Clinical trial NCT04551950
Conditions: Cervical Cancer
Keywords: Advanced cervical cancer Bintrafusp alfa M7824 INTR@PID Transforming growth factor-beta Programmed death-ligand 1
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2020-10-19; Completion date: 2022-06-30
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was 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.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: M7824 intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Bevacizumab intervention 5: Cisplatin intervention 6: Radiotherapy
Intervention descriptions: intervention 1: Participants received bintrafusp alfa until confirmed disease progression, death, unacceptable toxicity and study withdrawal maximum of 2 years (at the discretion of the Investigator). intervention 2: Carboplatin was administered intravenously as per standard of care. intervention 3: Paclitaxel was administered intravenously as per standard of care. intervention 4: Bevacizumab was administrated as indicated for standard of care. intervention 5: Cisplatin was administered intravenously as per standard of care. intervention 6: Participants received radiotherapy as per standard of care.

Protocol documents:
Prot_000.pdf: 




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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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Phase Ib Bintrafusp alfa Combination Therapy in Cervical Cancer
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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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Phase Ib Bintrafusp alfa Combination Therapy in Cervical Cancer
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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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Bintrafusp alfa (M7824)       
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Integrated Analysis Plan 
 
 
Clinical Trial Protocol 
Identification No. 
MS200647_0046 
Title: 
Safety Study of Bintrafusp alfa in Combination with Other Anti-
cancer Therapies in Participants with Locally Advanced or 
Advanced Cervical Cancer 
Study Phase 
Phase Ib 
Investigational 
Medicinal Product(s) 
Bintrafusp alfa 
Clinical Study Protocol 
Version 
06 Jul 2021/Version 2.0 
Integrated Analysis Plan 
Author 
Coordinating Author 
 
 EMD Serono  
 
Function 
Author(s) / Data Analyst(s) 
 
 
 
 
Integrated Analysis Plan 
Date and Version 
25 Jan 2022, Version 2 
Integrated Analysis Plan 
Reviewers 
Function 
Name 
 EMD Serono  
 
 Merck Healthcare KGaA 
 
 EMD Serono 
 
 Merck Healthcare KGaA 
 
 EMD Serono 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies. 
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate.  
Copyright © 2020 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 
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Bintrafusp alfa (M7824)       
Phase Ib Bintrafusp alfa Combination Therapy in Cervical Cancer 
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Approval Page  
Integrated Analysis Plan: MS200647_0046 
Safety Study of Bintrafusp alfa in Combination with Other Anti-cancer Therapies in Participants 
with Locally Advanced or Advanced Cervical Cancer 
Approval of the IAP by all responsible Merck Data Analysts has to be documented within 
ELDORADO via eSignature. With the approval, the Merck responsible for each of the analyses 
also takes responsibility that all reviewers’ comments are addressed adequately. 
By using eSignature, the signature will appear at the end of the document. 
  
 
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1 
Table of Contents  
  
Approval Page 
 ..............................................................................................................2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................6 
3 
Modification History ............................................................................9 
4 
Purpose of the Integrated Analysis Plan .............................................10 
5 
Objectives and Endpoints ...................................................................10 
6 
Overview of Planned Analyses ...........................................................11 
6.1 
Safety Monitoring Committee ............................................................12 
6.2 
Overview of Planned Analyses  ..........................................................12 
7 
Changes to the Planned Analyses in the Clinical Study Protocol ......12 
7.1 
COVID-19 Impact ..............................................................................12 
8 
Analysis Sets and Subgroups ..............................................................13 
8.1 
Definition of Analysis Sets .................................................................13 
8.2 
Subgroup Definition and Parameterization ........................................14 
9 
General Specifications for Data Analyses ..........................................15 
9.1 
Data Handling After Cut-off Date ......................................................15 
9.2 
Study Intervention ..............................................................................15 
9.3 
Definition of Baseline and Change from Baseline .............................15 
9.4 
Study Day / Study Treatment Day ......................................................16 
9.5 
Definition of Duration and ‘time since’ Variables .............................16 
9.6 
Conversion Factors .............................................................................16 
9.7 
Date of Last Contact ...........................................................................16 
9.8 
Time Window .....................................................................................17 
9.9 
Definition of On-treatment Period ......................................................17 
9.10 
Imputation of Missing Data ................................................................17 
9.11 
Presentation of Continuous and Qualitative Variables .......................21 
9.12 
Pooling of Centers ..............................................................................21 
9.13 
Unscheduled Assessments ..................................................................21 
9.14 
Preferred Term for analysis of World Health Organization’s Drug 
Dictionary (WHO-DD) coded data .....................................................22 
9.15 
Re-screened Participants .....................................................................22 
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9.16 
Data collected after reinitiated treatment ............................................22 
9.17 
Categorization of Participants for COVID-19 Impact Assessment ....22 
9.18 
Software ..............................................................................................23 
10 
Study Participants ...............................................................................23 
10.1 
Disposition of Participants and Discontinuations ...............................23 
10.2 
Protocol Deviations ............................................................................25 
10.2.1 
Important Protocol Deviations ............................................................25 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................26 
11 
Demographics and Other Baseline Characteristics .............................26 
11.1 
Demographics .....................................................................................26 
11.2 
Medical History ..................................................................................28 
11.3 
Other Baseline Characteristics ............................................................28 
11.3.1 
Disease History ...................................................................................28 
11.3.2 
Human Papillomavirus Status .............................................................29 
11.3.3 
PD-L1 Status .......................................................................................29 
11.3.4 
Skin Status History .............................................................................30 
 
 
11.4 
Prior Anticancer Therapy ...................................................................30 
12 
Previous or Concomitant Medications/Procedures .............................31 
12.1 
Previous and Concomitant Medications .............................................31 
12.2 
Premedications ....................................................................................32 
12.3 
Concurrent Procedures ........................................................................32 
12.4 
Subsequent Anticancer Treatment ......................................................33 
13 
Study Treatment: Compliance and Exposure .....................................33 
14 
Efficacy Analyses ...............................................................................38 
14.1.1 
Confirmed Objective Response according to RECIST 1.1 ................38 
14.1.2 
Progression-free Survival as per RECIST 1.1 ....................................40 
14.1.3 
Time to and Duration of Objective Response as per RECIST 1.1 .....42 
14.1.4 
Tumor Shrinkage in Target Lesions ...................................................43 
14.1.5 
Overall Survival ..................................................................................44 
15 
Safety Analyses ..................................................................................45 
15.1 
Dose-limiting Toxicities (Primary Endpoint) .....................................45 
15.2 
Adverse Events ...................................................................................45 
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15.2.1 
All Adverse Events .............................................................................49 
15.2.2 
Adverse Events Leading to Discontinuation of Study Intervention ...52 
15.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................53 
15.3.1 
Deaths .................................................................................................53 
15.3.2 
Serious Adverse Events ......................................................................54 
15.3.3 
Adverse Events of Special Interest .....................................................54 
15.4 
Clinical Laboratory Evaluation ...........................................................58 
15.5 
Vital Signs ..........................................................................................62 
15.6 
Other Safety or Tolerability Evaluations ............................................63 
16 
Analyses of Other Endpoints ..............................................................63 
16.1 
Pharmacokinetics ................................................................................63 
16.1.1 
Missing PK Data .................................................................................63 
16.1.2 
Descriptive PK Analysis .....................................................................65 
16.1.3 
Pharmacokinetic Non-Compartmental Analysis ................................66 
 
 
16.3 
Patient-reported Outcome ...................................................................69 
16.4 
 
16.5 
 
 
 
17 
References ...........................................................................................72 
18 
Appendices .........................................................................................72 
18.1.1 
Appendix 1 - List of Important Protocol Deviations ..........................72 
18.1.2 
Appendix 2 - Definition of NCI-CTCAE Grading .............................73 
 
 
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2 
List of Abbreviations and Definition of Terms  
Abbreviation 
Definition 
ADA 
Antidrug Antibody 
ADaM 
Analysis Data Model 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
ALP 
Alkaline Phosphatase 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUC0-t 
Area under the serum concentration-time curve from time zero to the 
last quantifiable concentration 
AUC0-∞ 
Area under the serum concentration-time curve from time zero 
extrapolated to infinity 
BMI 
Body Mass Index 
BSA 
Body Surface Area 
CEOI 
The concentration observed at the end of infusion 
CI 
Confidence Interval 
CL 
Total body clearance of drug from serum 
COVID-19 
Coronavirus disease 2019 
Cmax 
Maximum observed concentration in serum 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CSR 
Clinical Study Report 
Ctrough 
The concentration observed at the end of the dosing interval, before 
next dosing (corresponding to pre-dose or trough concentration for 
multiple dosing) 
CV% 
Coefficient of Variation (%) 
DBP 
Diastolic Blood Pressure 
DI 
Dose Intensity 
DLT 
Dose-limiting Toxicities 
DOR 
Duration of Response 
ECG  
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
Electronic Case Report Form 
eDISH 
Evaluation of Drug-Induced Serious Hepatotoxicity 
GeoCV% 
Geometric coefficient of variation 
GeoMean 
Geometric mean 
GFR 
Glomerular Filtration Rate 
 
 
IAP 
Integrated Analysis Plan 
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IC 
Immune Cells 
ICH 
International Council for Harmonization 
IHC 
Immunohistochemistry 
IPD 
Important Protocol Deviations 
IRR 
Infusion-related Reaction 
λZ 
Terminal first order (elimination) rate constant 
LLN 
Lower Limit of Normal 
<LLOQ 
Below the lower limit of quantification 
logStD 
Standard deviation of log-transformed data 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MSI 
Microsatellite instability 
MSS 
Microsatellite Stable 
nAb 
Neutralizing antidrug antibody 
NCA 
Non-Compartmental Analysis 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
nd 
Not determined 
OR 
Objective Response 
OS  
Overall Survival 
PD  
Progressive Disease 
PD-L1 
Programmed Death Ligand 1 
PFS  
Progression-free Survival 
PK 
Pharmacokinetic(s) 
 
 
PKAS 
Pharmacokinetic analysis set 
PR 
Partial Response 
PT 
Preferred Term 
Q1 
First Quartile 
Q3 
Third Quartile 
RBC 
Red Blood Cell 
RDI 
Relative Dose Intensity 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors Version 1.1 
SAE 
Serious Adverse Event 
SAF/FAS 
Safety/Full Analysis Set 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SI 
International System of Units 
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SMC 
Safety Monitoring Committee 
SMQ 
Standardized MedDRA Queries 
SoC 
Standard of Care 
SOC 
System Organ Class 
StD  
Standard Deviation 
t1/2 
Elimination half-life 
T4 
Thyroxine 
TC 
Tumor Cells 
TEAE 
Treatment-emergent Adverse Event 
TGFβ 
Transforming Growth Factor-Beta 
TLF 
Tables, Listings, and Figures 
tmax 
Time to reach Cmax 
TMB 
Tumor Mutational Burden 
TNM 
Tumor, Lymph Nodes, Metastasis 
TOR 
Time to Objective Response 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
Vz 
Volume of distribution during terminal phase 
WBC 
White Blood Cells 
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3 
Modification History  
Unique Identifier 
for IAP Version 
Date of IAP 
Version 
Author 
Changes from the Previous Version 
1 
 
 
 
Not Applicable 
2 
 
 
- 
Section 6: Added “Overview of Planned Analyses 
after Trial Discontinuation” and removed “Main 
Analysis” and “Final Analysis” 
- 
Section 7.1 and 10.1: added “Overview table of 
the impact by COVID-19” and updated listing of 
COVID-19 impact 
- 
Section 7.1 and 15.2.1: added “Table of 
treatment-emergent adverse events (TEAEs) 
associated to COVID-19”  
- 
Section 9.10: modification of imputation of 
missing data for previous and concomitant 
medication/procedure 
- 
Section 9.10: added details in the rules to define 
previous 
and/or 
concomitant 
medication/procedure 
- 
Section 13: specifying that for radiotherapy and 
brachytherapy, a dose is considered to be 
administered if the start date is non missing. 
- 
Section 15: considering bleeding events as AESIs 
- 
Section 15: “TGFβ-mediated skin adverse 
events” replaced by “TGF-β inhibition mediated 
skin adverse events” 
 
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4 
Purpose of the Integrated Analysis Plan  
The purpose of this integrated analysis plan (IAP) is to document technical and detailed 
specifications for the main and final analysis of data collected for protocol MS200647_0046.  
Results of the analyses described in this IAP will be included in the Clinical Study Report (CSR). 
Additionally, the planned analyses identified in this IAP may be included in regulatory 
submissions or future manuscripts. Any post-hoc or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective IAP will be clearly identified 
in the CSR.  
The IAP is based upon Section 9 (Statistical Considerations) of the study protocol and is prepared 
in compliance with International Council for Harmonization (ICH) Guideline E9. It describes 
analyses planned in the protocol apart from Safety Monitoring Committee (SMC) analyses. Details 
of the SMC analyses will be developed in a separate statistical analysis plan (SAP). 
 
5 
Objectives and Endpoints  
 
Table 1 
Study Objectives and Endpoints  
Objectives 
Endpoints 
IAP Section 
Primary 
 
To evaluate the safety and tolerability of 
bintrafusp alfa in combination with (1) 
chemotherapy with or without bevacizumab in 
participants with recurrent, persistent, or 
metastatic cervical cancer or (2) platinum 
therapy and definitive radiation in participants 
with locally advanced cervical cancer 
• 
Occurrence of DLTs 
• 
Adverse events (AEs) 
Section 15 
Secondary 
 
To evaluate the safety and tolerability of 
bintrafusp alfa in combination with (1) 
chemotherapy with or without bevacizumab in 
Japanese participants with recurrent, 
persistent, or metastatic cervical cancer or (2) 
platinum therapy and definitive radiation in 
Japanese participants with locally advanced 
cervical cancer 
• 
Occurrence of DLTs 
• 
Adverse events (AEs) 
Section 15 
To characterize PK profile of bintrafusp alfa 
• 
PK profile of bintrafusp alfa in terms of CEOI 
and Ctrough for all participants throughout the 
treatment period 
• 
PK profile of bintrafusp alfa in terms of AUC0-t, 
AUC0-∞, Cmax, tmax, and t1/2 in Cycle 1 
Section 16.1 
To evaluate the immunogenicity of bintrafusp 
alfa 
• 
Immunogenicity of bintrafusp alfa, as 
measured by ADA assay, from Day 1 pre-dose 
through the last Safety Follow-up Visit 
Section 16.4 
 
 
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6 
Overview of Planned Analyses  
Statistical analyses will be performed based on CDISC SDTM data. These SDTM data contain as 
clean as possible eCRF data, as well as external data including biomarker and PK data.  
Apart from the analyses for the SMC meetings, all data will be included up to a clinical cut-off 
date as described in the corresponding sections below. 
In addition to analyses for SMC meetings, main analysis and final analysis, additional analyses 
could be conducted during the study, e.g., for publication or decision-making purposes. 
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6.1 
Safety Monitoring Committee  
A SMC will be responsible for the safety evaluation in each cohort (Cohort 1A, Cohort 1B and 
Cohort 2) and will make recommendations for the study. Details can be found in the SMC Charter. 
The SMC will evaluate safety (including DLTs) and other available data after the 3rd as well as the 
8th evaluable participant completes the respective DLT observation period. Once a trigger is met, 
a data snapshot will be taken for provision of SMC outputs. There will be no data cut-off applied. 
The details of the analyses for SMC are provided in a separate SAP that was approved before the 
first SMC meeting. 
6.2 
Overview of Planned Analyses  
The data review outcome from the 3 randomized controlled studies in NSCLC and BTC 
(MS200647-0005, MS200647-0037, MS200647_0055) appears to indicate, consistently across 2 
indications, either poorer observed hazard ratios for PFS and OS in the experimental arms with 
bintrafusp alfa or low likelihood for bintrafusp alfa to add benefits compared to standard of care.  
Based on this, the decision was made to restrict the analyses on this study MS200647_0046. The 
analyses described in Sections 10 - 16 will not be performed as planned, instead  analyses based 
on the primary analysis data cutoff date of 
 will be performed for an abbreviated 
CSR (aCSR).  
The analyses considered relevant for this purpose are listed below: 
• Participant disposition 
• Protocol deviations 
• Demographic characteristics and baseline characteristics 
• Previous and concomitant medications 
• Treatment compliance and exposure 
• Efficacy (overall survival, progression-free survival, confirmed objective response, duration 
of response, tumor shrinkage) 
• Safety (adverse events, clinical laboratory evaluations, vital signs).  
In case a new safety signal is observed, an additional analysis will be done at end of study and 
included in a CSR addendum. In the other cases, no further analyses will be planned. 
7 
Changes to the Planned Analyses in the Clinical Study 
Protocol  
7.1 
COVID-19 Impact  
The COVID-19 outbreak was unforeseen at the time this protocol was finalized; therefore, 
analyses related to the COVID-19 pandemic were added later. 
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No changes to the analysis of the primary and efficacy endpoints will be performed due to the 
impact of COVID-19 outbreak. 
Instead, additional outputs will be generated to assess potential impacts of COVID-19 to this study 
including:  
• Overview table of the impact by COVID-19  
• Listing of COVID-19 impact 
• Listing of protocol deviations related to COVID-19 
• Table of treatment-emergent adverse events (TEAEs) associated to COVID-19 
• Listing of adverse events related to COVID-19. 
8 
Analysis Sets and Subgroups  
8.1 
Definition of Analysis Sets  
Screening Analysis Set 
The screening analysis set will include all participants who provided informed consent, regardless 
of the participant’s study intervention status in the study. 
Dose-limiting Toxicity Analysis Set 
The DLT set will include all participants who received at least one dose of study intervention and 
meet at least one of the following criteria: 
• Experienced at least one DLT during the DLT period (within 4 weeks after first 
administration of study intervention), regardless of the administered number of doses of 
study intervention/completion of the DLT period. 
• Received at least 80% of the planned cumulative dose during the DLT period of each 
treatment and completed the DLT period. 
Analyses will include participants as treated. 
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Safety/Full Analysis Set 
The safety/full analysis set (SAF/FAS) will include all participants who were administered any 
dose of any study intervention. Analyses will be performed as treated. 
Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set (PKAS) will include all participants who completed at least 1 
infusion of bintrafusp alfa, and who provided at least 1 sample with a measurable concentration of 
bintrafusp alfa. The pharmacokinetic antidrug antibody (ADA) analysis set (PKADA) is defined 
as a subpopulation of the PKAS and restricted to participants who have in addition at least one 
valid result of ADA at any time point. 
Analyses will include participants as treated. All PK analyses will be based on this analysis set (or 
subset). Refer to Section 16.1 for protocol deviations and handling relevant to PK. 
Immunogenicity Analysis Set 
All participants who were administered at least 1 infusion of bintrafusp alfa and have at least one 
valid ADA result. Analyses will include participants as treated. 
The following table summarizes the use of the analysis sets for the different analyses. 
Table 2 
Overview of the Analysis Sets Used in the Analyses 
 
Analysis Set 
Analyses 
SCR 
SAF/FAS 
DLT 
PK 
IMM 
Disposition of Participants 
 
 
 
 
 
Protocol Deviations 
 
 
 
 
 
Demographics and Other Baseline 
Characteristics 
 
 
 
 
 
Previous and Concomitant Therapies 
 
 
 
 
 
Compliance and Exposure 
 
 
 
 
 
  
 
 
 
 
 
Safety and Tolerability: Dose Limiting 
Toxicities (Primary) 
 
 
 
 
 
Other Safety and Tolerability (Secondary) 
 
 
 
 
 
Pharmacokinetics 
 
 
 
 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
DLT: dose-limiting toxicity; IMM: immunogenicity; PK: pharmacokinetic; SAF/FAS: safety/full analysis set; SCR: 
screening analysis set. 
8.2 
Subgroup Definition and Parameterization  
The safety profile will be specifically evaluated in the specific subpopulation of Japanese 
participants within each cohort. 
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9 
General Specifications for Data Analyses  
This section describes any general specifications not included in subsequent sections.  
Unless otherwise specified, all general (i.e., disposition of participants and discontinuations, 
protocol deviations, demographics and other baseline characteristics, and previous or concomitant 
medication), safety and efficacy analyses will be performed by cohort. The three cohorts will be 
labelled as Cohort 1A, Cohort 1B and Cohort 2, respectively. For demographics and baseline data 
a total column will also be presented. The specifications for PK data analysis are presented in 
Section 16.1, and, in case of discrepancies, Section 16.1 shall supersede this section for the purpose 
of PK data handling, analysis, and presentation. 
9.1 
Data Handling After Cut-off Date  
By its nature, data after cut-off may be incomplete and subject to further change and will not be 
used for summary statistics, statistical analyses, listings or imputations. 
Stop dates are not affected by this rule, e.g., a stop date of an adverse event (AE) which starts prior 
to the cut-off but stops after date of cut-off, will not be changed. 
9.2 
Study Intervention  
In this study, bintrafusp alfa, bevacizumab, chemotherapies (cisplatin, carboplatin, paclitaxel) and 
radiotherapy are considered as study interventions. The date of first study intervention 
administration will be defined as the earliest administration date of any interventions (bintrafusp 
alfa, bevacizumab, cisplatin, carboplatin, paclitaxel, radiation). The date of last study intervention 
administration will be defined as the latest administration date of any interventions.  
9.3 
Definition of Baseline and Change from Baseline  
In general, the last non-missing measurement prior to the administration of study intervention will 
be used as the baseline measurement for safety and efficacy analyses. If an assessment that is 
planned to be performed before treatment per protocol is performed on the same day as the first 
study intervention administration, but the assessment time is not available, it will be assumed that 
it was performed prior and will be considered as baseline. 
Unscheduled assessments will be used in the determination of baseline. However, if time is 
missing, an unscheduled assessment on study day 1 will be considered to have been obtained after 
study intervention. 
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be analyzed as if it was an unscheduled post-dose measurement. 
Participants who start intervention and discontinue the treatment on the same day may have 2 
different sets of data collected on study day 1 (one during study and one at end of treatment visit). 
Data reported at the end of treatment visit will not be eligible for baseline selection. 
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Absolute and percent changes from baseline are defined as follows: 
• absolute change = visit value – baseline value 
• percent change = 100 * (visit value – baseline value) / baseline value 
9.4 
Study Day / Study Treatment Day  
Day 1 is the day of start of first study intervention, the day before is Day -1 (no Day 0 is defined).  
Study day / Study treatment day are defined relative to Day 1. 
9.5 
Definition of Duration and ‘time since’ Variables  
Durations in days will be calculated by the difference of start and stop date + 1 (e.g., overall 
survival time [days] = date of death – date of first study intervention + 1) if not otherwise specified. 
The time since an event (e.g., time since initial cancer diagnosis) will be calculated as reference 
date minus date of event.  
9.6 
Conversion Factors  
The following conversion factors will be used to convert days into months or years:  
• 1 month = 30.4375 days 
• 1 year = 365.25 days 
9.7 
Date of Last Contact  
The date of last contact will be derived for participants not known to have died at the analysis cut-
off using the latest complete date prior to or at the data cut-off date from the following: 
• All participant assessment dates (e.g., blood draws [laboratory, PK], vital signs, ECOG 
performance status, electrocardiogram [ECG], tumor assessments)  
• Start and end dates of anticancer therapies administered after discontinuation of study 
intervention 
• AE start and end dates 
• Last known to be alive date from “Subject Status / Survival Follow-Up” eCRF page 
• Study intervention start and end dates 
• Date of discontinuation taken from the “Study Termination” eCRF page (do not use if reason 
for discontinuation is lost to follow-up) 
Only dates associated with actual examinations of the participant reported in the eCRF will be 
used in the derivation. Dates associated with a technical operation unrelated to participant status 
such as the date a blood sample was processed will not be used.  
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9.8 
Time Window  
No time windows are defined for the study. 
9.9 
Definition of On-treatment Period  
The on-treatment period will include the initial treatment period as well as the re-initiation of 
treatment period if any. Whether the participant reinitiates treatment (following the rules as 
outlined in the protocol) or not, the on-treatment period is defined as the time from the first study 
intervention administration to the last study intervention administration date + 30 days, or the 
earliest date of subsequent anticancer therapies minus 1 day, or the cut-off date, or death, 
whichever occurs first. 
For participants with treatment ongoing at the cut-off date, all data from the first administration of 
study intervention up to the cut-off date will be considered as on-treatment data. 
For immune-related AEs as listed in Section 15.3.3.2, an expanded on-treatment period will be 
used as a default for any analysis: 
Time from the first study intervention to the last study intervention date + 90 days, death OR to 
the earliest date of subsequent anticancer therapy minus 1 day, whichever occurs first, unless 
otherwise stated. 
Any systemic anticancer therapy, any anticancer surgery, any anticancer radiotherapy and any 
anticancer brachytherapy as documented in the ”Anti-cancer treatment after discontinuation”, 
“Surgery after discontinuation”, ”Radiotherapy after discontinuation” and “Brachytherapy after 
discontinuation” eCRF pages will be considered as subsequent anticancer therapy. 
9.10 
Imputation of Missing Data  
Unless otherwise specified, all data will be evaluated as observed, and no imputation method for 
missing values will be used. 
In all participant data listings, imputed values will be displayed and imputed information will be 
flagged. 
Partial dates, which are not to be imputed according to the IAP, will be presented in the format 
like “_____YYYY”. 
Missing statistics, e.g., when they cannot be calculated, will be presented as “nd” standing for not 
determined. For example, if n=1, the standard deviation (StD) cannot be computed and will be 
presented as “nd”. 
Incomplete dates will be handled as specified in the following table: 
Age Calculation 
Incomplete dates (date of informed consent, date of birth) for the calculation of age will be 
imputed as follows:  
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• In case of missing day for at least one date, but month and year available for both 
dates: the day of informed consent and the day of birth will be imputed to the 1st day 
of the month. 
• In case of missing month for at least one date, but year available for both dates, the 
day and the month of informed consent and the day and month of birth will be imputed 
to the 1st of January. 
• In all other cases, the incomplete dates will not be imputed.  
Disease history 
Incomplete dates for disease history (e.g. initial cancer diagnosis date, date of documented, 
locally advanced, inoperable or metastatic disease diagnosis, date of progression of 
disease prior to study entry) will be imputed as follows: 
• If the day is missing, it will be imputed to the 1st day of the month.  
• If both day and month are missing, the month and day will be imputed as January 1st. 
• If the date is completely missing, no imputation will be performed. 
Adverse events 
Incomplete AE-related dates will be imputed as follows: 
• In case the onset date is missing completely or missing partially but the onset month 
and year, or the onset year are equal to the start of study treatment then the onset 
date will be imputed by the minimum of start of study intervention and AE resolution 
date (if available after imputation).  
• In all other cases, the missing onset day or missing onset month will be imputed by 1. 
• Incomplete stop dates will be imputed by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of the participant’s death. In the latter 
case, the date of death will be used to impute the incomplete stop date.  
• In all other cases, the incomplete stop date will not be imputed.  
Previous and 
concomitant 
medication/procedure 
 
Incomplete dates for previous and concomitant medications will be imputed as follows:   
For start date of medication:   
• If the day is missing, it will be imputed to the 1st day of the month.  
• If both day and month are missing, the month and day will be imputed as January 1st.  
• If the date is completely missing, no imputation will be performed.   
For end date medication:   
• If the day is missing, it will be imputed to the last day of the month.  
• If both day and month are missing, the month and day will be imputed as December 
31st.   
• If the date is completely missing, no imputation will be performed.  
In case the imputation results in a date later than the date of participant's death, then the 
date of death will be used to impute the incomplete stop date.  
Dates of study 
intervention 
Start date of study interventions: 
• No imputation will be done. 
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End date of study interventions: 
• In case the last date of study intervention is missing or incomplete the date of last 
administration of study intervention will be taken from the treatment termination eCRF 
pages. 
• If the last date of study intervention is completely missing and there is no End of 
Treatment eCRF page and no death date the participant should be considered as 
ongoing and use the cut-off date for the analysis as the last dosing date 
• If the last date of study intervention is completely or partially missing and there is 
EITHER an End of Treatment eCRF page OR a death date available (before the cut-off 
date) then imputed last dose date is: 
= 31DECYYYY, if only Year is available and Year < Year of min (EOT date, death date) 
= Last day of the month, if both Year and Month are available and Year= Year of min 
(EOT date, death date) and Month < the month of min (EOT date, death date) 
= min (EOT date, death date), for all other cases 
Tumor assessments 
All investigation dates (e.g., X-ray, CT scan) must be completed with day, month and year. 
If there are multiple scan dates associated with an evaluation, i.e., radiological 
assessments occur over a series of days rather than the same day, the choice of date of 
assessment could impact the date of progression and/or date of response.  If there are 
multiple scan dates associated with an evaluation, the earliest of the scan dates associated 
with the evaluation will be used as the date of assessment. 
If one or more investigation dates for an evaluation are incomplete but other investigation 
dates are available, the incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the earliest of all investigation dates 
(e.g., X-ray, CT-scan).   
If all measurement dates for an evaluation have no day recorded, the 1st of the month is 
used.  
If the month is not completed, for any of the investigations for an evaluation, the respective 
assessment will be considered to be at the date which is exactly between the previous and 
the following assessment. If both previous and following assessments are not available, 
this assessment will not be used for any calculations. 
Subsequent 
Anticancer Treatment 
Incomplete dates for the start date of subsequent anticancer treatment (drug therapy, 
radiotherapy, brachytherapy, surgery) will be imputed as follows and will be used for 
determining censoring dates for efficacy analyses and in the derivation of the end of the 
on-treatment period: 
• If only day is missing, it will be imputed as the last day of the month unless the end 
date of subsequent anticancer treatment is before that date. In that case, the 
incomplete anticancer therapy start date will be imputed as the end date of the 
anticancer therapy. 
• If both day and month are missing, no imputation will be performed.  
Incomplete subsequent anticancer treatment stop dates will not be imputed.  
Death 
For the purposes of survival analyses only, partially missing death dates will be imputed as 
follows: 
• If only the day is missing, the death date will be imputed to the maximum of the (non-
imputed) day after the date of last known alive date and the 15th day of the month. 
• Otherwise it will not be imputed 
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Table 3 
Stopping rules for medication/procedure end dates 
End date of medication/procedure 
Stopping rule 
Day 
Month 
Year 
  
UNK 
UNK 
UNK 
After treatment start (ongoing) 
UNK 
UNK 
< Treatment start (year) 
Before treatment start 
UNK 
UNK 
>= Treatment start (year) 
After treatment start 
UNK 
< Treatment start (month and year) 
Before treatment start 
UNK 
>= Treatment start (month and year) 
After treatment start 
< Treatment start (complete date) 
Before treatment start 
>= Treatment start (complete date) 
After treatment start 
UNK = Unknown 
Table 4 
Rules to define previous and/or concomitant medication/procedure 
Start date of medication/procedure 
Stopping rule  
(see Table 3) 
Medication/procedure 
Day 
Month 
Year 
  
  
UNK 
UNK 
UNK 
Before treatment 
start 
Previous 
UNK 
UNK 
UNK 
After treatment 
start 
Previous and concomitant 
UNK 
UNK 
<= Treatment start 
(year) 
Before treatment 
start 
Previous 
UNK 
UNK 
<= Treatment start 
(year) 
After treatment 
start 
Previous and concomitant 
UNK 
UNK 
> Treatment start (year) 
and <= Treatment end 
+ 30 days (year) OR 
the earliest date of 
subsequent anticancer 
drug therapies minus 1 
day, whichever occurs 
first.  
After treatment 
start 
Concomitant 
UNK 
<= Treatment start (month and 
year) 
Before treatment 
start 
Previous 
UNK 
<= Treatment start (month and 
year) 
After treatment 
start 
Previous and concomitant 
UNK 
> Treatment start (month and 
year) and <= Treatment end + 30 
days (month and year) OR the 
earliest date of subsequent 
anticancer drug therapies minus 1 
day, whichever occurs first.  
After treatment 
start 
Concomitant 
<= Treatment start (date) 
Before treatment 
start 
Previous 
<= Treatment start (date) 
After treatment 
start 
Previous and concomitant 
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Start date of medication/procedure 
Stopping rule  
(see Table 3) 
Medication/procedure 
Day 
Month 
Year 
  
  
> Treatment start (date) and <= Treatment 
end + 30 days (date) OR the earliest date of 
subsequent anticancer drug therapies minus 
1 day, whichever occurs first.  
After treatment 
start 
Concomitant 
UNK = Unknown 
9.11 
Presentation of Continuous and Qualitative Variables  
Continuous (non-PK) variables will be summarized using descriptive statistics i.e.,  
• Number of participants (N), number of participants with missing values  
• Mean, standard deviation (StD) 
• Median, 25th percentile - 75th percentile (Q1-Q3) 
• Minimum (Min), and maximum (Max) 
If there are no missing values, the number of participants with missing values should be set to 0. 
Mean, median, Q1, Q3, Min, Max have the same precision as SDTM data (number of digits) for 
non-derived data. Statistics on derived data will be rounded to reasonable digits, whereas maximal 
digits will be available in ADaM datasets. StD is to be presented with one digit more than mean.  
Qualitative variables will be summarized by counts and percentages. Unless otherwise stated, the 
calculation of proportions will be based on the number of participants in the analysis set of interest. 
Therefore, counts of missing observations will be included in the denominator and presented as a 
separate category.  
Percentages will be reported to one decimal place. 
Descriptive statistics by nominal visit or time point, e.g., for laboratory measurements, will include 
only data from scheduled visits. In case of multiple available results for a scheduled visit, the result 
obtained at the earliest date will be considered. 
No statistical tests will be performed. If confidence intervals (CIs) are to be calculated, these will 
be two-sided with a confidence probability of 95%, unless otherwise specified in this IAP. 
9.12 
Pooling of Centers  
Due to the small number of participants enrolled in each cohort, data from different centers will 
be pooled for analysis. 
9.13 
Unscheduled Assessments  
As per database definition, unscheduled assessments are always linked to a scheduled timepoint 
(each unscheduled assessment is linked to the previous scheduled timepoint). 
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Safety data collected at an unscheduled timepoint (vital signs and laboratory data) will be analyzed 
according to the following scenario: 
• For shift tables, they will be taken into account in the derivation of the worst assessment during 
the on-treatment period. 
• For description at each post-baseline timepoint, the first available result (in chronological 
order) per timepoint will be taken into account in the analysis in case of multiple values. 
• For description at Baseline, unscheduled measurements will be considered as described in 
Section 9.3. 
Efficacy data collected at unscheduled visits will all be considered in the analysis. 
For immunogenicity analysis, unscheduled visits will be taken into account in the analysis. 
For PK analysis, unscheduled samples will not be linked to a scheduled timepoint and will be 
excluded from summaries. 
9.14 
Preferred Term for analysis of World Health Organization’s 
Drug Dictionary (WHO-DD) coded data  
For data coded according to WHO Drug B3 (e.g., concomitant medications), summaries will be 
done on the preferred term (PT) level where the PT corresponds to codes ending in 01001. With 
this approach, variations of salt forms of active ingredients will be analyzed under the same term, 
e.g. diphenhydramine and diphenhydramine hydrochloride will be analyzed as the same PT, 
diphenhydramine.  
9.15 
Re-screened Participants  
Re-screened participants will be only counted once in the screening analysis set, considering the 
latest screening (screening with latest informed consent).  
9.16 
Data collected after reinitiated treatment  
Data collected after reinitiation of treatment will be included in summary tables for all analyses. 
Data listings will include all data where those collected during the reinitiation of treatment will be 
flagged. 
9.17 
 Categorization of Participants for COVID-19 Impact 
Assessment   
For the assessment of COVID-19 impact on this study, participants will be categorized as being 
affected by COVID-19 (either due to infection or due to circumstances of social distancing 
affecting the capabilities of sites/hospitals etc.) based on the COVID-19 pandemic period defined 
as follows: 
• The start of COVID-19 pandemic will be defined by country as the earliest date of either the 
date of the first death from COVID-19 occurred in each country according to the published 
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data by European Centre for Disease Prevention and Control on 26th June 2020 
(https://www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-
distribution-covid-19-cases-worldwide) or 11 March 2020 (when the WHO declared COVID-
19 pandemic). 
• Post-pandemic could be defined as date (1) vaccination is released, (2) WHO declares COVID-
19 pandemic over, (3) region-specific calls are made to end social distancing measures with 
no relevant rise in cases thereafter. 
9.18 
Software  
All statistical analyses will be performed using statistical software SAS® (Statistical Analysis 
System, SAS-Institute, Cary NC, USA, Windows Version 9.4 or higher) in the SAS Grid 
environment.  
The computer program Phoenix® WinNonlin® Version 8.0, or higher (Certara, L.P., Princeton, 
New Jersey, USA) will be used to derive PK parameters applying non-compartmental analysis. 
10 
Study Participants  
The subsections below include specifications for reporting participant disposition and study 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided. 
10.1 
Disposition of Participants and Discontinuations  
All participants from the screening analysis set will be considered. 
The number and percentage of participants in each of the following disposition categories will be 
presented by cohort and total. These statistics will also be provided for the Japanese subpopulation. 
Percentages will be calculated based on the number of treated participants. 
• Total number of participants screened (i.e., all participants who gave informed consent) 
• Number of re-screened participants 
• Number of participants who did not continue beyond screening overall and grouped by the 
main reason (participant did not meet all eligibility criteria, withdrawn informed consent, 
progression of disease, adverse event, lost to follow-up, death, other) 
• Number and percentage of treated participants (at least one administration of study 
intervention) 
The end of treatment status will be summarized for each study intervention separately (bintrafusp 
alfa, bevacizumab, all chemotherapies and radiotherapy, as applicable) as follows: 
• Number and percentage of treated participants with the study intervention ongoing 
• Number and percentage of treated participants who completed or discontinued the study 
intervention period, overall and by primary reason (completed as per protocol, adverse event, 
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lost to follow-up, protocol non-compliance, death, progression of disease, withdrew consent, 
other) 
For participants who reinitiated bintrafusp alfa, the primary reason for treatment termination 
before bintrafusp alfa reinitiation will be considered. 
• Number and percentage of participants who reinitiated bintrafusp alfa 
• Number and percentage of participants who discontinued bintrafusp alfa after reinitiation 
The end of study status will be summarized by: 
• Number and percentage of participants with at least one study intervention ongoing  
• Number and percentage of participants off-treatment and in follow-up 
• Completed/Discontinued the study period, overall and by primary reason (study completed 
according to the protocol, adverse event, lost to follow-up, protocol non-compliance, death, 
withdrew consent, other) 
The number and percentage of participants included in each analysis set as defined in Section 8.1 
will be provided by cohort and overall. These statistics will also be provided for the Japanese 
subpopulation. Percentage will not be provided for the screening analysis set. 
Additionally, the number of participants in each analysis set will be provided overall, by region, 
by country within region, and by site. 
The listing of participant disposition will include all participants (i.e., including screening failures). 
The listing will include the following information (if applicable): cohort, participant identifier, 
ethnicity (Japanese/Non-Japanese), date of informed consent, included in the study, reason for 
exclusion, dates of first/last administration for each study intervention, reason off-treatment, date 
and reason off-study, population flags. When the reasons, such as the reason off-treatment is 
categorized as “Other, specify”, “Protocol non-compliance, specify” or “Withdrawal by subject, 
specify”, the verbatim text as entered in the eCRF will be presented in the listing.  
If any re-screened participants are observed, a listing of re-screened participants will be provided 
and will include the following information: cohort, participant identifier, date of informed consent, 
date of first administration of the study intervention, participant identifier at screen failure, date of 
informed consent at screen failure, date of screening failure, reason of screening failure. Note if 
participants are screened several times, all screening attempts will be listed. 
In addition, a listing of participants for which bintrafusp alfa has been reinitiated will be provided 
with the following information: cohort, participant identifier, ethnicity (Japanese/Non-Japanese), 
dates of first/last administration for each study intervention, reason for termination of each study 
intervention, first and last reinitiation bintrafusp alfa administration date, status at end of treatment 
reinitiation (completed, permanently discontinued), and primary reason for permanent bintrafusp 
alfa discontinuation. When the reason is categorized as “Other, specify”, “Protocol non-
compliance, specify” or “Withdrawal by subject, specify”, the verbatim text as entered in the eCRF 
will be presented in the listing. 
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Assessment of COVID-19 Impact 
In addition, for the assessment of COVID-19 impact on this study, an overview table will be 
presented by cohort with the following information: 
• Participants potentially affected by COVID-19 (i.e., participants who started treatment after 
start of the COVID-19 pandemic, or who started treatment prior to start of the COVID-19 
pandemic and are still ongoing after the start of the pandemic)  
• Participants with at least one COVID-19 impact    
• Participants with at least one COVID-19 impact in the following categories: adverse events, 
death, protocol deviations, missed drug administration, treatment administration modifications, 
missed tumor assessments, missed visits, tele visits replacing on-site visits, treatment 
discontinuation, study discontinuation 
• Number of participants with missed tumor assessments, missed visits, tele-visits replacing on-
site visits (1 / 2 / 3 / >3) 
A listing COVID-19 impact will be provided with the following information: cohort, participant 
identifier, age, race, ethnicity (Japanese/Non-Japanese), dates of first/last administration of each 
study intervention, date of first subsequent anticancer therapy as applicable, date of the event, visit, 
category, event, event description/reason. 
10.2 
Protocol Deviations  
Protocol deviations will be analyzed on the SAF/FAS analysis set. 
10.2.1 
Important Protocol Deviations  
Important protocol deviations (IPDs) are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being.  
The following summary tables and listings of important protocol deviations will be provided in 
the SAF/FAS by cohort and overall: 
• Frequency table (number and percentage) per category of important protocol deviations 
• Listing of important protocol deviations which will include participant identifier, ethnicity 
(Japanese/Non-Japanese), category of the deviation, and a description of the deviation. 
 A full list of potential protocol deviations including definition and categorization is maintained in 
Appendix 1. 
An additional listing of COVID-19 related PDs (including non-important PDs) will be provided. 
Considerations for PK: 
Protocol deviations or events will be reviewed by the study pharmacokineticist and biostatistician 
to identify deviations or events which have the potential to affect the PK results. Deviations 
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resulting in no evaluable PK results for a subject, and thus exclusion from PK summaries, will be 
documented as reasons for exclusion from these summaries. 
Changes to the procedures which may impact the quality of the PK data will be considered 
important protocol deviations and will be described within the CSR body text. Other events which 
may impact the quality of the PK data will be described within the CSR body text. These changes 
or events will include any circumstances that will alter the evaluation of the PK. Examples of 
important protocol deviations or important events for PK in terms of this study may include, but 
may not be limited to, the following: 
• Dose delayed outside the allowed window (and actual dosing time not recorded) 
• Dose change, missed dose, or incomplete/inaccurate dose 
• Pre-dose sample collected after the actual start of infusion 
• End-of-infusion sample collected before the actual end of infusion 
• Sample processing errors that may lead to inaccurate bioanalytical results 
For the above important protocol deviations or important events for PK, the relevant PK data will 
be excluded from summaries based on the PK analysis set. Other changes to the procedures or 
events which do not impact the quality of the PK data will not be considered important protocol 
deviations for PK. Common examples of minor (non-important) protocol deviations are a missed 
sample or minor deviations from sample collection times/windows. 
Refer to Section 16.1 for more details of protocol deviations and handling relevant to PK. 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set  
A listing of participants excluded from the PK and DLT analysis sets as well as the corresponding 
reasons will be provided. 
11 
Demographics and Other Baseline Characteristics  
Demographics and other baseline characteristics will be described on the SAF/FAS analysis set by 
cohort and overall. 
11.1 
Demographics  
Demographic characteristics and physical measurements will be summarized descriptively using 
the following information from the Screening/Baseline Visit eCRF pages. Demographics will also 
be separately summarized by cohort for Japanese participants. 
Demographic characteristics will be summarized using the following information: 
• Sex: female 
• Ethnicity: Hispanic or Latino, not Hispanic or Latino; Japanese, not Japanese 
• Race:  
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o For participants reporting one race only: White, Black or African American, Asian, 
American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, Not 
collected at the site, Other. 
o For participants reporting multiple races, all combinations will be reported under 
‘More than one race” category.  
• Age (years): summary statistics  
• Age categories: < 65 years, ≥ 65 years 
• Geographic Region: North America, Europe, Asia & Pacific 
• Body Surface Area (BSA) (m2) at Baseline 
• Height (cm) at Baseline 
• Weight (kg) at Baseline 
• Body Mass Index (BMI) (kg/m2) at Baseline 
• ECOG Performance status: 
o 0: Fully active, able to carry on all pre-disease performance without restriction 
o 1: Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
o 2: Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
o 3: Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
o 4: Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair 
o 5: Dead 
Specifications for computation (at ADaM level):  
• Age [years]: (date of given informed consent - date of birth + 1) / 365.25 
• The integer part of the calculated age will be used for reporting purposes. Note for rescreened 
participants, their latest informed consent date will be used. 
• See Section 9.10 for imputation rules. 
• BSA [m²] =ට 
ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡[𝑐𝑐𝑐𝑐]×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
3600
 
• BMI [kg/m²] = 
𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 [𝑘𝑘𝑘𝑘] 
ℎ𝑒𝑒𝑒𝑒𝑒𝑒ℎ𝑡𝑡[𝑐𝑐𝑐𝑐]2 × 10000 
• Investigator site codes will be used for the determination of the participant’s geographic 
region. 
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Demographic characteristics including cohort, participant identifier, race (including all reported 
races in case of “multiple” races, and details in case of “other” race), ethnicity, geographic region, 
age, body mass index, body surface area, weight and height will be presented in a listing.  
11.2 
Medical History  
Relevant past and ongoing medical conditions at Baseline will be summarized from the “Medical 
History Details” eCRF page, using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA), PT as event category and MedDRA system organ class (SOC) 
body term as Body System category.  
Medical history will be displayed in frequency tables, ordered by primary SOC and PT in 
alphabetical order. Each participant will be counted only once within each PT or SOC. 
Listing of medical history including cohort, participant identifier, age, race, ethnicity 
(Japanese/Non-Japanese), PT, condition (reported medical history term, HIV infection, multi-drug 
resistance preventing effective antiretroviral therapy, multi-drug resistance not preventing 
effective antiretroviral therapy, aids defining opportunistic infection and specification), start/end 
dates, related study condition, ongoing at screening and toxicity grade (when medical history is 
ongoing) will be presented. 
11.3 
Other Baseline Characteristics  
Other baseline characteristics will be summarized by cohort, overall and for Japanese participants. 
11.3.1 
Disease History  
Information on disease characteristics collected on the “Disease History” eCRF page will be 
summarized as follows: 
• Histological diagnosis (Squamous cell carcinoma, Adenocarcinoma, Adenosquamous cell 
carcinoma, Other) 
• Time since initial cancer diagnosis (months) 
• Time since documented, locally advanced, inoperable or metastatic disease diagnosis (months) 
• Time since last progression of disease prior to study entry (months) 
• TNM classification at initial diagnosis: each T, N, M category will be described (TX, T0, N1, 
etc.) 
• Measurable disease in the pelvis at study entry (Yes, No) 
Microsatellite instability (MSI) status (High, Low, Microsatellite stable (MSS), Unknown) will 
also be summarized. MSI status will be centrally determined with available tumor tissue sample 
collected at screening and will be provided as external data. Data related to central testing will be 
listed as specified in Section 16.5. 
A listing will also be provided including the following information: cohort, participant identifier, 
age, race, ethnicity (Japanese/Non-Japanese), histological diagnosis, date of initial cancer 
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diagnosis and time since initial cancer diagnosis (months), date of documented, locally advanced, 
inoperable or metastatic disease and time since documented, locally advanced, inoperable or 
metastatic disease (months), date of last progression and time since last progression of disease 
prior to study entry (months), TNM classification at initial diagnosis, status regarding the 
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11.3.4 
Skin Status History  
Skin status history is collected on the “Skin Status History” eCRF page and will be summarized 
by the frequency and percentage of participants having the following: 
• Personal history of frequent sunburn (Yes, No, Unknown) 
• Personal history of easy sunburn (Yes, No, Unknown) 
• Personal history of skin cancer (Yes, No, Unknown) 
• Personal history of significant UV exposure (Yes, No, Unknown) 
• Personal history of photosensitivity due to skin disorder (Yes, No, Unknown) 
• Personal history of photosensitivity due to medication (Yes, No, Unknown) 
• Family history of skin cancer in first degree relative (i.e., parents, siblings and/or children) 
(Yes, No, Unknown) 
• Participants having history of skin conditions (No condition, 1 condition, 2 conditions, 3 or 
more conditions) 
No condition: At least one of the seven items above ticked “No” and no items ticked “Yes”. 
1, 2, 3 or more conditions: 1, 2, 3 or more of the seven items above ticked “Yes”, 
respectively. 
A listing of skin status history will be provided including the following information: cohort, 
participant identifier, age, race, ethnicity (Japanese/Non-Japanese) and outcome for each type of 
skin status history. 
 
  
 
 
 
11.4 
Prior Anticancer Therapy  
The prior anti-cancer therapies are collected under the “Prior Anti-Cancer Drug Therapies Details” 
and “Prior Anti-Cancer Surgeries Details” and “Previous Pre-cancerous Procedures of the Cervix” 
eCRF pages. 
The number and percentages of participants in each of the following anticancer therapy categories 
will be tabulated: 
• Participants with at least one type of prior anticancer treatment (i.e., drug therapy, radiotherapy 
or surgery) 
• Participants with at least one prior anticancer drug therapy  
• Participants with at least one radiotherapy administered as part of a prior drug therapy 
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• Participants with at least one prior anticancer surgery 
• Participants with at least one prior pre-cancerous procedure of the cervix 
Previous anticancer drug therapy will be summarized as follows based on the number and 
percentage of participants with the following: 
• Number of prior anticancer drug therapy regimens:  0 / 1 / 2 / 3 / ≥ 4 
• Number of prior lines of therapy for metastatic/locally advanced disease: 0 / 1 / 2 / 3 / ≥ 4 
• Intent of therapy: Neoadjuvant / Adjuvant / Metastatic or Locally Advanced 
• Best response to last treatment regimen: Complete Response (CR) / Partial Response (PR) / 
Stable Disease (SD) / Progressive Disease (PD) / Non-Complete Response/Non-Progressive 
Disease (non-CR/non-PD) / Not Evaluable / Unknown 
Previous anticancer drug therapy (radiotherapy and drug), previous anticancer surgery and pre-
cancerous procedure of the cervix will be presented in separate listings as follows: 
• The previous anticancer drug therapy listing will contain cohort, participant identifier, age, 
race, ethnicity (Japanese/Non-Japanese), regimen name, intent of therapy and line number in 
case of metastatic/locally advanced, line number, best response, documented progression 
disease date, type of treatment (radiotherapy, drug), PT/medication name or location of 
radiotherapy, start date, end date, route for drug. This listing will be sorted by cohort, 
participant identifier, regimen number, type of treatment (radiotherapy, drug), start date, end 
date, location, PT.  
• The previous anticancer surgery listing will contain cohort, participant identifier, age, race, 
ethnicity (Japanese/Non-Japanese), date of surgery, name and location of surgery, curative 
intent of surgery (Y/N), and outcome of surgery. This listing will be sorted by cohort, 
participant identifier, surgery date, name of surgery and location of surgery. 
• The pre-cancerous procedure of the cervix listing will contain cohort, participant identifier, 
age, race, ethnicity (Japanese/Non-Japanese), name of procedure, start and end dates, reason 
for procedure (indication), reason for procedure. This listing will be sorted by cohort, 
participant identifier, date of procedure, start date and end date. 
12 
Previous or Concomitant Medications/Procedures  
The following analyses will be performed on the SAF/FAS analysis set by cohort and overall. 
12.1 
Previous and Concomitant Medications  
Previous medications are medications, other than study intervention and pre-medications for study 
intervention, which started before the first administration of any study intervention.  
Concomitant medications are medications, other than study intervention and pre-medications for 
study intervention, which are taken by participants any time during the on-treatment period, see 
Section 9.9. All medications starting the same day as the first administration of the study 
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intervention will be considered as concomitant. Medications starting at the 30th day after the last 
dose of study intervention will also be considered as concomitant. 
A medication may be classified as both concomitant and previous. The respective flags will be 
derived based on start and end date. See Section 9.10 for derivation. 
Concomitant medications will be summarized by number and percentage of participants from the 
“Concomitant medication details” eCRF page. Anatomical Therapeutic Chemical (ATC) level 2 
and PT will be tabulated as given from the WHO-DD dictionary most current version. If any 
concomitant medication is classified into multiple ATC classes, the medication will be 
summarized separately under each of these ATC classes. The summary tables will be sorted by 
decreasing frequency of drug class and decreasing frequency of drug name in a given drug class. 
In case of equal frequency regarding drug class (respectively drug name), alphabetical order will 
be used. In case any specific medication does not have an ATC classification level 2 coded term, 
it will be summarized under “Uncoded” category. Each participant will only be counted once, even 
if he/she received the same medication at different times. 
Previous and concomitant medications will be presented in a listing which will include: cohort, 
participant identifier, age, race, ethnicity (Japanese/Non-Japanese), PT, medication name as 
provided by the Investigator, start date/time, end date/time (ongoing if applicable), dose, dose 
units, frequency, route, reason for medication (indication), reason for medication. This listing will 
be sorted by cohort, participant identifier, start date and time, end date and time and PT. 
12.2 
Premedications  
Premedications are medications administered per protocol on the same day as, but prior to, a study 
intervention.  
Premedication for bintrafusp alfa will be based on “Premedication Bintrafusp alfa” eCRF page 
(participants for whom the question “Has the participant received premedications before bintrafusp 
alfa infusion?” is answered “Yes” at the corresponding visit). Premedication for chemotherapy 
will be based on “Premedication chemotherapy” eCRF page (participants for whom the question 
“Has the participant received premedications before chemotherapy infusion?” is answered “Yes” 
at the corresponding visit). 
A listing of premedication for bintrafusp alfa and chemotherapy will be provided. This listing will 
include cohort, participant identifier, age, race, ethnicity (Japanese/Non-Japanese), name of 
medication, start date/time of premedication, end date/time of premedication, study days since the 
first study intervention, dose, unit, route. These listings will be sorted by cohort, participant 
identifier, start date/time of premedication, end date/time of premedication and medication name. 
12.3 
Concurrent Procedures  
Concurrent procedures are reported according to the “Concomitant Procedures Details” eCRF 
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Concurrent procedures will be presented in a listing which will include cohort, participant 
identifier, age, race, ethnicity (Japanese/Non-Japanese), name of procedure (as provided by the 
Investigator), start date, end date, indication, reason for procedure, type of specimen collected, 
specimen property, cytology and diagnosis further to the specimen evaluation by the local (non-
study) pathologist. A flag will be displayed to identify each procedure as prior to treatment or on-
treatment. This listing will be sorted by cohort, participant identifier, start date, end date and 
procedure name. 
12.4 
Subsequent Anticancer Treatment  
Subsequent anticancer treatment is collected under the “Anti-cancer Treatment after 
Discontinuation Details”, “Radiotherapy after Discontinuation Details” (Cohort 2: radiotherapy 
administered while participant is still receiving study intervention is not considered as subsequent 
anticancer treatment), “Brachytherapy after Discontinuation Details”, and “Surgeries after 
Discontinuation Details” eCRF pages.  
Subsequent anticancer treatment will be presented in a listing including cohort, participant 
identifier, age, race, ethnicity (Japanese/Non-Japanese), preferred term/medication name, 
treatment type (medication, radiotherapy, surgery or brachytherapy), regimen name (if 
medication), best response (if medication), start date, end date (if medication, radiotherapy or 
brachytherapy), radiotherapy site/name of surgery/location (if radiotherapy, surgery or 
brachytherapy), curative intent of surgery, outcome of surgery. This listing will be sorted by 
cohort, participant identifier, start date, end date, treatment type, preferred term and medication 
name. 
13 
Study Treatment: Compliance and Exposure  
The following analyses will be performed on the SAF/FAS study population by cohort overall and 
for Japanese participants.  
For participants enrolled in Cohorts 1A and 1B, bintrafusp alfa is administered every 3 weeks until 
end of treatment. Cisplatin or carboplatin, paclitaxel and bevacizumab are administered as per 
standard of care (SoC) practices every 3 weeks until end of treatment. 
For participants enrolled in Cohort 2, bintrafusp alfa is administered every 3 weeks until end of 
treatment. Cisplatin is administered as indicated for SoC treatment as a radiation-sensitizing agent 
(e.g., every week for 5 weeks). Radiotherapy is administered as per SoC practices (e.g., 5 fractions 
per week over 5 weeks). Brachytherapy can also be administered per local SoC. 
More details for administration of bintrafusp alfa and other study interventions are given in Section 
6 of the protocol. 
All derived variables in this section will be based on “Bintrafusp alfa Administration Details”, 
“Cisplatin Administration Details”, “Carboplatin Administration Details”, “Paclitaxel 
Administration Details”, “Bevacizumab Administration Details”, “Radiotherapy Administration 
Details” and “Brachytherapy Administration Details” eCRF pages and will include the re-initiation 
phase if any. 
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For the analysis of compliance and exposure, a dose is regarded to be administered if the actual 
dose received is > 0 mg for study interventions other than radiotherapy and brachytherapy, and if 
the start date is non missing for radiotherapy and brachytherapy. 
Imputation for incomplete start and end dates of study treatments are described in Section 9.10. 
Duration of Therapy (Weeks) and Number of Administrations for each study intervention 
The duration of therapy (weeks) for bintrafusp alfa (Cohort 1A, 1B and 2) and every other study 
intervention is defined in Cohorts 1A and 1B as:  
duration of therapy= ൬date of last administration - date of first administration + 21
7
൰ 
The duration therapy (weeks) for cisplatin when received by participants in Cohort 2 is defined as 
follows: 
duration of therapy= ൬date of last administration - date of first administration + 7
7
൰ 
The duration therapy (weeks) for radiotherapy is defined as follows: 
duration of therapy= ൬date of last administration - date of first administration + 2
7
൰ 
The duration therapy (weeks) for brachytherapy is defined as follows: 
duration of therapy= ൬date of last administration - date of first administration + 1
7
൰ 
For each study intervention, the total number of administrations received will be calculated as the 
sum of all administrations received during the study. 
Cumulative Dose, Dose Intensity, and Relative Dose Intensity 
The cumulative actual dose of bintrafusp alfa (mg) is defined as the sum of all actual dose (mg) 
received by the participant as collected in the eCRF. 
The cumulative actual dose of bevacizumab (mg/kg) is defined as the sum over all visits of [actual 
dose (mg) received at visit i / weight (kg) at vist i]. 
The cumulative actual dose of cisplatin and paclitaxel (mg/m²) is defined as below: 
Cumulative actual dose (mg/m²) = sum over all visits of [actual dose (mg) received at visit i / body 
surface area [BSA] (m²) at visit i], where: 
BSA at a visit i (m²) =√൬height at Baseline (cm)*weight at visit i (kg) 
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The cumulative dose of carboplatin will be computed in mg and area under the curve (AUC) as 
the sum of all actual doses (mg and AUC respectively) received by the participant as collected in 
the eCRF. 
The cumulative actual dose of carboplatin (AUC) will also be derived from the actual dose 
expressed in mg using the Calvert equation as follows: 
Cumulative actual dose (AUC) = ෎
𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 (𝑚𝑚𝑚𝑚) 𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑖𝑖
𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺𝐺 𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹𝐹 𝑅𝑅𝑅𝑅𝑅𝑅𝑅𝑅 (𝐺𝐺𝐺𝐺𝐺𝐺) 𝑎𝑎𝑎𝑎 𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣 𝑖𝑖+ 25 
𝑛𝑛
𝑖𝑖=1
 
Where n is the number of visits, and GFR is estimated by calculated creatinine clearance (CrCl) 
using the Cockcroft-Gault equation: 
CrCl (mL/min) = (140 − age [years]) ∗ weight [kg] ∗ (0.85 for females only)
72 ∗ creatinine [mg/dL]
 
Conversion factor for creatinine: 1 mg/dL = 88.4 µmol/L. 
The GFR value will be capped at 125 mL/min. 
In case the weight or creatinine is not available at a visit, it will be imputed to the value observed 
at the previous visit. 
The cumulative actual dose for radiotherapy (Gy) is defined as the sum of all actual doses (Gy) 
received by the participant as collected in the eCRF. 
The cumulative actual dose for brachytherapy (Gy) is defined as the sum of all actual doses (Gy) 
received by the participant as collected in the eCRF. 
The dose intensity (DI) of bintrafusp alfa (mg/cycle) per 3-week period is defined as: 
DI= ൬
cumulative dose (mg) 
(duration of therapy (weeks))/3൰ 
 (Cohorts 1A and 1B) The DI of chemotherapy (mg/m²/cycle) (excluding carboplatin) per 3-week 
period is defined as: 
DI= ൬
cumulative dose (mg/m²)
(duration of therapy (weeks))/3൰ 
(Cohorts 1A and 1B) The DI of carboplatin (mg.min/mL/cycle) per 3-week period is defined as: 
DI= ൬cumulative dose (mg.min/mL)
(duration of therapy (weeks))/3൰ 
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It will be presented both from the cumulative dose (AUC) as directly provided by the Investigator 
and from the cumulative dose (AUC) as derived from the actual dose (mg) provided by the 
Investigator using the Calvert equation. 
(Cohorts 1A) The dose intensity (DI) of bevacizumab (mg/kg/cycle) per 3-week period is defined 
as: 
DI= ൬
cumulative dose (mg/kg)
(duration of therapy (weeks))/3൰ 
(Cohort 2) The dose intensity (DI) of cisplatin (mg/m²/week) per 1-week period is defined as: 
DI= ൬cumulative dose (mg/m²)
(duration of therapy (weeks))൰ 
For participants who reinitiated bintrafusp alfa during the study, the formula above will also apply. 
The relative dose intensity (RDI) of bintrafusp alfa is defined as the actual dose intensity divided 
by the planned dose per cycle and expressed in percentage. 
RDI (%) = 100 * ൬
DI
planned dose per cycle൰ 
The RDI of chemotherapy agents (%) is defined as follows: RDI (%) = 100 * (DI / planned DI), 
where the planned DI (mg/m²/cycle, mg/kg/cycle or AUC mg.min/mL/cycle) is the planned dose 
at week 1 day 1 (mg/m², mg/kg or AUC). 
As specified for the DI, the RDI of carboplatin will be presented using the actual doses (AUC) as 
provided by the Investigator in the eCRF and using the actual doses (AUC) as converted from mg 
to AUC using the Calvert equation. 
The following summary table will be provided for each study intervention by cohort: 
• Duration of therapy 
• Total number of administrations received  
• Cumulative actual dose 
• DI (not defined for radiotherapy) 
• RDI as continuous variable (not defined for radiotherapy), and categorized (< 80%, 80%-90%, 
> 90%) 
Dose Modification 
As per protocol, no dose modification is allowed for bintrafusp alfa. No summaries will be 
provided. 
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For all other study interventions, a dose reduction is observed when the answer to the question “Is 
there a change in dose?” = “Dose adjusted” and the planned dose collected at the respective visit 
is lower than that observed at the previous visit. 
The number of participants with at least one dose reduction, reasons for dose reduction (Adverse 
event / Other), as well as a categorization of the number of administrations with reduced dose (1, 
2, ≥ 3) will be summarized for each chemotherapy and bevacizumab by cohort.  
Therapy Delays 
Therapy delays will be derived for each administration of bintrafusp alfa, chemotherapy and 
bevacizumab as follows:  
• Therapy delay for bintrafusp alfa = start date of current infusion – start date of the previous 
infusion – 21 
• (Cohorts 1A and 1B) Therapy delay for chemotherapies and bevacizumab = start date of 
current infusion – start date of the previous infusion – 21 
• (Cohort 2) Therapy delay for cisplatin = start date of current infusion – start date of the 
previous infusion – 7 
If the result is > 0 day, this will be categorized as a delay. A participant may have more than one 
treatment delay throughout the study. 
The following will be summarized for each study intervention (radiotherapy and brachytherapy 
excluded) by cohort: 
• Number of participants with at least one delay, with no delay 
• The maximum length of delay per participant (no delay, 1-3 days, 4-8 days, 9-15 days, ≥ 16 
days) 
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Temporary Interruptions of Infusion 
Study drug infusion temporarily interrupted as recorded on each study intervention administration 
details page of the eCRF will be used for analysis. 
For each study intervention (excluding radiotherapy and brachytherapy), the number and 
percentage of participants with at least one temporary interruption and a summary of the reason(s) 
for temporary interruption (Adverse event, Other) will be provided. 
Individual Data Listings 
A listing of treatment exposure data will be provided for each study intervention. For bintrafusp 
alfa, chemotherapies and bevacizumab, it will include: cohort, participant identifier, age, race, 
ethnicity (Japanese/Non-Japanese), visit, infusion start date and time, infusion end date and time, 
change in dose and reason for change, infusion rate, planned dose (as applicable), actual dose, 
route, administration modification and reason for modification, treatment delay (days). 
For radiotherapy, the listings will include: cohort, participant identifier, age, race, ethnicity, visit, 
start date, end date, number of fractions and total dose. 
For brachytherapy, the listings will include: cohort, participant identifier, age, race, ethnicity 
(Japanese/Non-Japanese), visit, start date, end date, therapy type and total dose. 
Administrations received during the reinitiation phase will be flagged in the listings. These listings 
will be sorted by cohort, participant identifier, administration start date and administration end 
date.  
An additional listing of individual treatment exposure summary measures will be provided 
including cohort, participant identifier, age, race, ethnicity, study intervention, duration of therapy 
(weeks), total number of administrations received, cumulative dose of therapy (unit), dose intensity 
(unit), and relative dose intensity (%). 
Chemotherapy Switch 
A listing of chemotherapy switches will be provided based on the “Chemotherapy Switch” eCRF 
page. This listing will include cohort, participant identifier, age, race, ethnicity (Japanese/Non-
Japanese), initial and new chemotherapy regimens and reason for switch. 
14 
Efficacy Analyses  
 They will be conducted on the SAF/FAS analysis set for 
each cohort independently. 
 
  
 
 
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Kaplan-Meier Analysis 
Kaplan-Meier estimates (product-limit estimates) will be presented by cohort together with a 
summary of associated statistics including the median PFS time with two-sided 95% CIs. In 
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15 
Safety Analyses  
Safety analyses will be done on the SAF/FAS analysis set by cohort and according to the as-treated 
principle apart from the DLT analysis described in Section 15.1 where the DLT analysis set will 
be used. The analyses will also be specifically provided for Japanese participants within each 
cohort. 
15.1 
Dose-limiting Toxicities (Primary Endpoint)  
DLTs are those events reported on the “Adverse Event Details” eCRF page with the “Is this 
adverse event a dose limiting toxicity” field ticked “Yes”. 
A table of the occurrence of DLT AE will be provided by cohort including: 
• Number and percentage of participants who experienced a DLT during the DLT evaluation 
period 
• Number of DLTs per participant experienced during the DLT evaluation period (1 / 2 / ≥3) 
• DLT experienced during the DLT evaluation period by SOC and PT based on the latest 
available MedDRA version.  
A listing of DLTs will also be provided with the relevant information (see  Section 15.2.1 for the 
variables to be included).  
15.2 
Adverse Events  
Treatment emergent adverse events (TEAEs) are those events with onset dates occurring during 
the on-treatment period (on-treatment period defined in Section 9) or if the worsening of an event 
is during the on-treatment period. 
Changes in toxicity grade, seriousness or outcome of AEs are recorded as separate entries in the 
eCRF with associated end and start dates (start date equals end date of previous entry). Such entries 
reporting the same event in such immediately consecutive periods will be considered as one event 
in the analysis. These events will be kept as separate records in the database in order to maintain 
the full detailed history of the events. The start date of the initial record in the sequence is taken 
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as start date of the entire event, similarly the end date of the last event in the sequence is taken as 
end date of the entire event. The overall outcome of the adverse event is the outcome of the last 
event in the sequence. Duration of the AE and the TEAE flag will be adjusted accordingly in the 
analysis.  
All analyses described in this section will be based on TEAEs during on-treatment period if not 
otherwise specified and will be described by cohort. The AE listings will include all AEs (whether 
treatment-emergent or not). AEs outside the on-treatment period will be flagged in the listings. AE 
occurring during the reinitiation phase will be considered in the summary tables and will be flagged 
in the listings. 
Incomplete AE-related dates will be handled as stated in Section 9. 
Bintrafusp alfa Related Adverse Events are those AEs with relationship to bintrafusp alfa 
reported by the Investigator as related (i.e., answer to the question “Relationship with Bintrafusp 
alfa” = “Related” on “Adverse Event Details” eCRF page) and those of unknown relationship (i.e., 
no answer to the question “Relationship with Bintrafusp alfa”). 
Bevacizumab Related Adverse Events are those AEs with relationship to bevacizumab reported 
by the Investigator as related (i.e. answer to the question “Relationship with Bevacizumab” = 
“Related” on “Adverse Event Details” eCRF page) and those of unknown relationship (i.e., no 
answer to the question “Relationship with Bevacizumab”). 
Chemotherapy Related Adverse Events are those AEs with relationship to cisplatin or 
carboplatin or paclitaxel defined as follows:  
• For cisplatin reported by the Investigator as related (i.e. answer to the question “Relationship 
with Cisplatin” = “Related” on “Adverse Event Details” eCRF page) and those of unknown 
relationship (i.e., no answer to the question “Relationship with Cisplatin”). 
• For carboplatin reported by the Investigator as related (i.e. answer to the question 
“Relationship with Carboplatin” = “Related” on “Adverse Event Details” eCRF page) and 
those of unknown relationship (i.e., no answer to the question “Relationship with 
Carboplatin”).  
• For paclitaxel reported by the Investigator as related (i.e. answer to the question “Relationship 
with Paclitaxel” = “Related” on “Adverse Event Details” eCRF page) and those of unknown 
relationship (i.e., no answer to the question “Relationship with Paclitaxel”).  
Radiotherapy Related Adverse Events are those AEs with relationship to radiotherapy reported 
by the Investigator as related (i.e., answer to the question “Relationship with Radiotherapy” = 
“Related” on “Adverse Event Details” eCRF page) and those of unknown relationship (i.e., no 
answer to the question “Relationship with radiotherapy”). 
Brachytherapy Related Adverse Events are those AEs with relationship to brachytherapy 
reported by the Investigator as related (i.e., answer to the question “Relationship with 
Brachytherapy” = “Related” on “Adverse Event Details” eCRF page) and those of unknown 
relationship (i.e., no answer to the question “Relationship with brachytherapy”). 
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Serious Adverse Events (SAEs) are those events reported on the “Adverse Event Details” eCRF 
page with the “Serious Adverse Event” field ticked “Yes”. 
Adverse Events Leading to Dose Reduction of Chemotherapy Agent(s): AEs leading to dose 
reduction of cisplatin or carboplatin or paclitaxel are defined as follows:   
• For cisplatin consider answer to the question “Action(s) taken with Cisplatin” = “Dose 
reduced” on “Adverse Event Details” eCRF page).  
• For carboplatin consider answer to the question “Action(s) taken with Carboplatin” = “Dose 
reduced” on “Adverse Event Details” eCRF page).  
• For paclitaxel consider answer to the question “Action(s) taken with Paclitaxel” = “Dose 
reduced” on “Adverse Event Details” eCRF page).  
Adverse Events Leading to Dose Reduction of Bevacizumab are defined as AEs where 
“Action(s) taken with Bevacizumab” = “Dose reduced” on the “Adverse Event Details” eCRF 
page. 
Adverse Events Leading to Temporary Discontinuation of Bintrafusp alfa: answer to the 
question “Action(s) taken with M7824” = “Drug interrupted” on “Adverse Event Details” eCRF 
page. 
Adverse Events Leading to Temporary Discontinuation of Chemotherapy: AEs leading to 
temporary discontinuation of cisplatin or carboplatin or paclitaxel are defined as follows: 
• For cisplatin consider answer to the question “Action(s) taken with Cisplatin” = “Drug 
interrupted” on “Adverse Event Details” eCRF page. 
• For carboplatin consider answer to the question “Action(s) taken with Carboplatin” = “Drug 
interrupted” on “Adverse Event Details” eCRF page. 
• For paclitaxel consider answer to the question “Action(s) taken with Paclitaxel” = “Drug 
interrupted” on “Adverse Event Details” eCRF page. 
Adverse Events Leading to Temporary Discontinuation of at least one Chemotherapy: AEs 
leading to temporary discontinuation of cisplatin or carboplatin or paclitaxel (definition above). 
Adverse Events Leading to Temporary Discontinuation of Bevacizumab: answer to the 
question “Action(s) taken with Bevacizumab” = “Drug interrupted” on “Adverse Event Details” 
eCRF page. 
Adverse Events Leading to Temporary Discontinuation of Radiotherapy: answer to the 
question “Action(s) taken with Radiotherapy” = “Radiotherapy interrupted” on “Adverse Event 
Details” eCRF page. 
Adverse Events Leading to Temporary Discontinuation of Brachytherapy: answer to the 
question “Action(s) taken with Brachytherapy” = “Brachytherapy interrupted” on “Adverse Event 
Details” eCRF page. 
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Adverse Events Leading to Temporary Treatment Discontinuation: AEs leading to temporary 
discontinuation of at least one of the study interventions. 
Adverse Events Leading to Permanent Discontinuation of Bintrafusp alfa: AEs leading to 
permanent discontinuation of bintrafusp alfa (i.e. answer to the question “Action(s) taken with 
Bintrafusp alfa” = “Drug withdrawn” on “Adverse Event Details” eCRF page). 
Adverse Events Leading to Permanent Discontinuation of Chemotherapy: AEs leading to 
permanent discontinuation of study intervention for cisplatin or carboplatin or paclitaxel defined 
as follows:  
• For cisplatin consider answer to the question “Action(s) taken with Cisplatin” = “Drug 
withdrawn” on “Adverse Event Details” eCRF page. 
• For carboplatin consider answer to the question “Action(s) taken with Carboplatin” = “Drug 
withdrawn” on “Adverse Event Details” eCRF page. 
• For paclitaxel consider answer to the question “Action(s) taken with Paclitaxel” = “Drug 
withdrawn” on “Adverse Event Details” eCRF page. 
Adverse Events Leading to Permanent Discontinuation of at least one Chemotherapy: AEs 
leading to permanent discontinuation of cisplatin or carboplatin or paclitaxel (definition above). 
Adverse Events Leading to Permanent Discontinuation of Bevacizumab: AEs leading to 
permanent discontinuation of bevacizumab (i.e. answer to the question “Action(s) taken with 
Bevacizumab” = “Drug withdrawn” on “Adverse Event Details” eCRF page). 
Adverse Events Leading to Permanent Discontinuation of Radiotherapy: AEs leading to 
permanent discontinuation of radiotherapy (i.e. answer to the question “Action(s) taken with 
Radiotherapy” = “Radiotherapy withdrawn” on “Adverse Event Details” eCRF page). 
Adverse Events Leading to Permanent Discontinuation of Brachytherapy: AEs leading to 
permanent discontinuation of brachytherapy (i.e. answer to the question “Action(s) taken with 
Brachytherapy” = “Brachytherapy withdrawn” on “Adverse Event Details” eCRF page). 
Adverse Events Leading to Permanent Treatment Discontinuation: AEs leading to permanent 
discontinuation of at least one of the study interventions. 
Adverse Event Leading to Death: AEs leading to death (as recorded on the “Adverse Event 
Details” eCRF page, change in grade = “No” and outcome = “Fatal”, or grade = “Grade 5 or death 
related to AE” or serious adverse event = “Yes” and seriousness criteria include “Results in 
death”).  
Adverse Events of Special Interest (AESI): AESI will be identified according to a pre-specified 
search list of MedDRA Preferred Terms.  
Categories of AESIs considered include: 
• Infusion-related reaction (IRR) (see Section 15.3.3.1) 
• Immune-related adverse events (irAE) (see Section 15.3.3.2) 
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• TGF-β inhibition mediated Skin Reaction (see Section 15.3.3.3) 
• Anemia (see Section 15.3.3.4) 
• Bleeding events (see Section 15.3.3.5) 
15.2.1 
All Adverse Events  
Adverse events will be summarized by worst severity (according to National Cancer Institute - 
Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0) per participant, 
using MedDRA (latest version) preferred term as event category and MedDRA (latest version) 
primary system organ class (SOC) body term as Body System category.  
Unless otherwise stated AEs will be displayed in terms of frequency tables: PT and primary SOC 
in alphabetical order.  
Each participant will be counted only once within each SOC or PT. If a participant experiences 
more than one AE within a SOC or PT for the same recording period, only the AE with the 
strongest relationship or the worst severity, as appropriate, will be included in the summaries of 
relationship and severity. 
In case a participant has same events with missing and non-missing grades, the maximum of the 
non-missing grades will be displayed. 
An overall summary table of TEAEs will be presented with the following information:  
• TEAEs  
• Bintrafusp alfa related TEAEs 
• Chemotherapy related TEAEs 
• Bevacizumab related TEAEs  
• Radiotherapy related TEAEs  
• Brachytherapy related TEAEs  
• Serious TEAEs  
• Bintrafusp alfa related serious TEAEs 
• Chemotherapy related serious TEAEs 
• Bevacizumab related serious TEAEs  
• Radiotherapy related serious TEAEs  
• Brachytherapy related serious TEAEs  
• TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
• Bintrafusp alfa related TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
• Chemotherapy related TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
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• Bevacizumab related TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
• Radiotherapy related TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
• Brachytherapy related TEAEs NCI-CTCAE severity grade (≥3, ≥4)  
• TEAEs leading to death 
• Bintrafusp alfa related TEAEs leading to death 
• Chemotherapy related TEAEs leading to death 
• Bevacizumab related TEAEs leading to death  
• Radiotherapy related TEAEs leading to death  
• Brachytherapy related TEAEs leading to death  
• Adverse events of special interest (related and not related as assessed by the Investigator):  
o Infusion-related reaction (IRR) 
o Immune related AEs (irAEs) 
o TGF-β inhibition mediated skin adverse events 
o Anemia 
o Bleeding events 
• Bintrafusp alfa related adverse events of special interest:  
o Infusion-related reaction (IRR) 
o Immune related AEs (irAEs) 
o TGF-β inhibition mediated skin adverse events 
o Anemia 
o Bleeding events 
Tables for TEAEs frequency corresponding to each category below will be provided by MedDRA 
primary SOC (ordered alphabetically) and PT (ordered alphabetically). 
• TEAEs  
• Bintrafusp alfa related TEAEs 
• Chemotherapy related TEAEs 
• Bevacizumab related TEAEs  
• Radiotherapy related TEAEs 
• Brachytherapy related TEAEs  
• TEAEs leading to death 
• Bintrafusp alfa related TEAEs leading to death 
• Chemotherapy related TEAEs leading to death 
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• Bevacizumab related TEAEs leading to death  
• Radiotherapy related TEAEs leading to death  
• Brachytherapy related TEAEs leading to death 
The following frequency tables will be provided by worst grade (≥ 3, ≥ 4), SOC, and PT: 
• TEAEs by worst grade, SOC, and PT 
• Bintrafusp alfa related TEAEs by worst grade, SOC, and PT 
• Chemotherapy related TEAEs by worst grade, SOC, and PT 
• Bevacizumab related TEAEs by worst grade, SOC, and PT  
• Radiotherapy related TEAEs by worst grade, SOC, and PT  
• Brachytherapy related TEAEs by worst grade, SOC, and PT  
Clinicaltrials.gov and EudraCT Requirements 
Summary tables for non-serious TEAEs excluding SAEs (tabulated by SOC and PT) applying 
frequency threshold of 5% in at least one of the cohorts will be provided. 
The following listings will be provided: 
• Listing of all AE (whether treatment-emergent or not): TEAEs and AE occurring during 
reinitiation phase will be flagged 
• Listing of TEAEs (AEs occurring during reinitiation phase will be flagged) 
• Listing of non-TEAE for AEs occurring after enrollment (date of first signature of informed 
consent/date of first signature of first informed consent) but prior to the first dose of study 
intervention 
• Listing of AE with onset or worsening after the on-treatment period (AEs occurring during 
reinitiation phase will be flagged) 
• Listing of AEs with onset or worsening occurring during the reinitiation of the treatment 
Each AEs listing will include the following information: cohort, participant identifier, age, race, 
ethnicity (Japanese/Non-Japanese), first and last administration dates of each study intervention, 
preferred term, reported term for the AE, start or change date, end date (ongoing if missing), 
duration of AE (in days), day relative to the first study intervention, day relative to the most recent 
study intervention prior to AE onset/change, relationship with each study intervention, toxicity 
grade, causality factor, action(s) taken with each study intervention, other action(s) taken, 
seriousness (Y/N), AESI infusion-related (Y/N), AESI immune-related (Y/N), skin AESI (Y/N), 
rash with hyperkeratosis, KA and SCC of skin (Y/N), immune-related skin AEs possibly mediated 
by PD-[L]1 inhibition (Y/N), anemia AESI (Y/N), bleeding (Y/N), dose limiting toxicity AESI 
(Y/N). AEs occurring after COVID-19 pandemic start and participants who switched 
chemotherapy will be flagged. Each listing will be sorted by cohort, participant identifier, start 
date, end date and preferred term. 
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Evaluation of COVID-19 effects on AEs 
The direct effect of COVID-19 for AEs will be assessed via: 
• An overview table of treatment-emergent AEs associated to COVID-19 by MedDRA primary 
SOC, high level terms (HLT) and PTs (ordered alphabetically).  
• A listing of COVID-19 related AEs. The following listing will be generated using the ‘COVID-
19 related terms MedDRA 23.0 update Spreadsheet’ or later version, considering all ‘search 
terms for COVID-19-related’ =’Y’. Same information as for the listing of all AEs will be 
provided. 
15.2.2 
Adverse Events Leading to Discontinuation of Study 
Intervention  
A table presenting the overview of TEAEs leading to discontinuation (temporary or permanent) or 
dose reduction of treatment will be presented by cohort with the following information:  
• TEAEs leading to temporary discontinuation of at least one study intervention 
• TEAEs leading to temporary discontinuation of bintrafusp alfa 
• TEAEs leading to temporary discontinuation of chemotherapy 
• TEAEs leading to temporary discontinuation of bevacizumab 
• TEAEs leading to temporary discontinuation of radiotherapy 
• TEAEs leading to temporary discontinuation of brachytherapy 
• Bintrafusp alfa related TEAEs leading to temporary discontinuation of bintrafusp alfa 
• Chemotherapy related TEAEs leading to temporary discontinuation of chemotherapy 
• Bevacizumab related TEAEs leading to temporary discontinuation of bevacizumab 
• Radiotherapy related TEAEs leading to temporary discontinuation of radiotherapy 
• Brachytherapy related TEAEs leading to temporary discontinuation of brachytherapy 
• TEAEs leading to permanent discontinuation of at least one study intervention 
• TEAEs leading to permanent discontinuation of bevacizumab 
• TEAEs leading to permanent discontinuation of radiotherapy 
• TEAEs leading to permanent discontinuation of brachytherapy 
• Bintrafusp alfa related TEAEs leading to permanent discontinuation of bintrafusp alfa 
• Chemotherapy related TEAEs leading to permanent discontinuation of chemotherapy 
• Bevacizumab related TEAEs leading to permanent treatment discontinuation of bevacizumab 
• Radiotherapy related TEAEs leading to permanent treatment discontinuation of radiotherapy 
• Brachytherapy related TEAEs leading to permanent treatment discontinuation of 
brachytherapy 
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• TEAEs leading to dose reduction of at least one study intervention 
• TEAEs leading to dose reduction of at least one chemotherapy 
• TEAEs leading to dose reduction of bevacizumab 
• Chemotherapy related TEAEs leading to dose reduction of chemotherapy 
• Bevacizumab related TEAEs leading to dose reduction of bevacizumab 
Frequency tables summarizing the following actions taken in response to TEAEs will be prepared 
and presented by PT and primary SOC in alphabetical order: 
• TEAEs leading to temporary discontinuation of bintrafusp alfa 
• Bintrafusp alfa related TEAEs leading to temporary discontinuation of bintrafusp alfa 
• TEAEs leading to permanent discontinuation of bintrafusp alfa 
• Bintrafusp alfa related TEAEs leading to permanent discontinuation of bintrafusp alfa 
A listing of TEAEs leading to permanent treatment discontinuation and a listing of TEAEs leading 
to temporary discontinuation will also be provided with the relevant information (see Section 
15.2.1). 
15.3 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events  
15.3.1 
Deaths  
All deaths, deaths within 30 days after the last dose of the study intervention, death within 60 days 
after the first dose of the study intervention as well as the primary reason for death will be tabulated 
based on information from the “Death” eCRF pages. 
The following summaries will be provided: 
• Number and percentage of deaths 
• Number and percentage of deaths within 30 days after the last dose of study intervention 
• Number and percentage of deaths within 60 days after the first dose of study intervention 
• Primary reason for death  
o Progressive disease and/or disease related condition 
o Event unrelated to study treatment  
o Event related to study treatment 
o Unknown  
In addition, date and cause of death will be provided in an individual participant data listing 
together with the following information: cohort, participant identifier, analysis sets in which the 
participant is included, age, race, ethnicity (Japanese/Non-Japanese), dates of first/last doses of 
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each study intervention, number of infusions, day relative to the first and the last infusion, autopsy 
(yes/no/unknown), AEs with fatal outcome (list PTs of AEs with outcome=Fatal, as well as Grade 
5 AEs or Serious AEs resulting in death), flag for death within 30 days of last dose of study 
intervention and flag for death within 60 days of first dose of study intervention. 
15.3.2 
Serious Adverse Events  
The number of participants with serious AEs (SAEs) will be described by SOC and PT:  
• Serious TEAEs 
• Bintrafusp alfa related serious TEAEs 
• Chemotherapy related serious TEAEs 
• Bevacizumab related serious TEAEs 
• Radiotherapy related serious TEAEs 
• Brachytherapy related serious TEAEs 
A listing of serious TEAEs will also be provided including a flag identifying AEs occurring during 
the reinitiation phase (see Section 15.2.1).  
15.3.3 
Adverse Events of Special Interest  
A listing containing all pre-specified PT search terms that will be used during the identification 
process of the adverse events of special interest will be provided.   
15.3.3.1 
Infusion-Related Reaction (IRR) including Immediate 
Hypersensitivity  
IRRs are defined as adverse events with PTs according to a pre-specified MedDRA search list, 
and are divided into two subcategories: “Reactions” and “Signs and symptoms” based on the 
temporal relationship between the day of the infusion and onset of the event: 
Reactions of IRRs: should be considered when the onset is on the day of infusion (during or after 
the infusion if timing related to the infusion is available) or the day after the infusion (irrespective 
of resolution date) for any infusion-related reaction, drug hypersensitivity, anaphylactic reaction, 
hypersensitivity and/or Type 1 hypersensitivity. 
Signs and symptoms of IRRs and hypersensitivity/allergic reactions: should be considered 
when the onset is on the day of infusion (during or after the infusion if timing related to the infusion 
is available) and resolved completely, with the end date on the same day of the infusion or the day 
after for any of the following: pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, 
abdominal pain and urticaria.  
Note: all infusions (i.e., of bintrafusp alfa, chemotherapies and bevacizumab) are to be considered. 
IRRs, overall and by subcategories, will be summarized by the following variables: 
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• Number of participants with at least one IRR by the worst NCI-CTCAE toxicity grade (Grade 
1, Grade 2, Grade 3, Grade 4, Grade 5, missing grade) 
• Number of participants with IRR leading to permanent discontinuation of at least one study 
intervention 
• Time related to first onset (infusion 1, infusion 2, infusion 3, infusion 4 or later). The events 
will be assigned to the actual drug infusions that the participant received, not to the planned 
dates. An IRR is assigned to a drug infusion if its onset is on the same date (but not before 
dosing when timing related to the infusion is available) or the day following the drug infusion. 
A frequency table of IRR AEs by worst grade (any grade, Grade ≥ 3, Grade ≥ 4, Grade 5), SOC, 
and PT will also be provided. 
A listing of IRRs will be provided with the relevant information (see Section 15.2.1). 
15.3.3.2 
Immune-related Adverse Events  
irAEs will be identified programmatically. AEs which satisfy all the following criteria will be 
flagged as immune-related: 
• The AE PT matches a PT on the list of pre-selected MedDRA terms. 
• The AE onset or worsening occurs during the expanded on-treatment period for irAEs (see 
Section 9.9). 
• On the “AE” eCRF page, the question “Were corticosteroids, Immunosuppressants, hormonal 
therapy (e.g., Thyroid) or Insulin applied?” has the answer “Yes” selected. 
• On the “imAE SPECIFIC QUESTIONS” eCRF page, either: 
• The question “Does any of the following provide a clear etiology for the event, other than 
immune related AE?” has the answer “No” selected, indicating that the AE is not attributable 
to underlying cancer disease/PD, prior or concomitant medications/procedures, nor another 
medical condition such as an infection or pre-existing disease. 
OR  
• The “imAE SPECIFIC QUESTIONS” eCRF page indicates that a biopsy was performed and 
the question “Is the histopathology/biopsy consistent with an immune-mediated event?” has 
the answer “Yes” selected. 
Where criteria (1) through (3) are met, and entries for condition (4) are missing, the following 
rules will be applied:  
• If the answer to “Does any of the following provide a clear etiology for the event, other than 
immune related AE?” (4a) is missing, the event will be considered as irAE (irrespective of 
biopsy results).  
• If the answer to “Is the histopathology/biopsy consistent with an immune-mediated event?” 
(4b) is missing, or if no biopsy was performed, and condition (4a) is not satisfied, i.e., “Yes” 
is selected (i.e., at least one (clear) etiology of the event is provided) as the answer to the 
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question “Does any of the following provide a clear etiology for the event, other than immune 
related AE?”, the event will be considered as a non-irAE. 
PTs will be compiled into categories (subcategories): Immune-related rash, Immune-related 
colitis, Immune-related pneumonitis, Immune-related hepatitis, Immune-related nephritis and 
renal dysfunction, Immune-related endocrinopathies (adrenal insufficiency, hypogonadism, 
pituitary dysfunction, Type 1 diabetes mellitus, thyroid disorders), and Other immune-related 
adverse events (Anemia, Encephalitis, GVHD, Guillain-Barre Syndrome, Myasthenic syndrome, 
Myocarditis, Myositis, Neurologic events, Pancreatitis, Uveitis, Vasculitis, Other). PTs belonging 
to the category “Immune related endocrinopathies – Thyroid disorders” will also be compiled into 
sub-subcategories: Hyperthyroidism, Hypothyroidism, Thyroiditis. 
irAEs will be summarized by the following variables: 
• Any irAEs 
• irAEs by the worst grade (Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, missing grade) 
• irAEs leading to permanent discontinuation of at least one study intervention 
• Serious irAEs  
A frequency table of irAEs by worst grade (any grade, Grade ≥ 3, Grade ≥ 4, Grade 5), category, 
subcategory (for immune-related endocrinopathies and other immune-related adverse events), sub-
subcategory (for immune-related endocrinopathies – thyroid disorders) and PT will also be 
provided. 
A listing of irAEs will also be provided with the relevant information (see Section 15.2.1). 
15.3.3.3 
TGF-β inhibition mediated Skin Adverse Events  
To identify TGFβ inhibition mediated skin adverse events, MedDRA PT queries will be used to 
search for skin AEs of interest in the clinical database. PTs will be compiled into two categories: 
Narrow definition, and Broad definition. Further details (e.g., MedDRA PT queries) are regularly 
updated based on the current MedDRA version. 
Narrow definition: 
• Keratoacanthoma 
• Squamous cell carcinoma of skin 
Broad definition has additional PTs: 
• Hyperkerathosis 
• Actinic keratosis 
• Basal cell carcinoma 
• Lip squamous cell carcinoma 
• Bowen’s disease 
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The overall summary of skin TEAE will include the following categories for narrow and broad 
definition: 
• All skin TEAEs 
• All skin TEAEs by worst grade (Grade 1, Grade 2, Grade 3, Grade 4, Grade 5, missing grade) 
• Skin TEAEs leading to permanent discontinuation of at least one study intervention 
• Serious skin TEAEs  
A frequency table for skin TEAEs will be provided by MedDRA PTs (including both narrow and 
broad definition PTs). 
A listing of skin AEs will also be provided. This listing will specifically include, for the AEs 
identified from the PT list, the number of lesions, if a biopsy or an excision was done and if it 
confirmed the diagnosis, and the location for each lesion coming from eCRF page “TGFβ 
MEDIATED SKIN REACTION” if available. 
15.3.3.4 
Anemia  
To identify potential anemia AEs, MedDRA PT queries will be used to search for anemia AEs of 
interest in the clinical database. Further details (e.g. MedDRA PT queries) are regularly updated 
based on the current MedDRA version. 
• Anaemias NEC (HLT) 
• Anaemias haemolytic immune (HLT) 
• Anaemias haemolytic NEC (HLT) 
• Haemoglobin decreased (PT) 
A frequency table of treatment-emergent anemia AEs by worst grade (any grade, Grade ≥ 3, Grade 
≥ 4, Grade 5), SOC and PT will be provided. 
A listing of all anemia AEs will also be provided with the relevant information (see Section 15.2.1). 
Bintrafusp alfa related anemia will be flagged. 
15.3.3.5 
Bleeding Events  
Bleeding events are AEs belonging to the MedDRA SMQ Haemorrhage terms (excluding 
laboratory terms). Bleeding treatment-emergent events and bintrafusp alfa related bleeding events 
will be tabulated by SOC and PT sorted by alphabetical order. The worst grade per participant, per 
SOC, and per PT will be reported:  
• Any grade (including missing grade)   
• Grade 1 
• Grade 2 
• Grade 3 
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• Grade 4 
• Grade 5 
15.4 
Clinical Laboratory Evaluation  
Baseline and on-treatment laboratory values (including corresponding normal ranges), converted 
into standard units, will be used for analysis.  
Laboratory results will be classified according to the NCI-CTCAE criteria version 5.0 (see 
Appendix 2). Some of the toxicity gradings are based on laboratory measurements in conjunction 
with clinical findings. Non-numerical qualifiers will not be taken into consideration in the 
derivation of CTCAE criteria (e.g., hypokalemia Grade 1 and Grade 2 are only distinguished by a 
non-numerical qualifier and therefore Grade 2 will not be derived). 
Additional laboratory results that are not part of NCI-CTCAE will be presented according to the 
categories: below normal limit, within normal limits and above normal limit (according to the 
laboratory normal ranges). 
Values below the detection limit will be imputed by half of the detection limit. In case just a text 
value with an “> x” is reported it will be analyzed as +1 significant digit, e.g., “> 7.2 mmol” will 
be analyzed as 7.3. 
The following figures will be provided: 
• Boxplots of the laboratory values by timepoint (only baseline and on-treatment scheduled 
timepoints with at least 3 values will be presented) 
• Boxplots of the changes from baseline by timepoint (only on-treatment scheduled timepoints 
with at least 3 values will be presented) 
Boxplots for laboratory parameters where toxicity grades are defined based on the ratio of the 
parameter value and the upper limit of normal (ULN) will be displayed using the ratio of the 
measured value over ULN. This comprises alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), activated partial thromboplastin time (aPTT), bilirubin, 
and creatinine. 
Qualitative data based on reference ranges will be described according to the categories (i.e., 
Abnormal, Normal). Abnormalities classified according to NCI-CTCAE toxicity grading version 
will be described using the worst on-treatment grade. For those parameters which are graded with 
two directions of toxicities such as potassium (hypokalemia/hyperkalemia), the toxicities will be 
summarized separately. Low direction toxicity (e.g., hypokalemia) grades at Baseline and post-
baseline will be set to 0 when the variables are derived for summarizing high direction toxicity 
(e.g., hyperkalemia), and vice versa.  
For WBC differential counts (total neutrophil [including bands], lymphocyte, monocyte, 
eosinophil, and basophil counts), the absolute value will be used when reported. When only 
percentages are available (this is mainly important for neutrophils and lymphocytes, because the 
CTCAE grading is based on the absolute counts), the absolute value is derived as follows:  
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Derived differential absolute count = (WBC count) * (Differential %value / 100) 
If the range for the differential absolute count is not available (only range for value in % is 
available) then Grade 1 will be attributed to as follows:  
• Lymphocyte count decreased:   
• derived absolute count does not meet Grade 2-4 criteria, and 
• % value < % LLN value, and 
• derived absolute count ≥ 800/mm3 
• Neutrophil count decreased  
o derived absolute count does not meet Grade 2-4 criteria, and 
o % value < % LLN value, and 
o derived absolute count ≥ 1500/mm3 
For calcium, CTCAE grading is based on Corrected Calcium and Ionized Calcium (CALCIO), if 
available. Corrected Calcium is calculated from Albumin and Calcium as follows:  
• Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4], or 
• Corrected calcium (mmol/L) = measured total calcium (mmol/L) + 0.02 (40 – serum albumin 
[g/L]) 
Laboratory parameters with NCI-CTCAE grades available 
The following summaries will be provided for each gradable laboratory parameter: 
• Number and percentage of participants by worst (highest) on-treatment grade (>=1, >=3, >=4) 
• Shift in toxicity grading from baseline to worst (highest) on-treatment toxicity grade 
The above analyses apply to hematology and chemistry evaluations which can be graded per 
CTCAE, i.e.: 
• Hematology:  
Hemoglobin (HB) (anemia), Leukocytes (white blood cell decreased), Lymphocytes 
(lymphocyte count increased/decreased), Neutrophils / Absolute Neutrophils Count (ANC) 
(neutrophil count decreased), Platelet Count (PLT) (platelet count decreased). 
•  Serum Chemistry: 
Albumin (hypoalbuminemia), Alkaline Phosphatase (alkaline phosphatase increased), 
Alanine Aminotransferase (ALT) (ALT increased), Amylase (serum amylase increased), 
Aspartate Aminotransferase (AST) (AST increased), Total Bilirubin (blood bilirubin 
increased, Cholesterol (cholesterol high), Creatinine (creatinine increased), Creatine Kinase 
(CPK increased), Potassium (hypokalemia/ hyperkalemia), Sodium (hyponatremia/ 
hypernatremia), 
Magnesium 
(hypomagnesemia/hypermagnesemia), 
Calcium 
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(hypocalcemia/ hypercalcemia), Glucose (hypoglycemia), Gamma Glutamyl Transferase 
(GGT) (GGT increased), Lipase (lipase increased), Triglycerides (hypertriglyceridemia). 
• Urinalysis: 
Protein (proteinuria) 
Laboratory parameters with NCI-CTCAE grades that cannot be derived from laboratory 
values  
For all non-gradable parameters, the following summaries will be provided: 
• Number and percentage of participants by worst on-treatment value (classified as low, normal, 
high) 
In case the worst on-treatment value for a parameter can be either the lowest or the highest, 
both directions will be presented. 
• Shift from baseline to highest/lowest on-treatment value (classified as normal, high, low) 
This applies to the following parameters:  
• Hematology:  
Hematocrit, Red Blood Cell (RBC), Reticulocytes, Mean Corpuscular Hemoglobin (MCH), 
Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin Concentration 
(MCHC). 
• Serum Chemistry:  
Chloride, C-Reactive Protein, Glucose (hyperglycemia), Lactate Dehydrogenase (LDH), 
Phosphates (hypophosphatemia/hyperphosphatemia), Total Protein, Total Urea, Uric Acid.  
Separate listings of hematology and biochemistry will be provided. Each listing will include: 
cohort, participant identifier, age, race, ethnicity (Japanese/Non-Japanese), first/last date of study 
intervention, laboratory parameter (units), visit, date/time (study day), SI value, change in SI value 
from baseline, LLN, ULN, indicator of normal range (low, normal, high), toxicity grade(s) 
according to NCI-CTCAE (when applicable). Highest and lowest on-treatment value, baseline and 
post-baseline values after the on-treatment period as well as participants who switched 
chemotherapy will also be flagged.  
The following coagulation parameters will also be presented in a listing: prothrombin time, 
prothrombin time/standard prothrombin time, aPTT, aPTT/standard thromboplastin time, INR. 
Liver function tests 
ALT, AST, and total bilirubin will be used to assess possible drug induced liver toxicity. The ratios 
of test result over ULN will be calculated and classified for these three parameters during the on-
treatment period. 
The number and percentage of participants within each of the following liver function categories 
during the on-treatment period will be provided: 
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• ALT <3×ULN, ALT ≥ 3×ULN, ALT ≥ 5×ULN, ALT ≥ 10×ULN, ALT ≥ 20×ULN 
• AST <3×ULN, AST ≥ 3×ULN, AST ≥ 5×ULN, AST ≥ 10×ULN, AST ≥ 20×ULN 
• (ALT and AST) <3×ULN, (ALT or AST) ≥ 3×ULN, (ALT or AST) ≥ 5×ULN, (ALT or AST) 
≥ 10×ULN, (ALT or AST) ≥ 20×ULN 
• BILI < 2×ULN, BILI ≥ 2×ULN 
• Concurrent ALT ≥ 3×ULN and BILI ≥ 2×ULN 
• Concurrent AST ≥ 3×ULN and BILI ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and BILI ≥ 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and BILI ≥ 2×ULN and ALP > 2×ULN 
• Concurrent (ALT or AST) ≥ 3×ULN and BILI ≥ 2×ULN and ALP ≤ 2×ULN or missing 
Concurrent measurements are those occurring on the same date. 
Categories will be cumulative, i.e., a participant with an elevation of AST ≥ 10×ULN will also 
appear in the categories ≥ 5×ULN and ≥ 3×ULN.  
A plot of peak ALT versus peak total bilirubin during the on-treatment period, both relative to the 
ULN will be provided. This eDISH plot (evaluation of drug-induced serious hepatotoxicity) will 
be divided into 4 quadrants by the lines through ALT ≥ 3×ULN and total bilirubin ≥ 2×ULN. The 
left lower quadrant is then considered normal or insignificant elevations in liver chemistries, the 
upper left quadrant indicates participants with possible Gilbert’s cholestasis; the right upper 
quadrant are the possible Hy’s Law participants; the right lower quadrant is possible Temple’s 
Corollary (participants with ALT ≥ 3×ULN but not satisfying Hy’s Law). 
The same plot will be provided for AST. 
In addition, a listing of all total bilirubin, ALT, AST and ALP values for participants with an on-
treatment total bilirubin ≥ 2×ULN, ALT ≥ 3×ULN or AST ≥ 3×ULN will be provided. 
Routine urinalysis 
All test results for routine urinalysis will be presented in dedicated listings:  
• Urinalysis full parameters: pH, specific gravity, protein, glucose, ketones, nitrite, leukocytes 
by dipstick, occult blood, urobilinogen, bilirubin, color 
• Microscopic examination: erythrocytes, leukocytes, epithelial cells, bacteria, crystals, casts 
Hormonal tests 
All results for thyrotropin, thyroxine free (free T4) will be presented in a listing. 
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Pregnancy tests 
All results from serum or highly sensitive urine β-hCG pregnancy tests will be presented in a 
listing. 
Other screening tests 
All other screening tests results will be presented in dedicated listings:  
• Hepatitis screening: hepatitis B virus surface antigen, hepatitis B virus core antibody and 
hepatitis C virus antibody; hepatitis B virus DNA, hepatitis C virus RNA 
• HIV test, HIV RNA viral load, CD4 lymphocyte count 
• M. tuberculosis IFN gamma response by T-SPOT ELISPOT; tuberculosis skin test; M. 
tuberculosis IFN gamma response by QuantiFERON TB Gold ELISA 
15.5 
Vital Signs  
The following summaries will be prepared for vital signs:  body temperature, pulse rate, systolic 
blood pressure (SBP), diastolic blood pressure (DBP), respiration rate and oxygen saturation 
considering only participants with post-baseline values during on-treatment period: 
• Summary statistics over time (only present baseline value and on-treatment scheduled visits 
with at least three observations for the vital sign) 
The following potentially clinically significant abnormalities observed during the on-treatment 
period will be summarized: 
• ≤ 95 mmHg and decrease from baseline ≥ 20 mmHg in systolic blood pressure 
• ≥ 140 mmHg and increase from baseline ≥ 20 mmHg in systolic blood pressure 
• ≤ 45 mmHg and decrease from baseline ≥ 20 mmHg in diastolic blood pressure 
• ≥ 90 mmHg and increase from baseline ≥ 20 mmHg in diastolic blood pressure 
• ≤ 50 beats/min and decrease from baseline ≥ 20 beats/min in heart rate 
• ≥ 100 beats/min and increase from baseline ≥ 20 beats/min in heart rate 
• ≤ 20 breaths/min and decrease from baseline ≥ 5 breaths/min in respiratory rate 
• ≥ 20 breaths/min and increase from baseline ≥ 5 breaths/min in respiratory rate 
• ≥ 10% weight increase 
• ≥ 10% weight decrease 
A listing of vital signs will be provided including cohort, participant identifier, age, race, ethnicity 
(Japanese/Non-Japanese), vital sign parameter, visit, timepoint, date, time, value, unit, and change 
from baseline. Baseline values and post-baseline values collected after the on-treatment period will 
be flagged.  
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A second listing will also be provided for participants with at least one potentially clinically 
significant abnormality observed during the on-treatment period. For each participant, all results 
for a specific vital sign parameter with at least one on-treatment potentially abnormal and clinically 
significant value will be displayed. This listing will include cohort, participant identifier, age, race, 
ethnicity (Japanese/Non-Japanese), vital sign parameter, visit, timepoint, date, time, value, unit, 
and change from baseline. Baseline values and post-baseline values collected after the on-
treatment period as well as participants who switched chemotherapy will be flagged. 
15.6 
Other Safety or Tolerability Evaluations  
ECG 
Single 12-lead ECGs will be performed at screening then if clinically indicated and will be 
collected on the “Electrocardiogram” eCRF page. 
A listing of ECG values will be provided including cohort, participant identifier, age, race, 
ethnicity (Japanese/Non-Japanese), ECG parameter and unit, visit/time (study day), ECG date, 
value, change from baseline. Baseline values and post-baseline values collected after the on-
treatment period as well as participants who switched chemotherapy will be flagged. Qualitative 
ECG results will also be provided.  
ECOG Performance Status 
The ECOG Performance Status will be described from the data collected on the “ECOG 
Performance Status” eCRF page.  
ECOG performance status observed at each timepoint will be presented in a listing including 
cohort, participant identifier, age, race, ethnicity (Japanese/Non-Japanese), visit, date of visit, 
ECOG performance status. Baseline value and post-baseline values collected after the on-
treatment period as well as participants who switched chemotherapy will be flagged. 
16 
Analyses of Other Endpoints  
16.1 
Pharmacokinetics  
The analyses described in this section will be performed by the Clinical PK/PDyn group (CPK) of 
Translational Medicine, Merck Healthcare KGaA, Darmstadt, Germany, or by a Contract Research 
Organization selected by the Sponsor. Pharmacokinetic listings and individual data will be 
presented based on the SAF/FAS. Summaries and statistical analyses will be based on the PKAS. 
Only subgroup sample size with a minimal 3 subjects will be displayed. 
Participants who switched chemotherapy will be flagged in listings. Pharmacokinetic 
concentrations/parameters refer to bintrafusp alfa concentrations/PK parameters. 
16.1.1 
Missing PK Data  
Concentrations below the lower limit of assay quantification 
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Pharmacokinetic concentrations below the lower limit of quantification (<LLOQ) will be set to 
zero for calculating parameters and descriptive statistics. 
Pharmacokinetic concentrations <LLOQ, which are before the last quantifiable data point, will be 
taken as zero for calculating the area under the serum concentration-time curve of single dose 
profiles. Concentrations <LLOQ which occur after the last quantifiable data point will not be 
considered in the calculation of the terminal first order rate constant (λz). 
Deviations, missing concentrations, and anomalous values 
There will be no imputation of missing data. Concentrations will be set to missing in summary 
tables if the value is reported as no result. Pharmacokinetic concentrations which are erroneous 
due to a protocol violation (as defined in the clinical study protocol), documented handling error, 
or analytical error (as documented in the bioanalytical report) may be excluded from the PK 
analysis if agreed upon prior to performing a statistical analysis. In this case the rationale for 
exclusion must be provided in the relevant listing/table.  
Exclusions for concentration data descriptive statistics  
- 
Positive pre-dose values on day 1 
- 
Concentration observed at the end of infusion (CEOI) <LLOQ 
- 
In case of missed dose, exclude all concentrations until intended dosing is resumed  
- 
Concentration observed at the end of the dosing interval (Ctrough) values in case samples 
are taken at least 7 days late or early 
Exclusions for Non-Compartmental Analysis (NCA) 
- 
Positive pre-dose values on day 1 
- 
CEOI <LLOQ, which will be excluded from parameter derivation 
- 
In case of missed dose, exclude all concentrations until intended dosing is resumed 
Any other PK concentrations that appear implausible to the Pharmacokineticist/PK/PDyn Data 
Analyst without any documentation to explain the implausible value must not be excluded from 
the analysis. Any implausible data will be documented in the relevant listing/table. 
If a PK parameter cannot be derived from a participant’s concentration data, the parameter will be 
coded as NC (not calculated). Note that NC values will not be generated beyond the day that a 
participant discontinues the treatment. For statistical analyses, PK parameters coded as NC will be 
set to missing. 
If an individual participant has a known biased estimate of a PK parameter (due for example to a 
deviation from the assigned dose level), this participant/value will be excluded from the descriptive 
statistics, and instead the result will be listed only. 
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16.1.2 
Descriptive PK Analysis  
Presentation of PK Concentration Data 
A by-participant listing will present PK sample times, time deviations, and concentrations based 
on the SAF/FAS. Concentrations will be reported with the same precision as the source data. 
Tables 
Pharmacokinetic concentration data will be presented in tables and descriptively summarized by 
treatment and cohort (as appropriate) (cohorts 1A and 1B separately, and 1A/1B pooled), day, and 
nominal time using: n, arithmetic mean (Mean), StD, Min, median, Max, geometric mean 
(GeoMean), StD of log-transformed data (logStD), coefficient of variation (CV%), and geometric 
coefficient of variation (GeoCV%). Summaries will be based on the PKAS. 
Additional table(s) will summarize PK concentrations with further stratification by ADA subsets 
ever positive and never positive, based on the PKADA. Additional table(s) will summarize PK 
concentrations with stratification by ethnicities as applicable, based on the PKAS. Only subgroup 
sample size with a minimum of 3 subjects will be displayed. 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data: 
Mean, Min, median, Max, GeoMean:  
 
 
 
3 significant digits 
StD, logStD:  
 
 
 
 
 
 
4 significant digits 
CV%, GeoCV%: 
 
 
 
 
 
 
1 decimal place  
Figures 
Individual PK concentration-time profiles showing all subjects by treatment and cohort will be 
created using the actual time points and the numeric concentration data. Plots of individual data 
will be based on the SAF/FAS. Median, GeoMean, and Mean concentration-time profiles by 
treatment and cohort (cohorts 1A and 1B separately, and 1A/1B pooled) will be provided using 
scheduled (nominal) time points and the numeric concentration data. All concentration-time plots 
for PK data will be presented both on a linear and on a semi-logarithmic scale. Mean and GeoMean 
PK plots will include StD or logStD error bars when plotted on a linear scale. Only 
Mean/GeoMean/median data points with n ≥ 3 will be shown. Summary (Mean/median) PK plots 
will be based on the PKAS. 
Additional figures will present Mean, GeoMean, and median PK concentration-time profiles with 
further stratification by ADA subsets ever positive and never positive, based on the PKADA. 
Additional figures will present Mean, GeoMean, and median PK concentration-time profiles with 
stratification by race/ethnicities as applicable, based on the PKAS. Only subgroup sample size 
with a minimum of 3 subjects will be displayed. 
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16.1.3 
Pharmacokinetic Non-Compartmental Analysis  
The PK parameters listed below will be calculated for bintrafusp alfa using the actual time elapsed 
from dosing (or using scheduled time if actual time is not available), following the first dose only 
unless specified otherwise.  
Cmax  
Maximum observed concentration in serum 
tmax 
Time to reach Cmax 
AUC0-t 
Area under the serum concentration-time curve from time zero to the last 
quantifiable concentration 
Ctrough 
The concentration observed at the end of the dosing interval, before next 
dosing (serum trough concentration). This PK parameter will be taken 
directly from the observed bintrafusp alfa concentration-time data following 
first and multiple doses. 
CEOI 
The concentration observed at the end of infusion. This PK parameter will 
be taken directly from the observed bintrafusp alfa concentration-time data 
following first and multiple doses. 
When applicable the following parameters will also be calculated:  
AUC0-∞ 
Area under the serum concentration-time curve from time zero extrapolated 
to infinity. AUC0-∞ = AUC0-t + AUCextra, where AUCextra = Clastpred/ λz. 
AUCextra% 
Percentage of AUC0-∞ obtained by extrapolation, calculated by (1 －
[AUC0-t/AUC0-∞])×100. If AUCextra% is greater than 20.0%, AUC0-∞ and λz 
and parameters derived from them (e.g. t1/2, CL, and Vz) will be included in 
the Phoenix® WinNonlin® parameter outputs, summaries, and inferential 
statistics, but will be flagged. 
AUC0-504 
Area under the serum concentration-time curve from time zero to 504 -hours.  
This parameter will be calculated using nominal time at 504 -hours, by 
extrapolation/interpolation as necessary. 
t1/2 
Elimination half-life, calculated by ln2/λz 
λz 
Terminal elimination rate constant, determined from the terminal slope of 
the log-transformed concentration-time curve using linear regression on 
terminal data points of the curve 
CL 
Total body clearance of drug from serum. CL = Dose i.v. / AUC0-∞ 
Vz 
Volume of distribution during terminal phase. VZ = Dose/(AUC0-∞ * λz) 
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The following PK parameters will be calculated for diagnostic purposes and listed, but will not be 
summarized: 
• The time interval (h) of the log-linear regression to determine λz (t½, Interval). 
• Number of data points (t½, N) included in the log-linear regression analysis to determine λz. 
• Goodness of fit statistic (Rsq) for calculation of λz. If Rsq is <0.800, λz and parameters derived 
from it (e.g. t1/2, AUC0-∞, CL, and Vz) will be included in the Phoenix® WinNonlin® parameter 
outputs, summaries, and inferential statistics, but will be flagged. 
The regression analysis (determination of λz) should contain as many data points as possible (but 
excluding Cmax) and has to include concentration data from at least 3 different time points, 
consistent with the assessment of a straight line (the terminal elimination phase) on the 
log-transformed scale. The observation period over which the regression line is estimated should 
be at least twofold the resulting t1/2 itself. If this is <2.00 * t1/2, then λz and parameters derived from 
it (e.g. t1/2, AUC0-∞, CL, and Vz) will be included in the Phoenix® WinNonlin® parameter outputs, 
summaries, and inferential statistics, but will be flagged. Phoenix® WinNonlin® best fit 
methodology will be used as standard. The last quantifiable concentration should always be 
included in the regression analysis, while the concentration at tmax and any concentrations <LLOQ 
which occur after the last quantifiable data point should not be used. 
The calculation of the areas under the serum concentration-time curve will be performed using the 
mixed log-linear trapezoidal method (linear up, log down). Extrapolated areas will always be 
computed using the predicted last concentration that is estimated using the linear regression from 
terminal rate constant determination. The pre-dose samples will be considered as if they had been 
taken simultaneously with the administration. 
Presentation of PK Parameter Data 
Individual PK parameters will be listed by nominal study day based on the SAF/FAS.  
Pharmacokinetic parameters will be reported to 3 significant figures. In export datasets, as well as 
in the SDTM PP/XD domain, PK parameters will be provided with full precision and will not be 
rounded. Descriptive statistics of PK parameter data will be calculated using full precision values 
and rounded for reporting purposes only.  
Pharmacokinetic parameter data will be listed and descriptively summarized in tables by treatment 
(dose, e.g., 2400 mg) and cohort separately (cohorts 1A and 1B separately, and 1A/1B pooled), 
and day using: n, Mean, StD, CV%, Min, median, Max, GeoMean, logStD, GeoCV%, and the 
95% CI for the GeoMean (LCI 95% GM, UCI 95% GM). Summaries will be based on the PKAS. 
Additional table(s) will summarize NCA parameters following first infusion, Ctrough, and CEOI with 
further stratification by ADA subsets ever positive and never positive, based on the PKADA. 
Additional table(s) will summarize NCA parameters following first infusion with stratification by 
race/ethnicities as applicable, based on the PKAS. Additional table(s) may be added, if warranted, 
to summarize Ctrough and CEOI with stratification by race/ethnicities as applicable, based on the 
PKAS. Additional table(s) will summarize NCA parameters following first infusion with further 
sub-stratification by ADA subsets ever positive and never positive and, nested within, 
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race/ethnicities as applicable, based on the PKADA. Additional table(s) may be added, if 
warranted, to summarize Ctrough and CEOI with further sub-stratification by ADA subsets ever 
positive and never positive and, nested within, race/ethnicities as applicable, based on the PKADA. 
Additional table(s) will summarize Ctrough of ADA ever positive subjects with further sub-
stratification by ADA subgroups (e.g. Pre-existing, Treatment boosted, Treatment emergent, 
Transient positive, Persistent positive), based on the PKADA. Additional table(s) will summarize 
Ctrough of ADA Treatment-emergent subjects by PK day relative to day of seroconversion, based 
on the PKADA. Only subgroup sample size with a minimum of 3 subjects will be displayed. All 
above will be summarized by treatment (dose, e.g., 2400 mg across cohorts) and cohort separately 
(cohorts 1A and 1B separately, and 1A/1B pooled). 
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
Mean, Min, median, Max, GeoMean, 95% CI:  
3 significant digits 
StD, logStD:  
 
 
 
 
4 significant digits 
CV%, GeoCV%: 
 
 
 
 
1 decimal place  
Individual Ctrough and CEOI values will be plotted against actual time points on a linear scale, for all 
subjects by treatment and cohort. Plots of individual data will be based on the SAF/FAS. 
Arithmetic mean Ctrough ±StD and CEOI ±StD and GeoMean Ctrough ±logStD and CEOI ±logStD will 
be plotted versus nominal day on a linear scale. Median Ctrough and CEOI will also be plotted versus 
nominal day on a linear scale. Summary plots will be based on the PKAS. Additional figures will 
present Mean, GeoMean, and median Ctrough and CEOI with further stratification by ADA subsets 
ever positive and never positive, based on the PKADA. Additional figures may be added, if 
warranted, to present Mean, GeoMean, and median Ctrough and CEOI with stratification by 
ethnicities as applicable, based on the PKAS. Only subgroup sample size with a minimum 3 
subjects will be displayed. 
For ADA treatment-emergent subjects with at least one Ctrough measurement before and after ADA 
seroconversion, individual Ctrough will be plotted versus relative PK day for each cohort (for 
readability, split further into groups of 10 subjects or fewer as needed). Box plots will be prepared 
for Ctrough versus relative PK day.  
All above will be summarized by treatment (dose, e.g., 2400 mg across cohorts) and cohort 
separately (cohorts 1A and 1B separately, and 1A/1B pooled). 
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
 
  
 
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16.3 
Patient-reported Outcome  
Not applicable. 
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17 
References  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
Revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45:228-47. 
European Centre for Disease Prevention and Control. Data on COVID-19 geographic distribution 
by country. https://www.ecdc.europa.eu/en/publications-data/download-todays-data-geographic-
distribution-covid-19-cases-worldwide, accessed and downloaded on 26 June 2020. 
18 
Appendices  
18.1.1 
Appendix 1 - List of Important Protocol Deviations  
See document: List of Protocol Deviations – Appendix 1 
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18.1.2 
Appendix 2 - Definition of NCI-CTCAE Grading  
See document: NCI CTCAE V5.0 guidance.xlsx. 
 
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