An Open-label, Multicenter Follow-up Study to Collect Long-term Data on Participants From Multiple Bintrafusp Alfa (M7824) Clinical Studies
Phase: PHASE3
Conditions: Lung Cancer, Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.

M7824 
Bintrafusp alfa Program Rollover Study 
MS200647_0054 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
1/99 
 
 
 
Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: 
An Open-label, Multicenter Follow-up Study to 
Collect Long-term Data on Participants from 
Multiple Bintrafusp alfa (M7824) Clinical Studies 
Study Number: 
MS200647 0054 
Merck Compound: 
M7824 
Protocol Version: 
30 November 2021/Version 2.0 
Merck Registered Compound Name in 
Japan: 
Not applicable 
Study Phase: 
Phase III 
Short Title: 
Bintrafusp alfa Program Rollover Study 
Acronym or Abbreviation: 
Coordinating Investigator: 
Sponsor Name and Legal Registered 
Address: 
Sponsor: 
Affiliates of Merck KGaA, Darmstadt, Germany 
For all countries, except the US and Canada and 
Japan: 
Merck Healthcare KGaA, Darmstadt, Germany  
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250 
64293, 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 
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Bintrafusp alfa Program Rollover Study 
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Regulatory Agency Identifying 
Numbers: 
 
EudraCT: 2021-000179-36 
Keywords 
• Solid Tumors 
• Tumor response 
• Safety  
• Efficacy 
• Response Evaluation Criteria in Solid Tumors 
version 1.1 
• Programmed death ligand 1 
• Survival Follow-up 
• Human transforming growth factor β (TGFβ) 
receptor II 
• Performance Status 
 
 
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Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
13 May 2021 
2.0 
Global Amendment 
30 November 2021 
Protocol Version 2.0 (29-November-2021) 
Overall Rationale for the Amendment 
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. 
The primary purpose of this amendment is to update the benefit/risk of the study and the 
management of bleeding events. 
 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
Height,  
 
Free T4 and TSH tests to be done every 
6 weeks 
Changes are made to align with rest of the 
protocol section. 
Free T4 and TSH test timepoints are updated to 
reflect only during Treatment Phase. 
 
2.3 Benefit/Risk 
Assessment 
Revised text to add the discontinuation 
of 3 randomized controlled studies 
To update the benefit/risk section. 
2.3.1 Risk 
Assessment 
Table 2 
Editorial changes to clarify Impaired 
wound healing and embryofetal toxicity 
as an important potential risk for 
bintrafusp alfa 
Editorial changes for clarification. 
6.9 Special 
Precautions 
The section has been merged into 
Section 7.1 
Changes are made to align with the current 
protocol template. 
7.1 
Discontinuation 
of Study 
Intervention 
Discontinuation of study intervention for 
participants from Study 
MS200647_0005 is clarified. 
Discontinuation of study intervention is as 
specified in the parent protocol for participants 
from MS200647_0005. 
8.3.6.2 
Immune-related 
Adverse Evens 
Immune related pneumonitis has been 
added 
 
For some conditions like 
endocrinopathies, hepatitis action to be 
taken on study treatment has been 
deleted. 
The missing event has been added to complete 
list of irAEs. 
 
 
Information has been deleted to maintain 
consistency across protocols for the bitrafusp alfa. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.3.6.5 
Bleeding 
Adverse Events 
Guidance has been provided on 
bintrafusp alfa dose 
modification/interruption when Grade ≥ 3 
bleeding event and rapid decrease in 
hemoglobin is observed during the 
study. 
The dose modification/interruption guideline will 
help Investigator to ensure participants safety 
during the study. 
8.3.7 Other 
Important 
Potential Risks 
The section has been deleted as 
information is already presented in 
Section 2.3.1 
Information is already presented in Section 2.3.1 
Risk Assessment. Therefore, text has been 
deleted from Section 8.3.7. 
8.4 Treatment 
of overdose 
The definition of overdose is clarified 
To clarify overdose. 
11 Appendices 
Clinical 
laboratory tests 
Free T4 and TSH tests are removed 
from the list of tests at Screening 
To align with schedule of activities table as these 
tests to be done during Treatment Phase. 
Note: Minor changes have been performed throughout the protocol to address consistency pertaining to major 
changes done in the protocol or to add further clarity and precision. 
Free T4 = free thyroxine; TSH = thyroid-stimulating hormone; irAEs = Immune-related adverse events 
- 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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Table of Contents  
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................5 
Table of Tables 
 ..............................................................................................................8 
1 
Protocol Summary ................................................................................9 
1.1 
Synopsis ................................................................................................9 
1.2 
Schema ................................................................................................13 
1.3 
Schedule of Activities .........................................................................14 
2 
Introduction .........................................................................................19 
 
 
2.2 
Background .........................................................................................19 
2.3 
Benefit/Risk Assessment ....................................................................20 
2.3.1 
Risk Assessment .................................................................................21 
2.3.2 
Benefit Assessment .............................................................................23 
2.3.3 
Overall Benefit/Risk Conclusion ........................................................23 
3 
Objectives and Endpoints ...................................................................24 
4 
Study Design .......................................................................................25 
4.1 
Overall Design ....................................................................................25 
4.2 
Scientific Rationale for Study Design ................................................27 
4.2.1 
Participant Input into Design ..............................................................27 
4.3 
Justification for Dose ..........................................................................27 
4.4 
End of Study Definition ......................................................................28 
5 
Study Population .................................................................................28 
5.1 
Inclusion Criteria ................................................................................29 
5.2 
Exclusion Criteria ...............................................................................31 
5.3 
Lifestyle Considerations .....................................................................31 
5.3.1 
Meals and Dietary Restrictions ...........................................................31 
5.4 
Screen Failures ....................................................................................31 
6 
Study Intervention(s) ..........................................................................31 
6.1 
Study Intervention(s) Administration .................................................31 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................32 
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6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................33 
6.3.1 
Study Intervention Assignment ..........................................................33 
6.3.2 
Blinding ..............................................................................................33 
6.3.3 
Emergency Unblinding .......................................................................34 
6.4 
Study Intervention Compliance ..........................................................34 
6.5 
Concomitant Therapy .........................................................................34 
6.5.1 
Rescue Medicine .................................................................................35 
6.5.2 
Permitted Medicines ...........................................................................35 
6.5.3 
Prohibited Medicines ..........................................................................35 
6.5.4 
Other Interventions .............................................................................36 
6.6 
Dose Selection and Modification ........................................................36 
6.7 
Reinitiation Criteria ............................................................................36 
6.8 
Study Intervention after the End of the Study ....................................37 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................38 
7.1 
Discontinuation of Study Intervention................................................38 
7.1.1 
Temporary Discontinuation ................................................................41 
7.1.2 
Treatment Beyond Progression ...........................................................41 
7.1.2.1 
Treatment Beyond Disease Progression .............................................41 
7.1.2.2 
Continuation of Study Intervention After Local Treatment of 
Disease Progression ............................................................................41 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................42 
7.3 
Lost to Follow-Up...............................................................................43 
8 
Study Assessments and Procedures ....................................................43 
8.1 
Efficacy Assessments and Procedures ................................................44 
8.1.1 
Tumor Assessments ............................................................................44 
8.1.2 
Follow-up ............................................................................................45 
8.2 
Safety Assessments and Procedures ...................................................45 
8.2.1 
Physical Examinations ........................................................................46 
8.2.2 
Vital Signs ..........................................................................................46 
8.2.3 
Electrocardiograms .............................................................................46 
8.2.4 
Clinical Safety Laboratory Assessments ............................................46 
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8.3 
Adverse Events and Serious Adverse Events .....................................48 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ....................................................48 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events ...48 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events ...............49 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events .....49 
8.3.5 
Pregnancy ...........................................................................................49 
8.3.6 
Management of Adverse Events of Special Interest ...........................51 
8.3.6.1 
Infusion-related Reactions Including Immediate Hypersensitivity ....51 
8.3.6.2 
Immune-related Adverse Events .........................................................53 
8.3.6.3 
TGFβ inhibition mediated Skin Reactions .........................................54 
8.3.6.4 
Anemia ................................................................................................55 
8.3.6.5 
Bleeding Adverse Events ....................................................................56 
8.4 
Treatment of Overdose .......................................................................57 
8.5 
Pharmacokinetics ................................................................................58 
..........................................58 
..........................................58 
..........................................58 
8.9 
Immunogenicity Assessments ............................................................58 
8.10 
Health Economics OR Medical Resource Utilization and Health 
Economics ...........................................................................................58 
.......................58 
.......................58 
.......................58 
9.3 
Populations for Analyses ....................................................................59 
9.4 
Statistical Analyses .............................................................................59 
9.4.1 
Efficacy Analyses ...............................................................................59 
9.4.2 
Safety Analyses ..................................................................................60 
9.4.3 
Other Analyses ....................................................................................61 
9.4.4 
Sequence of Analyses .........................................................................61 
10 
References ...........................................................................................62 
11 
Appendices .........................................................................................63 
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Appendix 1 
Abbreviations ......................................................................................64 
Appendix 2 
Study Governance ...............................................................................67 
Appendix 3 
Contraception ......................................................................................72 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................74 
Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments ...........80 
Appendix 6 
Clinical Laboratory Tests ...................................................................81 
Appendix 7 
Pharmacokinetic Parameters ...............................................................83 
............................................................................84 
Appendix 9 
Country-specific Requirements ..........................................................85 
Appendix 10 
List of Bintrafusp alfa Studies from Which Participants May be 
Enrolled ...............................................................................................86 
Appendix 11 
Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 .......................................................................................................87 
Appendix 12 
Protocol Amendment History .............................................................96 
Appendix 13 
Sponsor Signature Page ......................................................................97 
Appendix 14 
Coordinating Investigator Signature Page ..........................................98 
Appendix 15 
Principal Investigator Signature Page .................................................99 
Table of Tables 
Table 1 
Schedule of Activities .........................................................................15 
Table 2 
Bintrafusp alfa - Identified and Potential Risks with Mitigation 
Strategies .............................................................................................21 
Table 3 
Objectives and Endpoints ...................................................................24 
Table 4 
Study Intervention ..............................................................................32 
Table 5 
Treatment Modification Guidance for Symptoms of Infusion-
Related Reactions Including Immediate Hypersensitivity .................52 
Table 6 
Evaluation Guidance of Suspected Anemia .......................................56 
Table 7 
Analyses Sets ......................................................................................59 
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• Participants who are currently on active bintrafusp alfa treatment (alone as a monotherapy or 
following discontinuation of other combination treatment agents) in an eligible parent study 
without treatment interruption at the time of rollover study enrollment. 
• Participants who: 
• 
Achieved confirmed complete response (CR), partial response (PR), or stable disease 
(SD) in an eligible parent study 
• 
Discontinued bintrafusp alfa treatment according to the parent study protocol 
• 
Subsequently developed disease progression 
• 
Are willing to re-start bintrafusp alfa treatment deemed potentially beneficial by the 
participants’ physicians. 
• Participants who: 
• 
Discontinued from bintrafusp alfa treatment in an eligible parent study due to an AE(s) 
that was subsequently well managed or resolved after stopping therapy  
• 
And are willing to re-start bintrafusp alfa treatment if deemed potentially beneficial by 
the participants’ physicians and provided that the parent study protocol permits 
reinitiation of bintrafusp alfa if a participant discontinued treatment due to toxicity. 
Note: Participants who have had AEs requiring permanent treatment discontinuation, like certain 
immune-related adverse events (irAEs) or certain bleeding events are excluded from participation 
in the rollover study. 
Participants can be transferred from their respective parent bintrafusp alfa study to this rollover 
study once the primary/main analysis in the parent study has been completed or after 
discontinuation of study before primary/main analysis has been completed. Participants may also 
be transferred upon Sponsor decision in case the parent study is terminated for any reason as 
specified in the parent study protocol and there is a medical need for participants to continue to be 
treated with bintrafusp alfa that cannot be otherwise supplied. The final decision whether to 
transfer participants from the parent study rests with the Sponsor. 
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Brief Summary: 
Brief Summary: 
This study is designed to provide continuous access to treatment with bintrafusp alfa for eligible 
participants from ongoing bintrafusp alfa parent studies, and to collect long-term safety and 
efficacy data: 
• Study Duration: All participants in this rollover study will be treated with bintrafusp alfa 
until meeting defined criteria in the initial study protocol (parent) for discontinuation, until 
study intervention is commercially accessible and provisioned via marketed product, or until 
end of study. The study also includes a 5 years survival follow-up after last dose of the study 
treatment. 
• Treatment Duration: Treatment under the rollover protocol according to the interval and 
dosing schedule in the parent protocol until discontinuation. 
• Treatment Frequency: 1200 mg once every 2 weeks; 2400 mg once every 2 weeks; 2400 mg 
once every 3 weeks. Other dose amount as specified in the participant’s parent protocol: 
once every 2 weeks.  
• Bintrafusp alfa is not available through an expanded access program. 
Number of Participants: The maximum number of participants who can enter from parent studies 
is not limited and is dependent on the number of eligible participants from the parent studies. Based 
on the current status of participants in the ongoing bintrafusp alfa parent studies, it is estimated 
that at least 10 participants will enter this study (as of April 2021 eCRF data). 
Study Intervention Groups and Duration: This is an open-label, single arm study. 
The study includes: 
• Treatment with bintrafusp alfa until disease progression per RECIST v1.1, clinical 
deterioration, unacceptable toxicity, or any other criterion for withdrawal from study 
intervention or study is fulfilled. 
• In the case of progressive disease, treatment may continue if the participant’s performance 
status (PS) has remained at least stable in the opinion of the Investigator, the participant will 
benefit from continued treatment, in the opinion of the Investigator and if other criteria are 
fulfilled as outlined in the protocol. 
• Participants who have experienced a confirmed CR should continue treatment for a maximum 
of 24 months after confirmation of response (at the discretion of the Investigator). If the 
Investigator believes that a participant with confirmed CR may benefit from treatment beyond 
24 months, it may be permissible to continue treatment after discussion with the Medical 
Monitor and the Sponsor’s Medical Responsible. 
• Participants with SD or PR who are receiving bintrafusp alfa should continue treatment until 
meeting criteria for discontinuation. 
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• Safety Follow-up will continue until 90 days after the last dose of bintrafusp alfa. The 90-day 
Safety Follow-up is allowed to be conducted via telephone calls unless there is medical 
necessity requiring a clinical visit. 
• Long-term Follow-up should be performed every 12 weeks after the Safety Follow-up 
according to the Schedule of Activities. Long-term Follow-up should be performed telephone 
calls unless there is medical necessity requiring a clinical visit 
• Survival Follow-up will continue until a maximum of 5 years after the last participant receives 
the last dose of bintrafusp alfa. This duration may be shortened at the discretion of the Sponsor 
for any given indication. 
Involvement of Special Committee(s): No 
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1.3 
Schedule of Activities  
The Schedule of Activities is presented in Table 1. 
 
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2 
Introduction  
Bintrafusp alfa (M7824) is an innovative first-in-class bifunctional fusion protein composed of 
the extracellular domain of the human transforming growth factor β (TGFβ) receptor II 
(TGFβRII or TGFβ Trap) covalently linked via a flexible linker to the C-terminus of each heavy 
chain of an immunoglobulin G1 (IgG1) antibody blocking programmed death-ligand 1 
(anti-PD-L1). Bintrafusp alfa is currently in clinical development with multiple ongoing Phase I 
to III clinical studies, in which bintrafusp alfa is being investigated as a monotherapy or in 
combination with other anticancer treatments in participants with different types of 
malignancies. 
Detailed information on the chemistry, pharmacology, efficacy, and safety of bintrafusp alfa is 
in the Investigator’s Brochure (IB). 
2.2 
Background  
Bintrafusp alfa is being developed as an immuno-oncology agent for treatment in a number of 
tumor types, including non-small cell lung cancer (NSCLC), biliary tract cancer (BTC), cervical 
cancer, and triple-negative breast cancer (TNBC). Bintrafusp alfa is designed to simultaneously 
target 2 pathways that have independent and complementary immunosuppressive functions in 
the tumor microenvironment. Programmed-death ligand 1 (PD-L1) signaling plays a key role in 
the immunosuppressive network that dampens T-cell activity and TGFβ functions as an autocrine 
or paracrine signal within the local tumor microenvironment, where it promotes tumor 
progression. 
The novel design of bintrafusp alfa, which binds all 3 isoforms of TGFβ and simultaneously 
inhibits the anti-PD-L1 pathway in the tumor microenvironment, may be more effective than 
agents targeting PD-L1 and TGFβ separately. Nonclinical experiments conducted by the Sponsor 
(Lan 2018) demonstrated that bintrafusp alfa strongly enhances antitumor activity and prolongs 
survival in mouse tumor models above the effect of either an anti-PD-L1 control antibody or the 
TGFβ Trap control alone (at the same molarity as bintrafusp alfa). 
The overall safety profile of bintrafusp alfa at 1,200 mg every 2 weeks as a monotherapy in close 
to 700 participants with various cancer types is manageable; no new safety signals emerged in 
the 2 Phase I studies (EMR200647-001 and MS200647-0008) compared with therapies targeting 
PD-L1 or TGFβ. Albeit limited experience to date, the safety profile in participants treated at a 
dose level of 2400 mg every 3 weeks appears to be consistent with the safety profile in patients 
treated at lower doses. 
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In addition, currently available safety data on bintrafusp alfa in combination with chemotherapy 
indicated no increased risks compared to what can be expected from current experience with 
chemotherapy and bintrafusp alfa alone. 
2.3 
Benefit/Risk Assessment  
Bintrafusp alfa, a first-in-class bifunctional fusion protein that targets the tumor 
microenvironment where it blocks both the cell intrinsic programmed cell death protein 1 
(PD-1)/PD-L1 interaction and the immunosuppressive TGFβ, is hypothesized to be more 
effective than agents that target only a single pathway. With the clinical activity of bintrafusp 
alfa observed in a number of tumor types, including NSCLC, biliary tract cancer, cervical cancer, 
and TNBC, together with the safety profile that appears to be manageable given the advanced 
disease of the studied populations, the benefit/risk evaluation is considered favorable to conduct 
this rollover study. The emerging safety profile of bintrafusp alfa across tumor types is 
manageable and consistent with other therapies targeting either PD-L1 (Brahmer 2012, 
D’Angelo 2018 and Kelly 2018) or TGFβ pathways (mainly referencing Phase I fresolimumab 
clinical study; Morris 2014). The risks of bintrafusp alfa are classified as presented in Table 2.  
The data review outcome from the 3 randomized controlled studies in NSCLC and BTC 
(MS200647_0037 [NCT03631706], MS200647_0055 [NCT04066491] and MS200647_0005 
[NCT03840902]), which have been discontinued in the course of 2021, appears to indicate, 
consistently across 2 indications, either poorer observed hazard ratios for progression free 
survival (PFS) and OS in the experimental arms with bintrafusp alfa or low likelihood for 
bintrafusp alfa to add benefits compared to standard of care. No new safety signal has been 
identified. The data review also showed that cases of early progression and death (i.e., within 
60 days after start of treatment) were observed more frequently with bintrafusp alfa: 16 patients 
(10.6%) versus 9 patients (5.9%) in NSCLC Stage IV first line (bintrafusp versus 
pembrolizumab, MS200647_0037); 11 patients (7.5%) versus 2 patients (1.3%) in BTC first line 
(bintrafusp in combination with chemotherapy versus placebo plus chemotherapy, 
MS200647-0055); immature data with 3 patients (4.1%) versus 2 patients (2.6%) in NSCLC 
Stage III (bintrafusp plus concurrent chemoradiation followed by bintrafusp maintenance versus 
chemoradiation followed by durvalumab, MS200647-0005). Early deaths were due to 
progressive disease, signs and symptoms of progressive disease, or known treatment toxicities. 
Two types of participants will be eligible for this study: participants on treatment with bintrafusp 
alfa in an eligible parent study after the primary/main analysis has been completed, and 
participants who have discontinued treatment in an eligible parent study and are reinitiating 
treatment in this rollover study (provided that the parent protocol allows reinitiation of 
treatment). Participants continuing treatment in the rollover study and demonstrating benefit 
from the active treatment will be transferred from the parent study to this rollover study. 
Participants reinitiating treatment in the rollover study have previously demonstrated benefit 
from bintrafusp alfa and reinitiation is deemed a reasonable option that may provide clinical 
benefit. Based on the available nonclinical and clinical data to date, inclusion in the rollover 
study, as specified in this protocol, is considered justifiable for both groups. 
Of note, participants that are reinitiating after discontinuing their prior course of bintrafusp alfa 
treatment due to an adverse event (AE) are required to have that AE completely resolved or well 
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Identified and Potential 
Risks of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Human transforming 
growth factor β (TGFβ) 
inhibition mediated skin 
reactionsa 
TGFβ inhibition mediated skin reactions are 
important identified risks because 
neutralization of TGFβ by bintrafusp alfa 
may induce the development of skin lesions 
such as hyperkeratosis, keratoacanthoma, 
cutaneous squamous cell carcinoma 
(Lacouture 2015). Such skin lesions have 
indeed been observed in the clinical studies 
with bintrafusp alfa, but not in patients 
treated with the anti-PD L1 antibody 
avelumab. Thus, it is plausible that skin 
tumors observed in patients treated with 
bintrafusp alfa may be related to the TGFβ 
signal pathway inhibition.   
Monitoring will include skin 
assessments as defined in the 
Schedule of Activities (see Table 
1). 
Management of TGFβ inhibition 
mediated skin reactions is 
described in Section 8.3.6.3. 
Anemia 
Anemia is considered an important 
identified risk. Toxicological findings with 
bintrafusp alfa in cynomolgus monkey 
indicated a decrease in hemoglobin, red 
blood cell count, and hematocrit. This 
decrease was fully reversible or showed 
trend towards recovery after treatment 
discontinuation. These nonclinical findings 
were also observed in clinical studies. The 
mechanism for the effect remains to be fully 
elucidated, however, the occurrence of 
hemorrhages may contribute to the 
observed effect. 
Management of anemia is 
described in Section 8.3.6.4. 
Bleeding adverse events 
Bleeding adverse events are considered 
important identified risk. Participants treated 
with bintrafusp alfa were commonly 
reported with mild to moderate mucosal 
adverse events such as epistaxis, 
hemoptysis, gingival bleeding and 
hematuria, and in lower frequencies, with 
Grade ≥ 3 hemorrhages including tumor 
bleeding. Other TGFβ inhibitors like 
fresolimumab are also known to be 
associated with bleeding (Morris 2014; 
Vincenti 2017). No bleeding events were 
observed during the nonclinical studies with 
bintrafusp alfa. 
Management of bleeding adverse 
events is described in 
Section 8.3.6.5. 
Identified Risks 
 
 
Infusion-related reactions 
Infusion-related reactions (IRRs) are known 
class effects of monoclonal antibodies 
including anti PD-L1 antibodies and have 
been observed in the clinical studies with 
bintrafusp alfa. However, the frequency and 
severity of IRRs was relatively low, and no 
premedication is required to prevent the 
occurrence of IRRs. Therefore, IRRs are 
classified as identified (non-important) risk. 
Special precautions and 
management of IRRs and 
immediate hypersensitivity 
reactions are described in 
Section 8.3.6.1. 
Important Potential Risks 
 
 
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Identified and Potential 
Risks of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Immune-related adverse 
events (irAEs) 
• Guillain-Barré syndrome 
• Uveitis 
• Pancreatitis 
• Myasthenia 
gravis/myasthenic 
syndrome 
irAEs like Guillain-Barré syndrome, uveitis, 
pancreatitis and myasthenia 
gravis/myasthenic syndrome have not been 
observed for bintrafusp alfa in the pooled 
monotherapy studies and are therefore 
considered as important potential risks, as 
these are known risks of the therapeutic 
drug class of anti-PD-1/anti-PD-L1 
antibodies including avelumab. 
Management of irAEs and 
instructions for study treatment 
discontinuation or interruption in 
case of irAEs is described in 
Section 8.3.6.2. 
Impaired wound healing 
Impaired wound healing is considered as 
an important potential risk (a theoretical risk 
based on literature findings) for bintrafusp 
alfa, given the role of TGFβ in wound 
healing, repair of skin and other tissue 
injuries (Pakyari 2013). 
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.  
Embryofetal toxicity 
Embryofetal toxicity is a known risk of anti-
PD-1/anti-PD-L1 antibodies, and therefore 
considered as important potential risk 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. 
An appropriate contraception 
warning is provided as part of the 
inclusion criteria. Participants with 
pregnancy or in lactation are 
prohibited from enrolling in 
bintrafusp alfa clinical trials and 
adequate contraceptive measures 
are recommended during the study 
to minimize or eliminate the 
potential risk to the developing 
fetus. 
for any serious events, an SAE Report Form has to be used (see Section 8.3.4). 
2.3.2 
Benefit Assessment  
Participants who will be enrolled in the rollover study to continue bintrafusp alfa treatment have 
been receiving bintrafusp alfa for a prolonged period of time in the parent study without toxicities 
requiring permanent treatment discontinuation, while experiencing clinical benefit from the 
treatment. 
The clinical activity of bintrafusp alfa is further summarized in the IB. 
2.3.3 
Overall Benefit/Risk Conclusion  
Participants enrolled in parent protocols with bintrafusp alfa treatment underwent benefit/risk 
assessments and, by means of their eligibility to participate in this rollover study, have an 
expected overall positive benefit from continuation or reinitiation of bintrafusp alfa treatment. 
Given the observed clinical activity of bintrafusp alfa in patients with a number of tumor types 
and the manageable safety profile observed in more than 700 participants in the Phase I and 
Phase II studies, the benefit/risk assessment is considered favorable to conduct this study. 
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4 
Study Design  
4.1 
Overall Design  
Study Design 
Open-label, single arm, rollover 
Control Method 
None 
Single or Multicenter 
Multicenter 
Control Group 
Not applicable 
Study Population Type 
Patients with solid tumor; see Sections 5.1 and 5.2. 
Participants can be transferred from their respective parent 
bintrafusp alfa study to this rollover study once the 
primary/main analysis in the parent study has been completed or 
after discontinuation of study before primary/main analysis has 
been completed. Participants may also be transferred upon 
Sponsor decision in case the parent study is terminated for any 
reason as specified in the parent study protocol and there is a 
medical need for participants to continue to be treated with 
bintrafusp alfa that cannot be otherwise supplied. The final 
decision whether to transfer participants from the parent study 
rests with the Sponsor. 
A full list of bintrafusp alfa clinical studies from which 
participants may be potentially enrolled after completion of the 
primary analysis or after discontinuation of study before 
primary/main analysis is provided in Appendix 10. 
Level and Method of 
Blinding 
Open-label 
Bias Minimalization 
Method(s) 
Not applicable 
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Study Intervention 
Assignment Method 
For participants who are continuing treatment with bintrafusp alfa 
and were previously assigned to a bintrafusp alfa dose based on 
body weight (i.e., a mg/kg dose) in a parent protocol, the Sponsor 
recommends switching to a flat dose of bintrafusp alfa 1200 mg 
every 2 weeks as they enroll in the rollover study, after 
consultation with the Sponsor Medical Lead. However, 
participants still on active treatment in their respective parent 
study may, if considered appropriate by the Investigator, opt to 
continue treatment at their ongoing dose level as they enter this 
rollover study, with treatment as follows: 
• Bintrafusp alfa administered on Day 1 of a 2-week cycle at the 
dose specified based upon the participant’s parent protocol and 
treatment assignment. 
OR 
• Bintrafusp alfa administered on Day 1 of a 3-week cycle at a 
dose of 2400 mg. 
Participants who are entering the rollover study after 
discontinuation of treatment in a parent study will reinitiate 
bintrafusp alfa as a monotherapy following the same treatment 
schedule as specified in their original parent protocol. These 
participants will reinitiate treatment as either: 
• Bintrafusp alfa administered on Day 1 of a 2-week cycle at a 
dose of either 1200 or 2400 mg 
OR 
• Bintrafusp alfa administered on Day 1 of a 3-week cycle at a 
dose of 2400 mg. 
Restarting treatment as a combination will not be allowed 
Involvement of Special 
Committee(s): 
No. 
Total Duration of Study 
Participation per 
Participant 
All participants in this rollover study will be treated with 
bintrafusp alfa until meeting criteria for discontinuation (see 
Section 7.1), until study intervention is commercially accessible 
and provisioned via marketed product, or until end of study (see 
Section 4.4). The study also includes a 5 years survival 
follow-up after last dose of the study treatment. 
Provisions for Study 
Extension or Entry into 
Rollover Studies 
This is a rollover study and it is designed to provide continuous 
access to treatment with bintrafusp alfa for eligible participants 
from ongoing bintrafusp alfa parent studies, and to collect 
long-term safety and efficacy data.  
Adaptive Aspects of 
Study Design 
Not applicable 
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4.2 
Scientific Rationale for Study Design  
Although not yet approved in any country, bintrafusp alfa has demonstrated meaningful clinical 
activity across various tumor types and treatment settings. In recent years checkpoint inhibitors 
have been increasingly used in clinical practice based on superior efficacy and manageable safety 
profile. Regardless of the tumor type or previous anticancer treatments, responses with bintrafusp 
alfa appear durable in nature, including ongoing responses > 1 year in several of the cohorts in 
parent studies. Overall, many responses were still ongoing at the time of database lock of parent 
studies.  
Enrollment in this study will provide continuous access to bintrafusp alfa treatment for 
participants from parent studies who may experience long-term clinical benefit. Collection of 
safety data for these participants will provide valuable information to physicians regarding the 
safety of prolonged treatment with bintrafusp alfa. Participants to be enrolled in this study have 
been on active bintrafusp alfa treatment without major toxicities requiring treatment 
discontinuation; therefore, from a long-term perspective it is considered appropriate to continue 
collection of treatment-related AEs. 
Overall survival is the most reliable efficacy endpoint in oncology studies to demonstrate 
treatment benefit in cancer subjects. Long-term OS data collection will be continued for 
participants in this study to further support clinical development of bintrafusp alfa. 
4.2.1 
Participant Input into Design  
Not applicable. 
4.3 
Justification for Dose  
In this rollover study, the doses and treatment schedules for bintrafusp alfa (administered as an 
intravenous [IV] infusion) were selected based on those used in the parent studies and include 
the following: 
• On Day 1 of a 2-week cycle at either a) the flat dose of 1200 mg or b) the dose specified 
based upon the participant’s parent protocol and treatment assignment. 
• On Day 1 of a 3-week cycle at a flat dose of 2400 mg. 
For participants who are continuing treatment with bintrafusp alfa and were previously assigned 
to a bintrafusp alfa dose based on body weight (i.e., a mg/kg dose) in a parent protocol, the 
Sponsor recommends switching to a flat dose of bintrafusp alfa 1200 mg every 2 weeks as they 
enroll in the rollover study, in consultation with the Sponsor Medical Lead. However, 
participants still on active treatment in their respective parent study may, if considered 
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appropriate by the Investigator, opt to continue treatment at their ongoing dose level as they enter 
this rollover study. 
Participants who are entering the rollover study after discontinuation of treatment in a parent 
study will restart bintrafusp alfa as a monotherapy at either 1200 mg or 2400 mg following the 
same treatment schedule as specified in their original parent protocol. 
These doses for bintrafusp alfa were selected based on safety/tolerability, pharmacokinetics 
(PK), pharmacodynamics (PD-L1 target occupancy in peripheral blood mononuclear cell and 
TGFβ plasma concentrations), and efficacy data in the parent studies, as well as population PK 
and exposure-response modeling and simulations.  
The 1200 mg every 2 weeks dose selection was based on the recommended Phase II dose for 
bintrafusp alfa, and the 2400 mg every 3 weeks dose selection was based on modeling and 
simulation data indicating this dose maintains target efficacious Ctrough,ss of bintrafusp alfa. 
Additionally, assessment of potential PK interactions and overlapping toxicities with 
chemotherapies was conducted to support 2400 mg every 3 weeks dose of bintrafusp alfa in the 
parent combination studies. Since most chemotherapies are administered every 3 weeks, the 
same dosing interval for bintrafusp alfa was preferred for convenience and compliance in the 
parent combination studies.  
Refer to the IB for additional details and data for dose justification. 
4.4 
End of Study Definition  
A participant has completed the study if he/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 of the last scheduled procedure shown in the SoA for 
the last participant in the study and when there are no other eligible parent studies ongoing from 
which participants could enroll in this rollover study. 
The survival follow-up will continue until up to a maximum of 5 years after the last participant 
receives the last dose of bintrafusp alfa. This duration may be shortened at the discretion of the 
Sponsor for any given indication. 
The Sponsor may terminate the study at any time once access to study intervention for 
participants still benefiting is provisioned via marketed product or another mechanism of access 
as appropriate. See also Appendix 2 for study and site closure. 
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 are considered when deciding whether a participant is suitable for this 
study. 
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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 
Study Governance. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Category 
Criterion 
Age 
1.  Are ≥ 18 years of age at the time of signing the informed consent. 
In Japan, if a participant is at least 18 but < 20 years of age, written 
informed consent from his/her parent or guardian will be required 
in addition to the participant’s written consent. 
Type of Participant 
and Disease 
Characteristics 
2. Are participants currently enrolled in an eligible bintrafusp alfa 
parent study (see Appendix 10) where the primary/main analysis has 
been completed or after discontinuation of study before primary/main 
analysis has been completed and who: 
• 
Are currently on active bintrafusp alfa treatment (alone as a monotherapy or 
following discontinuation of other combination treatment agents) in the parent 
study and without treatment interruption at the time of rollover study enrollment, 
OR. 
• 
Experienced a confirmed CR, PR, or SD in an eligible parent study, 
discontinued bintrafusp alfa treatment according to the parent study protocol, 
and subsequently developed disease progression and are willing to re-start 
bintrafusp alfa treatment deemed potentially beneficial by the participants’ 
physicians OR 
• 
Discontinued from bintrafusp alfa treatment in an eligible parent study due to an 
AE(s) that was subsequently well controlled or completely resolved after 
stopping therapy, provided that the parent study protocol permits reinitiation of 
bintrafusp alfa if a participant discontinued treatment due to toxicity and these 
participants are willing to re-start bintrafusp alfa treatment deemed potentially 
beneficial by the participants’ physicians. Participants who have had AEs 
requiring permanent treatment discontinuation, like certain irAEs or certain 
bleeding events (see Sections 6.8 and 2.3.1 for details) are excluded from 
participation in this Rollover study. 
Note: Prior to treatment reinitiation, the Investigator, in consultation with the study 
Medical Monitor as needed, must confirm that the benefit of reinitiating treatment 
outweighs any risk involved, including that which led to the prior treatment 
discontinuation. For participants with only SD at the time of discontinuation, the 
Investigator should confirm that no other reasonable treatment options are 
available. 
• 
Have completed End of treatment (EoT) assessment of a parent study. 
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Category 
Criterion 
Sex and 
Contraception/Barrier 
Requirements 
3. 
The allowed sex/sexes for the study:  
• 
Male 
• 
Female 
The investigator confirms that each participant agrees to use 
appropriate 
contraception 
and 
barriers, 
if 
applicable. 
The 
contraception, barrier, and pregnancy testing requirements are below.  
For female participants of childbearing potential or for male 
participants who have female partners of childbearing potential, the 
following applies: 
Participants on active treatment must agree to continue to use highly 
effective contraception (i.e., methods with a failure rate of less than 
1% per year; see Appendix 3) for both male and female participants 
if the risk of conception exists (Note: The effects of the study 
intervention on the developing human fetus are unknown (refer to 
Section 2.3.1); thus, women of childbearing potential and men must 
agree to use highly effective contraception as stipulated in national 
or local guidelines). Highly effective contraception must be used 28 
days prior to the first study intervention administration, for the 
duration of study intervention, and at least for 2 months (for female 
participants) or 4 months (for male participants) after stopping study 
intervention. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, the 
treating physician should be informed immediately. 
Informed Consent 
4. 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. 
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5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Category 
Criterion 
Medical Conditions 
1. Pregnancy or currently in lactation 
2. Known hypersensitivity to any of the study intervention 
 
ingredients. 
Prior/Concomitant 
Therapy 
3. For participants reinitiating treatment with bintrafusp alfa at 
study entry: have received any systemic anticancer 
therapies/treatments since discontinuing bintrafusp alfa treatment. 
4. Concurrent treatment with prohibited drugs (see Section 6.5.3) 
Prior/Concurrent 
Clinical Study 
Experience 
5. Participant has withdrawn consent from the parent study for 
any reason 
Other Exclusions 
6. Any other reason that, in the opinion of the Investigator, 
precludes the participant from participating in the study. 
5.3 
Lifestyle Considerations  
5.3.1 
Meals and Dietary Restrictions  
There are no dietary restrictions. 
5.4 
Screen Failures  
The Investigator will maintain an eligibility log to record details of all participants, to confirm 
eligibility, and if applicable, record reasons for exclusion. 
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  
Bintrafusp alfa will be administered as a monotherapy in this rollover study (see Table 4). 
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Table 4 
Study Intervention  
Intervention Name 
Bintrafusp alfa 
Type  
Drug 
Dose 
Formulationa 
Sterile concentrate solution for infusion 
Unit Dose 
Strength(s) 
10 mg/mL in single-use glass vials (600 mg provided per vial) 
Dose Amount 
• 
1200 mg 
• 
2400 mg 
• 
Other dose amount as specified in the participant’s parent protocol 
Frequency 
• 
1200 mg: once every 2 weeks 
• 
2400 mg: once every 2 weeks 
• 
2400 mg: once every 3 weeks 
• 
Other dose amount as specified in the participant’s parent protocol: once every 
2 weeks 
Route of 
Administration 
Intravenous infusion 
Dosing 
Instructions 
• 
Flat dose of 1200 mg administered over 1 hour (-10/+20 minutes, i.e., over 50 to 
80 minutes) once every 2 weeks. 
• 
Flat dose of 2400 mg administered over a minimum of 1 hour (-10/+20 minutes) and 
up to 2 hours (-10/+20 minutes) once every 3 weeks. 
• 
Flat dose of 2400 mg administered over a minimum of 1 hour (-10/+20 minutes) and 
up to 2 hours (-10/+20 minutes) once every 2 weeks 
• 
Other dose amount, as specified in the participant’s parent protocol, administered 
over 1 hour (-10/+20 minutes, i.e., over 50 to 80 minutes) once every 2 weeks. 
Use 
Experimental 
Sourcing 
Provided centrally by the Sponsor  
Packaging and 
Labeling 
Study Intervention will be provided in vial. Each vial will be packaged and labeled per all 
applicable regulatory requirements and Good Manufacturing Practice Guidelines. 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability  
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
• Upon receipt of the study intervention(s), the Investigator or designee will 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) will be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, per the labeled storage conditions, 
and with access limited to the Investigator and authorized site staff. 
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• 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. 
• 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 for study 
interventions prepared at the site, and the participant numbers. 
• The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study intervention(s) provided 
were fully reconciled. 
• Unused study intervention(s) will 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. 
• 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 for the destruction process. 
• A Study Monitor will periodically collect the study intervention(s) accountability forms. 
• Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Pharmacy Manual 
• Bintrafusp alfa should be stored in a refrigerator (2°C to 8°C) 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  
Sites will be required to discontinue participants in the parent study Interactive Web Response 
System (IWRS) before contacting the rollover study IWRS for enrollment. The rollover study 
IWRS will assign new unique patient identifiers number to participants in chronological order at 
the time of informed consent signature for parent study participants continuing in the rollover 
study. 
6.3.2 
Blinding  
Blinding Method 
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This is an open-label, single-arm study; thus, study intervention is not blinded to participants or 
Investigators. 
Assignment Method Retention 
Not applicable, as this is an open-label study and blinding will not be used. 
6.3.3 
Emergency Unblinding  
Not applicable. 
6.4 
Study Intervention Compliance  
In this study, participants will receive study intervention at the study site. When participants are 
dosed at the site, they will receive study intervention directly from the Investigator or designee, 
under medical supervision. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the electronic case report form (eCRF). The 
dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. 
A record of the number of bintrafusp alfa vials dispensed to and taken by each participant will 
be maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded in the CRF. 
Noncompliance is defined as a participant missing > 1 consecutive 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 6 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 CRF all concomitant therapies (e.g., medicines or nondrug interventions) used 
from the time the participant signs the informed consent until completion of the study, including 
any changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information. 
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the electronic eCRF, noting 
the name, dose, duration, and indication of each drug. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
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6.5.1 
Rescue Medicine  
Not applicable 
6.5.2 
Permitted Medicines  
The only permitted medications are the following: 
1. Any medications (other than prohibited in Section 6.5.3) 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 8.3.6). Note that premedication 
should be administered prior to bintrafusp alfa dosing and should be based upon clinical 
judgment and presence and severity of prior infusion reactions 
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. 
6.5.3 
Prohibited Medicines  
The following treatments must not be administered within 14 days before the start of study 
intervention or throughout 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 (prior administration of 
bintrafusp alfa in an eligible parent study within 14 days before enrollment in this rollover 
study is allowed). 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, for prophylaxis and 
management of radiographic contrast allergy or the management of irAEs and other AEs) 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. 
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• Concomitant local or regional treatment (radio/chemo-embolization) is prohibited. 
• Other systemic anti-cancer therapy. 
• Live vaccines are prohibited. Administration of inactivated vaccines (e.g., inactivated 
influenza vaccines) or approved SARS-COV-2 vaccines is allowed. 
• 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. 
• 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. 
6.5.4 
Other Interventions  
Palliative organ-sparing radiotherapy may be administered only for specific clinical indications 
during the study treatment period. The assessment of progressive disease (PD) will be made 
according to RECIST v1.1 and not based on the necessity for palliative radiotherapy. 
6.6 
Dose Selection and Modification  
The doses and treatment schedules for bintrafusp alfa in this study were selected based on those 
used in the parent studies (see Section 4.1, Section 4.3, and Section 6.1 for details). 
For participants who are continuing treatment with bintrafusp alfa and were previously assigned 
to a bintrafusp alfa dose based on body weight (i.e., a mg/kg dose) in a parent protocol, the 
Sponsor recommends switching to a flat dose of bintrafusp alfa 1200 mg every 2 weeks as they 
enroll in the rollover study, in consultation with the Sponsor Medical Lead. Otherwise, dose 
modification of bintrafusp alfa is not allowed except for management of bleeding AEs. 
Modifications of the infusion rate due to IRRs are described in Section 7.1. 
Doses cannot be delayed beyond the treatment window (± 3 days). Participants must skip the 
dose if the treatment window is missed. Every attempt should be made to perform applicable 
assessments in Table 1 for any missed visits. Complete the next visit following the SoA 
(see Table 1). 
6.7 
Reinitiation Criteria  
For participants who discontinue bintrafusp alfa treatment during this rollover study, one 
reinitiating course of treatment at the same dose and schedule is allowed at the discretion of the 
Investigator and with agreement of the Study Medical Responsible: 
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• Participants who enter into this rollover study on active treatment will be eligible for one 
reinitiating course of treatment during this rollover study, regardless of whether or not they 
reinitiated treatment in a parent study. 
• Participants who reinitiate treatment with bintrafusp alfa at study entry into this rollover study 
will be eligible for one more reinitiation (second reinitiation) if treatment is discontinued 
during this rollover study. 
The following participants are eligible for reinitiation: 
• Participants who are experiencing a CR, a PR, or SD at the time of treatment discontinuation 
in the rollover study, and then subsequently develop disease progression after stopping 
therapy, but prior to the end of the study. 
• Participants who discontinue from treatment in the rollover study due to an AE that is 
subsequently well managed or resolved, as assessed by the Investigator, 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 Section 1.3). 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 SD 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 study 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 intervention. Additionally, 
relevant safety laboratory assessments, including both full hematology and full chemistry results 
within 2 weeks, must be available and verified. The clinical Investigator will determine whether 
additional evaluation and work-up are required on a case-by-case basis. 
6.8 
Study Intervention after the End of the Study  
After a participant has completed the study, has withdrawn consent, or has been withdrawn early, 
no further treatment is foreseen within the scope of this protocol. If required and in accordance 
with the study site’s SOC, symptom-guided appropriate treatment may be administered per the 
generally accepted medical practice and depending on the participant’s individual medical needs. 
On withdrawal from the study, participants may receive care they and their physicians agree 
upon. 
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7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
Duration of study intervention/criteria for treatment discontinuation will follow guidelines stated 
in the respective parent protocols. 
Participants from all studies except for Study MS200647_0005: 
Participants (except those from Study MS200647_0005) who have experienced a confirmed CR 
should continue treatment for a maximum of 24 months after confirmation of response (at the 
discretion of the Investigator). If the Investigator believes that a participant with confirmed CR 
may benefit from treatment beyond 24 months, it may be permissible to continue treatment after 
discussion with the Medical Monitor and the Sponsor’s Medical Responsible. 
Participants with SD or PR who are receiving bintrafusp alfa should continue treatment until 
meeting criteria for discontinuation. 
Participants from Study MS200647_0005: 
For participants from Study MS200647_0005, study intervention will continue until 
unacceptable toxicity, confirmed PD assessed by Investigator (unless participant meets the 
criteria for study intervention beyond progression), or for up to 26 doses in total across both the 
MS200647_0005 parent and MS200647_0054 rollover studies since the completion of cCRT 
doses in the MS200647_0005 parent study, whichever occurs first. 
All Participants: 
Participants may be discontinued from study intervention for any of the following reasons, one 
reinitiating course of treatment may be allowed (see Section 6.7): 
• 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 that is clinically relevant and affects the participant's 
safety, OR 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 (e.g., disruption of operations due to natural 
disasters, interruption of laboratory or facility accreditation, participant moving to another 
country, resignation of key staff). (See Sections 7.1 and Section 8.3.6 for TEAEs and AESIs 
that require treatment discontinuation). 
• PD per RECIST v1.1, with the exception that participants receiving treatment may continue 
post PD if the participant’s Eastern Cooperative Oncology Group Performance Status (ECOG 
PS) has remained at least stable, and if in the opinion of the Investigator, the participant will 
benefit from continued treatment (See Section 7.1.2). 
• Unacceptable toxicity 
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• Drug must not be given to a known pregnant participant (see to Appendix 3) 
• Use of a prohibited concomitant drug, as defined in Section 6.5.3 if discontinuation is 
considered necessary by Investigator/Sponsor. 
Any treatment-emergent AE, especially of Grade 4 or recurrent event of Grade 3, that is assessed 
as related to bintrafusp alfa may require treatment interruption or permanent discontinuation of 
bintrafusp alfa treatment. 
Grade 4 treatment-related TEAEs: Any Grade 4 treatment-related TEAEs require permanent 
treatment discontinuation, except: 
a. Endocrinopathies that have been controlled by hormone replacement, 
b. 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, 
c. If an alternative explanation is identified for Grade 4 non tumor bleeding. 
Grade 3 treatment-related TEAEs: Participants with any recurrent Grade 3 treatment-related 
TEAEs should be permanently discontinued. Exceptions may be considered for the following 
after discussion with Medical Monitor (see also relevant management guidance sections): 
a. Transient Grade 3 flu-like symptoms or fever that is controlled with medical 
management. 
b. Transient Grade 3 fatigue, local reactions, headache, nausea, emesis that 
resolves to Grade ≤ 1 or baseline. 
c. Tumor flare phenomenon defined as local pain, irritation, or rash localized at 
sites of known or suspected tumors. 
d. Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis. 
e. Grade 3 hemoglobin (Hgb) decrease (< 8.0 g/dL) that is clinically manageable 
with blood transfusions or erythroid growth factor use. 
f. Increases 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). 
g. Keratoacanthoma (KA) and cutaneous squamous cell carcinoma (cSCC). 
h. 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.).  
If persistent Grade 3 treatment-related AEs (excluding endocrinopathies controlled with 
hormone replacement therapy) either do not resolve or improve to Grade 1 within 12 weeks after 
last dose of study intervention, treatment must be permanently discontinued. If a Grade 2 
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treatment-related TEAE improves to Grade ≤ 1 or completely resolves by the day before the next 
infusion, study intervention may be continued. 
Grade 2 treatment-related TEAE 
If a Grade 2 treatment-related TEAE does not improve to Grade 1 or completely resolve 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. In any case, if ≥ 2 doses are missed due to AE, the Medical Monitor should be 
consulted. 
Immune-related AEs, IRRs, anemia, TGFβ inhibition mediated skin reactions, and 
bleeding AEs  
Permanent study intervention discontinuation may be recommended, so the relevant section must 
be reviewed: 
• For suspected irAEs, general guidance and management are provided in Section 8.3.6.2. 
Recommended guidance and management for specific irAEs as per published guidelines is 
provided in the current National Comprehensive Cancer Network (NCCN) guideline 
available at http://www.nccn.org.  
• IRR and hypersensitivity reaction management guidance are presented in Section 8.3.6.1. 
• Anemia management guidance is presented in Section 8.3.6.4. 
• TGFβ inhibition mediated skin reactions management guidance is provided in Section 8.3.6.3. 
• For guidance and management of bleeding AEs, see Section 8.3.6.5. 
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for the End of Treatment and Safety Follow-up. The Schedule of activity (see Table 
1) indicates data to be collected at the time of discontinuation of study intervention and follow-
up and for any further 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) for 
further details refer to Table 1. 
• 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 and subsequent anticancer therapy.  
• 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 30-day Safety Follow-up period. 
• Liver Injury: 
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The Investigator will consider discontinuation of study intervention for abnormal liver 
function if the Investigator believes that it is in best interest of the participant. 
• Cardiac changes (e.g., QTc): 
If a clinically significant finding is identified (including changes from baseline in QT 
interval corrected using Bazett’s formula [QTcB] or Fridericia’s formula [QTcF] after 
enrollment, the Investigator or qualified designee will determine if the participant can 
continue in the study and if any change in participant management is needed. This review 
of the electrocardiogram (ECG) printed at the time of collection will be documented. Any 
new clinically relevant finding is reported as an AE. 
7.1.1 
Temporary Discontinuation  
See Sections 7.1 and 8.3.6 for guidance on temporary discontinuation from study intervention.  
7.1.2 
Treatment Beyond Progression  
7.1.2.1 
Treatment Beyond Disease Progression  
Participants will receive bintrafusp alfa as outlined in the SoA (see Table 1) until disease 
progression. Bintrafusp alfa treatment may continue post the initial determination of disease 
progression according to RECIST v1.1 as long as the following criteria are met: 
• 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 (for example, central nervous system 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. 
7.1.2.2 
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 v1.1. 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 or benefit from radiotherapy, 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 v1.1. 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 discontinue from the study at any time, at his/her own request or 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 (see Table 1). The SoA specifies the data to collect at study 
discontinuation and follow-up, and any additional evaluations that need to be completed. In 
any case, the appropriate End of Treatment eCRF visit must be completed. In case of 
withdrawal, subjects will be asked to continue safety and survival follow-up, which includes 
the collection of data on survival and subsequent anticancer therapy. After completion of the 
Follow-up period or after the End of Treatment visit, whatever is applicable, the appropriate 
eCRF section for Trial Termination must be completed. 
• If the participant revokes consent for 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. 
• A participant has the right at any time to request destruction of any biological samples taken. 
The investigator will document this in the site study records and the eCRF and inform the 
Sponsor. The samples will be destroyed. 
• The Investigator will secure the safety of the study participants and make every attempt to 
collect data. If a participant fails to attend the scheduled study assessments, the Investigator 
must determine the reasons and the circumstances as completely and as accurately as 
possible. 
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7.3 
Lost to Follow-Up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions will be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee will make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 
2) if necessary, send a certified letter (or an equivalent local method) to the participant’s last 
known mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner or caretaker (where allowed by local regulations) for 
information. These contact attempts will be documented in the participant’s medical record. 
• If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”. 
8 
Study Assessments and Procedures  
• Study assessments and procedures and their timing are summarized in the SoA (see Table 
1). 
• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All eligibility evaluations will be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain an eligibility log to 
record details of all participants, to confirm eligibility, and if applicable, record reasons for 
exclusion. 
• Prior to performing any study assessments that are not part of the participant’s routine 
medical care, the Investigator will obtain written informed consent as specified in Appendix 
2 Study Governance. 
• Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the informed consent form (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. 
• No more than 15 mL of blood may be drawn in a 24-hour period, and no more than 30 mL 
of blood in a 4-week period. 
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8.1 
Efficacy Assessments and Procedures  
The following secondary efficacy endpoint will be assessed: 
• OS, defined as the time (in months) starting from the baseline date of the parent study to the 
date of death due to any cause. For participants alive at the time of data analysis or who are 
lost to follow-up, OS will be censored at the last recorded date that the participant is known 
to be alive. 
8.1.1 
Tumor Assessments  
For participants continuing on bintrafusp alfa treatment, tumor response assessment will be 
conducted, at a frequency according to site SOC/institutional guidelines, by computed 
tomography (CT) scan or magnetic resonance imaging (MRI) for the same anatomical regions 
as in the parent study. Baseline/nadir tumor assessments from the parent studies (performed 
before the first dose of bintrafusp alfa) will be used for response or progression determination 
according to RECIST v1.1 (see Appendix 11). In general, all lesions detected at the parent study 
baseline should be followed using the same imaging methodology and preferably the same 
imaging equipment at subsequent tumor evaluation visits, if possible, however the frequency of 
assessments should follow site SOC/institutional guidelines. 
For participants reinitiating treatment with bintrafusp alfa at entry into this rollover study (or 
reinitiating treatment after treatment discontinuation in the rollover study; see Section 6.7), new 
baseline tumor assessments will be used to estimate tumor burden and for comparison with 
subsequent measurements. Lesions detected at the parent study baseline should be followed, in 
addition to any new lesions identified in the rebaseline assessment. As a general guidance, it is 
preferable not to select new target lesions, and follow any new lesions presenting at the start of 
this continuation study as non-target lesions. Any new lesions in other anatomic areas, especially 
but not limited to the brain, should be imaged using institutional standard imaging for following 
disease in that region. 
The tumor response assessments will be performed at a frequency according to site 
SOC/institutional guidelines (e.g., every 6 months or 12 weeks), calculated from the last 
assessment performed in the parent study (see Table 1), until PD is assessed by the Investigator 
according to RECIST v1.1, or until 30 days after the end of treatment with bintrafusp alfa, 
whichever occurs later, including for participants who discontinued treatment prior to disease 
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progression, as well as for participants who reinitiate bintrafusp alfa treatment upon entry into 
this rollover study after development of PD in a parent study. 
Treatment decisions will be made by the Investigator based on the Investigator’s assessment of 
tumor status. Tumor lesions will be categorized in target and non-target lesions as described in 
RECIST v1.1 (see Appendix 11). 
Results for these evaluations will be recorded with as much specificity as possible so that 
pre- and post-treatment results will provide the best opportunity for evaluating tumor response 
and/or progression. 
8.1.2 
Follow-up  
For participants without PD according to RECIST v1.1 at treatment discontinuation, sites will 
be asked to continue collection of all available tumor assessments performed according to SOC 
until determination of disease progression. Subsequent anticancer treatment should be 
documented after discontinuation of study intervention. 
Participants will be followed up every 12 weeks (± 2 weeks) for survival and assessment of 
subsequent anticancer therapy. The survival follow-up will continue until a maximum of 5 years 
after the last participant receives the last dose of bintrafusp alfa (see Section 4.4). Under some 
circumstances, participants may not be followed for the entire duration of survival follow-up in 
this study (see also Section 7.3 and Appendix 11). The Sponsor may terminate the study at any 
time once access to study intervention for participants still benefiting is provisioned via marketed 
product or another mechanism of access as appropriate. 
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, ECGs, 
and laboratory tests. The baseline status and medical history of the participant is assessed at the 
baseline of the respective parent study. 
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. 
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).  
Ongoing events at the 12-week Safety Follow-up visit should continue to be monitored and 
documented until resolution or resolution with sequelae. All 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 
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the Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. 
If a liver function test is elevated in a Hepatitis B virus (HBV) or Hepatitis C virus (HCV) 
positive participant, HBV DNA or HCV ribonucleic acid (RNA) must be monitored to exclude 
the possibility of reactivation of viral hepatitis. In case of viral reactivation, follow the HBV and 
HCV management guidelines. 
8.2.1 
Physical Examinations  
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
• A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
• Investigators will 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. 
8.2.2 
Vital Signs  
• Height (at screening visit only) and weight on screening and per SoA on subsequent study 
visits as described in Table 1 will be measured and recorded. 
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed per SoA as 
described in Table 1. 
• Blood pressure and pulse measurements will be assessed in semi supine position with a 
completely automated device. Manual techniques will be used only if an automated device 
is not available. 
• Blood pressure and pulse measurements will be recorded in semi supine position by at least 
5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, 
cell phones) and measured with an automated device. Manual techniques will be used only 
if an automated device is not available. 
• Blood oxygen saturation (SpO2) will be measured with a pulse oximeter and recorded in the 
eCRF. 
8.2.3 
Electrocardiograms  
• Single 12-lead ECG 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 will be clearly identified.  
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• 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 will receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study will be forwarded to the Sponsor or 
designated organization. 
The Investigator will review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports will be filed with the source documents. 
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8.3 
Adverse Events and Serious Adverse Events  
The definitions of an AE and a SAE are in Appendix 4 Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up and Reporting. 
The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. The 
Investigator remains responsible for following up AEs that are serious or that caused the 
participant to discontinue the study intervention as specified in Section 8.3.3. 
Requests for follow-up will usually be made via the Study Monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information  
• All AEs will be collected from the signing of the ICF until 90 days as specified in the SoA.  
• All SAEs will be collected from the signing of the ICF until 90 days of last dose of the study 
treatment at the time points specified in the SoA (Table 1). Beyond this reporting period, any 
new unsolicited SAEs that the Investigator spontaneously reports to the Sponsor will be 
collected and processed. 
• All SAEs will be recorded and reported to the Sponsor or designee immediately and under 
no circumstance will this exceed 24 hours, as indicated in Appendix 4. The Investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available using the 
same procedure that was used for the initial report. 
• Investigators are not obligated to actively solicit AEs or SAEs after the end of study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator will 
promptly notify the Sponsor. 
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. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are in Appendix 4. 
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8.3.3 
Follow-up of Adverse Events and Serious Adverse Events  
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and AESIs (as defined in Section 8.3), will be followed 
until resolution, stabilization, the event is otherwise explained, or the participant is lost to 
Follow-up (as defined in Section 7.3). Reasonable attempts to obtain this information will be 
made and documented. It is also the Investigator’s responsibility to ensure that any necessary 
additional therapeutic measures and Follow-up procedures are performed. Further information 
on Follow-up procedures is in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events  
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening 
and deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
Individual Case Safety Reports will be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators, as necessary. 
An Investigator who receives an Individual Case Safety Report describing a SUSAR or other 
specific safety information (e.g., Emerging Safety Issue Report, summary or listing of 
SAEs/SUSARs) from the Sponsor will review and then file it along with the IB in the 
Investigator’s Site File and will notify the IRB/IEC, if appropriate according to local 
requirements. 
In this global clinical multicenter study, the Sponsor is in the best position to determine an 
unanticipated problem (as defined in US Regulations 21 CFR 312.66). The Sponsor will 
immediately notify all Investigators 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. An unanticipated problem is a SAE that by its nature, incidence, severity, or 
outcome has not been identified in the current version of the risk analysis report, specified in 
Section 2.3. 
8.3.5 
Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the outcome of the 
pregnancy is known. 
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• If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of 
learning of the pregnancy and will follow the procedures specified below for collection of 
pregnancy information. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner, who becomes pregnant while the participant is in this study. 
• After obtaining signed consent from the pregnant female partner directly, the Investigator 
will record the pregnancy information on the appropriate form and submit it to the Sponsor 
within 24 hours of learning of the pregnancy. The female partner will also be followed to 
determine the outcome of the pregnancy. Information on the status of the mother and child 
will be forwarded to the Sponsor. Generally, the Follow-up will be no longer than 6 to 
8 weeks following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
Female Participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect Follow-up information on the participant and the neonate, and the information 
will be forwarded to the Sponsor. Generally, Follow-up will not be required for longer than 
6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be 
reported, regardless of fetal status (presence or absence of anomalies) or indication for the 
procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as specified in Section 8.3.4. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
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8.3.6 
Management of Adverse Events of Special Interest  
Adverse events of special interest (AESIs) are serious or nonserious AEs that are of clinical 
interest and should be closely followed. 
For this study, AESIs include only the following: 
• Infusion-related reactions including immediate hypersensitivity. 
• Immune-related adverse events. 
• TGFβ inhibition mediated skin reactions. 
• Anemia. 
• Bleeding AEs. 
8.3.6.1 
Infusion-related Reactions Including Immediate 
Hypersensitivity  
Infusion-related reactions, including immediate hypersensitivity, are defined in this section. 
IRRs are AESIs and identified risks for bintrafusp alfa. 
Infusion-Related Reactions 
Infusion-related reactions are signs or symptoms experienced by participants during study 
intervention administration or within 1 day thereafter. An assessment for possible IRR should be 
triggered based on the clinical picture and temporal relationship to drug administration.  
Possible IRRs are defined based on following 2 lists of Medical Dictionary for Regulatory 
Activities (MedDRA) Preferred Terms (PTs) and temporal relationship criteria. Events are 
divided into reactions versus signs and symptoms: 
• Reactions 
include 
the 
PTs 
Infusion-Related 
Reaction, 
Drug-Hypersensitivity, 
Hypersensitivity, Type-1-Hypersensitivity and Anaphylactic Reaction. These PTs should be 
considered when onset is during the infusion or within 1 day thereafter.   
• Signs and symptoms of infusion-related reactions include the PTs Pyrexia, Chills, Flushing, 
Hypotension, Dyspnea, Wheezing, Back Pain, Abdominal Pain and Urticaria. These PTs 
should be considered, if the onset occurs during or within 1 day after an infusion and resolves 
within 2 days. 
Management of Infusion-Related Reactions 
Current experience in more than 700 study participants revealed that IRRs to bintrafusp alfa 
occur seldomly and are generally mild to moderate in severity. Therefore, administration of a 
premedication is generally not required.  
If an investigator deems necessary to administer a premedication prior to bintrafusp alfa infusion 
to a particular participant, an antihistamine (e.g., 25 to 50 mg diphenhydramine) and paracetamol 
(acetaminophen, 500 to 650 mg intravenously or equivalent oral dose) is recommended. 
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Premedication should be administered based upon clinical judgment and presence/severity of 
prior infusion reactions. This regimen may be modified based on local treatment standards and 
guidelines as appropriate provided it does not include systemic glucocorticoids. 
Management of symptoms should follow the guidelines shown in Table 5. 
Table 5 
Treatment Modification Guidance for Symptoms of Infusion-Related 
Reactions Including Immediate Hypersensitivity  
NCI-CTCAE v5.0 Grade 
Treatment Modification  
Grade 1 – mild 
Mild transient reaction: in general, 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. 
Hold infusion if deemed necessary by the Investigator. 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 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  
Increase monitoring of vital signs as medically indicated 
as participants are deemed medically stable by the 
attending Investigator.  
If symptoms resolve quickly, 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 not improving, consider administration of 
glucocorticoids and stop the infusion for that day. 
If the participant has a second IRR Grade ≥ 2 on the 
slower infusion rate despite premedication, the infusion 
should be stopped and the investigator may consider 
withdrawal of this participant from the study. 
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- 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 
For Grade 3 or 4 IRRs, permanent discontinuation of 
study intervention is mandated. 
Once the infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain decreased for all 
subsequent infusions.  
For all types and grades of infusion reactions, details about drug physical constitution, method of preparation, and 
infusion must be recorded. 
Participants should be instructed to report any delayed reaction immediately. 
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology 
Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs.  
Immediate Hypersensitivity Reaction 
Hypersensitivity reactions may require immediate intensive care. Bintrafusp alfa should be 
administered in a setting that allows immediate access to an intensive care unit or equivalent 
environment and administration of therapy for anaphylaxis, such as the ability to implement 
immediate resuscitation measures. Potent steroids (e.g., dexamethasone), catecholamines (e.g. 
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epinephrine), allergy medications (IV antihistamines), bronchodilators, or equivalents and 
oxygen should be available for immediate access. 
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. 
Flu-Like Symptoms 
Treatment is based on clinical assessment and at the discretion of the Investigator. 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. 
8.3.6.2 
Immune-related Adverse Events  
Immune-related AEs are specific to immunotherapies and vary by organ system. Immune-related 
AEs are AESIs. 
The following irAEs are important identified risks for bintrafusp alfa.  
• 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 
• 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. 
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 preventing progression into severe forms of toxicity that otherwise may become 
life-threatening and difficult to manage or warrant permanent discontinuation from the study. 
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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 are provided in the current NCCN 
guideline is available at http://www.nccn.org 
Requirements in addition to NCCN guidelines: 
• 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. 
8.3.6.3 
TGFβ inhibition mediated Skin Reactions  
Skin assessments will be performed for all participants per the SoA (see Table 1). For 
participants who are reinitiating treatment with bintrafusp alfa after treatment discontinuation 
within the rollover study, a rebaseline skin assessment should also be performed. 
Skin AEs, possibly due to TGFβ inhibition, including hyperkeratosis, KA, and/or cSCC, are 
AESIs and important identified risks for bintrafusp alfa. The distribution of lesions tends to be 
in sun-exposed areas. 
Management guidelines for potential TGFβ 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 TGFβ mediated skin lesions such as 
hyperkeratosis, KA and cSCC should be based on local guidelines/SoC. Lesion evaluation 
should include excision biopsy of one representative lesion to confirm diagnosis. 
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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 TGFβ mediated skin lesions. 
8.3.6.4 
Anemia  
Anemia is an AESI 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, 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. Routine blood test parameters are required in this rollover study per the SoA (see Table 
1). 
2. Transfusion should be performed at the discretion of the Investigator based on clinical 
assessment and considered when the participant experiences severe 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 treatment-related anemias is provided in Table 6. 
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Table 6 
Evaluation Guidance of Suspected Anemia  
Basic Anemia Evaluation 
1. 
CBC with emphasis on red cell indices (e.g., Hgb, hematocrit, MCV, RDW, MCH, MCHC, reticulocytes 
counts). 
2. 
If indicated and at clinical discretion, the following should be considered: 
a. 
Iron studies (TIBC, Ferritin, Fe) 
b. 
Serum Folate and Vit B12 values 
c. 
Coagulation factors (PT, PTT, INR) 
d. 
Fecal occult blood testing 
e. 
Urinalysis 
f. 
Hormone panel: TSH, Erythropoietin 
g. 
Peripheral blood smear for cell morphological assessment 
Further Recommendation Based on Suspected Etiology (in Addition to Basic Anemia Testing) 
Suspected hemolysis: 
Bilirubin level, LDH, Coombs test, fibrinogen, haptoglobin, d-Dimer 
Consider Hematology consultation. 
 
Suspected bleeding: 
Consider imaging/interventional radiology consultation as indicated 
Consider endoscopy, as clinically indicated. 
Consider imaging, as clinically indicated. 
 
Suspected aplastic anemia: 
 
Hematology consultation. 
Consider bone marrow aspiration/morphologic evaluation. 
CBC = complete blood count; Hgb = hemoglobin; INR = international normalized ratio; LDH = lactate 
dehydrogenase; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; 
MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin time; RDW = red blood cell 
distribution width; TIBC = total iron binding capacity; and TSH = thyroid-stimulating hormone. 
8.3.6.5 
Bleeding Adverse Events  
Bleeding AEs are AESIs and considered important identified risk.  
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 7 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. If Grade ≥ 3 bleeding event is 
observed, regardless of causality with the study intervention, upon resumption of study 
intervention bintrafusp alfa dose should be reduced by 50% (600 mg once every 2 weeks for 
participants dosed with 1200 mg, 1200 mg once every 2 weeks for participants dosed with 
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2,400 mg). Once there is stable resolution and no recurrence of bleeding on reduced dose, 
Investigator is encouraged to communicate with Medical Monitor on potential dose re-escalation 
after careful benefit-risk assessment. 
For Grade 4 non-tumor bleeding, treatment must be permanently discontinued if no alternative 
explanation is identified. 
In case of rapid decrease of hemoglobin (Hgb), such as a decrease greater than 2.0 g/dL across 
a 2 weeks period (or 3.0 g/dL across a 3 week period), withhold the subsequent cycles of study 
intervention until Hgb is stabilized and do a thorough assessment of bleeding (for example, upper 
and lower GI endoscopy, enhancement CT etc.); if Grade 1 or greater bleeding is observed or 
suspected, withhold the bintrafusp alfa until the bleeding is resolved/controlled and resume the 
dose of bintrafusp alfa reduced by 50%. Once Hgb decrease is recovered to ≤ Grade 1 or baseline 
and stably controlled, the Investigator is encouraged to communicate with Medical Monitor to 
re-escalate the dose. The dose of bintrafusp alfa may be re-escalated to full dose once Hgb is 
stabilized without further need for blood transfusion in the subsequent cycles. The timing of re 
escalation may need a case-by-case decision. See Section 8.3.6.4 regarding stabilization of 
anemia. 
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. If Grade ≥ 3 bleeding event had been observed, 
regardless of causality with the study intervention, upon resumption of the study intervention 
bintrafusp alfa dose should be reduced by 50%. Once there is stable resolution and no recurrence 
of bleeding on reduced dose, Investigator is encouraged to communicate with Medical Monitor 
potential dose re-escalation after careful benefit-risk assessment. Treatment should be 
permanently discontinued if the Investigator considers the participant to be at risk for additional 
severe bleeding. In case of rapid decrease of Hgb, see Section 8.3.6.5 Mucosal/Non-tumor 
Bleeding. 
8.4 
Treatment of Overdose  
For this study, any dose of bintrafusp alfa greater than 2 times of the planned dose within a 
24-hour time period will be considered an overdose. This is based on dose escalation study data 
in which participants safely received up to 30 mg/kg bintrafusp alfa every 2 weeks (including 
with doses > 2400 mg) with no observed dose limiting toxicity at 30 mg/kg and not reaching 
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 not associated with an AE or a SAE, any overdose is recorded in the eCRF and 
reported to global patient safety in an expedited manner. Overdoses are reported on a SAE 
and Overdose Report Form, following the procedure in Appendix 4. 
8.5 
Pharmacokinetics  
Not applicable 
8.10 
Health Economics OR Medical Resource Utilization and 
Health Economics  
Not applicable 
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9.3 
Populations for Analyses  
The analysis populations are specified below (see Table 7). The final decision to exclude 
participants from any analysis population will be made during a data review meeting prior to 
database lock. 
Table 7 
Analyses Sets  
Analysis Set 
Description 
Full (FAS) 
For each parent study, the FAS will be defined as in the protocol of the parent study. 
Safety (SAF) 
For each parent study, the SAF will be defined as in the protocol of the parent study. 
FAS = Full Analysis Set; SAF = Safety Analysis Set. 
9.4 
Statistical Analyses  
Full details of all planned analyses will be described in the study IAP. Additional specifications 
may be provided in separate IAPs or addenda to existing Statistical Analysis Plans (SAPs) or 
IAPs of parent protocols. Major modifications of planned analyses will be reflected in a protocol 
amendment or in the clinical study report. 
For the purpose of statistical analyses, data from the respective parent protocol will be merged 
with the data that were recorded under the rollover protocol for the participants of the parent 
study. Endpoint analyses will be based upon the analysis sets defined in the respective parent 
protocols. 
For the rollover study, Follow-up analyses of safety and efficacy will be performed using the 
methodology described in the respective parent study protocol. The baseline time point from the 
parent study will be the baseline for safety and efficacy analyses. 
In order to provide overall estimates of treatment effects, data will be pooled across study centers. 
The factor ‘center’ will not be considered in statistical models or for subgroup analyses due to 
the high number of participating centers in contrast to the anticipated small number of 
participants randomized at each center. 
In general, continuous variables will be summarized using number (n), mean, standard deviation, 
median, first and third quartiles, minimum, and maximum. Categorical variables will be 
summarized using counts and percentages of participants in each category. 
The calculation of proportions will be based on the number of participants in the analysis set of 
interest, unless otherwise specified in the study IAP. Statistical analyses will be performed using 
SAS® Software, Version 9.4 (SAS Institute Inc., Cary, NC, USA) or higher or 
(R Core team, 2013). 
9.4.1 
Efficacy Analyses  
All efficacy analyses will be performed on the Full Analysis population. 
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As stated in the previous section, endpoint analyses will be based on the analysis sets defined in 
the respective parent protocols. Further details on efficacy endpoint analyses will be specified in 
the IAP and finalized before database lock. 
9.4.2 
Safety Analyses  
All safety analyses will be performed on the Safety Analysis population defined in the protocol 
of the respective parent study. 
The on-treatment period is defined as the time from the first dose of study intervention 
administration in the parent study 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, but are not limited to, TEAEs, SAEs, treatment-related AEs, AESIs, 
irAEs, and IRRs, as well as clinical laboratory assessments, vital signs, 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. 
TEAEs are those events with onset dates occurring during the on-treatment period or if the 
worsening of an event is during the on-treatment period. Severity of AEs will be graded using 
the version of CTCAE toxicity grades used in the respective parent study. 
All premature terminations will be summarized by primary reason for treatment 
discontinuation/withdrawal. 
As stated in the previous section, safety analyses will focus on the occurrence of new AEs that 
have not been reported in the parent studies to assess if they lead to changes in the safety 
assessment, as given in the clinical study report of the respective parent study. 
Participants will be analyzed according to the actual treatment they receive. The specifics for 
analysis methods will be defined in the IAP and finalized before database lock. 
 
Endpoint 
Statistical Analysis Methods 
Primary 
To evaluate clinical safety 
of bintrafusp alfa in 
participants with solid 
tumors who continue 
treatment after completion 
of the primary/main 
analyses in parent 
bintrafusp alfa studies. 
The safety endpoints will be tabulated using descriptive statistics using MedDRA 
preferred terms and system organ class. 
Secondary 
Not applicable 
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9.4.3 
Other Analyses  
Not applicable 
9.4.4 
Sequence of Analyses  
Analyses will be conducted once the last participant is off treatment. Any other analyses per 
indication or per parent protocol will be conducted at time points that remain to be determined, 
e.g., for the purpose of reporting to Health Authorities or for scientific publications. 
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10 
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Postow MA, Sidlow R, Hellman MD. Immune-Related Adverse Events Associated with Immune 
Checkpoint Blockade. N Engl J Med. 2018 Jan 11;378(2):158-168.  
R Core Team. R: A language and environment for statistical computing. R Foundation for 
Statistical Computing, Vienna, Austria 2013. URL http://www.R-project.org/.  
Vincenti F, Fervenza FC, Campbell KN, et al. A Phase 2, Double-Blind, Placebo-Controlled, 
Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal 
Segmental Glomerulosclerosis. Kidney Int Rep. 2017 Apr 7;2(5):800-10.  
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11 
Appendices  
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Appendix 1 
Abbreviations   
 
AE(s) 
Adverse event(s) 
AESIs 
Adverse events of special interest 
AECI 
Adverse events of clinical importance 
anti-PD-L1 
Antibody blocking programmed death-ligand 1 
ALT 
Alanine aminotransferase 
ART 
Antiretroviral therapy 
AST 
Aspartate aminotransferase 
BOR 
Best overall response 
CI 
Confidence Interval 
CR 
Complete response 
CRF 
Case report form 
cSCC 
Cutaneous squamous cell carcinoma 
CT  
Computed tomography  
 
 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic case report form 
IWRS 
Interactive Web Response System 
FAS 
Full Analysis Set 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
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HRT 
Hormonal replacement therapy 
IAP 
Integrated Analysis Plan 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
irAEs 
Immune-related adverse events 
IRB 
Institutional Review Board 
IRR 
Infusion-related reactions 
IV 
Intravenous 
KA 
Keratoacanthoma 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events 
NCCN 
National Comprehensive Cancer Network 
NIMP 
Non-Investigational Medicinal Product 
NSCLC 
Non-small cell lung carcinoma 
OS 
Overall survival  
ORR 
Overall response rate 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed death ligand 1 
 
 
PK 
Pharmacokinetic(s) 
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PR 
Partial response 
PT 
Preferred term 
PS 
Performance status 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE(s) 
Serious adverse event(s) 
SD 
Stable disease 
SoA 
Schedule of activities 
SoC 
Standard of care 
SUSAR 
Suspected unexpected serious adverse reaction 
TGFβ 
Transforming growth factor β 
TNBC 
Triple-negative breast cancer 
TEAE(s) 
Treatment-emergent adverse event(s) 
WOCBP 
Woman of childbearing potential 
 
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Appendix 2 
Study Governance  
Financial Disclosure 
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative (where allowed by local laws and 
regulations) and answer all questions on the study. 
• Participants will 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 Good Clinical Practice 
(GCP); local regulations; internal conference on harmonization (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 will 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. 
Data Protection 
• The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. Any participant records or datasets that are transferred to the Sponsor will contain 
the identifier only; participant names or any identifiable information will not be transferred. 
• The Sponsor will inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure will also be explained to the 
participant and pregnant partners (if applicable), who will be required to give consent for 
their data to be used, as specified in the informed consent. 
• The participant will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality. 
Study Administrative 
The Coordinating or Principal Investigator listed on the title page represents all Investigators 
for decisions and discussions on this study, per ICH GCP. The Coordinating Investigator will 
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provide expert medical input and advice on the study design and execution and is responsible 
for the review and signoff of the clinical study report. 
Details of structures and associated procedures will be defined in a separate Operations 
Manual. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
• Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable ICH GCP Guidelines 
• For studies with Japanese site, the Japanese ministerial ordinance on GCP 
• Applicable laws and regulations 
• The protocol, protocol amendments (if applicable), ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) will be submitted to an IRB/IEC for review and 
approval before the study is initiated. 
• For studies with Japanese sites. 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 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. 
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 
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call center, whereby the health care providers will be given access to the appropriate Sponsor 
(or designee) physician to assist with the medical emergency. 
Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable. 
The Sponsor is entirely responsible for AEs that are associated with this study and cause 
damage to the health of the participants, except for AEs caused by an intentional and/or 
significant deviation on the part of the Investigator, the study site, and/or the participant. The 
Sponsor takes out insurance to fulfill the responsibility. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator or other relevant study-appointed committees or groups. 
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. 
• 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 Clinical Study Report according to ICH Topic E3 will be written 
by the Sponsor or the designated CRO in consultation with the Coordinating Investigator. The 
first publication will be a publication of the results of the analysis of the endpoints that will 
include data from all study sites that participated in the parent study. The Investigators will 
inform the Sponsor in advance of any plans to publish or present data from the study. Any 
publications and presentations of the results (abstracts in journals or newspapers, oral 
presentations etc), either in whole or in part, by Investigators or their representatives will require 
pre-submission review by the Sponsor.  
The Sponsor will not suppress or veto publications, but maintains the right to delay publication 
in order to protect intellectual property rights. 
Data Quality Assurance 
• All participant study data will be recorded on printed or 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 CRF. Details for managing CRFs are in the Study Reference Manual. 
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• The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF. 
• 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. 
• Quality Tolerance Limits (QTLs) will be pre-defined in the applicable project management 
database to identify systematic issues that can impact participant safety and/or reliability of 
study results. These pre-defined parameters will be monitored during the study and important 
deviations from the QTLs and remedial actions taken will be summarized in the clinical study 
report. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan or 
contracts. 
• The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once 
quality control and quality assurance procedures have been completed. Details will be 
outlined in Data Management documents and procedures. 
• Study Monitors will perform ongoing source data verification to confirm that data in the CRF 
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 maintain source documents that support the data recorded in the CRFs. 
• Data recorded on CRFs that are transcribed from source documents will be consistent with 
the source documents or the discrepancies will be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records will be available. 
• 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 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. 
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• Definition of what constitutes source data is found in case report form guidelines. 
Study and Site Start and Closure 
• The study start date is the date when the clinical study will be open for recruitment. 
Study and Site Termination 
• The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended closure. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound 
• If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any third-party service providers 
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  
Woman of Childbearing Potential  
Definitions: 
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 one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
 
Documentation can come from the site personnel’s review of the female’s medical 
records, medical examination, or medical history interview. 
 
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis, androgen insensitivity), Investigator discretion applies 
to determine study entry. 
3. A postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range. 
• A female on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if she 
wishes to continue her HRT during the study. Otherwise, she must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment. 
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Contraception Guidance: 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulation* 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system  
• 
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. 
* Not approved in Japan 
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 is evaluated in relation 
to the duration of the study. 
• 
* Not approved in Japan 
Acceptable Methods 
• 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
• 
Male or female condom with or without spermicide**. Male condom and female condom cannot be used 
together (due to risk of failure with friction) 
• 
Cervical cap*, diaphragm, or sponge with spermicide* 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods) 
* Not approved in Japan 
** Not available in Japan 
Contraceptive use by men or women is consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies. 
Highly effective methods have a failure rate of < 1% per year when used consistently and correctly. Typical use 
failure rates differ from those when used consistently and correctly. 
If locally required, in accordance with Clinical Trial Facilitation Group guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
Acceptable methods are considered effective, but not highly effective (i.e. have a failure rate of ≥ 1% per year). 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. 
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• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the form sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the form within 24 hours after becoming aware of the event. 
• Additional documents (e.g. laboratory reports, autopsy report, hospital discharge letter) 
and relevant pages from the CRF may be required in addition (e.g. medical history, 
concomitant medication). The data provided will be consistent with the information in the 
CRF. 
Reporting of Pregnancies 
• Pregnancy will be reported whether related to the study intervention using the applicable 
paper form. 
• The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event. 
• Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee. 
Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments  
Not applicable 
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Appendix 6 
Clinical Laboratory Tests  
Protocol-Required Clinical Laboratory Assessments 
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 
Lipase 
Chloride 
Albumin 
 
C-reactive 
protein 
Amylase 
 
 
Routine Urinalysis 
Physical appearance (color and transparency) 
• Specific gravity by dipstick 
• pH, glucose, protein, blood/hemoglobin, ketones, bilirubin, urobilinogen, 
nitrite, leukocytes by dipstick 
Microscopic examination (if blood or protein is abnormal).  
Urine culture by suspicion of urinary tract infection 
Other Screening 
Tests 
• Follicle-stimulating hormone (FSH) and estradiol (as needed if not a 
woman of childbearing potential [WOCBP] only) 
• Serum or highly sensitive urine human chorionic gonadotropin (hCG) 
pregnancy test (WOCBP only) 
• 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 As clinically indicated in participants with a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 
If hepatitis B surface antigen positive and hepatitis B core antibody positive, then reflex to quantitative HBV DNA 
polymerase chain reaction (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). 
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Laboratory 
Assessments 
Parameters 
c Not required for all participants. Only applicable for participants with a history of HIV. Testing as clinically 
indicated for participants with known history of HIV. Participants must be adequately consented per local 
regulations for any HIV-related testing. 
d Results must be reviewed by the Investigator within 3 days prior to dosing.  
 
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Appendix 7 
Pharmacokinetic Parameters  
Not applicable 
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Appendix 9 
Country-specific Requirements  
Not applicable 
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Appendix 10 
List of Bintrafusp alfa Studies from Which Participants May 
be Enrolled  
A list of the potential parent bintrafusp alfa studies from which participants may be enrolled into 
this rollover study is provided below. For the other parent studies, the Sponsor will inform 
investigators when participants may be transferred to the rollover study. 
• EMR200647-001: A Phase I, open-label, multiple-ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of MSB0011359C in 
subjects with metastatic or locally advanced solid tumors and expansion to selected 
indications. 
• MS200647_0005: A Multicenter, Double Blind, Randomized, Controlled Study of M7824 
with Concurrent Chemoradiation Followed by M7824 versus Concurrent Chemoradiation 
Plus Placebo Followed by Durvalumab in Participants with Unresectable Stage III Non-small 
Cell Lung Cancer. 
• MS200647-0008: A Phase I, open-label, multiple-ascending dose trial to investigate the 
safety, tolerability, pharmacokinetics, biological and clinical activity of MSB0011359C in 
subjects with metastatic or locally advanced solid tumors with expansion to selected 
indications in Asia. 
• MS200647_0017: 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. 
• MS200647_0020: A Phase II, Multicenter, Open Label Study of Bintrafusp alfa (M7824) 
Monotherapy in Participants with HMGA2-expressing Triple-Negative Breast Cancer. 
• MS200647_0024: A Phase Ib/II, Open-Label Study of M7824 in Combination with 
Anti-cancer Therapies in Participants with Stage IV Non-small Cell Lung Cancer. 
• MS200647_0037: An Adaptive Phase III, Multicenter, Randomized, Open-Label, Controlled 
Study of M7824 (bintrafusp alfa) versus Pembrolizumab as a First line Treatment in Patients 
with PD-L1 Expressing Advanced Non-small Cell Lung Cancer. 
• MS200647_0046: Safety Study of Bintrafusp alfa in Combination with Other Anti-cancer 
Therapies in Participants with Locally Advanced or Advanced Cervical Cancer. 
• MS200647_0047: A Phase II, Multicenter, Open label Study to Investigate the Clinical 
Efficacy of M7824 Monotherapy in Participants With Locally Advanced or Metastatic Biliary 
Tract Cancer Who Fail or are Intolerant to First line Platinum Based Chemotherapy. 
• MS200647_0055: A Phase II/III, Multicenter, Randomized, Placebo controlled Study of 
Gemcitabine Plus Cisplatin With or Without Bintrafusp alfa (M7824) as First line Treatment 
of Biliary Tract Cancer. 
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Appendix 11 
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 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
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• 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 
sum diameters will be used as reference to further characterize any objective tumor regression 
in the measurable dimension of the disease.  
Non-target Lesions 
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All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at Baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(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: Computed Tomography 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. 
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 
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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 
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 
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 
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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 PR 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 qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the participant has only non-measurable disease. This circumstance arises in some 
Phase III 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 
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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. 
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. 
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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, PD=progressive disease, SD=stable disease. 
See text for more details. 
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.  
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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, 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. 
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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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Appendix 12 
Protocol Amendment History  
The information for the current amendment is on the title page. 
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Appendix 15 
Principal Investigator Signature Page  
Study Title: 
An Open-label, Multicenter Follow-up Study to Collect 
Long-term Data on Participants 
from 
Multiple 
Bintrafusp alfa (M7824) Clinical Studies 
Regulatory Agency Identifying 
Numbers: 
IND: 
 
EudraCT: 2021-000179-36 
Clinical Study Protocol Version: 30 November 2021/Version 2.0 
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 on 
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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