan or contracts.
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. PDF files of the eCRFs will be 
downloaded from the system by the Investigators at study completion. 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.
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Data recorded on printed or electronic eCRFs that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available.
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 SIV training materials and online study 
modules.
Study and Site Start and Closure
Study Start 
!
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. This 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:
o
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
o
Inadequate recruitment of participants by the Investigator
o
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 contract research 
organization(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.
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Appendix 3
Contraception
Contraceptive use by 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. 
o
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 enrollment.
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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.
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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.
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 adverse event reporting period, as defined in Section 8.3.2. 
Adverse Events of Special Interest
Infusion-related reactions including hypersensitivity, irAEs, TGF-β inhibition mediated skin 
reactions, anemia, and bleeding AEs are all considered as AESIs for bintrafusp alfa.
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
The Recommendations for irAE Management
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 G4 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.
Table of Tables
Table A1
Management of Skin irAEs in Patients Treated With ICPis.............102
Table A2
Management of GI irAEs in Patients Treated With ICPis................107
Table A3
Management of Lung irAEs in Patients Treated With ICPis ...........111
Table A4
Management of Endocrine irAEs in Patients Treated With ICPis ...112
Table A5
Management of Musculoskeletal irAEs in Patients Treated With 
ICPis .................................................................................................117
Table A6
Management of Renal irAEs in Patients Treated With ICPis...........121
Table A7
Management of Nervous System irAEs in Patients Treated With 
ICPis .................................................................................................123
Table A8
Management of Hematologic irAEs in Patients Treated With 
ICPis .................................................................................................128
Table A9
Management of Cardiovascular irAEs in Patients Treated With 
ICPis .................................................................................................135
Table A10
Management of Ocular irAEs in Patients Treated With ICPis.........137
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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
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
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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%-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 
aboveInitiate 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
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, 
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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 (eg, 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.
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.
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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
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., 
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
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Abbreviations: 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; TENS, toxic epidermal 
necrolysis.
liver function test elevations in the setting of 
DRESS/DIHS)
(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
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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
May also include supportive care with medications such 
as Imodium if infection has been ruled out
Should consult with gastroenterology for G2 or higher
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2.0 GI Toxicities
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 versus 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-a blocker. The decision should be made on an individual basis from gastroenterology and 
oncology evaluation. This is based on case series showing promising results
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.
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2.0 GI Toxicities
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 3-10x3 
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)
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
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2.0 GI Toxicities
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-a 
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.
*not approved in Japan. 
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibody; AST, 
aspartate aminotransferase; CBC, complete blood count, 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; 
GI, gastrointestinal; HIV, human immunodeficiency virus; 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.
Abbreviations: 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).
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.
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4.0 Endocrine Toxicity
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
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.
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4.0 Endocrine Toxicity
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
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.
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4.0 Endocrine Toxicity
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.
Abbreviations: 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; 2L, second-line; 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
If failure of improvement after 4 weeks or worsening in 
meantime, consider synthetic or biologic DMARD
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5.0 Musculoskeletal Toxicities
Synthetic: methotrexate, leﬂunomide
Biologic: consider anticytokine therapy such as TNF-a 
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 TB 
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
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
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5.0 Musculoskeletal Toxicities
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
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
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5.0 Musculoskeletal Toxicities
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.
Abbreviations: ADL, activities of daily living; ALT, alanine aminotransferase; ANA, antinuclear antibodies; AST, 
aspartate aminotransferase; CCP, citrullinated protein antibody; CK, creatine kinase; CRP, C-reactive protein; 
DMARD, disease-modifying antirheumatic drug; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, 
Grade; HLA, human leukocyte antigen; ICPi, immune checkpoint inhibitor; IL, interleukin; irAE, immune-related 
adverse event; IV, intravenous; IVIG, intravenous immunoglobulin; LDH, lactate dehydrogenase; MRI, magnetic 
resonance imaging, NSAID, nonsteroidal anti-inﬂammatory drug; PCP, Pneumocystis pneumonia; RF, rheumatoid 
factor; TB, tuberculosis; 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
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 
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6.0 Renal Toxicities
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.
Abbreviations: 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.
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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 antistriated 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
Electrodiagnositic 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.
Diagnostic work-up
G1
Screen for reversible neuropathy causes: diabetic screen, B12, folate, TSH, HIV, consider serum protein 
electrophoresis, and other vasculitic and autoimmune screen Neurologic consultation
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7.0 Nervous System Toxicities
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
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
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7.0 Nervous System Toxicities
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
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
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7.0 Nervous System Toxicities
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.
Abbreviations: AChR, acetylcholine receptor; ACTH, adrenocorticotropic hormone; ADL, activities of daily living; ANA, 
antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; CBC, complete blood count; CNS, central nervous 
system; CPK, creatine phosphokinase; CRP, C-reactive protein; CSF, cerebrospinal fluid; ECG, electrocardiogram; 
EEG, electroencephalogram; EMG, electromyography; ESR, erythrocyte sedimentation rate; G, Grade; GI, 
gastrointestinal; HIV, human immunodeficiency virus; 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; WBC, white blood cell count.
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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 PTNIR 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, penicillins, 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; < 6.2to4.9mmol/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 0157, 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 every 2 
weeks
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
Flow cytometry to evaluate loss of GPI-anchored proteins
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8.0 Hematologic Toxicities
Type and screen patient for transfusions and notify blood bank that all transfusions need to be irradiated and 
ﬁltered
Grading
Management
G1: Nonsevere, < 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
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
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8.0 Hematologic Toxicities
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)
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)
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8.0 Hematologic Toxicities
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
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.
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Abbreviations: AE, adverse event; ANC, absolute neutrophil count; ATG, antithymocyte globulin; CBC, complete 
blood count; CMV, cytomegalovirus; CNS, central nervous system; CT, computed tomography; CXR, chest x-ray; 
DIC, disseminated intravascular coagulation; EBV, Epstein-Barr virus; ECG, electrocardiogram; ER, extended 
release; FE, ferritin; G, Grade; GPI, glycosylphosphatidylinositol; Hgb, hemoglobin; HHV6, human herpesvirus 6; HIV, 
human immunodeficiency virus; HLA, human leukocyte antigen; 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; RBC, red blood cell count; 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
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
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9.0 Cardiovascular Toxicities
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.
Abbreviations: BNP, brain natriuretic peptide; CT, computed tomography; CTPA, computed tomography pulmonary 
angiography; CXR, chest x-ray; DVT, deep vein thrombosis; ECG, electrocardiogram; G, Grade; 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
G4: 20/200 or worse
Permanently discontinue ICPi
Emergent ophthalmology referral
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10.0 Ocular Toxicities
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.
Abbreviations: ICPi, immune checkpoint inhibitor; G, Grade; irAE, immune-related adverse event; IV, intravenous, 
TNF, tumor necrosis factor.
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Appendix 6
Clinical Laboratory Tests
Laboratory 
Assessments
Parameters
Hematology
Platelet countd
Mean Corpuscular 
Volume (MCV)
White blood cell (WBC) 
Count with Differentiald:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes (%)
Mean corpuscular 
hemoglobin concentration 
(MCHC)
Hemoglobind
Mean corpuscular
hemoglobin (MCH)
Hematocrit
Activated partial 
thromboplastin time 
(aPTT)a
Red blood cell countd
Prothrombin timea
Absolute lymphocyte countd
International normalized
ratio (INR)a
Absolute neutrophil countd
Biochemistry
Blood Urea 
Nitrogen/Total 
urea
Potassium
Aspartate 
Aminotransferased
Bilirubin (total, 
indirect/direct)d
Creatinined
Sodium
Alanine 
Aminotransferased
Total Protein
Glucose
Calcium
Alkaline phosphatase
Tuberculin skin test, 
QuantiFERON-TB-Gold, 
or T-SPOT (for patients 
with active tuberculosis 
[as defined in Exclusion 
Criteria #5, Section 5.2], 
perform at baseline and 
as clinically indicated) 
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
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 Screeningb: Hepatitis B surface antigen; Hepatitis B core antibody and 
Hepatitis C antibody
!
HIV; HIV virus RNA, quantitative; and CD4 lymphocyte countc
a Coagulation parameters collected at Baseline and as clinically indicated, thereafter (See Table 1).
b 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).
c Not required for all patients. Testing required for patients with known history of HIV. 
d Results must be reviewed by the Investigator within 3 days prior to dosing. 
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Appendix 9
Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1
The text below was obtained from the following reference: Eisenhauer 2009.
Definitions
Response and progression will be evaluated in this study using the international criteria proposed 
by the RECIST Committee (Version 1.1). Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
!
10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm)
!
10 mm caliper measurement by clinical exam (when superficial)
!
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung).
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At Baseline and in Follow-up, only the short axis will be measured 
and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging techniques are 
all non-measurable.
Bone lesions:
!
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.
!
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
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considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
!
Blastic bone lesions are non-measurable.
Cystic lesions:
!
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts.
!
Cystic lesions thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same participant, these are preferred for selection as 
target lesions.
Lesions with prior local treatment:
!
Tumor lesions situated in a previously irradiated area, or in an area subjected to other local 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such 
lesions would be considered measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, should be 
identified as target lesions and recorded and measured at Baseline. Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the image is 
obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may 
be axial, sagittal, or coronal). The smaller of these measures is the short axis. For example, an 
abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies 
as a malignant, measurable node. In this example, 20 mm should be recorded as the node 
measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) should 
be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
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sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at Baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
Baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at Baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical examination.
No photographs, no skin lesion measurement by calipers and no measurements on chest X-ray will 
be done in this study.
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the 
original source article cited above, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the next. 
If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI 
is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in studies where recurrence following CR or surgical resection 
is an endpoint.
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Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit; however, they must normalize for a participant 
to be considered in CR. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific guidelines 
for both CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective tumor 
assessment for use in first-line studies in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (e.g., residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse 
event (AE) of treatment (e.g., with certain taxane compounds or angiogenesis inhibitors), the 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or SD in order 
to differentiate between response (or SD) and PD.
RESPONSE CRITERIA
Evaluation of Target Lesions
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm.
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 
mm. (Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on study. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the Baseline examination), even 
if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms (CRFs) or other data 
collection methods may therefore be designed to have target nodal lesions recorded in a separate 
section where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, 
SD, and PD, the actual short axis measurement of the nodes is to be included in the sum of target 
lesions.
Target lesions that become ‘too small to measure’. While on study, all lesions (nodal and 
non-nodal) recorded at Baseline should have their actual measurements recorded at each 
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subsequent evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at Baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’. When this occurs it is important that a value be recorded on the eCRF. If 
it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should 
be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. (Note: It is less likely that this rule will be 
used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat, such as in the retroperitoneum; however, if a lymph node is believed to be 
present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in 
this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). The measurement of these lesions is 
potentially non-reproducible; therefore, providing this default value will prevent false responses 
or progressions based upon measurement error. To reiterate, however, if the radiologist is able to 
provide an actual measure, that should be recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’.
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
When the participant also has measurable disease. In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in the presence of SD or partial response in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest ‘increase’ in the size of 1 or more non-target lesions is usually not sufficient to quality for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare.
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When the participant has only non-measurable disease. This circumstance arises in some Phase 
III studies when it is not a criterion of study entry to have measurable disease. The same general 
concept applies here as noted above; however, in this instance there is no measurable disease 
assessment to factor into the interpretation of an increase in non-measurable disease burden. 
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are truly non-measurable), a useful test that can be applied when assessing participants for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: i.e., an increase in tumor burden representing an additional 
73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient 
to require a change in therapy’. If ‘unequivocal progression’ is seen, the participant should be 
considered to have had overall PD at that point. While it would be ideal to have objective criteria 
to apply to non-measurable disease, the very nature of that disease makes it impossible to do so; 
therefore, the increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (e.g., some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). This is particularly important when the participant’s Baseline lesions 
show partial or CR. For example, necrosis of a liver lesion may be reported on a CT scan report as 
a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at Baseline 
is considered a new lesion and will indicate PD. An example of this is the participant who has 
visceral disease at Baseline and while on study has a brain CT or MRI ordered which reveals 
metastases. The participant’s brain metastases are considered to be evidence of PD even if he/she 
did not have brain imaging at Baseline.
If a new lesion is equivocal, e.g., because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely 
a new lesion, then progression should be declared using the date of the initial scan.
While fludeoxyglucose positron emission tomography (FDG-PET) response assessments need 
additional studies, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a.
Negative FDG-PET at Baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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b. No FDG-PET at Baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
Evaluation of Best Overall Response
The best overall response (BOR) is the best response recorded from the start of the study 
intervention until the End-of-Treatment taking into account any requirement for confirmation. On 
occasion, a response may not be documented until after the end of therapy, so protocols should be 
clear if post-treatment assessments are to be considered in determination of BOR. Protocols must 
specify how any new therapy introduced before progression will affect best response designation. 
The participant’s BOR assignment will depend on the findings of both target and non-target disease 
and will also take into consideration the appearance of new lesions. Furthermore, depending on 
the nature of the study and the protocol requirements, it may also require confirmatory 
measurement. Specifically, in non-randomized studies where response is the primary endpoint, 
confirmation of PR or CR is needed to deem either 1 the ‘BOR’. 
The BOR is determined once all the data for the participant is known. Best response determination 
in studies where confirmation of complete or PR IS NOT required: Best response in these studies 
is defined as the best response across all time points (for example, a participant who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a BOR of PR). When SD is 
believed to be best response, it must also meet the protocol-specified minimum time from baseline. 
If the minimum time is not met when SD is otherwise the best time point response, the participant’s 
best response depends on the subsequent assessments. For example, a participant who has SD at 
first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same participant lost to follow-up after the first SD assessment would be 
considered inevaluable.
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
CR
Non-CR/non-PD
Not Evaluated
No
No
Partial response
Partial response
Partial response
Non-PD or not all evaluated
No
Partial response
SD
Not all evaluated
Non-PD or not all evaluated
Non-PD
No
No
SD
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, NE=not evaluable, SD=stable disease, PD=progressive disease.
See text for more details.
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Note:
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that participants with CR may 
not have a total sum of ‘zero’ on the eCRF. 
In studies where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the study must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most studies, it is reasonable to consider a participant with time point responses of PR-NE-PR as 
a confirmed response.
Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time should be reported as ‘symptomatic deterioration’. 
Every effort should be made to document objective progression even after discontinuation of 
treatment. Symptomatic deterioration is not a descriptor of an objective response; it is a reason for 
stopping study therapy. 
Conditions that define ‘early progression, early death, and inevaluability’ are study-specific and 
should be clearly described in each protocol (depending on treatment duration, and treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of CR. The use of FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In non-randomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure the responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies. However, in all other circumstances, i.e., in 
randomized studies (Phase II or III) or studies where SD or progression are the primary endpoints, 
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confirmation of response is not required since it will not add value to the interpretation of the study 
results. However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the study protocol.
Duration of Overall Response
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of participants achieving SD for a minimum period of time is an endpoint of importance 
in a particular study, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD.
Note: The DOR and SD as well as the progression-free survival are influenced by the frequency 
of follow-up after baseline evaluation. It is not in the scope of this guideline to define a standard 
follow-up frequency. The frequency should take into account many parameters including disease 
types and stages, treatment periodicity, and standard practice. However, these limitations of the 
precision of the measured endpoint should be taken into account if comparisons between studies 
are to be made.
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Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities 
and throughout the 
protocol, as applicable
Updated note for
 
) and blood sample for ADA. 
To update the collection time to within 
4 hours prior to study intervention infusion.
Appendix 2 Study 
Governance
4.4 End of Study 
Definition
Description of end of study includes 
allowance for further enrollment in 
China.
This allowance for additional enrollment in 
China beyond the end of global enrollment 
(if needed) is intended to satisfy local 
regulatory requirements.
5.1 Inclusion Criterion #2
The patient population for enrollment 
was modified to specify patients with 
prior platinum as adjuvant or 
neo-adjuvant treatment should have 
disease progression or recurrence 
within 6 months. Also, patients who 
previously only received platinum as 
a radiosensitizer are not eligible.
This change is intended to provide a more 
homogeneous patient population and 
incorporates regulatory feedback received 
for this study. 
5.1 Inclusion Criterion #9a
Added text as per the FDA guidance 
document & American 
Gastroenterological Association 
(AGA) guidance for HIV/HBV/HCV.
To clarify the treatment of participants 
infected with HBV at study entry.
5.4 Screen Failures
Added information about the 
Screening period extension.
To clarify that the Screening extension will 
be allowed as long as all Screening 
parameters will have been collected within 
28 days from first study intervention. 
6.9.2 Immune-related 
Adverse Events
6.9.3 Skin Adverse 
Events
Added definition of which AEs are 
considered AESIs.
To provide clarification for the Investigator.
Added details about definition of SD.
To provide clarification on the SD criteria
that measurements must meet.
8.2.2 Vital Signs
Updated vital signs measurements.
To add seated position. 
9.3 Populations for 
Analyses
Updated Table 11 Analysis 
Populations.
To replace ITT with FAS.
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Section # and Name
Description of Change
Brief Rationale
9.4.4 Sequence of 
Analyses
Adjustment for the estimation of the 
timelines for the final analysis and 
additional analyses for the potential 
to continue enrollment to achieve the 
desired 15% of study population 
enrolled in China.
This allowance for additional enrollment in 
China beyond the end of global enrollment 
(if needed) is intended to satisfy local 
regulatory requirements.
Appendix 2 Study 
Governance
Added additional text or modified the 
previous text.
Modifications based on changes to 
protocol template version 14 and updates 
based on regional requirements.  
Appendix 9 Response 
Evaluation Criteria in 
Solid Tumors (RECIST) 
Version 1.1
Addition of RECIST 1.1 as an 
Appendix.
For consistency across the development 
program.
Appendix 12 Coordinating 
Investigator Signature 
Page
Title page
Updated to be consistent with the 
current information.
Administrative update.
Throughout the protocol
Minor editorial and formatting 
revisions; correction of minor 
typographical errors.
To make minor revisions for correctness, 
readability, consistency of language across 
the bintrafusp alfa development program, 
and for compliance with current Sponsor 
guidelines.
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Appendix 11
Sponsor Signature Page
Study Title:
A Phase II, Multicenter, Open Label Study of Bintrafusp 
alfa 
(M7824) 
Monotherapy 
in 
Participants 
with 
Advanced, Unresectable Cervical Cancer with Disease 
Progression During or After Platinum-Containing 
Chemotherapy
Regulatory Agency Identifying 
Numbers:
, EudraCT: 2019-003583-40
Clinical Study Protocol Version:
22 June 2021/Version 3.0
I approve the design of the clinical study:
____________________________________
____________________________
Signature
Date of Signature
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Appendix 12
Coordinating Investigator Signature Page
Study Title:
A Phase II, Multicenter, Open Label Study of Bintrafusp 
alfa 
(M7824) 
Monotherapy 
in 
Participants 
with 
Advanced, Unresectable Cervical Cancer with Disease 
Progression During or After Platinum-Containing 
Chemotherapy
Regulatory Agency Identifying 
Numbers:
 EudraCT: 2019-003583-40
Clinical Study Protocol Version:
22 June 2021/Version 3.0
Site Number:
I approve the design of the clinical study, 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.
____________________________________
____________________________
Signature
Date of Signature
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Appendix 13
Principal Investigator Signature Page
Study Title:
A Phase II, Multicenter, Open Label Study of Bintrafusp 
alfa 
(M7824) 
Monotherapy 
in 
Participants 
with 
Advanced, Unresectable Cervical Cancer with Disease 
Progression During or After Platinum-Containing 
Chemotherapy
Regulatory Agency Identifying 
Numbers:
, EudraCT: 2019-003583-40
Clinical Study Protocol Version:
22 June 2021/Version 3.0
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:
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