Safety Study of Bintrafusp Alfa in Combination With Other Anti-cancer Therapies in Participants With Locally Advanced or Advanced Cervical Cancer (INTR@PID 046)
Phase: PHASE1
Conditions: Cervical Cancer
Sponsor: EMD Serono Research & Development Institute, Inc.



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Protocol Amendment Summary of Changes
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
02-Jul-2020
2.0
Global Amendment
06-Jul-2021
Protocol Version 2.0 (06-July-2021)
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The primary purpose of this amendment is to update the risk classification.
Section # and Name
Description of Change
Brief Rationale
Title Page
Revised “Amendment Number“ row
Removed “Medical Responsible” field
Removed “Protocol Version”, “Replaces 
Version”, “Approval Date” and „Medical 
Monitor Contact Information“ rows. 
To be consistent with current Sponsor 
protocol template (Version 15).
2.3 Benefit/Risk Assessment
Risk classification has been revised 
and the list of events has been updated 
accordingly.
The statement referring to the number 
of patients treated with bintrafusp alfa 
monotherapy has been removed.
The risk reclassification was based on 
in-depth analysis of a pooled safety 
dataset of N = 765 participants who 
received bintrafusp alfa monotherapy 
at 1200 mg Q2W.
The information on the number of 
participants treated with bintrafusp 
alfa is provided in the IB.
5 Study Population
Appendix 2 Study 
Governance
Edits related to informed consent 
process.
To be consistent with current Sponsor 
protocol template (Version 15).
7.3 Lost to Follow-up
Edit related to Lost to Follow-up 
information.
To be consistent with current Sponsor 
protocol template (Version 15).
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Section # and Name
Description of Change
Brief Rationale
6.8.2 Bintrafusp alfa
8.3.6 Adverse Events of 
Special Interest
Appendix 4 Adverse Events: 
Definitions and Procedures 
for Recording, Evaluating, 
Follow-up, and Reporting
Risk categorization has been revised 
and the list of events has been updated 
accordingly.
The risk reclassification was based on 
in-depth analysis of a pooled safety 
dataset of N = 765 participants who 
received bintrafusp alfa monotherapy 
at 1200 mg Q2W.
8.3.6.1Infusion-related 
Reactions Including 
Hypersensitivity
Infusion-related reactions are 
reclassified from “important identified 
risk” to “identified risk” for bintrafusp 
alfa.
8.3.6.1, Table 10 Treatment 
Modification of Bintrafusp 
alfa for Symptoms of 
Infusion-Related Reactions 
Including Hypersensitivity
Additional details of treatment 
modifications for severe or life-
threatening reactions have been added.
8.3.6.2 Immune-related 
Adverse Events
Risk categorization has been revised 
and the list of events has been updated 
accordingly.
8.3.6.3 TGF-β Inhibition 
Mediated Skin Reactions
Skin Adverse Events have been 
renamed to TGF-β Inhibition Mediated 
Skin Reactions.
8.3.6.4 Anemia
Term “treatment-related anemia events” 
has been revised to “anemia” and 
reclassified from “important potential 
risk” to “important identified risk” for 
bintrafusp alfa.
8.5.6.5 Bleeding Events
Bleeding events are reclassified from 
“potential risk” to “important identified 
risk” for bintrafusp alfa.
8.3.7.1 Impaired Wound 
Healing
The risk name “Alterations in Wound 
Healing or Repair of Tissue Damage” 
has been changed to “Impaired Wound 
Healing”.
6.8.4.1 Risk Management for 
Chemotherapy
Text has been updated to clarify dosing 
delays requiring discontinuation of 
chemotherapy are >3 weeks from the 
day of scheduled administration.
To clarify study procedures.
Note: Minor changes have been performed throughout the protocol to address consistency pertaining to major 
changes made in the protocol or to add further clarity and precision.
- Confidential –
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................5
List of Tables
..............................................................................................................9
List of Figures
..............................................................................................................9
1
Protocol Summary ..............................................................................10
1.1
Synopsis..............................................................................................10
1.2
Schema................................................................................................14
1.3
Schedule of Activities.........................................................................15
1.3.1
Schedule of Activities for Cohort 1....................................................15
1.3.2
Schedule of Activities for Cohort 2....................................................23
2
Introduction.........................................................................................35
2.1
2.2
Background.........................................................................................36
2.3
Benefit/Risk Assessment ....................................................................37
3
Objectives and Endpoints ...................................................................39
4
Study Design.......................................................................................40
4.1
Overall Design....................................................................................40
4.2
Scientific Rationale for Study Design ................................................43
4.2.1
Endpoints............................................................................................43
4.2.2
Selection of Combination and Study Population................................43
4.3
Justification for Dose..........................................................................44
4.4
End of Study Definition......................................................................44
5
Study Population.................................................................................44
5.1
Inclusion Criteria ................................................................................45
5.2
Exclusion Criteria...............................................................................48
5.3
Lifestyle Considerations .....................................................................51
5.4
Screen Failures....................................................................................51
6
Study Intervention(s) ..........................................................................51
6.1
Study Intervention(s) Administration.................................................51
6.1.1
Bintrafusp alfa ....................................................................................52
6.1.2
Chemotherapy and Bevacizumab .......................................................52
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7.1.3.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression............................................................................71
7.2
Participant Discontinuation/Withdrawal From the Study...................72
7.3
Lost to Follow-Up...............................................................................73
8
Study Assessments and Procedures....................................................73
8.2
Safety Assessments and Procedures ...................................................75
8.2.1
Physical Examinations........................................................................75
8.2.2
Vital Signs ..........................................................................................76
8.2.3
Electrocardiograms.............................................................................76
8.2.4
Clinical Safety Laboratory Assessments ............................................76
8.3
Adverse Events and Serious Adverse Events.....................................77
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................77
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...78
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............78
8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....78
8.3.5
Pregnancy ...........................................................................................79
8.3.6
Adverse Events of Special Interest.....................................................80
8.3.6.1
Infusion-related Reactions Including Hypersensitivity ......................80
8.3.6.2
Immune-related Adverse Events.........................................................83
8.3.6.3
TGF-β Inhibition Mediated Skin Reactions .......................................85
8.3.6.4
Anemia................................................................................................86
8.3.6.5
Bleeding Events..................................................................................87
8.3.7
Other Potential Risks for Bintrafusp alfa............................................88
8.3.7.1
Impaired Wound Healing ...................................................................88
8.3.7.2
Embryofetal Toxicity..........................................................................88
8.4
Treatment of Overdose .......................................................................88
8.5
Pharmacokinetics................................................................................89
8.6
Pharmacodynamics.............................................................................90
8.7
8.8
8.9
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8.10
Health Economics...............................................................................92
9.3
Populations for Analyses ....................................................................92
9.4
Statistical Analyses.............................................................................93
9.4.1
Efficacy Analyses ...............................................................................93
9.4.2
Safety Analyses ..................................................................................93
9.4.3
Other Analyses....................................................................................94
9.4.4
Sequence of Analyses.........................................................................95
10
References...........................................................................................96
11
Appendices .........................................................................................98
Appendix 1
Abbreviations......................................................................................98
Appendix 2
Study Governance.............................................................................101
Appendix 3
Contraception....................................................................................109
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting..............................................111
Appendix 5
Clinical Laboratory Tests .................................................................118
Appendix 6
Appendix 7
Response Evaluation Criteria in Solid Tumors (RECIST) Version 
1.1 .....................................................................................................121
Appendix 8
Protocol Amendment History...........................................................130
Appendix 9
Sponsor Signature Page....................................................................131
Appendix 10
Coordinating Investigator Signature Page........................................132
Appendix 11
Principal Investigator Signature Page...............................................133
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List of Tables
Table 1
Schedule of Activities for Cohort 1....................................................15
Table 2
Schedule of Activities for PK and ADA Sampling in Cohort 1.........22
Table 3
Schedule of Activities During cCRT in Cohort 2...............................23
Table 4
Schedule of Activities After cCRT in Cohort 2..................................29
Table 5
Schedule of Activities for PK and ADA Sampling in Cohort 2.........34
Table 6
Objectives and Endpoints ...................................................................39
Table 7
Administration of Bintrafusp alfa (M7824)........................................52
Table 8
Predosing Consideration for Cisplatin................................................66
Table 9
Predosing Consideration for Carboplatin ...........................................67
Table 10
Treatment Modification of Bintrafusp alfa for Symptoms of 
Infusion-Related Reactions Including Hypersensitivity.....................82
Table 11
Evaluation Guidance of Suspected Anemia .......................................87
Table 12
Pharmacokinetic Parameters...............................................................89
Table 13
Analysis Set ........................................................................................93
Table 14
Efficacy Analysis................................................................................93
Table 15
Safety Analysis ...................................................................................94
Table 16
Protocol-Required Clinical Laboratory Assessments.......................118
List of Figures
Figure 1
Study Schema .....................................................................................14
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
Cohort 1A: 8 participants will be treated with bintrafusp alfa (2400 mg every 3 weeks) + 
cisplatin or carboplatin + paclitaxel + bevacizumab. Selection of cisplatin or carboplatin is 
at the Investigator discretion.

Cohort 1B: 8 participants will be treated with bintrafusp alfa (2400 mg every 3 weeks) + 
cisplatin or carboplatin + paclitaxel. Selection of cisplatin or carboplatin is at the Investigator 
discretion.
If the first 8 participants of each subcohort separately include fewer than 3 participants from Japan, 
the Sponsor may elect to continue enrollment to include 3 participants from Japan to evaluate the 
safety of this combination in Japanese participants. If the first 8 participants of each subcohort 
separately include fewer than 3 participants from Europe or the United States, enrollment may 
continue in Europe and the United States to include at least 3 participants from any of these 
countries.
Cohort 2: 
Participants with locally advanced cervical cancer will be treated with bintrafusp alfa (2400 mg 
every 3 weeks) combined with definitive radiation and radiation-sensitizing platinum therapy 
(cisplatin) during cCRT, followed by maintenance with bintrafusp alfa monotherapy (2400 mg 
every 3 weeks). 
If the first 8 participants include fewer than 3 participants from Japan, enrollment may continue in 
Japan to include at least 3 participants from Japan to evaluate the safety of this combination in 
Japanese participants. If the first 8 participants of this cohort include fewer than 3 participants from 
Europe or the United States, enrollment may continue in Europe and the United States to include 
at least 3 participants from any of these countries.
Disclosure Statement: This is a non-randomized, non-blinded study conducted with Cohorts 1 
(Cohort 1A and Cohort 1B) and 2.
Number of Arms: 3 cohorts (1A, 1B, and 2)
Blinding: No blinding
Number of Participants:
In total, approximately 24 participants will be enrolled in this study. For each of the cohorts (1A, 
1B, and 2), at least 8 participants will be enrolled to evaluate the safety of each combination 
treatment. 
The Safety Monitoring Committee (SMC) will evaluate the safety in each cohort separately after 
the3rd and after the 8th evaluable participant completes the respective dose-limiting toxicity (DLT)
period. In the case more participants are included and complete the DLT period as per enrollment, 
all the participants will continue to be evaluated by the SMC, if required. In addition, the SMC 
will evaluate the safety from all participants as needed. 
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During the DLT observation period, in the event a participant discontinues for reasons other than 
adverse events (AE) or is otherwise non-evaluable, the Sponsor may elect to add an additional
participant.
Study Intervention Groups and Duration: 
The study includes:

Up to 28-day Screening period. 

The DLT observation period of 4 weeks from the Week 1, Day 1 (W1D1) visit for all 
cohorts.

Treatment until progressive disease (PD) by Response Evaluation Criteria in Solid Tumors 
Version 1.1 and subsequent confirmation (at the next imaging visit at least 28 days after 
the detection of PD) unacceptable toxicity, study withdrawal, or death. 

In case of PD, treatment may continue if the participant’s Eastern Cooperative Oncology 
Group Performance Status has remained at least stable, and if in the opinion of the 
Investigator, the participant will benefit from continued treatment, and if other criteria are 
fulfilled as outlined in the protocol.

Cohort 1 participants will continue chemotherapy until complete response (CR) (as 
clinically indicated) and/or unacceptable toxicity due to chemotherapy, after which, 
bintrafusp alfa ± bevacizumab (depending on cohort) may be continued until 2 years or 
unacceptable toxicity as indicated for bintrafusp alfa and/or bevacizumab. If the 
Investigator believes that a participant may benefit from treatment beyond 2 years, it may 
be permissible to continue treatment after discussion with the Medical Monitor and the
Sponsor’s Medical Responsible. 

Cohort 2 participants should continue maintenance treatment (bintrafusp alfa) for a 
maximum of 2 years (at the discretion of the Investigator). If the Investigator believes that 
a participant may benefit from treatment beyond 2 years, it may be permissible to continue 
treatment after discussion with the Medical Monitor and the Sponsor’s Medical 
Responsible.

All participants should continue treatment until confirmed disease progression or any other 
discontinuation criterion is met (e.g., unacceptable toxicity, withdrawal of consent).

Safety Follow-up Visits are at 28 days (± 5 days) and 12 weeks (± 2 weeks) after the last 
dose of study intervention according to the Schedule of Activities.

Long-term Follow-up should be performed every 12 weeks (± 2 weeks) after the Safety 
Follow-up.

Survival Follow-up will continue until the end of study. After the stipulated end of study, 
Survival Follow-up may continue until the last participant has died or at the discretion of 
the Sponsor.
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Involvement of Special Committee(s): Yes
The SMC will evaluate the safety (including DLTs) and other available data. The specific working 
procedures will be described in an SMC charter.
1.2
Schema
Figure 1
Study Schema
1L=first-line,
cCRT= concomitant chemoradiation therapy, DLT=dose-limiting toxicity, PK=pharmacokinetics, 
q3w=every 3 weeks.
a For Cohort 1A and Cohort 1B, if the first 8 participants of each subcohort separately include fewer than 3 participants 
from Japan, the Sponsor may elect to continue enrollment to include 3 participants from Japan to evaluate the safety 
of this combination in Japanese participants. If the first 8 participants of each subcohort separately include fewer than 
3 participants from Europe or the United States, enrollment may continue in Europe and the United States to include 
at least 3 participants from any of these countries.
b For Cohort 2, if the first 8 participants include fewer than 3 participants from Japan, enrollment may continue in Japan 
to include at least 3 participants from Japan to evaluate the safety of this combination in Japanese participants. If the 
first 8 participants of this cohort include fewer than 3 participants from Europe or the United States, enrollment may 
continue in Europe and the United States to include at least 3 participants from any of these countries. 
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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 receptor II (TGF-βRII or TGF-β 
Trap) covalently linked via a flexible linker to the C-terminus of each heavy chain of an 
immunoglobulin (IgG1) antibody blocking programmed death-ligand 1 (PD-L1).
Detailed information on the chemistry, pharmacology, efficacy, and safety of bintrafusp alfa is in 
the Investigator’s Brochure (IB).
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2.2
Background
Cervical cancer is the third most common cancer in women and remains one of the most common 
causes of cancer death among women worldwide. It is diagnosed in over 13,000 women in the 
United States each year. The human papilloma virus (HPV), the primary cause of cervical cancer, 
is implicated in over 90% of cases (Arbyn 2014; Howlader 2019). Although diagnosis is often 
made at earlier stages, metastatic or recurrent cervical cancer develop in a third of the women 
(Gadducci 2015; Howlader 2019). 
For the majority of patients with recurrent, persistent, or metastatic cervical cancer, the first-line 
standard of care is chemotherapy with platinum and taxane in combination with bevacizumab with 
an overall response rate of 48% and a median OS of approximately 17 months (Dyer 2019;
Tewari 2017). For women with locally advanced cervical cancer, with node involvement with 
International Federation of Gynecology and Obstetrics (FIGO) Stages IB2 to IVA, the standard of 
care is primarily chemoradiation. Benefit of chemoradiation decreases with increasing stage 
(CCCMAC 2008) and prognosis for patients with Stage III/IV disease is poor with 4-year OS rates 
of 55% (Dyer 2019) and 2-year rates of relapse over 40% (Rose 2015).
Recently, molecular characterization of cervical cancer by The Cancer Genome Atlas also 
identified both PD-L1 and TGF-β signaling as frequently dysregulated in this disease (The Cancer 
Genome Atlas Research Network 2017, Roszik 2018). TGF-β is historically known to be 
expressed in a majority of cervical cancer tissues, and its expression correlates with the extent of 
tumor stroma infiltrate (Hazelbag 2002). Furthermore, the role of TGF-β in cervical cancer 
pathogenesis is supported by data including 1) TGF-β1 upregulation by HPV oncoprotein E6 and 
E7 (Peralta-Zaragoza 2006), and 2) the correlation of poor prognosis in cervical cancer and the 
expression of plasminogen activator inhibitor-1, a molecule strongly and dose-dependently 
induced by TGF-β (Hazelbag 2004). 
Bintrafusp alfa has shown promising clinical activity with durable responses in participants with 
chemotherapy refractory cervical cancer in Phase I Study EMR200647-001. In the Phase I Study, 
as of 17 April 2019 (refer to current IB for more details), a total of 25 participants with recurrent 
or persistent cervical cancer following standard of care treatment were treated for advanced 
disease. The median treatment duration was 9.6 (range 2.0 to 72.0) weeks. The results are 
summarized: 

Objective response rate (ORR) of 24% (95% CI: 9.4, 45.1) with 6 confirmed responses per 
Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); 5/6 responses 
were ongoing at data cutoff (median duration of response [DoR] not reached; range, 4.2 to 
30.4 months). 

One additional participant developed a partial response (PR) after initial confirmed disease 
progression, bringing the total clinical response rate to 28% (95% CI: 12.1, 49.4). This 
additional participant’s PR was ongoing for 8.7 months at data cutoff, with 73.3% disease 
shrinkage after initial progressive disease (PD). 
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4
Study Design
4.1
Overall Design
This Phase Ib open-label study is to evaluate the safety and tolerability of bintrafusp alfa in 
combination with other anti-cancer therapies in participants with locally advanced or advanced 
cervical cancer. Bintrafusp alfa will be combined with platinum therapy and paclitaxel with or 
without bevacizumab in participants with recurrent, persistent, or metastatic cervical cancer 
(Cohort 1A and 1B) or with platinum therapy and definitive radiation in participants with locally 
advanced cervical cancer (Cohort 2). Further combination regimens with other anti-cancer 
therapies may be added by protocol amendment. 
See Section 5 for more details on the patient population.
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This study will be conducted with Cohort 1 (Cohort 1A and Cohort 1B) and Cohort 2 in parallel. 
The allocation of participants to Cohort 1A or Cohort 1B will be based on Investigator decision 
and also other factors including but not limited to study inclusion/exclusion criteria and local 
standard of care.
Cohort 1
Participants must have primary Stage IVB, recurrent or persistent squamous cell carcinoma, 
adenosquamous carcinoma, or adenocarcinoma of the cervix not amenable to curative treatment 
with surgery and/or radiation therapy and not have been treated with systemic chemotherapy.

Cohort 1A: 8 participants will be treated with bintrafusp alfa (2400 mg every 3 weeks) + 
cisplatin or carboplatin + paclitaxel + bevacizumab. Selection of cisplatin or carboplatin is 
at the Investigator discretion. 

Cohort 1B: 8 participants will be treated with bintrafusp alfa (2400 mg every 3 weeks) + 
cisplatin or carboplatin + paclitaxel. Selection of cisplatin or carboplatin is at the 
Investigator discretion.
If the first 8 participants of each subcohort separately include fewer than 3 participants from Japan, 
the Sponsor may elect to continue enrollment in Japan to include at least 3 participants from Japan. 
If the first 8 participants of each subcohort separately include fewer than 3 participants from 
Europe or the United States, enrollment may continue in Europe and the United States to include 
at least 3 participants from any of these countries.
In cases where toxicity is readily attributable to 1 (or more) agents of the combination, it is 
acceptable to discontinue 1 (or more) agent while continuing other components of the combination 
treatment, if deemed appropriate by Investigator. Scan should be performed when any of the study 
intervention is discontinued (see Section 7.1 for details). 
Cohort 2: 
Participants with locally advanced cervical cancer will be treated with bintrafusp alfa (2400 mg 
every 3 weeks) combined with definitive radiation and radiation-sensitizing platinum therapy 
(cisplatin) during cCRT, followed by maintenance with bintrafusp alfa monotherapy (2400 mg
every 3 weeks). 
If the first 8 participants include fewer than 3 participants from Japan, enrollment may continue in 
Japan to include at least 3 participants from Japan to evaluate the safety of this combination in 
Japanese participants. If the first 8 participants of this cohort include fewer than 3 participants from 
Europe or the United States, enrollment may continue in Europe and the United States to include 
at least 3 participants from any of these countries.
The cCRT period is approximately 5 weeks plus any additional period for brachytherapy not 
exceeding a total of 8 weeks as detailed in Table 3 and Table 4. The cCRT period is considered 
from the first dose of radiation to the last dose of radiation or chemotherapy, whichever occurs 
last. The period for cCRT can be extended up to 1 week in case of technical and logistical issues 
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and if participants require withholding of the study intervention due to toxicities. 
In case cCRT is terminated early due to toxicity, participants in Cohort 2 are allowed to continue 
bintrafusp alfa; similarly, if bintrafusp alfa is discontinued, cCRT may continue. The first dose of 
bintrafusp alfa during maintenance should be at least 3 weeks from the last dose of bintrafusp alfa 
and not before tumor assessment and End-of-cCRT Visit has been performed. The first dose of 
maintenance bintrafusp alfa may be delayed to next scheduled dose if clinically indicated.
The overall study design is shown in Figure 1. A detailed Schedule of Activities is provided in 
Section 1.3.
The study includes:

Up to 28-day Screening period. Screening will be performed within 28 days prior to Day 1 
of study intervention administration. If there are no clinically significant findings at 
Screening and the individual meets all the protocol-defined inclusion and none of the 
exclusion criteria, the individual will be considered eligible for participation in the study. 
See Section 5.4 for screen failures.

The DLT (as defined in Section 6.6.2) observation period of 4 weeks from the Week 1, 
Day 1 (W1D1) visit for all cohorts.

Treatment until PD by RECIST 1.1 and subsequent confirmation (at the next imaging visit 
at least 28 days after the detection of PD), unacceptable toxicity, study withdrawal, or 
death. 

The treatments for Cohorts 1 (Cohort 1A and Cohort 1B) and 2 are as specified in
Section 1.3.

In case of PD, treatment may continue 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, and if other 
criteria are fulfilled as outlined in the protocol (see Section 7.1.3).

Cohort 1 participants will continue chemotherapy until complete response (CR) (as 
clinically indicated) and/or unacceptable toxicity due to chemotherapy, after which, 
bintrafusp alfa ± bevacizumab (depending on cohort) may be continued until 2 years or 
unacceptable toxicity as indicated for bintrafusp alfa and/or bevacizumab. If the 
Investigator believes that a participant may benefit from treatment beyond 2 years, it may 
be permissible to continue treatment after discussion with the Medical Monitor and the 
Sponsor’s Medical Responsible. 

Cohort 2 participants should continue maintenance treatment (bintrafusp alfa) for a 
maximum of 2 years (at the discretion of the Investigator). If the Investigator believes that 
a participant may benefit from treatment beyond 2 years, it may be permissible to continue 
treatment after discussion with the Medical Monitor and the Sponsor’s Medical 
Responsible. 

All participants should continue treatment until confirmed disease progression or any other 
discontinuation criterion is met (e.g., unacceptable toxicity, withdrawal of consent). 
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
Safety Follow-up Visits are at 28 days (± 5 days) and 12 weeks (± 2 weeks) after the last 
dose of study intervention according to the Schedule of Activities (see Section 1.3). The 
12-week Safety Follow-up is allowed to be conducted via telephone calls or patient chart 
reviews unless there is medical necessity requiring a clinical visit.

Long-term Follow-up should be performed every 12 weeks (± 2 weeks) after the Safety 
Follow-up according to the Schedule of Activities (see Section 1.3). Long-term Follow-up 
should be performed by chart reviews or telephone calls unless there is medical necessity 
requiring a clinical visit.

Survival Follow-up will continue until the end of study as defined in Section 4.4. After the 
stipulated end of study, Survival Follow-up may continue until the last participant has died 
or at the discretion of the Sponsor.
See Section 4.4 for the end of study definition.
4.2
Scientific Rationale for Study Design
4.2.1
Endpoints
The primary endpoint of the study is occurrence of DLTs and AEs.
4.2.2
Selection of Combination and Study Population
In Cohort 1, bintrafusp alfa will be combined with standard of care treatment regimens for 
participants with recurrent, persistent, or metastatic cervical cancer. The global Phase III Study 
GOG-240 evaluated cisplatin plus paclitaxel ± bevacizumab as well as nonplatinum containing 
doublet ± bevacizumab (Tewari 2017). The results have led to the wide use of carboplatin or 
cisplatin plus paclitaxel ± bevacizumab as a standard of care for the treatment of 
metastatic/recurrent/persistent cervical cancer. Bevacizumab use with this combination may vary 
depending on factors such as access and reimbursement depending on local restrictions as well as 
clinical conditions.  
Given the activity of bintrafusp alfa seen in more heavily pretreated cervical cancer participants, 
there is a rationale to combine an active, novel immunotherapy with a standard of care regimens 
(Cohort 1A: carboplatin or cisplatin plus paclitaxel and bevacizumab; Cohort 1B: carboplatin or 
cisplatin plus paclitaxel) in first-line recurrent, persistent or metastatic participants for evaluation. 
This study will assess the safety of this combination as well as antitumor activity, 
pharmacokinetics (PK), and immunogenicity.  
In Cohort 2, bintrafusp alfa will be combined with standard of care treatment for participants with 
locally advanced cervical cancer. Concurrent chemoradiotherapy using weekly cisplatin has been 
the backbone of standard of care treatment for patients with locally advanced cervical cancer for 
over 2 decades and continues to be the backbone for active investigation as to how to further refine 
and improve this regimen to build upon its success but also improve outcomes for patients. In this 
setting there is strong rationale to incorporate immunotherapies that may further enhance tumor 
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response. Incorporation of bintrafusp alfa is justified in this setting as early activity in more 
refractory patients shows promise in generating antitumor response. 
4.3
Justification for Dose
The dose for bintrafusp alfa in this study is 2400 mg administered as an intravenous infusion once 
every 3 weeks. Since most chemotherapies are administered every 3 weeks, the same dosing 
interval for bintrafusp alfa is preferred for convenience and compliance.
The 2400 mg every 3 weeks dose selection was based on the following:

Phase I data, population PK and exposure-response modeling and simulations were used 
to select 1200 mg every 2 weeks for bintrafusp alfa monotherapy studies and estimate target 
efficacious Ctrough,ss (refer to the IB). Specifically, the following data from Phase I
Study EMR200647-001 and Study 
 were used: safety/tolerability and PK, 
such as PD-L1 target occupancy in peripheral blood mononuclear cells and TGF-β trapping 
in blood, as well as efficacy in second-line NSCLC cohorts from Study EMR200647-001. 
Modeling and simulation were used to select 2400 mg every 3 weeks dose as the dose that
maintains target efficacious Ctrough,ss of bintrafusp alfa. Available safety/tolerability data at 
2400 mg dose and exposures associated with 2400 mg dose in monotherapy Phase I studies 
were evaluated. 

Assessment of potential of PK interactions and overlapping toxicities with chemotherapies
was conducted to support 2400 mg every 3 weeks dose of bintrafusp alfa in
Studies MS200647_0024 and MS200647_0055. 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 participants treated at lower doses (monotherapy 
setting). No new safety issues were observed in participants treated at a dose of 2400 mg
(see Section 2.2 and current IB for more details).  
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 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 3 years after treatment start of the last participant or 
until all the participants discontinued the study, whichever occurs first.
The Sponsor may terminate the study at any time once access to study intervention for participants 
still benefitting is provided via a rollover study, expanded access, marketed product, or another 
mechanism of access as appropriate. See 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 
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nonmedical conditions are considered when deciding whether a participant is suitable for this 
study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant or the participant’s legal representative (where 
allowed by local laws and regulations) has provided written informed consent, as indicated in 
Appendix 2.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are 18 years of age, at the time of signing the informed consent. In Japan, if a participant 
is at least 18 but < 20 years of age, written informed consent from her parent or guardian 
will be required in addition to the participant’s written consent.
Type of Participant and Disease Characteristics
a) Specifically, criteria for participants enrolling into Cohort 1:
2. Are participants with documented persistent, recurrent, or metastatic squamous cell 
carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix. 
3. Have not been treated with systemic chemotherapy (including neoadjuvant and adjuvant 
regimens) and is not amenable to curative treatment (such as with surgery and/or radiation). 
4. Prior radiation with or without radio-sensitizing chemotherapy is allowed. 
b) Criteria for participants enrolling into Cohort 2: 
5. Are participants with documented evidence of cervical adenocarcinoma, squamous cell 
carcinoma, or adenosquamous carcinoma FIGO 2018 (Bhatla 2019, Corrigendum 2019) 
Stages IB2 to IVA.
6. Have not received prior chemotherapy or radiotherapy for cervical cancer.
Criteria for all participants:
7. Archival tumor tissue sample or newly obtained (preferred) core or excisional biopsy of a 
tumor lesion is required and should be made available during the Screening period prior to 
enrollment. Specifications for tumor material are described in the Laboratory Manual. 
Patients for which a new biopsy is not possible or medically inadvisable, may be deemed 
eligible after consultation with the Medical Monitor/Sponsor. Participants enrolled in 
Cohort 1A should also consult Exclusion Criteria 26 with regards to timing of new biopsy.  
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8. Have ECOG PS of 0 to 1 at study entry and Day 1 of treatment with bintrafusp alfa. 
9. Life expectancy ≥ 12 weeks as judged by the Investigator.
10. Have adequate organ function:
a.
Adequate hematological function defined by absolute neutrophil count (ANC) 
≥1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL.
b.
Adequate hepatic function defined by a total bilirubin level ≤ the upper limit of normal 
(ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels 
≤1.5 × ULN and alkaline phosphatase ≤ 2.5 × ULN. For participants with liver 
involvement in their tumor, AST ≤ 5.0 × ULN, ALT ≤ 5.0 × ULN, and bilirubin 
≤3.0 × ULN are acceptable.
c.
Adequate renal function defined by creatinine ≤ 1.5 × ULN or calculated creatinine 
clearance (CrCL) ≥ 50 mL/min for participant with creatinine > 1.5 × ULN 
(glomerular filtration rate can also be used).
Note: CrCL should be calculated per institutional standard. If no local guideline is 
available, CrCL should be calculated using the Cockcroft-Gault Method:
CrCL = ([140-age] × weight [kg] × [0.85 for females only]) / (72 × creatinine)
d.
Adequate coagulation function defined as international normalized ratio (INR) or 
prothrombin time ≤ 1.5 × ULN unless the participant is receiving anticoagulant 
therapy, and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless the 
participant is receiving anticoagulant therapy.
11. Participants with known human immunodeficiency virus (HIV) infections are eligible if 
the following criteria are met (FDA Guidance on Cancer Clinical Trial Eligibility 2019):
a.
If clinically indicated, patients must be stable on antiretroviral therapy (ART) for at 
least 4 weeks and agree to adhere to ART. If not clinically indicated, consult Medical 
Monitor.
b.
Participants with HIV infection should have no evidence of documented multidrug 
resistance that would prevent effective ART.
c.
Have an HIV viral load of < 400 copies/mL at Screening. 
d.
Have CD4+ T-cell (CD4+) counts ≥ 350 cells/µL. 
e.
For patients with a history of an AIDS-defining opportunistic infection within the last 
12 months, patients may be eligible only after consultation and agreement with the 
Medical Monitor.  
f.
If prophylactic antimicrobial drugs are indicated, patient may still be considered 
eligible upon agreement with the Medical Monitor.   
12. Participants with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections are 
eligible if the following criteria are met (FDA Guidance on Cancer Clinical Trial Eligibility 
2019):
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a.
Patients with serologic evidence of chronic HBV infection must have an HBV viral 
load below the limit of quantification and, if medically indicated, be on a stable dose 
of antiviral therapy.
b.
Patients with a history of HCV infection should have completed curative antiviral 
treatment and require HCV viral load below the limit of quantification. 
c.
Patients on concurrent HCV treatment should have HCV below the limit of 
quantification.
Sex
13. Are female. 
A female is eligible if she is not pregnant or breastfeeding, and at least one of the 
following conditions applies:

Not a woman of childbearing potential 
OR
If a woman of childbearing potential, use a highly effective contraceptive method (i.e., 
with a failure rate of < 1% per year), preferably with low user dependency, as described 
in Appendix 3 for the following time periods: 
Before the first dose of the study intervention(s), if using hormonal contraception: 
Has completed at least one 4-week cycle of an oral contraception pill and either 
had or has begun her menses.
OR
Has used a depot contraceptive or extended-cycle oral contraceptive for least 
28 days and has a documented negative pregnancy test using a highly sensitive 
assay.
During the intervention period
After the study intervention period (i.e., after the last dose of study intervention is 
administered) for at least 2 months (6 months for participants who receive 
bevacizumab). Contraceptive measures should be continued as per guidance 
specified in labeling document for approved chemotherapies. If not specified, 
continue measures similar to the investigational agent, i.e., for at least 2 months 
(6 months for participants who receive bevacizumab) after the last dose of study 
intervention and agree not to donate eggs (ova, oocytes) for reproduction during 
this period.
The Investigator evaluates the effectiveness of the contraceptive method in relationship to 
the first dose of study intervention. 
Have a negative serum or highly sensitive urine pregnancy test, as required by local 
regulations, within 24 hours before the first dose of study intervention. If a urine test cannot 
be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required.
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Additional requirements for pregnancy testing during and after study intervention are in 
Sections 8.2.4 and 8.3.5.
The Investigator reviews the medical history, menstrual history, and recent sexual activity 
to decrease the risk for inclusion of a female with an early undetected pregnancy.
Informed Consent
14. Capable of giving signed informed consent, as indicated in Appendix 2, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
For all participants:
Medical Conditions
1. Participants with active central nervous system (CNS) metastases causing clinical 
symptoms or metastases that require therapeutic intervention are excluded. Participants 
with a history of treated CNS metastases (by surgery or radiation therapy) are not eligible 
unless they have fully recovered from treatment, demonstrated no progression for at least 
4 weeks, and are not using steroids for at least 7 days prior to the start of study intervention. 
2. Receipt of any organ transplantation, including allogeneic stem-cell transplantation, but 
with the exception of transplants that do not require immunosuppression (e.g., corneal 
transplant, hair transplant).
3. Significant acute or chronic infections including but not limited to: 
a. Participants with active tuberculosis (history of exposure or history of positive 
tuberculosis test; plus presence of clinical symptoms, physical, or radiographic findings).
b. Active bacterial or fungal infection requiring systemic therapy (except as indicated, 
discuss alternative scenarios with the Medical Monitor).
4. Active autoimmune disease that might deteriorate when receiving an immunostimulatory 
agent, except:
a. Participants with diabetes Type 1, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid 
disease not requiring immunosuppressive treatment are eligible.
b. Participants requiring hormone replacement with corticosteroids are eligible if the 
steroids are administered only for the purpose of hormonal replacement and at 
doses ≤10 mg of prednisone or equivalent per day.
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c. Administration of steroids for other conditions through a route known to result in a 
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.
5. Any history of anaphylaxis, or recent (within 5 months) history of uncontrollable asthma,
known severe hypersensitivity (Grade ≥ 3 National Cancer Institute-Common Terminology 
Criteria for Adverse Events Version 5.0 [NCI-CTCAE v5.0]) to any study intervention or 
any component in the formulations.
6. Persisting Grade > 1 NCI-CTCAE v5.0 toxicity (except alopecia and vitiligo) related to 
prior therapy; however, sensory neuropathy Grade ≤ 2 is acceptable.
7. Has drug-induced interstitial lung disease OR has had a history of drug-induced 
pneumonitis that has required oral or intravenous steroids.
8. Clinically significant cardiovascular/cerebrovascular disease including: cerebral vascular 
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior 
to enrollment), unstable angina, congestive heart failure (New York Heart Association 
Classification Class ≥ II), or serious cardiac arrhythmia. 
9. Participants with history of bleeding diathesis or recent major bleeding events (i.e.,
Grade ≥2 bleeding events in the month prior treatment) considered by the Investigator as 
high risk for investigational drug treatment are also excluded.
10. Severe and/or clinically relevant acute or chronic diseases which, in the opinion of the 
Investigator, might impair the participant’s tolerance for the study or ability to consistently 
participate in study procedures. 
Prior/Concomitant Therapy
11. Has received prior cancer treatment with any other immunotherapy or checkpoint 
inhibitors, such as anti-programmed death-1 (PD-1), anti-PD-L1, anti-PD-L2, 
anti-cytotoxic T-cell lymphocyte-associated antigen-4 (CTLA-4), or any other 
immune-modulating mAb (e.g., any other antibody or drug specifically targeting T-cell 
co-stimulation, checkpoint pathways or immune-suppressive pathways [e.g., TGF-β]). 
Also see Section 5.1.
12. Concurrent treatment with prohibited drugs (see Section 6.5.2). 
13. Systemic therapy with immunosuppressive agents within 7 days before the start of study 
intervention; or use of any investigational drug within 28 days before the start of study 
intervention. 
14. Has received or will receive a live vaccine within 30 days prior to the first administration 
of study intervention. Seasonal flu vaccines that do not contain a live virus are permitted. 
Prior/Concurrent Clinical Study Experience
15. Participants, who received chemotherapy, radiation therapy (with the exception of 
palliative radiotherapy delivered in a normal organ-sparing technique), or biological 
therapy (e.g., antibodies) within 4 weeks, or who have been treated with small molecule 
therapeutics or investigational agents within 4 weeks prior to starting bintrafusp alfa or 
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who have not recovered from the side effects of such therapy (except for alopecia or 
potentially neuropathy).
Other Exclusions
16. Major surgery within 28 days before the start of study intervention (diagnostic biopsy, for 
example, is not considered major surgery).
17. Pregnancy or breast feeding. 
18. Known active alcohol or drug abuse.
19. Grade ≥ 2 peripheral neuropathy as defined by NCI-CTCAE v5.0 criteria (paclitaxel).
Exclusion Specific to Participants Enrolling in Cohort 1A: 
Given the specific toxicities related to bevacizumab, the local physician is responsible for 
ensuring a participant is clinically appropriate to receive bevacizumab. The following specific
exclusion criteria are applicable only for participants enrolling in Cohort 1A (exclusion criteria
related to bevacizumab):
20. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg 
and/or diastolic blood pressure > 100 mmHg). Anti-hypertensive therapy to achieve these 
parameters is allowable.
21. Prior history of hypertensive crisis or hypertensive encephalopathy. 
22. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Screening.
23. History of hemoptysis (≥ one-half teaspoon of bright red blood per episode) within 1 month 
prior to Screening.
24. Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic 
anticoagulation).
25. Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for 
therapeutic purposes.

Prophylactic anticoagulation for the patency of venous access devices is allowed, 
provided the activity of the agent results in an INR < 1.5 × ULN and aPTT is within 
normal limits within 14 days prior to Screening. 

Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day) is 
permitted.
26. Core biopsy or other minor surgical procedure, excluding placement of a vascular access 
device, within 7 days prior to the first dose of bevacizumab.
27. History of abdominal or tracheoesophageal fistula or gastrointestinal (GI) perforation 
within 6 months prior to Screening.
28. Clinical signs of GI obstruction or requirement for routine parenteral hydration, parenteral 
nutrition, or tube feeding.
29. Evidence of abdominal free air not explained by paracentesis or recent surgical procedure.
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30. Serious, nonhealing wound, active ulcer, or untreated bone fracture. 
31. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine 
collection. All participants with ≥ 2+ protein on dipstick urinalysis at Baseline must 
undergo a 24-hour urine collection and must demonstrate ≤ 1 g of protein in 24 hours.
5.3
Lifestyle Considerations
Not applicable.
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once within 2 weeks from original screen failure date. Rescreened participants will be 
assigned a new participant number.
For the participants whose indication for screen failure may resolve (e.g., abnormal laboratory 
value that may correct, or prohibited concomitant medication that will be discontinued, or 
prohibited procedure that will be completed), Screening period may be extended for up to 2 weeks 
after discussion with the Medical Monitor. 
For participants who have been rescreened or their Screening period was extended, baseline tumor 
scans must be within indicated time window (See Section 1.3). 
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
Cohort 1A: the order of infusion is bintrafusp alfa bevacizumab cisplatin or carboplatin plus 
paclitaxel.
Cohort 1B: the order of infusion is bintrafusp alfa cisplatin or carboplatin plus paclitaxel.
Cohort 2: the order of treatment during cCRT is bintrafusp alfa cisplatin radiotherapy.
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6.1.1
Bintrafusp alfa
Table 7
Administration of Bintrafusp alfa (M7824)
Intervention Name
bintrafusp alfa (M7824)
Dose Formulation
Sterile concentrate solution for infusion
Unit Dose Strength(s)/ Dosage Level(s)
10 mg/mL in single-use glass vials
Route of Administration
Intravenous infusion
Dosing Instructions
Flat dose of 2400 mg administered over a minimum of 1 hour and 
up to 2 hours
Sourcing
Provided centrally by the Sponsor
Packaging and Labeling
Each vial will be packaged and labeled per all applicable 
regulatory requirements and Good Manufacturing Practice 
Guidelines.
Current experience in 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 (see Section 8.3.6.1).
If an Investigator deems necessary to administer a premedication 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) 30 to 60 minutes prior to bintrafusp alfa infusion is 
recommended. Premedication should be administered for subsequent bintrafusp alfa doses 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 corticosteroids.
6.1.2
Chemotherapy and Bevacizumab
Study interventions other than bintrafusp alfa are to be administrated as indicated for standard of 
care treatment. Refer to each agent´s Summary of Product Characteristics or package insert for 
more information. The descriptions below are general guidelines; modifications per local standard 
of care are allowed after prior agreement with the Sponsor medical representative.  
Depending on the local regulations, chemotherapy agent(s) may be either sourced from a local 
hospital pharmacy or supplied by the Sponsor (or designated service provider) and will be 
packaged/labeled according to local requirements. All participants may be premedicated with oral 
or injectable steroids according to the approved product label and/or standard practice. A 
corticosteroid-sparing approach for antiemetic prophylaxis should be preferred and evaluated on a 
case-by-case and chemotherapy regimen basis. Drugs used in premedication must be reported in 
the electronic case report form (eCRF). See specific labels for dose modification. 
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Cisplatin
Cisplatin is administered intravenously as per standard of care, for example 50 mg/m2 every 
3 weeks in Cohort 1 or 40 mg/m2 (a maximum of 70 mg as total dose) weekly for 5 weeks in 
Cohort 2. All the medications used as hydration (drugs and fluids) must be reported in the eCRF.
Carboplatin
Carboplatin is administered intravenously as per standard of care, for example AUC 5 every 
3 weeks in Cohort 1.
Paclitaxel
Paclitaxel is administered intravenously as per standard of care (e.g., 175 mg/m2 over 3 hours) 
every 3 weeks in Cohort 1.
Bevacizumab
Bevacizumab is to be administrated as indicated for standard of care treatment, 15 mg/kg every 
3 weeks in Cohort 1A. First infusion is to be administered over 90 minutes. Second infusion is to 
be administered over 60 minutes if first infusion was tolerated; all subsequent infusions are to be 
administered over 30 minutes if infusion over 60 minutes was tolerated.
6.1.3
Radiation
Radiation is intended to be administered per standard of care practices. As a general guideline, this 
is anticipated to be 40 to 50 Gy External Beam Radiation Therapy (EBRT). Brachytherapy is 
allowed per local standard of care with typical doses of 25 to 30 Gy. Variations to the 
guidelines/practices above are allowed after prior agreement with the Sponsor medical 
representative.
The Schedule of Activities (Section 1.3.2) reflects an example of standard of care EBRT 
administration of 5 fractions per week over 5 weeks. Radiotherapy should be completed within 
8 weeks. The period for cCRT can be extended up to 1 week in case of technical and logistical 
issues and if participants require withholding of the study intervention due to toxicities.
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 
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6.3
Measures to Minimize Bias: Study Intervention Assignment
and Blinding
6.3.1
Study Intervention Assignment
Participants will be assigned to each cohort based on the eligibility criteria and the Investigator’s 
assessment. The allocation of participants to cohorts per determination by the Investigator will be 
recorded in the Interactive Web Response System (IWRS). Enrollment will be controlled by IWRS 
to ensure that over enrollment into a single cohort does not occur.
The IWRS will be used to assign a unique participant identifier number to eligible participants at 
the time of informed consent signature. Participant identifiers will be comprised of digits 
representing the study number, the site number, and the participant number, which is allocated 
sequentially.
6.3.2
Blinding
This is an open-label study; thus, study intervention is not blinded to participants or Investigators. 
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 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.
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 eCRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
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Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Permitted Medicines
The only permitted medications are the following:
1. Any medications (other than prohibited in Section 6.5.2) that are considered necessary for 
the participants’ welfare and will not interfere with the study intervention may be given at 
the Investigator’s discretion.
2. Other drugs to be used for non-steroid premedication (antihistamine and acetaminophen) 
for the treatment of anaphylactic reactions, IRRs, and severe hypersensitivity 
reactions/flu-like symptoms and irAEs (see Section 8.3.6).
3. Blood transfusions and erythroid growth factors are permitted as clinically indicated.
4. Secondary prophylaxis with granulocyte-colony stimulating factor (G-CSF) is allowed if 
clinically indicated per Investigator assessment.
5. Corticosteroids use on study as a premedication for intravenous contrast allergies/reactions 
(related to scans).
6. Corticosteroids use for hormonal replacement and at low doses (typically ≤ 10 mg of 
prednisone or equivalent per day).
7. Administration of steroids through a route known to result in a minimal systemic exposure 
(topical, intranasal, intraocular, or inhalation) is acceptable.
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.
6.5.2
Prohibited Medicines
The following treatments must not be administered during the 28-day Screening period and for the 
duration of study intervention. If the administration of a nonpermitted concomitant drug becomes 
necessary during the study, the participant will be withdrawn from study intervention (the Sponsor 
may be contacted to discuss whether the study intervention must be discontinued).

Immunotherapy, 
immunosuppressive 
drugs 
(e.g., 
chemotherapy 
or 
systemic 
corticosteroids), or other experimental pharmaceutical products are prohibited. Exceptions 
are allowed for short-term treatment of allergic reactions, as otherwise described in the 
protocol, or for the treatment of irAEs, specifically:
o
Short-term administration of systemic steroid (i.e., for allergic reactions, for 
prophylaxis and management of radiographic contrast allergy or the management 
of irAEs) is allowed. 
o
Steroids with no or minimal systemic effect (topical, intranasal, intro-ocular, 
inhalation) are allowed.
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
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 prednisolone per day.

Premedication with steroids for bintrafusp alfa is not allowed.

Concomitant local or regional treatment (radio/chemo-embolization) is prohibited.

Other systemic anti-cancer therapy.

Live vaccines are prohibited. Administration of inactivated vaccines is allowed (e.g., 
inactivated influenza vaccines).

Any traditional Chinese medication used as anti-cancer treatment (regardless of the type of 
cancer) is prohibited. Traditional Chinese medication for indications other than anti-cancer 
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, antinausea medications, antihistamines, diuretics, antianxiety 
medications, and medication for pain management, including narcotic agents.
6.5.3
Other Interventions
Palliative organ-sparing radiotherapy may be administered only for specific clinical indications 
during the study. The assessment of PD will be made according to RECIST 1.1 and not based on 
the necessity for palliative radiotherapy.
6.6
Dose Selection and Modification
Doses cannot be delayed beyond the treatment window. Participants must skip dose if the treatment 
window is missed. Every attempt should be made to perform applicable assessments as in 
Section 1.3 for any missed visits. Complete the next visit following the Schedule of Activities.
Dose modification of bintrafusp alfa is not allowed. For other study interventions used in this 
study, dose modification may be performed as per label.
6.6.1
Safety Monitoring Committee
During this study, the SMC will periodically evaluate the safety (including DLTs) and other 
available data. Evaluations will be done once the 3rd as well as the 8th evaluable participant of a 
respective cohort has finished the DLT period.
The SMC will decide if the combinations as defined in this protocol should be continued and are 
safe for future studies. The SMC will recommend appropriate risk mitigation measures, if 
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necessary. Furthermore, if deemed appropriate by SMC, additional participants could be enrolled 
to further evaluate the safety of a specific cohort. All participants will be reviewed by the SMC 
once the last evaluable participant has completed the DLT period.
Specifically, the SMC will evaluate:

If DLTs are observed in ≥1 out of 3 participants or ≥3 of the 8 participants, respectively, 
the SMC will give a recommendation regarding clearing the corresponding combination or 
risk mitigation measures, as appropriate, based on a review of all relevant parameters 
including AEs and serious adverse events (SAEs) and risk-benefit assessment for that 
cohort. Furthermore, if deemed appropriate by SMC, additional participants could be 
enrolled to further evaluate the safety of a specific cohort.

The corresponding combination will be cleared when DLTs are observed in ≤ 2 out of 
8 participants. 
The probability for observing DLTs in ≥ 3 out of 8 participants is 4% if the underlying true rate is 
10%, increases to 52% if the underlying true rate is 33%. Similarly, the probability for observing 
DLTs in ≥ 1 out of 3 participants is 27% if the underlying true rate is 10%, increases to 70% if the 
underlying true rate is 33% and to 78% if the underlying true rate is 40%. 
The specific working procedures including the full membership, mandate, and processes will be 
described in an SMC charter, which will be established before first informed consent signed.
6.6.2
Definition of Dose-limiting Toxicity 
This is not a dose escalation study. However, this study is evaluating DLTs in order to assess the 
safety and tolerability of the combination of bintrafusp alfa plus existing standard of care 
treatments in Cohort 1 (Cohort 1A and Cohort 1B) and 2 (treatments are described in Section 4.1). 
A DLT is defined as any of the following AEs according to the NCI-CTCAE v5.0 assessed by the 
Investigator and/or the Sponsor and judged to be related to study intervention occurring during the 
DLT observation period of 4 weeks following the first dose of bintrafusp alfa (W1D1 visit) for 
each participant.
A DLT must be confirmed by the SMC.
During the DLT observation period, in the event a participant discontinues for reasons other than 
AE or is otherwise non-evaluable, the Sponsor may elect to add an additional participant. 
Participants with severe hypersensitivity reaction to paclitaxel during the DLT period should be 
discontinued from study and replaced for DLT assessment.
DLTs are defined as:

Grade 4 nonhematologic toxicity (not laboratory)

Grade 4 hematologic toxicity lasting ≥7 days despite medical intervention

Grade 3 nausea, vomiting, and diarrhea lasting ≥3 days despite optimal supportive care
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
Any Grade 3 or Grade 4 nonhematologic laboratory value if:
o
The abnormality leads to hospitalization, or
o
The abnormality persists for ≥7 days

Febrile neutropenia Grade 3 or Grade 4:
o
Grade 3 is defined as ANC < 1,000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥ 38°C (100.4°F) for more than 1 hour
o
Grade 4 is defined as ANC < 1,000/mm3 with a single temperature of > 38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated

Thrombocytopenia < 25,000/mm3 if associated with:
o
A bleeding event which does not result in hemodynamic instability but requires an 
elective platelet transfusion, or
o
A life-threatening bleeding event which results in urgent intervention and 
admission to an intensive care unit

Bleeding events ≥ Grade 3 that occur within 5 days of bintrafusp alfa treatment (regardless 
of causality)

Prolonged delay (> 3 weeks) in initiating Cycle 2 due to treatment-related toxicity

Grade 5 toxicity
The following are NOT considered as DLTs:

Grade 3 IRRs resolving within 6 hours from the end of infusion and controlled with medical 
management.

Transient (< 3 days) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolves 
to Grade ≤ 1.

Transient (< 2 days) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management.

Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor that resolve to Grade ≤2 within 7 days.

Skin lesion related to TGF-β inhibition (i.e., keratoacanthoma [KA], squamous cell 
carcinoma) that is local and can be resected with negative resection margins.

Grade 3 skin toxicity other than radiation dermatitis that resolves to ≤ Grade 1 in less than 
7 days after medical management (e.g., immunosuppressant treatment) has been initiated.

Grade 3 radiation dermatitis that resolves to Grade ≤2 with supportive measures within 
5 weeks.

Grade 3 asymptomatic increases in liver function tests: AST, ALT, alkaline phosphatase,
or lipase that resolve to ≤ Grade 1 within 7 days after medical management (e.g.,
immunosuppressant treatment) has been initiated.
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
Single laboratory values out of normal range that are assessed as unrelated to study 
intervention according to the Investigator and/or do not have any clinical correlate and 
resolve to ≤ Grade 1 within 7 days with adequate medical management.

Grade 3 diarrhea persisting < 3 days after initiation of medical management.

Isolated Grade 4 lymphopenia without clinical correlate.

Any Grade 3 autoimmune thyroid-related toxicity that clinically resolves to ≤ Grade 2 
within 7 days of initiating therapy.

Any death due to the underlying disease or extraneous causes.
Additionally, the SMC may identify DLT as:

Related AEs (outside of the DLT period) that in the opinion of the SMC is of potential 
clinical significance and considered to reflect an unacceptable risk.
6.7
Study Intervention After the End of the Study
After a participant has completed the study, has withdrawn consent, or has been withdrawn early, 
symptom guided appropriate treatment will be administered, if required, in accordance with the 
study site’s standard of care and generally accepted medical practice and depending on the 
participant’s individual medical needs.
On withdrawal from the study, participants may receive care they and their physicians agree upon.
The Sponsor will not provide any additional care to participants after they leave the study because 
such care would not differ from what is normally expected for patients with advanced cervical 
cancer.
6.8
Special Precautions
6.8.1
General Guidance
In any case, if ≥2 doses of bintrafusp alfa are missed due to AE, the Medical Monitor should be 
consulted. The Medical Monitor should also be notified in the event of significant delay/omission 
of standard of care therapy due to AE. 
During the DLT period, if one drug in a combination is delayed due to toxicity in a participant, the 
other drugs in the combination should be delayed in the participant. After the DLT period, if one 
drug in a combination needs to be delayed, the Medical Monitor should be consulted if the 
participant should be allowed to receive other drugs in the combination.
6.8.2
Bintrafusp alfa
Any treatment-emergent adverse event (TEAE) that is assessed as related to bintrafusp alfa, may 
require permanent or transient discontinuation of bintrafusp alfa treatment. 
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Single laboratory values out of the normal range that do not have any clinical correlate do not 
necessarily need treatment interruption. Questions or concerns with regard to management and/or 
follow-up of TEAEs should be discussed with the Medical Monitor.
Immune-related AEs, IRRs including hypersensitivity, anemia, TGF-β inhibition mediated skin 
reactions, and bleeding events are managed and followed up in their respective sections as 
indicated below. Permanent study intervention discontinuation may be recommended, so the 
relevant section must be reviewed:

For suspected irAEs, general management by NCI-CTCAE v5.0 toxicity grading is listed 
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 guidance are presented in Section 8.3.6.1.

Anemia guidance is presented in Section 8.3.6.4.

Potential TGF-β inhibition mediated skin reactions guidance and management are provided 
in Section 8.3.6.3.

For guidance and management of bleeding events, see Section 8.3.6.5. 
General guidance for bintrafusp alfa:
Inability to reduce corticosteroid dose to 10 mg or less of prednisolone or equivalent per day 
within 12 weeks after an irAE is an indication for permanent treatment discontinuation (except 
for use of steroids as hormone substitution).
Persistent endocrinopathies controlled with hormone replacement therapy generally do not 
require permanent treatment discontinuation, however, persistent Grade 2 treatment-related 
AEs that either do not resolve or improve to Grade 1 within 12 weeks after last dose of study 
intervention is an indication for permanent treatment discontinuation.
In general, the following applies for TEAEs related to bintrafusp alfa that are not covered by the 
recommendations for irAE management in
the current NCCN guideline available at 
http://www.nccn.org:
Grade 4 treatment-related TEAEs
1. 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 alternative explanation is identified for Grade 4 non-tumor bleeding.
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See the current NCCN guideline available at http://www.nccn.org for guidance on specific Grade 
4 irAEs, as most require permanent treatment discontinuation.
Grade 3 treatment-related TEAE 
1. Participants with any recurrent Grade 3 treatment-related AEs that recur should be 
permanently discontinued. Exceptions may be considered for the following after discussion 
with Medical Monitor:
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 decrease (< 8.0 g/dL) that is clinically manageable with blood 
transfusions or erythroid growth factor use.
f.
Increases in ECOG PS ≥3 that resolves to ≤2 by Day 1 of the next infusion (i.e., 
infusions should not be given if the ECOG PS is ≥3 on the day of treatment and should 
be delayed until ECOG PS ≤2).
g. Keratoacanthoma 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.). 
2. AST or ALT > 5 times ULN or total bilirubin > 3 times ULN must be permanently 
discontinued, except for participants with liver metastases (for example) who begin 
treatment with Grade 2 AST or ALT. These participants should be discontinued if AST or 
ALT increases by ≥50% relative to baseline and lasts for at least 1 week.
3. Persistent Grade 3 AEs (excluding endocrinopathies controlled with hormone replacement 
therapy) that either do not resolve or improve to Grade 1 within 12 weeks after last dose of 
treatment must be permanently discontinued. 
See the current NCCN guideline available at http://www.nccn.org for guidance on specific Grade 3 
irAEs as many require permanent treatment discontinuation, including pneumonitis and nephritis.
Grade 2 treatment-related TEAE
1. If a Grade 2 treatment-related TEAE resolves to Grade ≤ 1 by the day before the next 
infusion, study intervention may be continued.
2. If a Grade 2 treatment-related TEAE does not resolve to Grade ≤ 1 by the day before the 
next infusion, but it is manageable and/or not clinically relevant, the Medical Monitor 
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should be consulted to assess if it is clinically reasonable to administer the following 
infusion.
Note that treatment recommendations regarding continuation, hold, or discontinuation by grade 
are different depending on the specific toxicity (see the current NCCN guideline available at 
http://www.nccn.org). Toxicity grading is assigned based on NCI-CTCAE v5.0. 
6.8.3
Bevacizumab
Participants who receive bevacizumab must be monitored as per local standards and approved 
labeling documents recommendations for GI perforations, GI, GI-vaginal and tracheoesophageal
fistula, wound healing complications, hemorrhage, arterial and venous thromboembolic events, 
hypertension, posterior reversible encephalopathy syndrome, renal injury and proteinuria, IRRs, 
embryofetal toxicity, ovarian failure, congestive heart failure.
6.8.3.1
Risk Management for Bevacizumab
In general, bevacizumab will not be dose reduced; however, if the patient’s weight changes by 
≥10% during the study, the dose of bevacizumab will be recalculated.
If chemotherapy is held for a low ANC or thrombocytopenia, bevacizumab will also be held.
Bevacizumab should be withheld or discontinued according to approved product label and/or 
standard practice for GI perforations and fistulae, wound healing complications, hemorrhage, 
thromboembolic events, hypertension, posterior reversible encephalopathy syndrome, renal injury 
and proteinuria, IRR, and congestive heart failure. 
6.8.4
Cisplatin, Carboplatin, and Paclitaxel
Cisplatin
Participants who receive cisplatin must be monitored for nephrotoxicity, ototoxicity, neuropathy, 
and hepatic toxicities in addition to myelosuppression and hypersensitivities, including 
anaphylaxis. Cisplatin should not be employed in participants with hearing impairment. Caution 
must be observed in case of nausea, vomiting, and dehydration. Premedication with antiemetics 
and hydration and other precautionary measures are performed according to local standards and 
approved labeling documents.
Carboplatin
Participants who receive treatment with carboplatin should be monitored for symptoms of 
myelosuppression and hematologic toxicities, hypersensitivity reactions, nausea and vomiting,
hepatic toxicity/portal hypertension, renal toxicity, ototoxicity,
central and peripheral 
neurotoxicities as per labeling recommendations. Hemolytic uremic syndrome has been reported 
rarely. Precautionary measures and premedication with antiemetics should be performed according 
to approved label and local treatment standards. Use of desensitization protocols according to local 
standards and approved labeling documents is allowed.
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Paclitaxel
Participants who receive treatment with paclitaxel should be monitored for severe hypersensitivity 
reactions including anaphylaxis. All participants should be pretreated with corticosteroids, 
diphenhydramine, and H2 antagonists as per labeling recommendations. Participants who 
experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with the drug.
It is required to monitor for myelosuppression, cardiac function, and peripheral neuropathies. 
Precautionary measures as per local standards and approved labeling documents have to be 
followed.
6.8.4.1
Risk Management for Chemotherapy
Refer to the respective label for a full list of adverse reactions for each of the chemotherapy agent 
used in this study. 
The Investigator should consider chemotherapy discontinuation for any of the following:

Any drug-related AE which recurs after 2 prior dose reductions for the same drug-related 
AE requires discontinuation of the chemotherapy agent(s) which was/were previously dose 
reduced. 

Any Grade ≥ 3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the chemotherapy agent(s) assessed as causing the reaction. The other 
study intervention(s) assessed as not related to the hypersensitivity reaction or infusion 
reaction may be continued. 

Any Grade 4 drug-related AE deemed by the Investigator as inappropriate to be managed 
by dose reduction(s) requires discontinuation of chemotherapy agent(s) assessed as causing 
the event. The other study intervention(s) assessed as not related to the event may be 
continued.

Any event that leads to delay in dosing of any study intervention(s) for > 3 weeks from the 
day of scheduled administration requires discontinuation of the chemotherapy agent(s) 
with the following exception: 
o
Dosing delays lasting > 2 weeks from the scheduled administration that occur for 
non-drug-related reasons may be allowed after discussion with Medical Monitor. 

Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued 
chemotherapy dosing. Investigators should consult the local labeling for the chemotherapy 
drugs being administered to any given participant for additional guidance on dose 
discontinuation.

If the participant experienced Grade 3 or 4 nonhematological toxicity (except for fatigue, 
transient arthralgia, and myalgia), treatment with chemotherapy should be withheld until 
the participant recovers completely or to Grade 1 toxicity. If recovery to Grade 1 toxicity 
does not occur within 2 weeks, chemotherapy should be discontinued. At the discretion of 
the Investigator, administration of bintrafusp alfa could be continued according to the 
treatment schedule. A discussion between the Investigator and Sponsor's Medical 
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Responsible should take place. Dose delays outside the allowed window (± 3 days) and 
dose reductions for bintrafusp alfa are not permitted.
Dose modifications (dose delays) and dose reductions for toxicities should be made according to 
the approved product label(s) and/or standard practice. Discontinuation of chemotherapy due to 
AEs should also be done in accordance with the approved product label and/or standard practice 
and discussed with the Sponsor.

See Table 8 for predosing considerations for cisplatin.

See Table 9 for predosing considerations for carboplatin.
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Table 8
Predosing Consideration for Cisplatin
Issue/Indication
Recommended Steps
Pre-emesis
Follow current MASCC/ESMOa or NCCNb guidelines for chemotherapy-induced 
nausea and vomiting for a “high risk” regimen
Hydration/
nephrotoxicity
Per package insert/SmPC for cisplatinc. Cisplatin causes severe cumulative 
nephrotoxicity. A urine output of 100 mL/hour or greater will tend to minimize 
cisplatin nephrotoxicity. Adequate hydration must therefore be maintained to 
cause sufficient diuresis prior to, during and after treatment with cisplatin. Next to 
intravenous infusion, forced diuresis may be required and moreover participants 
are to be requested to drink appropriate quantities of liquids for 24 hours after 
cisplatin infusion to ensure adequate urine secretion.
Some institute may provide inpatient planned hydrated to reduce the risk of renal 
toxicity due to cisplatin; such planned hospital admission will not be considered 
for SAE reporting criteria.
Myelosuppression/
neutropenia
Refer to the current package insert/SmPC for modifications in dose and 
schedule of cisplatinc. First dose of cisplatin should be withheld if platelet count 
is less than 100,000 cells/mm3 or neutrophil count is less than 1,500 cells/mm3. 
Dose modifications for subsequent administrations will be based on the 
neutrophil and platelet nadir from the preceding cycle.
According to NCI-CTCAE v5.0 FN is defined as ANC < 1,000/mm3 and a single 
temperature of > 38.3°C (101°F) or a sustained temperature of ≥ 38°C (100.4°F) 
for more than 1 hour. FN treatment should be done per local practice and 
reported in eCRF. FN Prophylaxis: Primary prophylaxis with G-CSF in order to 
reduce the risk of FN is not recommended, according to NCCN guidelines for the 
use of myeloid growth factors (v1.2018)d. Secondary prophylaxis with G-CSFs 
should be considered and the benefit-risk associated with their use must be 
carefully evaluated. Investigators must be aware that the use of G-CSF during 
chemoradiation is associated with increased of increased incidence of severe 
thrombocytopenia and anemia. Participants receiving G-CSF during 
chemoradiation must be closely monitored for these adverse events. The 
dosage instructions should follow the local guidelines or the NCCN guidelines. 
Ototoxicity/
neurotoxicity
Per SmPC for cisplatinc. Cisplatin is proven to be cumulative ototoxic and 
neurotoxic. Neurologic examination and monitoring of potential ototoxicity are to 
be performed prior to each cisplatin dosing and during the treatment.
ANC=absolute neutrophil count, ASCO=American Society of Clinical Oncology, eCRF=electronic case report form, 
ESMO=European Society for Medical Oncology, FN=febrile neutropenia, G-CSF=granulocyte-colony stimulating 
factor, MASCC=Multinational Association of Supportive Care in Cancer, NCI-CTCAE=National Cancer 
Institute-Common Terminology Criteria for Adverse Events, NCCN=National Comprehensive Cancer Network, 
SAE=serious adverse events, SmPC=summary of product characteristics.
a Annals of Oncology 21 (Supplement 5): v232–v243, 2010.
b NCCN Guideline for Patients® - Antiemesis version 1/2019.
c https://www.medicines.org.uk/emc/medicine/25944.
d NCCN guidelines Myeloid growth factors version 1, 2018.
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Table 9
Predosing Consideration for Carboplatin
Adverse Reaction
Recommended Steps
Nausea or vomiting
Follow current MASCC/ESMO or NCCNa guidelines for chemotherapy-induced
nausea and vomiting for a “high risk” regimen.
Hematological toxicities
Per package insert/SmPC of carboplatinb can cause leukopenia, neutropenia,
and thrombocytopenia which are dose-dependent and dose-limiting. Peripheral
blood counts should be monitored before start of treatment with carboplatin and
then at weekly intervals and, in case of toxicity, until recovery is achieved.
Neurotoxicity
Refer to the current package insert/SmPC and local guidance for modifications
in dose and schedule. Carboplatin dose should be reduced for Grade 3 or
Grade 4 neurotoxicity.
Renal toxicity
Per SmPC of carboplatin, impairment of renal function is more likely in patients
who have previously experienced nephrotoxicity as a result of cisplatin therapy.
Dosage reduction or discontinuation of carboplatin therapy is required in the
presence of severe alteration in renal function tests.
Ototoxicity
Auditory defects have been reported during carboplatin therapy; concomitant
use of Carboplatin with aminoglycosides should be approached with caution
because of nephrotoxicity and ototoxicity, particularly in patients with kidney 
failure.
ESMO=European Society for Medical Oncology, MASCC = Multinational Association of Supportive Care in 
Cancer, NCCN=National Comprehensive Cancer Network, SmPC = summary of product characteristics.
a NCCN Guidelines Antiemesis version 2/2016.
b https://www.medicines.org.uk/emc/product/3787/smpc.
Carboplatin should be discontinued in case of severe and persistent myelosuppression as per SmPC 
recommendation.
Calculated CrCL must be ≥ 50 mL/min prior to the administration of platinum chemotherapy. 
Platinum may be delayed for up to 2 weeks to allow the participant time to recover from the 
toxicity. If a participant’s CrCl value has not returned to ≥ 50 mL/min within 2 weeks after the 
previous dose, platinum must be discontinued. 
For treatments held due to toxicity, treatment should be resumed only after toxicity has decreased 
to Grade ≤1. Toxicities that are not able to resolve to Grade ≤1 within 2 weeks should warrant 
consideration for discontinuing agent(s) responsible for toxicity.  
Cardiac rhythm disturbances have occurred infrequently in patients treated with paclitaxel in 
clinical studies; however, most patients were asymptomatic, and cardiac monitoring is not 
required. Cardiac events should be managed as follows: 

Asymptomatic bradycardia: no treatment required.

Symptomatic arrhythmia during infusion: stop paclitaxel infusion, manage arrhythmia 
according to standard practice. Paclitaxel treatment will be discontinued. 

Chest pain and/or symptomatic hypotension (< 90/60 mmHg or requires fluid 
replacement): stop paclitaxel infusion. Perform an electrocardiogram (ECG). Administer 
intravenous diphenhydramine and dexamethasone if hypersensitivity is considered. Also 
consider epinephrine or bronchodilators if chest pain is not thought to be cardiac. Paclitaxel 
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treatment will be discontinued, and cardiovascular support should be given as appropriate. 
If appropriate, the advice of a cardiologist should also be sought. 
Patients who had a mild to moderate hypersensitivity reaction to paclitaxel have been successfully 
rechallenged, but the administration of prophylactic medication and intensive monitoring of vital 
signs is recommended:

Mild symptoms: complete paclitaxel infusion. Supervise at bedside. No treatment required. 

Moderate symptoms: stop paclitaxel infusion. Administer intravenous diphenhydramine 
25 to 50 mg and dexamethasone 10 mg. Resume paclitaxel infusion after recovery of 
symptoms at a low rate, 20 mL/hour for 15 minutes, then 40 mL/hour for 15 minutes, then 
if no further symptoms, at full-dose rate until infusion is complete. If symptoms recur, stop 
paclitaxel infusion. Paclitaxel treatment will be discontinued. 

Severe life-threatening symptoms: stop paclitaxel infusion. Administer intravenous
diphenhydramine and dexamethasone as above. Add epinephrine or bronchodilators if 
indicated. Paclitaxel treatment will be discontinued. 

Moderate or severe hypersensitivity reactions should be recorded as an AE.
6.8.5
Chemoradiation
Toxicities of cCRT may arise to different degrees at different timepoints in various subpopulations 
and scenarios. First, with regards to chemotherapy, the presence of important variables such as 
age, PS, and pre-existing comorbidities plays a large role in how well the participants can tolerate 
cCRT. Some participants may also benefit from chemotherapy alterations in doses, intervals or 
even specific compounds and regimens. Second, from the radiotherapy perspective, because 
advanced radiotherapy techniques have developed, and image-guided radiotherapy has now 
become the standard of care, fewer radiotherapy-related toxicities are expected (Verma 2017). 
Risk management of chemoradiation side effects mainly includes early detection, study 
intervention modification and prompt toxicity management. If feasible, radiotherapy interruptions 
and dose reductions for manageable acute toxicities should be avoided by employing supportive 
care.
Management and work-up must be done in accordance with labeling instructions and local 
institutional guidelines and in discussion with the Medical Monitor. 
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Participants may be discontinued from study intervention for any of the following reasons, one 
reinitiating course of treatment may be allowed (see Section 7.1.2).

A participant may discontinue from the study intervention at any time at her own request 
(i.e., withdrawal of consent), and without giving a reason.
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
Occurrence of an exclusion criterion, which is clinically relevant and affects the 
participant's safety, if discontinuation is considered necessary by the Investigator and/or 
Sponsor.

A participant may be discontinued at any time at the discretion of the Investigator for 
safety, behavioral, compliance, or administrative reasons (see Sections 6.8, 8.3.6, and 
8.3.6.5 for TEAEs and adverse events of special interest [AESIs] that require treatment 
discontinuation). 

Progressive Disease per RECIST 1.1, subsequently confirmed, with the exception that 
participants receiving treatment may continue past PD if the participant’s ECOG PS has 
remained at least stable, and if in the opinion of the Investigator, the participant will benefit 
from continued treatment (see Section 7.1.3 for all details).

Unacceptable toxicity.

Some TEAEs and AESIs require withdrawal from treatment. See Sections 6.8, 8.3.6, and 
8.3.6.5 for additional details. Participants who discontinue study intervention will be 
followed on study until resolution of toxicity or until disease progression.

Drug must not be given to a known pregnant participant.

Use of a prohibited concomitant drug, as defined in Section 6.5.2, if discontinuation is 
considered necessary by Investigator/Sponsor.

Participants should be discontinued per discontinuation recommendation in approved 
labeling documents for chemotherapies and bevacizumab.
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for follow-up. The Schedule of Activities
indicates data to be collected at the time of discontinuation of study intervention and follow-up 
and for any further evaluations that needs to be completed.
In case of discontinuation from the study intervention(s):

For participants in Cohort 1A, a scan should be performed within approximately 2 weeks 
when any drug of the combination is discontinued. Scheduling this scan should be 
evaluated based on current timing relative to next planned scan and/or most recently 
completed scan. In situations where local regulations do not permit this additional scan, 
omission will not be a deviation. The rest of the treatments should continue to follow 
Schedule of Activities.

For participants in Cohort 1A, a scan should be performed when any regimen of the 
combination is discontinued, the rest of the treatment should follow Schedule of Activities. 

The day of End-of-Treatment will correspond to the day of withdrawal (or within 7 days)
when all study interventions in a participant are discontinued.  

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. 
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
Participants will be asked to continue Safety and Survival Follow-up. After completion of 
the follow-up period or after the End-of-Treatment Visit, whichever is applicable, the 
appropriate eCRF section for Study Termination must be completed. 

If the participant is enrolled into a new study or any new therapy post-withdrawal from 
study intervention, the Safety Follow-up Visit should be scheduled prior to the start of the 
new treatment irrespective of the 28-day Safety Follow-up period. 
The Schedule of Activities specifies the data to collect at study intervention discontinuation and 
follow-up, and any additional evaluations that needs to be completed.
7.1.1
Temporary Discontinuation
See Sections 6.8, 8.3.6, and 8.3.6.5 for guidance on temporary discontinuation from study 
intervention. 
7.1.2
Reinitiation
One reinitiating course of treatment of bintrafusp alfa at the same dose and schedule is allowed at 
the discretion of the Investigator and agreement of the Study Medical Responsible for: 

Participants who are experiencing stable disease (SD), a PR, or CR at the time of 
discontinuation, and then subsequently develop disease progression after stopping therapy, 
but prior to the end of the study.
The participant should reinitiate treatment at the treatment phase visit where they left off according 
to the Schedule of Activities (see Section 1.3). Participants who reinitiate treatment should stay on 
study and should be treated and monitored according the Schedule of Activities for the rest of the 
study.
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. A discussion with the 
study team is warranted to determine whether PK/biomarker testing is indicated upon restarting 
treatment.
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7.1.3
Treatment Beyond Progression
7.1.3.1
Treatment Beyond Initial Progression
Participants will receive bintrafusp alfa as outlined in the Schedule of Activities until disease 
progression. Bintrafusp alfa may continue past the initial determination of disease progression 
according to RECIST 1.1 as long as the following criteria are met:

Treatment with bintrafusp alfa is ongoing

No new unacceptable treatment or disease-related toxicity

Tolerance of study interventions

At least stable ECOG PS

Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (e.g., CNS metastases).
A radiographic assessment should be performed within 4 to 9 weeks of original PD to determine 
whether there has been a decrease in the tumor size, or continued PD. The assessment of clinical 
benefit should be balanced by clinical judgment as to whether the participant is clinically 
deteriorating and unlikely to receive any benefit from continued treatment with bintrafusp alfa.
7.1.3.2
Treatment Beyond Confirmed Progression
After confirmed PD, if the Investigator feels that the participant continues to achieve clinical 
benefit by continuing treatment, the participant should remain on the study and continue to receive 
monitoring according to the Schedule of Activities (see Section 1.3). The decision to continue 
treatment beyond confirmed PD should be discussed with the Medical Monitor and documented 
in the study records.
Participants who continue beyond progression will be evaluated for further tumor response as per 
the protocol schedule. Treatment should be discontinued permanently upon documentation of 
further, unequivocal disease progression unless there are no alternative therapeutic options and the 
benefit-risk assessment is favorable in consultation between the Investigator and the Medical 
Monitor. In case of continuation of treatment beyond PD, treatment will be discontinued once any 
other criteria for withdrawal are met.
7.1.3.3
Continuation of Study Intervention After Local Treatment of 
Disease Progression
If disease progression is due to brain metastases, participants may continue study interventions 
after the local treatment of the brain lesions provided that the above criteria are met in addition to 
the following:

Tumor assessment showing disease progression has been performed and was documented 
according to RECIST 1.1. prior to the procedure.
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
Brain metastases have been treated locally and are clinically stable for at least 2 weeks 
prior to reinitiation of study interventions. 

There are no ongoing neurological symptoms that are related to the brain localization of 
the disease (sequelae that are a consequence of the treatment of the brain metastases are 
acceptable).

Participants must be either off steroids or on a stable or decreasing dose of ≤ 10 mg daily 
prednisone (or equivalent).  

Benefit-risk assessment to continue study intervention is favorable 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 1.1 prior to the procedure.

It has been at least 2 weeks and the participant has fully recovered from the surgery.

Benefit-risk assessment to continue study intervention is favorable under consideration of 
any alternative treatment options as assessed by the Investigator.
7.2
Participant Discontinuation/Withdrawal From the Study

A participant may withdraw from the study at any time, at her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons.

At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the Schedule of Activities. The Schedule of Activities specifies the 
data to collect at study discontinuation and follow-up, and any additional evaluations that 
needs to be completed.

If the participant withdraws consent for future involvement in the study, any data collected 
up to that point may still be used, but no future data can be generated, and any biological 
samples collected will be destroyed (refer to the ICF).

A participant has the right at any time to request destruction of any biological samples 
taken. The Investigator will document this in the site study records.
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7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions will be taken if a participant fails to return to the 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, 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 Schedule of 
Activities.

No protocol waivers or exemptions are allowed.

Immediate safety concerns are discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study 
intervention.

Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.

All screening evaluations will be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened, to confirm eligibility, and if applicable, record 
reasons for screening failure.

Prior to performing any study assessments that are not part of the participant’s routine 
medical care, the Investigator will obtain written informed consent as specified in
Appendix 2.

Procedures conducted as part of the participant’s routine medical care (e.g., blood count) 
and obtained before signing of the ICF may be used for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the Schedule of Activities.
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
A brief physical examination (at all other scheduled visits other than Screening) will 
include, at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen 
(liver and spleen).

Investigators 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 will be measured and recorded.

Vital signs including body temperature, pulse rate, respiratory rate, and blood pressure will 
be assessed and recorded in the eCRF.

Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, pulse, and respiratory rate.

Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.

Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (e.g., television, cell phones).

Blood oxygen saturation (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 Schedule of Activities (Section 1.3)
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 5 at the time points listed in the Schedule of Activities (Section 1.3). All samples 
will be clearly identified. 

Additional tests may be performed at any time during the study, as determined necessary 
by the Investigator or required by local regulations.

The tests will be performed by the local laboratory.

The Sponsor 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.
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
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 eCRF. The 
laboratory reports will be filed with the source documents.

If a participant has a clinically significant abnormal laboratory test value that is not present 
at Baseline, the test should be closely monitored until the test value has returned to the 
normal range or the Investigator has determined that the abnormality is chronic or stable. 

The report of the results must be retained as a part of the participant’s medical record or 
source documents.

Pregnancy testing (serum or highly sensitive urine test, as required by local regulations) 
will be conducted at monthly intervals during study intervention administration and at the 
time points specified in the Schedule of Activities (Section 1.3), including at the end of 
relevant systemic exposure of the study intervention. 

HIV testing is not mandatory. History of HIV infection will be collected, if known, as part 
of the medical history. If a test is performed at any point at Screening or while on study, a 
site must consent the participant for HIV testing as per local standard guidance. 

If a liver function test is elevated in an HBV- or HCV-positive participant, HBV 
deoxyribonucleic acid (DNA) or HCV ribonucleic acid (RNA) must be monitored to 
exclude the possibility of reactivation of viral hepatitis. In case of viral reactivation, follow 
the HBV and HCV management guidelines.
8.3
Adverse Events and Serious Adverse Events
The definitions of an AE and a SAE are in Appendix 4.
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 or study, 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 SAEs and related nonserious AEs will be collected from the signing of the ICF until 12 weeks 
Safety Follow-up Visit at the time points specified in the Schedule of Activities (Section 1.3). 
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Beyond this reporting period, any new unsolicited SAEs that the Investigator spontaneously 
reports to the Sponsor will be collected and processed.
All AEs will be collected from the signing of the ICF until the 28 days Safety Follow-up Visit at 
the time points specified in the Schedule of Activities (Section 1.3).
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 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.
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 AESI (as defined in Section 8.3.6), 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 
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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 current version of the 
Investigator Brochure 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 serious adverse event 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 will be collected after the start of study 
intervention and until the outcome of the pregnancy is known.

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
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.
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
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.
8.3.6
Adverse Events of Special Interest
Adverse events of special interest (AESI) are serious or nonserious AEs that are of clinical interest 
and should be closely followed.
For this study, AESI for bintrafusp alfa include the following:

Infusion-related reactions including hypersensitivity

Immune-related AEs

TGF-β inhibition mediated skin reactions

Anemia

Bleeding AEs
Continuous monitoring of such events for bintrafusp alfa is required. Upon Sponsor’s decision, 
expedited reporting of AESIs in this study is not required, as there is already a high amount of 
experience with bintrafusp alfa from previous studies of the program.
8.3.6.1
Infusion-related Reactions Including Hypersensitivity
Infusion-related reactions, including hypersensitivity, are defined in this section. Infusion-related 
reactions are AESIs and identified risks for bintrafusp alfa.
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Infusion-Related Reactions
Infusion-related reactions are defined as any signs or symptoms experienced by participants 
occurring during or within 1 day of study intervention administration. An assessment for possible 
IRR should be triggered based upon the development of specific symptoms within 24 hours of an 
infusion.  
These possible IRRs are identified based on a list of Medical Dictionary for Regulatory Activities 
preferred terms and criteria based on the timely relationship to an infusion. Events are divided into 
reactions versus signs and symptoms:

Infusion-related reactions should be considered when onset is on the day of infusion 
(during or after the infusion) or the day after the infusion (irrespective of resolution date) 
for IRR, drug hypersensitivity, anaphylactic reaction, hypersensitivity, and Type 1 
hypersensitivity. 

Signs and symptoms of IRR and hypersensitivity/allergic reactions should be considered 
when onset is on the day of infusion (during or after the infusion) and resolved completely 
with the end date within 2 days after onset of (but not limited to) pyrexia, chills, flushing, 
hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. 
Management of Infusion-Related Reactions
Current experience in study participants revealed that IRRs to bintrafusp alfa occur seldomly and 
are generally mild to moderate in severity. Therefore, administration of a premedication for 
bintrafusp alfa is generally not required. 
If an Investigator deems necessary to administer a premedication 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) 30 to 60 minutes prior to bintrafusp alfa infusion is 
recommended. Premedication should be administered for subsequent bintrafusp alfa doses 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 corticosteroids. 
Management of symptoms should follow the guidelines shown in Table 10.
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Table 10
Treatment Modification of Bintrafusp alfa for Symptoms of Infusion-
Related Reactions Including Hypersensitivity
NCI-CTCAE v5.0 Grade
Treatment Modification 
Grade 1 – mild

Mild transient reaction; infusion interruption not 
indicated; intervention not indicated.

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator.
Grade 2 – moderate

Therapy or infusion interruption indicated but if 
responds promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for 24 hours.

Stop the infusion of the study intervention-caused 
IRR.

Increase monitoring of vital signs as medically 
indicated as participants are deemed medically 
stable by the attending Investigator. 

If symptoms resolve quickly or decreased to 
Grade 1, resume infusion at 50% of original rate 
with close monitoring of any worsening otherwise 
dosing held until resolution of symptoms with 
mandated premedication for the next scheduled 
visit. 

If worsens to Grade 3 or 4, follow treatment 
modification guidelines accordingly.
Grade 3 or Grade 4 – severe or life-threatening

Grade 3: Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae.

Grade 4: Life-threatening consequences; urgent 
intervention indicated.

Stop the infusion of study intervention-caused IRR 
immediately and disconnect infusion tubing from the 
participant with additional appropriate medical 
measures and closely monitor until deemed 
medically stable by the attending Investigator. 
Hospitalization and/or close monitoring is 
recommended.

Administration of glucocorticoids may be required.
IRR=infusion-related reactions, IV=intravenous, NCI-CTCAE=National Cancer Institute-Common Terminology 
Criteria for Adverse Event, NSAIDs=nonsteroidal anti-inflammatory drugs. 
Once the bintrafusp alfa infusion is interrupted or rate reduced to 50% of previous infusion rate, it must remain 
decreased for all subsequent infusions. For Grade 3 or 4 IRRs, bintrafusp alfa discontinuation is mandated. 
For all types and grades of infusion reactions, details about drug physical constitution, method of preparation, and 
infusion must be recorded.
In the event of a Grade 2 IRR that does not improve or worsens after implementation of the 
treatment modifications indicated in Table 10 (including reducing the infusion rate by 50%), the 
Investigator may consider treatment with corticosteroids and the infusion should be stopped for 
that day. At the next infusion, the Investigator may consider the addition of H2 blocker 
antihistamines (e.g., famotidine), in addition to the above provided recommended optional 
premedication regimen, for selected participants. However, prophylactic steroids are not 
permitted. At the next dose, if the participant has a second IRR Grade ≥2 on the slower infusion 
rate, with the addition of further medication to premedication, the infusion should be stopped, and 
the Investigator may consider withdrawal of this participant from the study.
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Hypersensitivity Reaction
If a hypersensitivity reaction occurs, the participant must be treated according to the best available 
medical practice. A complete guideline for the emergency treatment of anaphylactic reactions 
according to the Working Group of the Resuscitation Council United Kingdom and can be found 
at https://www.resus.org.uk/pages/reaction.pdf. Participants should be instructed to report any 
delayed reactions to the Investigator immediately.
Symptoms may include, but are not limited to: 

Impaired airway

Decreased oxygen saturation (< 92%)

Confusion

Lethargy

Hypotension

Pale/clammy skin

Cyanosis.
Management of hypersensitivity includes: 

Epinephrine injection and intravenous dexamethasone

Participant should be placed on cardiac, blood pressure, heart rate, and oxygen saturation 
monitoring immediately

Alert intensive care unit for possible transfer if required. 
Prophylaxis of Flu-Like Symptoms
For prophylaxis of flu-like symptoms, a nonsteroidal anti-inflammatory drug, e.g., ibuprofen 
400 mg or comparable nonsteroidal anti-inflammatory drug dose, may be administered 2 hours 
before and 8 hours after the start of each intravenous 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 considered AESIs. 
In general, the spectrum of irAEs is similar for bintrafusp alfa compared with other checkpoint 
inhibitors. Effective risk management of these toxicities (irAEs) primarily caused due to inhibition 
of PD-L1 and PD-1 pathways is based on key recommendations (Champiat 2016). Participant 
education for on-time reporting of symptoms of potential irAEs and prompt clinical assessment is 
critical for effective management and quicker resolution of immune-mediated toxicities, thus 
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 following irAEs are important identified risks for bintrafusp alfa:

Immune-related hepatitis

Immune-related pneumonitis

Immune-related colitis

Immune-related nephritis and renal dysfunction

Immune-related endocrinopathies (thyroid disorders, adrenal insufficiency, Type 1 
diabetes mellitus, pituitary disorders)

Immune-related rash

Other immune-related events (myositis, myocarditis, encephalitis)
The following irAEs are important potential risks for bintrafusp alfa:

Guillain-Barré syndrome

Uveitis

Pancreatitis

Myasthenia gravis/myasthenic syndrome.
The Medical Monitor may be involved as needed for follow-up. Details of the diagnostic work-up 
will be requested by the study team. 
Recommended guidance and management for specific irAEs as provided in the current NCCN 
guideline available at http:/
According to American Society of Clinical Oncology Clinical Practice Guideline (Brahmer 2018), 
treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In general, 
management by NCI-CTCAE v5.0 grading is listed below:

Grade 1: study intervention should be continued with close monitoring, with the exception 
of some neurologic, hematologic, and cardiac toxicities. 

Grade 2: study intervention may be suspended for some Grade 2 toxicities, with 
consideration of resuming when symptoms revert to Grade 1 or less. Corticosteroids may 
be administered (initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent). 

Grade 3: study intervention is generally suspended and the high-dose corticosteroids 
(prednisone 1 to 2 mg/kg/day or methylprednisolone 1 to 2 mg/kg/day) treatment should 
be initiated. Corticosteroids should be tapered over the course of at least 4 to 6 weeks. 
Some refractory cases may require infliximab or other immunosuppressive therapy. 

Grade 4: in general, permanent discontinuation of study intervention is recommended, with 
the exception of endocrinopathies that have been controlled by hormone replacement.
Permanent treatment discontinuation is required in case of immune-related Grade 4 
rash/inflammatory dermatitis, nephritis, autoimmune hemolytic anemia, hemolytic uremic 
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syndrome, aplastic anemia, immune thrombocytopenia, acquired thrombotic thrombocytopenic 
purpura, inflammatory arthritis, myositis, and polymyalgia-like syndrome.

For Grade 1 immune-related pneumonitis: continue treatment. If clinically indicated, 
monitor participants weekly or more frequently as needed with history, physical 
examination, and pulse oximetry. If symptoms appear and/or changes in the physical 
examination are noted, treat as Grade 2.

For myositis: in case of management with rituximab, treatment should be discontinued.
For 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 it does not resolve within 14 days. Permanent treatment discontinuation is not 
required when the AE is manifested 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.
Recommended guidance and management for specific irAEs are provided in the current NCCN 
guideline available at http://www.nccn.org.
8.3.6.3
TGF-β Inhibition Mediated Skin Reactions
TGF-β inhibition mediated skin reactions, including hyperkeratosis, KA, and/or cSCCs, are 
important identified risks and AESI for bintrafusp alfa.
Skin assessments are performed at Screening period and every 6 weeks for all participants per 
Schedule of Activities (see Section 1.3). Baseline skin assessments include a detailed medical 
history of genetic or iatrogenic skin conditions, skin type, significant ultraviolet exposure/sun 
damage of skin, geographical location, and occupational or environmental exposure to radiation 
or chemicals.  
Management guidelines for potential TGF-β inhibition mediated skin reactions are:
1. Discontinuation or interruption is not required in most cases. Continuation of treatment 
should be evaluated by the Investigator. 
2. Emollients may continue to be used.
3. Diagnostic and treatment plan should be developed in collaboration between Investigator 
and dermatologist. In general, treatment of TGF-β inhibition mediated skin lesions such as 
hyperkeratosis, KA, and cSCC should be based on local guidelines/standard of care. Lesion 
evaluation should include excision biopsy of one representative lesion to confirm 
diagnosis.
4. Treatment and follow-up for KA and cSCC will depend on number and localization of 
lesions:

For single lesions: Full excision may be recommended. 
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
In case of multiple lesions or location not suitable for full excision, other treatment 
options may be offered by the dermatologist, such as: 
o
Mohs surgery, cryotherapy, or other standard treatment options depending on the 
pathology.
o
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 Medical Monitor, as needed, for management of TGF-β inhibition mediated 
reactions.
8.3.6.4
Anemia
Anemia is an AESI (refer to IB) and important identified risk for bintrafusp alfa. Notably, there 
are many reasons for anemia in patients with advanced cancer, therefore a thorough investigation 
of new anemia cases of unspecified etiology is requested.
For new anemia events, items queried may include, but are not limited to, detailed relevant past 
medical and treatment history, bruising tendency, history of blood transfusions and/or dependency, 
and a request for an updated eCRF including details such as concomitant medications, all 
laboratory data, updated dosing information, and recent tumor evaluation scans. 
General guidance for anemia management and evaluation:
1. Participants must enter the study with hemoglobin values at least 9 g/dL; routine blood test 
parameters are required in the Schedule of Activities (see Section 1.3).
2. All relevant hematologic testing for anemias should be done prior to a blood transfusion, 
if clinically feasible.
3. Transfusion should be performed at the discretion of the Investigator based on clinical 
assessment and considered when the participant experiences significant anemia. An 
attempt should be made to initiate work-up (as specified below) for the cause of anemia 
prior to transfusion, if clinically feasible, to not confound this work-up. In general, blood 
transfusions and erythroid growth factors are permitted as clinically indicated.
Guidance for evaluation of suspected anemias is provided in Table 11.
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Table 11
Evaluation Guidance of Suspected Anemia
Baseline Anemia Evaluation 
a.
CBC with emphasis on red cell indices (e.g., Hgb, hematocrit, MCV, RDW, MCH, MCHC, reticulocyte 
counts).
b.
If indicated and at clinical discretion, the following should be considered:
a.
Iron studies (TIBC, Ferritin, Fe)
b.
Serum folate and Vitamin B12 values
c.
Coagulation factors (PT, aPTT, 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 Baseline 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
aPTT=activated partial thromboplastin time, CBC=complete blood count, Fe=Iron, 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, 
RDW=red blood cell distribution width, TIBC=total iron binding capacity, TSH=thyroid-stimulating hormone.
8.3.6.5
Bleeding Events
Bleeding events are AESIs and considered an important identified risk for bintrafusp alfa (refer to 
the IB).
8.3.6.5.1
Mucosal/Non-Tumor Bleeding
Participants treated with bintrafusp alfa were commonly reported with mild to moderate mucosal 
AEs such as epistaxis, hemoptysis, gingival bleeding, and hematuria. In general, these reactions 
resolve without discontinuation of treatment. 
For Grade 2 non-tumor bleeding, see Section 6.8.2 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.
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For Grade 4 non-tumor bleeding, treatment must be permanently discontinued if no alternative 
explanation is identified.  
8.3.6.5.2
Tumor Bleeding
Participants treated with bintrafusp alfa were reported in lower frequencies, with Grade ≥ 3 
hemorrhages including tumor bleeding. For Grade ≥ 2 tumor bleeding, study treatment must be 
held until the event recovers to Grade ≤ 1. Treatment should be permanently discontinued if the 
Investigator considers the participant to be at risk for additional severe bleeding.
8.3.7
Other Potential Risks for Bintrafusp alfa
8.3.7.1
Impaired Wound Healing
Impaired wound healing is considered an important potential risk (a theoretical risk based on 
literature findings) for bintrafusp alfa, given the role of TGF-β in wound healing. Management 
should be discussed with the Medical Monitor for participants requiring surgery on study. It is 
recommended to hold study intervention for approximately 4 weeks post major surgery for 
observation. Postoperative wound healing will be closely monitored.
8.3.7.2
Embryofetal Toxicity
Embryofetal toxicities are a known risk of the PD-1/PD-L1 targeting class and are considered 
important potential risks for bintrafusp alfa. Animal models link the PD-1/PD-L1 signaling 
pathway with maintenance of pregnancy through induction of maternal immune tolerance to fetal 
tissue. Embryofetal toxicity is an important potential risk of bintrafusp alfa. An appropriate 
contraception warning is provided as part of the inclusion criteria. Pregnant and breastfeeding 
women are not allowed in the bintrafusp alfa study, and adequate contraceptive measures are 
recommended during the study to minimize or eliminate the potential risk to the developing fetus.
Respective safety measures to mitigate risks comprise inclusion/exclusion criteria for participation 
in clinical studies with bintrafusp alfa, guidance for prevention, monitoring, and medical 
management of potential risks, as well as guidance on study intervention interruption or 
discontinuation.
8.4
Treatment of Overdose
For this study, any dose of bintrafusp alfa greater than 2 times (i.e., > 4800 mg) more than 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 DLT at 30 mg/kg and not reaching 
maximum tolerated dose (refer to the IB). Safety at significantly higher doses has not been 
clinically evaluated.
For chemotherapeutic agents used in this study, any single dose exceeding 20% of recommended 
chemotherapy dose regimen will be considered overdose.
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
In case of overdose with clinical correlation, symptomatic treatment must be used; there 
are no known antidotes for the compound.

In the event of an overdose, the study intervention infusion should be discontinued, and 
participants should be observed closely for any signs of toxicity. Supportive treatment 
should be provided if clinically indicated. 
Even if 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
The following PK parameters will be calculated, when appropriate:
Table 12
Pharmacokinetic Parameters
Symbol
Definition
Ceoi
The observed concentration at the end of the infusion period
Ctrough
The concentration observed immediately before next dosing (corresponding to pre-dose 
or trough concentration for multiple dosing)
AUC0-t
The area under the concentration-time curve (AUC) from time zero (= dosing time) to the 
last sampling time (tlast) at which the concentration is at or above the lower limit of 
quantification. Calculated using the mixed log-linear trapezoidal rule (linear up, log down)
AUC0-∞
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted 
value for the concentration at tlast, as estimated using the linear regression from λz
determination. AUC0-∞= AUC0-tlast +Clast pred/ λz
Cmax
Maximum observed concentration
tmax
The time to reach the maximum observed concentration collected during a dosing interval 
(unless otherwise defined, take the first occurrence in case of multiple/identical Cmax
values)
t½
Apparent terminal half-life. t1/2 = ln (2)/λz

Whole blood samples of approximately 3.5 mL will be collected for measurement of serum 
concentrations of bintrafusp alfa. Collection times are specified in the Schedule of 
Activities (Section 1.3). A maximum of 2 samples may be collected at additional time 
points during the study if warranted and agreed upon between the Investigator and the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded to 
calculate actual time elapsed since the prior dose administration. The sampling timing may 
be altered during the study based on newly available data (e.g., to obtain data closer to the 
time of peak plasma concentrations) to ensure appropriate monitoring.

The quantification of bintrafusp alfa in serum will be performed using a validated 
immunoassay method. Concentrations will be used to evaluate the PK of bintrafusp alfa.

Remaining samples collected for analyses of bintrafusp alfa concentration may also be used 
to evaluate immunogenicity and safety or efficacy aspects related to concerns arising 
during or after the study.
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
Details on processes for collection and handling of these samples are in the Laboratory 
Manual. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICF.

Pharmacokinetics and antidrug antibody (ADA) samples will be collected according to 
Schedule of Activities for PK and ADA Sampling in Cohort 1 (1A and 1B; Table 2) and 
Cohort 2 (Table 5). Pharmacokinetics and ADA samples collected at the same time points 
may be used interchangeably if the dedicated sample has insufficient quantity as the 
participants will have consented to all collections and tests. 

The PK parameters will be summarized using descriptive statistics (Table 12). Individual 
as well as mean concentration-time plots will be depicted.
8.6
Pharmacodynamics
Not applicable.
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Table 15
Safety Analysis
Endpoint
Statistical Analysis Methods
Primary
Occurrence of DLTs
AEs
Count and rate of DLT per cohort will be presented with 95% Clopper-Pearson CI
in the DLT analysis set.
The Safety Analysis will include all safety analysis reporting outcomes, e.g., AEs, 
AESIs and laboratory tests outcomes.
The safety endpoints will be tabulated using descriptive statistics including:

The incidence of TEAEs, SAEs, treatment-related AEs, and AESIs, irAEs will 
be summarized by Preferred Term and System Organ Class for each treatment 
cohort and will be described in terms of severity and relationship to treatment.

The worst on-treatment grades for chemistry and hematology laboratory results 
will be summarized.

Shifts in toxicity grading from Baseline to highest grade during the on-treatment 
period will be displayed. 

For laboratory tests without an NCI-CTCAE grade definition results will be 
presented categorically (e.g., below, within, or above normal limits). 
Further details of safety analyses (including AEs, clinical laboratory assessments, 
vital signs, physical examination, ECG parameters, and ECOG PS) will be 
provided in the IAP.
AE=adverse event, AESIs=adverse events of special interest, CI=confidence interval, DLT=dose-limiting toxicity, 
ECOG PS= Eastern Cooperative Oncology Group Performance Status, ECG=electrocardiogram, IAP=Integrated 
Analysis Plan, irAE=immune-related AE, NCI-CTCAE=National Cancer Institute-Common Terminology Criteria for 
Adverse Events, SAE=serious adverse event, TEAE=treatment-emergent adverse event.
9.4.3
Other Analyses
Subgroup Analysis of Efficacy
Analysis of efficacy variables may be performed on subgroups of interest as needed. The detailed 
subgroups will be outlined in the IAP. 
PK and Immunogenicity Analyses
Samples for PK and ADA assessments will be collected as per the Schedule of Activities (see 
Section 1.3). 
Serum concentrations of bintrafusp alfa will be determined by a validated method at the times 
listed in the Schedule of Activities (see Section 1.3).
Details on the PK,
 and
analyses will be in the IAP that will 
be finalized before database lock. Integrated analyses across studies, such as the population PK 
analysis and pharmacodynamic analyses will be presented separately from the main CSR. The 
population pharmacokinetic analysis and exposure-response may be performed using combined 
data from several bintrafusp alfa clinical studies and will be specified in a separate IAP. 
Analyses of PK endpoints will be specified in the IAP finalized before database lock.
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Listings of drug concentration, TEAEs, and efficacy measures may be prepared for ADA 
ever-positive and/or nAb positive participants. 
9.4.4
Sequence of Analyses
More details will be described in the IAP.
The following analyses will be performed:

The SMC will evaluate DLT in each cohort after the 3rd as well as after the 8th evaluable 
participant completes the DLT observation period in the respective cohort.

In the case more participants are included and complete the DLT period as per enrollment, 
all the participants will continue to be evaluated by the SMC, if required. The SMC will 
evaluate further information on a regular basis to evaluate the safety of the combination in 
each cohort, details will be available in the SMC charter.

The main analysis of each cohort will include safety and efficacy assessment and will be 
conducted at least 12 months after the treatment start in the last recruited participant in the 
respective cohort.

The final analysis will be conducted after end of study for safety assessment 
 
Additional analysis during the study might be conducted, e.g., for publication or decision-making 
purposes. More details will be described in the IAP.
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References
Arbyn M, Tommasino M, Depuydt C, et al. Are 20 human papillomavirus types causing cervical 
cancer? J Pathol. 2014;234(4):431-5.
Bhatla N, Berek JS, Cuello Fredes M, et al. Revised FIGO staging for carcinoma of the cervix 
uteri. Int J Gynaecol Obstet. 2019;145(1):129-35.
Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in 
patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology 
Clinical Practice Guideline. J Oncol Pract. 2018;14(4):247-49.
Boussios S, Seraj E, Zarkavelis G, et al. Management of patients with recurrent/advanced cervical 
cancer beyond first line platinum regimens: Where do we stand? A literature review. Crit Rev 
Oncol Hematol. 2016;108:164-74.
Champiat S, Lambotte O, Barreau E, et al. Management of immune checkpoint blockade 
dysimmune toxicities: a collaborative position paper. Ann Oncol. 2016;27(4):559-74.
Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration. Reducing uncertainties 
about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis 
of individual patient data from 18 randomized trials. J Clin Oncol. 2008;26(35):5802-12.
Chung HC, Ros W, Delord JP, et al. Efficacy and Safety of Pembrolizumab in Previously Treated 
Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 
2019;37(17):1470-8.
Corrigendum to “Revised FIGO staging for carcinoma of the cervix uteri” Int J Gynaecol Obstet. 
2019;147(2):279-80.
Dyer BA, Zamarin D, Eskandar RN, et al. Role of Immunotherapy in the Management of Locally 
Advanced and Recurrent/Metastatic Cervical Cancer. J Natl Compr Canc Netw. 2019;17(1):91-7.
Eisenhauer EA, Therasse P, Bogaerts et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 45(2): 228-47.
FDA Guidance on Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, 
or Hepatitis C Virus Infections, March 2019.
Gadducci A, Fabrini MG, Lanfredini N, et al. Squamous cell carcinoma of the vagina: natural 
history, treatment modalities and prognostic factors. Crit Rev Oncol Hematol. 2015;93(3):211-24.
Hazelbag S, Gorter A, Kenter GG, et al. Transforming growth factor-beta1 induces tumor stroma 
and reduces tumor infiltrate in cervical cancer. Hum Pathol. 2002;33(12):1193-9.
Hazelbag S, Kenter GG, Gorter A, et al. Prognostic relevance of TGF-beta1 and PAI-1 in cervical 
cancer. Int J Cancer. 2004;112(6):1020-8.
Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, Ruhl J, Tatalovich Z, Mariotto A, 
Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2016, 
National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/csr/1975_2016/, based on 
November 2018 SEER data submission, posted to the SEER web site, April 2019.
Marth C, Landoni F, Mahner S, et al. Cervical cancer: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv72-iv83.
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Park SS, Dong H, Liu X, et al. PD-1 Restrains Radiotherapy-Induced Abscopal Effect. Cancer 
Immunol Res. 2015;3(6):610-9.
Peralta-Zaragoza O, Bermúdez-Morales V, Gutiérrez-Xicotencatl L, et al. E6 and E7 oncoproteins 
from human papillomavirus type 16 induce activation of human transforming growth factor beta1 
promoter throughout Sp1 recognition sequence. Viral Immunol. 2006;19(3):468-80.
Phippen NT, Leath CA 3rd, Havrilesky LJ, et al. Bevacizumab in recurrent, persistent, or advanced 
stage carcinoma of the cervix: is it cost-effective? Gynecol Oncol. 2015;136(1):43-7.
Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin 
Oncol. 2015;33(17):1974-82.
Rose PG, Java J, Whitney CW, et al. Nomograms predicting progression-free survival, overall 
survival, and pelvic recurrence in locally advanced cervical cancer developed from an analysis of 
identifiable prognostic factors in patients from NRG Oncology/Gynecologic Oncology Group 
Randomized Trials of Chemoradiotherapy. J Clin Oncol. 2015;33(19):2136-42. 
Roszik J, Ring KL, Wani KM, et al. Gene expression analysis identifies novel targets for cervical 
cancer therapy. Front Immunol. 2018;9:2102.
Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for Advanced Cervical Cancer: Final Overall 
Survival and Adverse Event Analysis of a Randomised, Controlled, Open-Label, Phase 3 Trial 
(Gynecologic Oncology Group 240). Clin Trial Lancet. 2017;390(10103):1654-63.
The Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization 
of cervical cancer. Nature. 2017;543(7645):378-84.
Verma V, Simone CB, Werner-Wasik M. Acute and Late Toxicities of Concurrent 
Chemoradiotherapy for Locally-Advanced Non-Small Cell Lung Cancer. Cancers (Basel). 
2017;9(9):120. 
Yan Y, Kumar AB, Finnes H, et al. Combining immune checkpoint inhibitors with conventional 
cancer therapy. Front Immunol. 2018;9(1739):1-13. 
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Appendices
Appendix 1
Abbreviations
ADA
Antidrug antibody
AEs
Adverse events
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
cCRT
Concomitant chemoradiation therapy
CNS
Central nervous system
CR
Complete response
CrCL
Creatinine clearance
CRF
Case Report Form
CRO
Contract Research Organization
cSCC
Cutaneous squamous cell carcinoma
CSR
Clinical study report
CT
Computed tomography
D
Day
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
DoR
Duration of response
EBRT
External Beam Radiation Therapy
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
FAS
Full Analysis Set
FIGO
International Federation of Gynecology and Obstetrics
GCP
Good Clinical Practice
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G-CSF
Granulocyte-colony stimulating factor
GI
Gastrointestinal
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
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
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board
IRR
Infusion-related reaction
IWRS
Interactive Web Response System
KA
Keratoacanthoma
N
Number of participants
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute-Common Terminology Criteria for Adverse Event
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
PD
Progressive disease
PD-1
Programmed death-1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PK
Pharmacokinetic
PR
Partial response
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PS
Performance status
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
Ribonucleic acid
SAE
Serious adverse event
SAF
Safety Analysis Set
SD
Stable disease
SMC
Safety Monitoring Committee
SUSAR
Suspected unexpected serious adverse reactions
TEAE
Treatment-emergent adverse event
TGF-β
Transforming growth factor-β
TMB
Tumor mutational burden
ULN
Upper limit of normal
W1D1
Week 1 Day 1
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with enough, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the 
participant or 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; International Council for Harmonisation (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.
Participants who are rescreened are required to sign a new ICF.
Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. 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 her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by 
appropriate IRB/IEC members, and by regulatory authority inspectors. All such persons will 
strictly maintain participants’ confidentiality.
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Study Administrative
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the CSR.
The study will appear in the following clinical studies registries: ClinicalTrials.gov.
Details of structures and associated procedures will be defined in a separate Operations Manual.
This will be prepared under the supervision of the Clinical Trial Leader in close collaboration with 
the responsible units at the Sponsor.
The Sponsor will coordinate the study and will provide the support for a Contract Research 
Organization (CRO) for some activities of the study. Sponsor Global Clinical Operations will 
perform oversight of the activities performed by the CRO.
The Clinical Trial Supplies department of the Sponsor will supply the study medication of 
bintrafusp alfa, which will be distributed to the sites by Fisher Clinical Services.
Participants enrollment will be managed by an interactive voice response system or an Interactive 
Web Response System.
Safety laboratory assessments will be performed locally by investigational sites. Pharmacokinetic 
(PK), 
 will be performed under the 
responsibility and/or supervision of the Sponsor. 
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany, or its designated 
representatives will supervise drug safety and the timely reporting of AEs and SAEs.
Quality assurance of the study conduct will be performed by the Development Quality Assurance 
Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics will supervise the statistical analyses (with the exception 
of the PK data analyses that will be outsourced to a CRO).
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and the following:
Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
Applicable ICH GCP Guidelines
The Japanese ministerial ordinance on GCP 
Applicable laws and regulations
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The Investigator will submit the protocol, protocol amendments (if applicable), ICF, Investigator 
Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and the IRB/IEC 
will review and approve them before the study is initiated.
For study sites in Japan, the Sponsor initiates the study at a site after obtaining written approval 
from the Head of the study site, based on favorable opinion/approval from the concerned IRB.
Any protocol amendments (i.e., changes to the protocol) will be documented in writing and require 
IRB/IEC approval before implementation of changes, except for changes necessary to eliminate 
an immediate hazard to study participants. When applicable, amendments will be submitted to the 
appropriate Health Authorities.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.

Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures.

Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations.
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Review Committees
The following committee will be involved in the study: 
Safety Monitoring Committee:
To ensure participants’ safety during the study, a SMC will periodically review safety data. The 
SMC consists of permanent members of the Sponsor and/or CRO (GPS Product Lead, Medical 
Lead, Biostatistician, Medical Advisor) and the Coordinating Investigator. The SMC charter will 
specify whether additional members, e.g., external experts, treating Investigators will be required. 
The full membership, mandate, and processes of the SMC is detailed in the SMC charter.
Emergency Medical Support
The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as participating 
in a clinical study. Also, these give health care providers access to any information about this 
participation that may be needed to determine the course of medical treatment for the participant. 
The information on the Emergency Medical Support card may include the process for emergency 
unblinding (if applicable).
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The first point of contact for all emergencies will be the clinical study Investigator caring for the 
participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer any 
questions. Any subsequent action (e.g., unblinding) will follow the standard process established 
for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical emergency.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
The Sponsor is entirely responsible for AEs that are associated with this study and cause damage 
to the health of the participants, except for AEs caused by an intentional and/or significant 
deviation on the part of the Investigator, the study site, and/or the participant. The Sponsor takes 
out insurance to fulfill the responsibility.
Clinical Study Report
After study completion, the Sponsor will write a CSR in consultation with the Coordinating 
Investigator.
Publication
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter studies 
only in their entirety and not as individual site data. In this case, a Coordinating Investigator will 
be designated by agreement.
Authorship will be determined by agreement and in line with International Committee of Medical 
Journal Editors authorship requirements.
Dissemination of Clinical Study Data
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 and will be submitted in 
accordance with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
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Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff who had 
been made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study.
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study intervention and therefore may be 
disclosed as required to other clinical Investigators, to the USA Food and Drug Administration, 
and to other government agencies. The Investigator also understands that, to allow for the use of 
the information derived from the clinical study, the Investigator has the obligation to provide the 
Sponsor with complete test results and all data developed in the study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement.
Data Quality Assurance
All participant study data will be recorded on printed or electronic CRFs 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 Operations Manual.
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.
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.
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The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional 
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
retention period without the Sponsor’s written approval. No records may be transferred to another 
location or party without the Sponsor’s written notification.
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
The Investigator will keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file will identify each participant, contain 
the following demographic and medical information for the participant, and will be as 
complete as possible:
Participant’s full name, date of birth, sex, height, and weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the study)
Study identifier (i.e., the Sponsor’s study number) and participant’s study number.
Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site
Any medical examinations and clinical findings predefined in the protocol
All AEs
Date that the participant left the study, including any reason for early withdrawal from the 
study or study intervention, if applicable.
All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document will have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records will be performed, documented, signed and dated by the Investigator.
Data recorded on printed or electronic 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.
The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will be signed and dated by the Investigator and kept in the study file.
Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator or in Japan: a record retainer designated by the Head of the study site ensures 
that no destruction of medical records is performed without the Sponsor’s written approval.
Definition of what constitutes source data is found in eCRF guidelines.
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Study and Site Start and Closure
First Act of Recruitment
The study start date is the date when the clinical study will be open for recruitment.
The first act of recruitment is when the first participant is screened and signs the ICF and 
will be the study start date.
Study Closure and Site Termination
The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a site closure 
visit has been completed.
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include:
o
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines
o
Inadequate recruitment of participants by the Investigator
o
Discontinuation of further development of the Sponsor’s compound
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. The 
Investigator will promptly inform the participants and assure appropriate participant therapy and/or 
follow-up. 
The whole study may also be terminated prematurely in the event of any of the following:

New information leading to unfavorable risk-benefit judgment of the study intervention, 
for example, due to:
o
evidence of inefficacy of the study intervention,
o
occurrence of significant previously unknown treatment-related adverse events or 
unexpectedly high intensity or incidence of known treatment-related adverse
events, or
o
other unfavorable safety findings.
(Note: Evidence of inefficacy may arise from this study or from other studies; unfavorable safety 
findings may arise from clinical or nonclinical examinations, for example, toxicology.)

Sponsor’s decision that continuation of the study is unjustifiable for medical or ethical 
reasons.
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Health Authorities and IECs/IRBs will be informed about the termination of the study in 
accordance with applicable regulations (Head of study site will also be informed in Japan).
The whole study may be terminated or suspended upon request of Health Authorities.
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Appendix 3
Contraception
Contraceptive use by females will be consistent with local regulations on contraception methods 
for those participating in clinical studies. 
Woman of Childbearing Potential
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 woman of childbearing potential is not: 
1. Premenarchal 
2. A premenopausal female with 1 of the following: 

Documented hysterectomy 

Documented bilateral salpingectomy 

Documented bilateral oophorectomy. 
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview. 
For a female with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion applies to determine 
study entry. 
3. A postmenopausal female 

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 

A high follicle-stimulating hormone 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 follicle-stimulating hormone measurement is required in the postmenopausal range. 
A female on HRT and whose menopausal status is in doubt will be required to use one of the 
non-estrogen hormonal highly effective contraception methods if she wishes to continue her HRT 
during the study. Otherwise, she must discontinue HRT to allow confirmation of postmenopausal 
status before study enrollment.
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CONTRACEPTIVES ALLOWED DURING THE STUDY
Highly Effective Methods That Have Low User Dependency 

Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation* 

Intrauterine device

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 woman of childbearing potential and the 
absence of sperm has been confirmed. Otherwise, use an additional highly effective 
method of contraception. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation 

Oral 

Intravaginal* 

Transdermal* 

Injectable* 

Progestogen-only hormone contraception associated with inhibition of ovulation 

Oral 

Sexual abstinence: a highly effective method only if defined as refraining from 
intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study. 
Notes: 
Contraceptive use by men or women is consistent with local regulations on the use of 
contraceptive methods for clinical study participants. 
Highly effective methods are those with a failure rate of < 1% per year when used 
consistently and correctly.
Typical use failure rates differ from those when used consistently and correctly. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception for this study. Male condom and female condom 
cannot be used together (due to risk of failure with friction). 
*Not approved in Japan.
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Recording and Reporting of DLTs

Each event that meets the DLT criteria, as specified in Section 6.6.2, will be recorded in 
the CRF within 24 hours after awareness of the event.

Serious DLTs will be reported in an expedited manner, using the SAE reporting process, 
as specified above.

Notification of each DLT related event (non-serious and serious) will be reported to the 
Sponsor or its designee within 24 hours from the date of awareness.
Reporting of AESIs
Infusion-related reactions including hypersensitivity, irAEs, TGF-β inhibition mediated skin 
reactions, anemia, and bleeding AEs are all considered as AESIs for bintrafusp alfa.
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.
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Appendix 5
Clinical Laboratory Tests
Table 16
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 (for patients 
with active tuberculosis 
(see Section 5.2), perform 
at Baseline and as 
clinically indicated)
Lipase
Chloride
Albumin
C-reactive
protein
Amylase
Routine Urinalysis

Specific gravity

Physical appearance (color, transparency), pH, glucose, protein, blood/hemoglobin, 
ketones, bilirubin, urobilinogen, nitrite, leukocytes by dipstick

Extensive analysis (If indicated according to findings of routine analysis) one or both of 
the following:

Microscopic examination (if blood or protein is abnormal).

Culture / Antibiogram
Other Screening 
Tests

FSH and estradiol (as needed if not a woman of childbearing potential only)

Serum or highly sensitive urine β-hCG pregnancy test

Free T4 and TSH

Hepatitis Screeningb: Hepatitis B surface antigen; Hepatitis B core antibody and 
Hepatitis C antibody

HIV; HIV virus RNA, quantitative; and CD4 lymphocyte countc
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Laboratory 
Assessments
Parameters
a Coagulation parameters collected at Baseline and as clinically indicated, thereafter (See Section 1.3).
b If hepatitis B surface antigen positive and hepatitis B core antibody positive, then reflex to quantitative HBV DNA 
(PCR); if hepatitis B core antibody positive alone, then reflex to quantitative hepatitis B DNA (PCR); if hepatitis C 
antibody positive, then reflex to quantitative hepatitis C RNA (PCR).
c Not required for all patients. Testing required for patients with known history of HIV. 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 8
Protocol Amendment History
The information for the current amendment is on the title page. 
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Appendix 11
Principal Investigator Signature Page
Study Title:
Safety Study of Bintrafusp alfa in Combination with Other 
Anti-cancer Therapies
in Participants with Locally 
Advanced or Advanced Cervical Cancer
Regulatory Agency Identifying 
Numbers:
, EudraCT: 2020-001561-36
Clinical Study Protocol Version:
06 July 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 for
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements.
____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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