A Phase 2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR-707) Combined With Other Anticancer Therapies for the Treatment of Participants With Head and Neck Squamous Cell Carcinoma (HNSCC)
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of Head and Neck
Sponsor: Sanofi

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.0, dated 28-JAN-2021 
Page 1 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 03 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with other 
anticancer therapies for the treatment of participants 
with head and neck squamous cell carcinoma (HNSCC) 
Protocol number: 
ACT16903 
Amendment number: 
03 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
Acronym:  
A study of SAR444245 combined with other anticancer 
therapies for the treatment of participants with HNSCC 
(Master Protocol) 
Pegathor Head and Neck 204
Study phase: 
Phase 2 
Sponsor name: 
Sanofi Aventis Recherche & Développement 
Legal registered address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin, 
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s):
IND: 
EudraCT:
NCT
WHO: 
IND156423 
2021-002105-99 
NCT05061420
U1111-1251-5073 
Date: 
22-Dec-2021 
Total number of pages: 126 
VV-CLIN-0616194 4.0
1
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Substudy/substudies 
impacted by 
amendment 
Date, version 
Amended Master Clinical 
Trial Protocol 03   
All 
01, 02, 04, 05 
22 December 2021, version 1 
(electronic 4.0) 
Amended Master Clinical 
Trial Protocol 02   
All 
01, 02, 04, 05 
19 August 2021, version 1 
(electronic 3.0) 
Amended Master Clinical 
Trial Protocol 01   
All 
01, 04, 05 
26 July 2021, version 1 
(electronic 2.0) 
Master Clinical Trial Protocol 
All 
11 June 2021, version 1 
(electronic 1.0) 
Amended protocol 03 (22 December 2021) 
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth 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 main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Spanish (Agency for Medicine and 
Health Products [AEMPS]), Italian (Medicines Agency [AIFA]) and German (Federal Institute for 
Drugs and Medical Devices [BfArM]) Health Authorities after initial review. Other changes have 
been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page and 1.1 Synopsis 
The following study name: “Pegasus 
Head and Neck 204” has been removed 
from the protocol title and the new study 
acronym “Pegathor Head and Neck 204” 
has been added on the cover page. 
For consistency across the program 
1.1 Synopsis 
The priority of recruitment for 
participants eligible to both Cohort B1 
and Cohort B2 has been specified. 
To specify the priority of recruitment 
between both Cohorts B1 and B2 
VV-CLIN-0616194 4.0
2
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 3 Objectives and Endpoints: 
Table 2, 9.4.3.1 Time to response, and 
9.4.3.2 Duration of response 
Definitions of Time to response and 
Duration of response have been revised 
as follows: 
• Time to response (TTR) defined as the
time from the first administration of
investigational medicinal product (IMP)
to the first tumor assessment at which
the overall response was recorded as
PR or CR that is subsequently confirmed
and determined by investigator per
RECIST 1.1.
• Duration of response (DoR), defined as
the time from first tumor assessment at
which the overall response was
recorded as PR or CR that is
subsequently confirmed until
documented progressive disease (PD)
determined by investigator per RECIST
1.1 or death from any cause, whichever
occurs first.
For clarification 
1.1 Synopsis and 4.1 Overall Design 
Under the definition of End of Treatment 
and Follow-up for participants who 
discontinue study treatment with PD, the 
following text “or until start of another 
anticancer therapy or final cohort cut-off, 
whichever comes first” has been 
removed. 
For clarification 
1.1 Synopsis, 4.1 Overall Design, and 
9.4.3.4 Progression-free survival 
The study cut-off date has been 
replaced by cohort cut-off for final 
analysis. 
For clarification 
1.1 Synopsis and 6.1.2.1 Premedication for 
SAR444245 
Oral administration of diphenhydramine 
is now permitted, in addition to IV 
administration. 
Intravenous administration of 
acetaminophen is now permitted, in 
addition to oral administration. 
To allow local approved dosing 
regimens to be followed 
1.1 Synopsis, 6.1.2.1 Premedication for 
SAR444245, 10.12 Appendix 12: Table 8 
Risk assessment 
1.1 Synopsis and 9.4.3.5 Adverse Events 
Analyses of adverse events (AEs) 
related to specific IMP have been 
removed as treatment-related treatment-
emergent adverse events (TEAEs) will 
be analyzed overall, regardless of the 
drug. 
To assess treatment-related AE of 
the regimen as whole (SAR444245 
with other anticancer therapies) 
VV-CLIN-0616194 4.0
3
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 4 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA) 
The following text: “Tumor biopsy during 
treatment period should be limited to 
non-target lesions or new lesions if their 
pathologic etiology is ambiguous” has 
been removed from footnote “g”. 
For clarification 
1.3 Schedule of Activities (SoA), 
5.2 Exclusion Criteria, 10.2 Appendix 2: 
Clinical laboratory tests, and 
10.8 Appendix 8: Country-Specific 
Requirements 
Requirement for human 
immunodeficiency virus (HIV), hepatitis 
B and C serologies has been added at 
screening for participants in Italy and 
specified in exclusion criteria E15 and 
E16, SoA in footnote “f”, laboratory tests 
and country-specific requirements 
sections.  
To clarify that serology for HIV, 
hepatitis B and C should be tested at 
screening in Italian participants 
1.3 Schedule of Activities (SoA), 
Troponin test has been added at 
screening, at C4D1, and as clinically 
indicated during treatment period until 
Follow-up visit 1. 
To allow assessments of any 
potential cardiotoxicity 
8 Study Assessments and Procedures, 
The following text has been added: 
“A comprehensive medical history will be 
assessed for any cardiovascular signs or 
symptoms prior to treatment, along with 
a baseline ECG, echocardiogram and 
troponin level”. 
8.2 Safety assessments, 8.2.3 
Electrocardiograms and left ventricular 
ejection fraction (LVEF) 
Troponin has been added as an 
example of cardiac enzymes within 
additional evaluation to carry out when 
clinically indicated. 
The following text has also been added 
for evaluations during treatment and 
post treatment follow-up: 
“During treatment, or post treatment 
follow-up: Troponin will be performed at 
Cycle 4 Day 1. In case of a suspicion of 
a drug related cardiac event (eg, 
including signs/symptoms of cardiac 
disease, ECG and/or echo changes, 
troponin elevation, etc.), Investigators 
are encouraged to do ECG, 
echocardiography and/or cardiac 
biomarker tests, as medically indicated, 
including cardiology consultation”.  
and 10.2 Appendix 2: Clinical laboratory 
tests 
Troponin has been added to “other 
screening tests”. 
VV-CLIN-0616194 4.0
4
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 5 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA) and 
10.2 Appendix 2: Clinical laboratory tests 
The following footnote (“k” in the SoA 
and “d” in Section 10.2): “Urinalysis 
using dipstick for glucose, blood, pH, 
protein, ketones, leukocytes and 
microscopic examination (if blood or 
protein is abnormal) will be performed 
every 4 cycles during the Treatment 
period and as clinically indicated” has 
For clarification 
1.5.1 All cohorts 
In the footnote b, “after flush” has been 
changed to “(EOI) precisely ±5 minutes”. 
For clarity 
2.2.1.2 Rationale for combining with 
cetuximab 
The reference No. 9 was revised to 
support the benefit of SAR444245 in 
combination with cetuximab. 
To update the reference for 
consistency 
4.1 Overall design 
For the cohort cut-off date for the final 
analysis, the following wording: “or all 
participants within a cohort have 
completed study” has been removed. 
For consistency 
4.3 Justification for dose 
This section has been updated with the 
most recent data available from Phase 1 
Hammer study.  
To include all available data in 
support of the safety of the RP2D 
5.1 Inclusion Criteria, 8.2.5 Pregnancy 
testing, 8.3.5 Pregnancy, and 10.2 
Appendix 2: Clinical laboratory tests 
In I05, the requirement for contraception 
for male participants has been changed 
from “at least 210 days [corresponding 
to time needed to eliminate study 
intervention(s) plus an additional 
90 days (a spermatogenesis cycle)] after 
the last dose of study intervention” to “at 
least 3 days [corresponding to time 
needed to eliminate SAR444245] after 
the last dose of SAR444245”. 
To change measures for male 
participants as per Clinical Trials 
Facilitation and Coordination Group 
(CTFG) guideline on 
“recommendations related to 
contraception and pregnancy testing 
in clinical trials version 1.1” of 
21 Sept 2020. As SAR444245 is not 
genotoxic, there is no need to extend 
the requirement for contraception to 
90 days (3 months) for male 
participants, but to take into account 
the 5 half-lives of the study 
intervention before its elimination. 
VV-CLIN-0616194 4.0
5
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 6 
Section # and Name 
Description of Change 
Brief Rationale 
The recommended duration for 
continuing contraception after last dose 
of study intervention has been changed 
for female participants in Cohorts A1, 
A2, and B1 (SAR444245 plus 
pembrolizumab) from 180 days to 
120 days, and 60 days in Cohort B2 
(SAR444245 plus cetuximab), and the 
requirement of extension extra 30 days 
(1 month) has been removed. 
None of the products in combination 
is genotoxic in this study, there is no 
need to extend the requirement for 
contraception to 30 days (1 month) 
corresponding to a menstrual cycle 
for female participants 
5.2 Exclusion Criteria 
E 18 has been changed from “Known 
severe hypersensitivity (≥ Grade 3) to or 
contraindication for the use of any study 
intervention, including premedication to 
be administered in this study, as well as 
PEG or any pegylated drug” to “Known 
severe hypersensitivity (≥ Grade 3) to or 
contraindication for the use of any study 
intervention or components thereof, 
including premedication to be 
administered in this study, as well as 
PEG or any pegylated drug and E. coli-
derived protein”. 
To clarify that patients with known 
hypersensitivity to any excipient of 
the study interventions and 
hypersensitivity to any E. Coli-
derived protein must be excluded 
E 23 has been changed from: 
“Participation in a concurrent clinical 
study in the treatment period” 
To 
“Current enrollment or past participation 
in a study of an investigational treatment 
or has used an investigational device 
within 28 days prior to the first dose of 
study treatment.  
Note:  Participants who have entered the 
follow-up phase of an investigational 
study may participate as long as it has 
been 28 days after the last dose of the 
previous investigational treatment”. 
For clarification 
5.4 Screen Failures 
The following text: “A participant may be 
rescreened only once” has been added. 
For clarity 
6.1.3 Hydration guidelines for SAR444245 
administration 
l
For consistency 
VV-CLIN-0616194 4.0
6
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 7 
Section # and Name 
Description of Change 
Brief Rationale 
6.2 
Preparation/handling/storage/accountability 
The text was revised as shown below: 
“Under no circumstances will the 
Investigator supply IMP to a third party 
(except for DTP shipment, for which a 
courier company has been approved by 
the Sponsor), allow the IMP to be used 
other than as directed by this clinical trial 
protocol, or dispose of IMP in any other 
manner”. 
For correction. Direct-to-patient 
shipment of investigational medicinal 
product (IMP) is not possible in this 
study 
6.8.2 Prohibited concomitant medications 
and 10.12 Appendix 12: Risk assessment 
The following sentence in Section 6.5.2 
has been deleted: “Participants requiring 
medication(s) that are metabolized by 
the liver and have narrow therapeutic 
index require close monitoring (drug 
blood levels or other surrogate of drug 
exposure) when on study treatment. If a 
participant cannot be closely monitored, 
he/she should be removed from the 
trial.” 
In Table 8, the row for drug-drug 
interactions has been deleted. 
Based on new de-risking in-vitro data 
7.1.1 Permanent discontinuation, 
8.3 Adverse events (AEs), Serious adverse 
events (SAEs) and other safety reporting, 
10.1.3 Informed consent process, and 
10.11.1 Informed consent 
“If allowed by local regulations” has 
been added after “legally authorized 
representative” to cover for country-
specific regulations. 
To allow flexibility per country 
specific regulations 
8.1.1 Assessment of objective response 
using the most appropriate modality 
according to the nature of the measurable 
lesion(s) 
Imaging of head has been added to 
baseline scans. 
For consistency 
8.2.2 Vital signs 
For the collection of vital signs from 
Cycle 2 to Cycle 4, “at baseline” has 
been changed to “prior to IMP dosing”. 
The following bullet point has been 
added: “From Cycle 5 and beyond, vital 
signs will be collected prior to IMP 
administration”. 
For clarification 
8.3.1 Time period and frequency for 
collecting AE and SAE information 
The instruction to stop collecting AE and 
SAE/AESI information should the 
participant initiate another anticancer 
therapy has been removed. All AEs and 
SAEs/AESIs are to be collected until 
30 days and 90 days, respectively, 
following cessation of study treatment. 
For consistency with Sanofi 
standards 
VV-CLIN-0616194 4.0
7
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 8 
Section # and Name 
Description of Change 
Brief Rationale 
8.6 Biomarkers 
The following sentence: “This method 
will only apply to samples from clinical 
sites not exhibiting feasibility constrains 
on handling/shipment” has been added 
for i
. 
To improve flexibility in case local 
constrains exist 
Concerning collection of samples, the 
following text “will be stored for a period 
of up to 15 years after the last 
participant’s last visit for potential re-
analyses” has been changed to “may be 
used for further research if consent is 
provided (see Section 8.9)”. 
Harmonization per Sanofi standard 
terminology 
8.9 Use of biological samples and data for 
future research and 10.5 Appendix 5: 
Genetics 
The text was revised to state that the 
duration of storage for biological 
samples and relating data is up to 
25 years. The duration of biological 
sample storage was previously given as 
a maximum of 15 years. 
For consistency with the latest 
Sanofi standards 
9.3 Populations for Analyses 
The efficacy population definition was 
revised to "All participants from the 
exposed population with at least one 
evaluable post-baseline tumor 
assessment or who permanently 
discontinued study treatment”. 
To characterize the efficacy 
excluding participants newly enrolled 
9.4.3.6 Clinical laboratory evaluations and 
9.4.5 Other safety analyse(s) 
Descriptive statistics for laboratory 
variables and vital signs will be 
performed only when relevant. The 
following text was deleted: “These 
analyses will be performed using local 
measurements for laboratory variables”. 
These analyses will be done as 
needed following analyses of 
abnormalities according to NCI-
CTCAE grade 
9.4.5 Other safety analyse(s) 
“ECG” was removed from quantitative 
analyses. 
ECG data are not collected 
systematically during the treatment 
period 
10.1.6 Dissemination of clinical study data 
The text has been revised as follows: 
“Sanofi shares information about clinical 
trials and results on publicly accessible 
websites for each completed sub study 
and final study results”. 
Per CTFG guidance 2019: 
Recommendation Paper on the 
Initiation and Conduct of Complex 
Clinical Trials 
10.1.9 Study and site start and closure 
The wording has been revised to specify 
“provided by the Sponsor” after “study 
treatment”. 
For clarification 
10.2 Appendix 2: Clinical laboratory tests 
Regarding blood chemistry/hematology 
assessments, “D2” has been removed 
from the footnote “a” of Table 7. 
For consistency 
VV-CLIN-0616194 4.0
8
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 9 
Section # and Name 
Description of Change 
Brief Rationale 
10.9 Appendix 9: Response evaluation 
criteria in solid tumors (RECIST) 1.1 
“Or progressive disease” has been 
removed from the sentence 
“Confirmatory scans should also be 
obtained at least 4 weeks following initial 
documentation of objective response or 
progressive disease”. 
To correct a typographical error 
11. References 
List of references has been updated. 
For consistency 
Throughout the document 
Minor editorial corrections have been 
made. Abbreviations have been revised. 
For consistency 
 
VV-CLIN-0616194 4.0
9
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 10 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 03 .............................................................................. 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2
TABLE OF CONTENTS ................................................................................................................................ 10
LIST OF TABLES ......................................................................................................................................... 15
LIST OF FIGURES ........................................................................................................................................ 15
1
PROTOCOL SUMMARY ............................................................................................................... 16
1.1 
SYNOPSIS ..................................................................................................................................... 16 
1.2 
SCHEMA ........................................................................................................................................ 23 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 24 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 29 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 30 
1.5.1 
All cohorts ...................................................................................................................................... 31 
2
INTRODUCTION ............................................................................................................................ 32
2.1 
STUDY RATIONALE...................................................................................................................... 32 
2.2 
BACKGROUND ............................................................................................................................. 33 
2.2.1 
Rationale for combining with other anti-tumor agents ................................................................... 33 
2.2.1.1 
Rationale for combining with checkpoint inhibitor .......................................................................... 33 
2.2.1.2 
Rationale for combining with cetuximab ........................................................................................ 34 
2.2.2 
Rationale for HNSCC and selected participant population ............................................................ 34 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 34 
2.3.1 
Risk assessment ............................................................................................................................ 34 
2.3.1.1 
Aldesleukin experience .................................................................................................................. 35 
2.3.1.2 
SAR444245 .................................................................................................................................... 36 
2.3.1.3 
NKTR-214 (bempegaldesleukin) clinical data ................................................................................ 37 
2.3.2 
Benefit assessment ........................................................................................................................ 38 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 38 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 39 
2.3.4.1 
Risks in the context of COVID-19 .................................................................................................. 39 
3
OBJECTIVES AND ENDPOINTS ................................................................................................. 41
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 42 
VV-CLIN-0616194 4.0
10
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 11 
4
STUDY DESIGN ............................................................................................................................ 43
4.1 
OVERALL DESIGN ........................................................................................................................ 43 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 45 
4.2.1 
Participant input into design ........................................................................................................... 45 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 45 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 47 
5
STUDY POPULATION .................................................................................................................. 48
5.1 
INCLUSION CRITERIA .................................................................................................................. 48 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 50 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 54 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 54 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 54 
5.3.3 
Activity ............................................................................................................................................ 54 
5.3.4 
Hydration ........................................................................................................................................ 54 
5.4 
SCREEN FAILURES...................................................................................................................... 54 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION ........................................................................................................................ 55 
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 56
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 56 
6.1.1 
Investigational medicinal products ................................................................................................. 56 
6.1.2 
Noninvestigational medicinal products........................................................................................... 57 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 57 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 57 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 58 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 58 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 59 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 59 
6.5 
DOSE MODIFICATION .................................................................................................................. 59 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 59 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 59 
VV-CLIN-0616194 4.0
11
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 12 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 60 
6.8.1 
Acceptable concomitant medications ............................................................................................. 60 
6.8.2 
Prohibited concomitant medications .............................................................................................. 61 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 62 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 62 
7.1.1 
Permanent discontinuation ............................................................................................................ 62 
7.1.1.1 
Unacceptable adverse events leading to permanent intervention discontinuation ........................ 62 
7.1.2 
Temporary discontinuation ............................................................................................................. 63 
7.1.3 
Rechallenge ................................................................................................................................... 63 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 64 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 64 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 66 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 66 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 67 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 68 
8.2.1 
Physical examinations ................................................................................................................... 68 
8.2.2 
Vital signs ....................................................................................................................................... 69 
8.2.3 
Electrocardiograms and left ventricular ejection fraction (LVEF) ................................................... 69 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 70 
8.2.5 
Pregnancy testing .......................................................................................................................... 70 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 71 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 71 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 71 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 71 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 72 
8.3.5 
Pregnancy ...................................................................................................................................... 72 
8.3.6 
Cardiovascular and death events .................................................................................................. 73 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 73 
8.3.8 
Adverse event of special interest ................................................................................................... 73 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 74 
8.4 
PHARMACOKINETICS .................................................................................................................. 74 
VV-CLIN-0616194 4.0
12
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 13 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 75 
8.6 
BIOMARKERS ............................................................................................................................... 75 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 76 
8.8 
HEALTH ECONOMICS .................................................................................................................. 76 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 77 
9
STATISTICAL CONSIDERATIONS .............................................................................................. 78
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 78 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 78 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 79 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 79 
9.4.1 
General considerations .................................................................................................................. 79 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 80 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 80 
9.4.3.1 
Time to response ........................................................................................................................... 80 
9.4.3.2 
Duration of response ...................................................................................................................... 80 
9.4.3.3 
Clinical benefit rate......................................................................................................................... 80 
9.4.3.4 
Progression-free survival ............................................................................................................... 81 
9.4.3.5 
Adverse events .............................................................................................................................. 81 
9.4.3.6 
Clinical laboratory evaluations ....................................................................................................... 82 
9.4.3.7 
Other secondary endpoints ............................................................................................................ 83 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 83 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 83 
9.4.4.2 
Biomarker endpoints ...................................................................................................................... 83 
9.4.5 
Other safety analyse(s) .................................................................................................................. 83 
9.4.6 
Other analysis ................................................................................................................................ 83 
9.5 
INTERIM ANALYSES  ................................................................................................................... 84 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 85
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 85 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 85 
10.1.2 
Financial disclosure........................................................................................................................ 86 
10.1.3 
Informed consent process .............................................................................................................. 86 
10.1.4 
Data protection ............................................................................................................................... 87 
10.1.5 
Committees structure ..................................................................................................................... 89 
10.1.6 
Dissemination of clinical study data ............................................................................................... 89 
10.1.7 
Data quality assurance .................................................................................................................. 90 
VV-CLIN-0616194 4.0
13
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 14 
10.1.8 
Source documents ......................................................................................................................... 90 
10.1.9 
Study and site start and closure ..................................................................................................... 91 
10.1.10 Publication policy ........................................................................................................................... 92 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 92 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 94 
10.3.1 
Definition of AE .............................................................................................................................. 94 
10.3.2 
Definition of SAE ............................................................................................................................ 96 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 97 
10.3.4 
Reporting of SAEs.......................................................................................................................... 99 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 100 
10.4.1 
Definitions .................................................................................................................................... 100 
10.4.2 
Contraception guidance ............................................................................................................... 101 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 102 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 103 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................. 103 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 103 
10.8.1 
Amendment for Germany ............................................................................................................. 103 
10.8.2 
Amendment for Italy ..................................................................................................................... 103 
10.9 
APPENDIX 9: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 ........ 104 
10.10 
APPENDIX 10:
 .................................................................................................................... 108 
10.10.1 Response and stable disease duration (RECIST 1.1 
) ........................................... 110 
10.10.2 Methods of measurement ............................................................................................................ 110 
10.11 
APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 111 
10.11.1 Informed consent ......................................................................................................................... 112 
10.11.2 Study procedures ......................................................................................................................... 112 
10.11.3 Statistical analysis ........................................................................................................................ 112 
10.11.4 Temporary discontinuation ........................................................................................................... 113 
10.12 
APPENDIX 12: RISK ASSESSMENT .......................................................................................... 113 
10.13 
APPENDIX 13: ASTCT ASSESSMENT FOR ICANS AND CRS ................................................ 118 
VV-CLIN-0616194 4.0
14
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 15 
10.14 
APPENDIX 14: ABBREVIATIONS ............................................................................................... 119 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 121 
11 
REFERENCES ............................................................................................................................. 124 
 
LIST OF TABLES  
Table 1 - Overview of study cohorts .............................................................................................................. 19 
Table 2 - Objectives and endpoints ............................................................................................................... 41 
Table 3 - Overview of study cohorts .............................................................................................................. 43 
Table 4 - Overview of IMP administered ....................................................................................................... 56 
Table 5 - Estimated objective response rate (ORR) and 90% CI for core phase ......................................... 78 
Table 6 - Populations for analyses ................................................................................................................ 79 
Table 7 - Protocol-required laboratory assessments .................................................................................... 93 
Table 8 - Risk assessment .......................................................................................................................... 113 
Table 9 - Encephalopathy assessment ICE tool for ICANS Grading .......................................................... 118 
Table 10 - ASTCT ICANS consensus grading for adults ............................................................................ 118 
Table 11 - ASTCT CRS consensus grading ............................................................................................... 119 
 
LIST OF FIGURES  
Figure 1 - Overall study schema ................................................................................................................... 23 
 
VV-CLIN-0616194 4.0
15
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 16 
1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing 
the clinical benefit of SAR444245 (THOR-707) combined with other anticancer 
therapies for the treatment of participants with head and neck squamous cell 
carcinoma (HNSCC)  
Brief title: 
A study of SAR444245 combined with other anticancer therapies for 
the treatment of participants with HNSCC (Master Protocol) 
Rationale: 
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the interleukin (IL)-2 α receptor, while retaining stimulatory activity for cells expressing the 
moderate affinity IL-2 βγ receptor. The first in human clinical study with SAR444245 
(TCD16843/HAMMER, hereafter referred to as HAMMER) demonstrated that treatment with 
SAR444245 leads to expansion of CD8+ T cells and natural killer (NK) cells (with higher IL-2 βγ 
receptor expression) with negligible IL-2Rα induced effect on immunosuppressive Treg cells 
expansion, vascular leak syndrome related eosinophils expansion and IL-5 release. 
Most patients with locally advanced head and neck squamous cell carcinoma (HNSCC) present 
with a high risk of recurrence, and approximately 10% of HNSCC patients present with metastatic 
disease. The disease is associated with a low quality of life (QoL) and high suicide rate. Despite 
advances in surgery and radiotherapy, 5-year survival rates for patients [excluding Epstein Barr 
Virus (EBV)-related nasopharyngeal] with HNSCC across all stages remain 40%-50% for tumors 
caused by traditional carcinogens [Human Papilloma virus (HPV)-negative]. The median overall 
survival (OS) for patients with refractory/metastatic (R/M) disease is 10 to 13 months. Standard of 
care for R/M disease in the 1st line setting includes platinum-based doublet chemotherapy with 
pembrolizumab or cetuximab, or pembrolizumab monotherapy. In the 2nd line standard of care 
could be nivolumab monotherapy, pembrolizumab monotherapy, cetuximab, methotrexate, or a 
taxane, each of which is associated with response proportions of 10%-15%. 
Mechanistically, SAR444245 could potentiate immuno-oncology agents that are intended to 
expand innate and adaptive immune cells. In addition, SAR444245 may enhance antibody-
dependent cellular cytotoxicity (ADCC) for IgG1 antibodies such as cetuximab utilizing NK cells 
as an important effector cells. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with other anti-cancer therapies will result in a significant increase in the percentage of patients 
with HNSCC experiencing an objective response to establish safety and preliminary anti-tumor 
activity.
VV-CLIN-0616194 4.0
16
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 17 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 in combination with various anticancer therapies by identifying early signals. This 
design is with the flexibility to open new treatment cohorts as new treatment combinations 
become available and close existing treatment arms that demonstrate minimal clinical activity or 
unacceptable toxicity. 
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
Objectives and endpoints 
  
Objectives 
Endpoints 
Primary 
•
To determine the antitumor activity of
SAR444245 in combination with other anti-
cancer therapies in patients with HNSCC
•
Objective response rate (ORR) defined as proportion of
participants who have a confirmed complete response
(CR) or partial response (PR) determined by Investigator
per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 (1)
Secondary 
•
To assess the safety profile of SAR444245
when combined with other anti-cancer
therapies
•
Incidence of TEAEs, SAEs, laboratory abnormalities
according to National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI CTCAE)
V 5.0 and American Society for Transplantation and
Cellular Therapy (ASTCT) consensus grading (2)
•
To assess other indicators of antitumor activity
•
Time to response (TTR) defined as the time from the
first administration of investigational medicinal product
(IMP) to the first tumor assessment at which the overall
response was recorded as PR or CR that is
subsequently confirmed and determined by Investigator
per RECIST 1.1
•
Duration of Response (DoR), defined as the time from
first tumor assessment at which the overall response
was recorded as PR or CR that is subsequently
confirmed until documented progressive disease (PD)
determined by Investigator per RECIST 1.1 or death
from any cause, whichever occurs first
•
Clinical benefit rate (CBR) including confirmed CR or PR
at any time or stable disease (SD) of at least 6 months
(determined by investigator per RECIST 1.1)
•
Progression free survival (PFS), defined as the time
from the date of first IMP administration to the date of
first documented disease progression determined by
Investigator as per RECIST 1.1, or death due to any
cause, whichever occurs first
•
To assess the concentrations of SAR444245
•
Plasma concentrations of SAR444245
•
To assess the immunogenicity of SAR444245
•
Incidence of anti-drug antibodies (ADAs) against
SAR444245
VV-CLIN-0616194 4.0
17
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 18 
Objectives 
Endpoints 
Exploratory 
 
 
Overall design: 
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with HNSCC. 
Brief summary:  
The study consists of a core phase for all cohorts, with a safety run-in and an expansion phase for 
specific cohorts. The results of an interim analysis after the core phase will decide if the 
expansion phase will be opened.  
Table 1 provides an overview by study intervention and disease type of the different cohorts that 
will be assessed in the study. A graphical presentation of the study schema is shown in Figure 1.  
VV-CLIN-0616194 4.0
18
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 19 
Table 1 - Overview of study cohorts  
Cohort 
Study intervention 
Disease 
A1 
SAR444245 + pembrolizumab 
R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1 
A2 
SAR444245 + cetuximab + pembrolizumab 
R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1 
B1 
SAR444245 + pembrolizumab 
R/M HNSCC treated with PD1/PD-L1-based regimen & platinum-
based regimen after failure of no more than 2 regimens for R/M 
disease 
B2 
SAR444245 + cetuximab 
R/M HNSCC treated with platinum-based regimen & cetuximab-naïve 
after failure of no more than 2 regimens for R/M disease 
CPS: combined positive score; HNSCC: Head and neck squamous cell carcinoma; PD1: Programmed cell death protein 1; PD-L1: 
programmed cell death-ligand 1; R/M: Recurrent/metastatic. 
Participants who are eligible for both Cohorts A1 (to receive SAR444245 and pembrolizumab) 
and A2 (to receive SAR444245, pembrolizumab and cetuximab) should be enrolled in Cohort A1 
until Cohort A1 enrollment is completed.  
Participants who are eligible for both Cohorts B1 (to receive SAR444245 and pembrolizumab) 
and B2 (to receive SAR444245 and cetuximab) should be enrolled in Cohort B1 until Cohort B1 
enrollment is completed. 
Further details guiding the enrolment in each cohort are provided in individual substudies. 
Number of participants: 
Overall, in the core phase (all cohorts), approximately 40 participants will be enrolled per cohort. 
Note: Enrolled participants are all participants from screened participants who have been 
allocated to an intervention regardless of whether the intervention was received or not. 
Intervention groups and duration: 
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment Period: enrolled participants will receive continuous treatment until PD, 
unacceptable AE, other full permanent discontinuation criteria as described in Section 6 or 
completion of Cycle 35.  
• End of Treatment and Follow-up. End of Treatment Visit will occur 30 days ±7 days 
from last IMP administration or prior to initiation of further therapy. Participants will then 
enter the Observation period and will be followed differently depending on the reason 
leading to end of treatment (EOT): 
1. Participants who discontinue study treatment without  PD or who complete 35 cycles of 
treatment without PD , will be followed for safety (as per Schedule of Activities [SoA]) 
and tumor imaging assessments every 3 months ±7 days from last IMP administration, 
until PD, start of another anticancer therapy, final cohort cut-off, whichever comes first, 
before moving to the Survival Phone Call Follow-Up Period. 
VV-CLIN-0616194 4.0
19
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 20 
2. Participants who discontinue study treatment with PD will be followed for safety in the
Follow-Up Visit 1 occurring 3 months ±7 days from last IMP administration, before
moving to the Survival Phone Call Follow-Up Period.
Participants who move into the Survival Phone Call Follow-Up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Information on the first 
subsequent anticancer treatment, best reported response, and date of progression will also be 
collected. Updated survival status may be requested by the Sponsor at any time during the course 
of the study. Survival Phone Call Follow-Up will continue until death, participant request to 
discontinue from follow-up, or final cohort cut-off, or upon cancellation of Survival follow-up at 
the discretion of the Sponsor at any prior timepoint.  
After the cohort cut-off date for the primary objective response rate (ORR) analysis, participants 
can continue to receive IMP, if clinical benefit is observed, until permanent discontinuation 
criteria described in Section  7.1.1 are met, and will continue to undergo all assessments as per the 
SoA. 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of primary objective) will be 3 years from cohort last patient-in (LPI). After this cut-off 
date for the final analysis, the participants still receiving study treatment in that specific cohort 
will be followed up as the cohorts after early termination described in Section 10.1.9. 
Study intervention(s) 
Investigational medicinal product 
SAR444245 
•
Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion
in a single-dose vial with an extractable volume of 1 mL.
•
Route of administration: intravenous (IV) infusion.
•
Dose regimen: 24 μg/kg administered as an IV infusion over 30 mins every 3 weeks on
Day 1 of each cycle (21 days per cycle) for up to 35 cycles or until PD.
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
See substudy protocols for other IMPs. 
Noninvestigational medicinal products 
Premedication for SAR444245 
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, 30 to 60 minutes prior to SAR444245 
infusion (no longer than 60 minutes) for the first 4 cycles: 
VV-CLIN-0616194 4.0
20
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 21 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or oral route (PO) (or equivalent), and 
then optionally thereafter, as needed. 
• Diphenhydramine 25 to 50 mg IV or PO (or equivalent eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter, as needed. 
SAR444245 premedication may be optional after 4 cycles 
• For a participant who has no IRR during the first 4 cycles: Premedication for the 
subsequent infusions is optional at the Investigator’s discretion. However, if during the 
subsequent infusions without premedication the participant experiences an IRR (any 
grade), premedication must be restarted for all subsequent infusions.  
• If a participant develops an IRR Grade <2 during their first cycle only and then 
experiences no further IRRs during their next 3 cycles: The Investigator may consider 
omitting premedication for the next cycle. If no IRR is observed during the next cycle 
without premedication, premedication is optional for the subsequent cycles at the 
Investigator’s discretion. However, if during the next cycle without premedication the 
participant experiences an IRR (any grade), premedication must be restarted for all 
subsequent cycles. 
Statistical considerations: 
• Analysis of primary endpoint:  
- 
Objective response rate (ORR) and best overall response (BOR) will be summarized 
for the efficacy population with descriptive statistics. In addition, two-sided 
90% confidence intervals (CI) for ORR will be computed using the Clopper-Pearson 
method. 
• Analysis of secondary efficacy endpoints:  
- 
The time to response (TTR) will be summarized on the subgroup of participants who 
have achieved confirmed objective response in the efficacy population.  
- 
The duration of response (DoR) will only be summarized on the subgroup of participants 
who have achieved confirmed objective response in the efficacy population. 
- 
The clinical benefit rate (CBR) will be estimated by dividing the number of participants 
with clinical benefit by the number of participants in the efficacy population. 
- 
The progression free survival (PFS) will be summarized on the efficacy population using 
Kaplan-Meier methods. The median PFS times and associated 90% CI will be provided. 
• Analysis of secondary safety endpoints: 
- 
Number and percentage of participants experiencing treatment-emergent adverse 
events (TEAEs) by primary System Organ Class (SOC) and Preferred Term (PT) will 
be summarized by National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) V5.0 (all grades and Grade ≥3) for the exposed 
population. Similar summaries will be prepared for treatment-related TEAEs, TEAEs 
leading to permanent partial intervention discontinuation (any of the IMP 
VV-CLIN-0616194 4.0
21
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 22 
components), TEAEs leading to full intervention discontinuation, TEAEs leading to 
dose modification, serious TEAEs, TEAEs with fatal outcome, adverse events of 
special interest (AESIs), and AEs/SAEs occurring during the post-treatment period. In 
addition, the number (%) of participants with any Grade 5 AE (TEAE and post-
treatment) and participants who died by study period (treatment-emergent period, post-
treatment period) and reasons for death will be summarized. Immune Cell-Associated 
Neurotoxicity Syndrome (ICANS) and cytokine release syndrome (CRS) events will 
be graded using American Society for Transplantation and Cellular Therapy (ASTCT) 
Consensus Grading and will be summarized separately. 
- 
Hematology and clinical chemistry results will be graded according to the 
NCI-CTCAE V5.0, when applicable. Number and percentage of participants with 
laboratory abnormalities (all grades and by grade) using the worst grade during the on-
treatment period will be provided for the exposed population. 
• Analysis of other secondary endpoints: 
- 
Plasma concentrations of SAR444245 will be summarized with descriptive statistics 
by each cohort.  
Data Monitoring/Other committee: Yes (see Section 10.1.5 for details).
VV-CLIN-0616194 4.0
22
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 23
1.2 
SCHEMA 
Figure 1 - Overall study schema 
DLT: dose limiting toxicity. 
Safety run-in: prior core phase, participants in the substudy will be treated in a safety run-in to confirm safe dose level for the regimen 
Core phase: substudy designed to treat participants only in a core phase or after safety run in. 
Expansion phase: after the core phase to gather more safety data with the confirmed dose, the substudy may be expanded to enroll more participants and accumulate evidence of clinical activity. 
VV-CLIN-0616194 4.0
23
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 24
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Informed consent 
Inclusion/Exclusion 
criteria 
X 
IRT contact 
X 
X 
X 
X 
X 
Demography, 
medical/surgical and 
disease history 
X 
See Section 8 
Full physical examination 
X 
X 
Directed physical 
examination
X 
X 
X 
X 
X 
X 
See 
 Section 8.2.1 
Body weight/Heighte 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
See 
 Section 8.2.2 
SpO2 
X 
As clinically indicated 
VV-CLIN-0616194 4.0
24
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 25
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Performance status 
(ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
As clinically indicated 
See 
 Section 8.2.3 
LVEF 
X 
As clinically indicated 
See 
 Section 8.2.3 
Laboratory assessments 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically indicated 
See 
 Section 8.2.3 
& Section 10.2 
Pregnancy test 
X 
X 
X 
X 
X 
X 
X 
See 
Section 8.2.5,  
Section 8.3.5 
& 
Section 10.2 
Blood 
chemistry/hematology 
X 
X 
X 
X 
X 
X 
X 
X 
See 
 Section 10.2 
Coagulation 
X 
As clinically indicated 
See 
Section 10.2 
Urinalysisk 
X 
X 
X 
X 
X 
See 
Section 10.2 
VV-CLIN-0616194 4.0
25
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 26
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Hepatitis serology 
CD4 counts & Viral Load 
 Xf 
As clinically indicated 
See 
Section 10.2 
HPV p16 status for 
participants with 
oropharyngeal cancer 
X 
PK 
See PK Flow-Chart in Section 1.5 
ADA 
See PK Flow-Chart in Section 1.5 
Exploratory biomarkers 
PDy - Blood and tumor 
tissue collectiong 
See Biomarkers Flow-Chart Section 1.4 
Disease assessment 
CT/MRIh 
X 
X 
X 
X 
X 
X 
See 
 Section 8.1 
Brain imagingi 
X 
See 
Section 8.1 
IMP Administration 
(SAR444245 
administration) 
X 
X 
X 
AE/SAE assessmentj 
X 
Continuously throughout treatment period 
X 
See 
 Section 8.3 
VV-CLIN-0616194 4.0
26
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 27
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Prior medication 
(within 28 days 
prior to first 
dose) 
Concomitant medication 
Continuously throughout treatment period 
See 
Section 6.8 
First subsequent 
anticancer therapy 
X 
X 
 X 
X 
X 
Survival status 
X 
a Evaluation: There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as part of screening within 3 days prior to first IMP administration. During the study treatment period, all 
assessments must be performed, and results should be reviewed by the investigator prior to IMP administration at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be 
collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are performed and can be signed more than 28 days prior to first IMP administration. Screening time 
indicates the maximum time frame relative to the first IMP administration in which assessments used to support eligibility are done. 
b Cycle: A treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the Cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation Period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1. For participant’s convenience, 
all Follow-up assessments may occur during the same visit as that when tumor assessments are performed. 
d Survival Phone Call Follow-Up Period: Participant who moves into the Survival Follow-up Period should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. 
Information on the first subsequent anticancer treatment, best reported response, and date of progression will also be collected. Updated survival status may be requested by the Sponsor at any time during the 
study. 
e Weight/Height: Height is required at baseline only. Weight is required at Screening and prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most recent 
weight assuming it was assessed in a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible considering the 
variability of local process from site to site.  If the infusion is prepared with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each cycle. 
VV-CLIN-0616194 4.0
27
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03  
22-Dec-2021 
SAR444245-ACT16903 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 28 
f 
For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.8). 
g If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
h CT/MRI: The initial tumor imaging will be performed within 28 days prior to the C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP or more frequently if clinically indicated in the first 
45 weeks. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging technique should be used in a participant throughout the trial. After 
Week 45 tumor imaging should be performed every 12 weeks (84 ±7 days). CT scan of the head, neck, chest and abdomen (pelvis is optional) and any other locations with suspicion or evidence of disease 
involvement is required for the baseline assessment and during treatment period until PD. After the first documentation of response or the first documentation of progression (if the participant is clinically stable) per 
RECIST 1.1, confirmatory imaging should be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor 
assessment is not needed for participants who start another anti-cancer therapy.  
i 
Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of 
the brain as a site of disease as per protocol tumor assessment schedule. In all other cases, the lesions must be treated. Two additional scans obtained at least 4 weeks apart, should be obtained to document 
disease stability AFTER local treatment administration to the brain metastases has been completed. If participants receive systemic therapy during these 4 weeks stabilization at the treating physician's discretion, 
this systemic therapy will be considered as part of prior anti-cancer therapy. Participants with previously treated brain metastases may participate provided they are stable, which is defined as lack of progression 
on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to 
baseline or resolved, and the participant is not using steroids for at least 14 days prior to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment. 
j 
AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5.0, ICANS and cytokine release syndrome (CRS) will be graded using ASTCT criteria integrated with central laboratory cytokine results 
(2). 
k Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) will be performed every 4 cycles during the Treatment period and as 
clinically indicated. 
 
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; ALK: anaplastic lymphoma kinase; ASTCT: American Society for Transplantation and Cellular Therapy; C: Cycle; CRF: case report form; CT: computed 
tomography; D: Day; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end-of-treatment; HPV: Human Papilloma virus; ICANS: Immune effector cell-associated neurotoxicity syndrome; 
ICF: informed consent form; IMP: investigational medicinal product; IRT: Interactive Response Technology; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer 
Institute-Common terminology criteria for adverse events; PD: progressive disease; PD L1: programmed cell death ligand 1; PDy = pharmacodynamic; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in 
Solid Tumors;
; SAE: serious adverse event; SpO2: oxygen saturation.  
 
VV-CLIN-0616194 4.0
28
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03  
22-Dec-2021 
SAR444245-ACT16903 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 29 
1.4 
BIOMARKER FLOWCHART  
 
VV-CLIN-0616194 4.0
29
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
22-Dec-2021
SAR444245-ACT16903 
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 30 
1.5 
PHARMACOKINETIC FLOWCHART 
The sampling time-points for pharmacokinetic (PK) and ADA for/against SAR444245 and/or 
other IMPs may be updated during the course of the study based on the updated knowledge of 
drug behavior upon notification from the Sponsor. 
VV-CLIN-0616194 4.0
30
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903   
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 31 
1.5.1 All cohorts 
Cycle 
Treatment Cycle 1 
Treatment Cycles 2, 3, 4, 6, 8, 
10 + every 4th cycle thereafter 
EOT visit 
30 (±7) days after last IMP admin
Day
D1 
D2 
D8 
D1
Time after start of SAR444245 
dosing 
SOI 
EOI 
Any time 
Any time 
SOI 
EOI 
SAR444245 PK sample 
P00b 
P01 
P00b 
SAR444245 ADA sample 
AB00a 
AB01 
AB00a 
ABF00 
aa Samples collected strictly before start of infusion (SOI). 
b EOI samples must be taken at end of infusion (EOI) precisely ±5 minutes. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOI: end of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: start of infusion. 
VV-CLIN-0616194 4.0
31
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 32 
2 
INTRODUCTION  
SAR444245 is a recombinant human IL-2 with a site-specific substitution of a non-native azido 
lysine amino acid residue which is bio-conjugated to a single linear 30 kDa PEG. SAR444245 is 
being developed as an immuno-oncology treatment to be administered every 2 weeks (Q2W) or 
less frequently (every 3 weeks [Q3W] in the present study) in patients with cancer. 
 The site-specific pegylation of IL-2 in SAR444245 provides a “non-
alpha” pharmacologic profile for SAR444245 that is designed to prevent engagement of the high 
affinity IL-2Rα, while maintaining CD8+ T cell anti-tumor activity and resulting in an improved 
safety profile relative to aldesleukin. Aldesleukin is approved in the United States (US) for the 
following indications: the treatment of metastatic renal cell carcinoma (RCC) and metastatic 
melanoma, with the same or limited approval status in other countries. Its use has resulted in 
durable CR in some patients with anti-tumor effects via elevations in CD8+ T cells (naïve, 
effector, and memory T cells). However, widespread use of aldesleukin is limited by its low 
response rate, short half-life (t1/2), and severe toxicities including primarily vascular leak 
syndrome (VLS), and CRS. 
In contrast to native IL-2 and aldesleukin, SAR444245 does not have high potency at the 
IL-2Rα/β/γ receptor expressed on Treg cells because the site-specific pegylation blocks IL-2Rα 
engagement. Due to this re-programmed receptor bias, SAR444245 induces proliferation of 
peripheral CD8+ T and natural killer (NK) cells in vivo as observed in mice and non-human 
primates (NHP) with negligible effect on the expansion of immunosuppressive Treg cells. 
Furthermore, SAR444245 does not bind IL-2Rα, and does not activate cells that express low 
levels of the high affinity IL-2Rα, such as Type 2 innate lymphoid cells (ILC-2s), eosinophils, and 
endothelial cells. Thus, it is expected to have a greatly reduced risk of VLS, and therefore a wider 
therapeutic window as compared to aldesleukin. In preclinical NHP studies, no signs of VLS were 
observed at a dose of SAR444245 that was 
 higher than the dose eliciting maximal 
expansion of peripheral CD8+ T cells. Therefore, in the clinic, SAR444245 is expected to have a 
wider therapeutic window as compared to aldesleukin due to a greatly reduced risk of VLS. 
Furthermore, the site-specific pegylation extends the plasma t1/2 of IL-2 in SAR444245 in mice 
and NHP to 9-13 h versus 85 min for aldesleukin in patients. 
2.1 
STUDY RATIONALE  
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models. The first-in-human clinical study with SAR444245 
(TCD16843/HAMMER, hereafter referred to as HAMMER) demonstrated that treatment with 
SAR444245 leads to expansion of CD8+ T cells and NK cells (with higher IL-2 βγ receptor 
expression) with negligible IL-2Rα induced effect on immunosuppressive Treg cells expansion, 
vascular leak syndrome related eosinophils expansion and IL-5 release. 
VV-CLIN-0616194 4.0
32
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 33 
Most patients with locally advanced HNSCC present with a high risk of recurrence, and 
approximately 10% of HNSCC patients present with metastatic disease (4). Disease associated 
with a low QoL and high suicide rate. Despite advances in surgery and radiotherapy, 5-year 
survival rates for patients [excluding EBV-related nasopharyngeal] with HNSCC across all stages 
remain 40%-50% for tumors caused by traditional carcinogens [Human Papilloma Virus (HPV)-
negative]. The median OS for patients with refractory/metastatic (R/M) disease is 10 to 
13 months. Standard of care for R/M disease in the 1st line setting includes platinum-based 
doublet chemotherapy with pembrolizumab or cetuximab, or pembrolizumab monotherapy. In the 
2nd line standard of care could be nivolumab monotherapy, pembrolizumab monotherapy, 
cetuximab, methotrexate, or a taxane, each of which is associated with response proportions of 
10%-15%. 
Mechanistically, SAR444245 could potentiate immuno-oncology agents that are intended to 
expand innate and adaptive immune cells. In addition, SAR444245 may enhance antibody-
dependent cellular cytotoxicity (ADCC) for IgG1 antibodies such as cetuximab utilizing NK cells 
as important effector cells. 
2.2 
BACKGROUND  
 
2.2.1 Rationale for combining with other anti-tumor agents  
2.2.1.1 Rationale for combining with checkpoint inhibitor  
Based on preclinical pharmacology studies, SAR444245 is expected in the clinic to demonstrate 
synergistic anti-tumor activity when administered together with an antibody targeted to the 
PD-(L)1 pathway. The rationale for this approach is that T cell receptor (TCR) activation 
following engagement of tumor cell-presented antigens induces the surface expression of PD-1 on 
the activated T cell. Expression of programmed death-ligand 1 (PD-L1) on cancer cells induces 
PD-1 mediated silencing of TCR signaling and CD28 co-stimulation, effectively silencing the 
cytolytic activity of CD8+ T cells (5, 6). PD-1 inhibitory antibodies such as pembrolizumab have 
shown clinical efficacy by reinvigorating those cells. 
SAR444245 is an ideal agent to combine with an anti-PD-1 antibody because it induces the 
polyclonal expansion of CD8+ T cells and their infiltration into tumors and inhibiting the PD-1 
pathway prevents PD-L1 mediated silencing of those cells. These effects of combination 
treatment have been shown to be additive with increased anti-tumor activity in the syngeneic 
mouse CT-26 colon cancer model; a survival benefit was also demonstrated. Furthermore, studies 
using human mixed lymphocyte reactions to model TCR-mediated T cell responses to presented 
tumor antigens show that an anti-PD-1 antibody enhances interferon gamma (IFNγ) release from 
T cells, addition of SAR444245 on anti-PD-1 antibody further enhanced IFNγ production by 
T cells. It indicates the potential of this combination to enhance durable anti-tumor effects.  
VV-CLIN-0616194 4.0
33
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 34 
2.2.1.2 Rationale for combining with cetuximab 
SAR444245 can activate NK cells thus leading to enhanced antibody-dependent cellular-mediated 
cytotoxicity (ADCC) in target cells.  
Cetuximab is an IgG1 monoclonal antibody against the ligand binding domain of EGFR, which is 
abnormally activated in many epithelial cancers, including colon cancer and HNSCC (7). The 
mechanism of action of cetuximab include ADCC via NK cells (8), in addition to EGFR 
blockade.  
A study that added SAR44425 into co-culture of human PBMC with EGFR expressing CA27 
HNSCC cells and cetuximab, showed an enhanced cytotoxicity against cancer cells. It indicated 
that SAR444245 may improve anti-tumor efficacy of cetuximab (9). 
2.2.2 Rationale for HNSCC and selected participant population 
Squamous cell carcinoma of the head and neck (HNSCC) is the 9th leading cancer by incidence 
worldwide and constitutes 90% of all head and neck cancers (10). In the US, approximately 
50 000 new cases of HNSCC and more than 10 000 deaths occur per year (11, 12, 13, 14). 
Squamous cell carcinoma of the head and neck (HNSCC) is a biologically diverse and 
genomically heterogeneous disease that arises from the squamous mucosal lining of the upper 
aerodigestive tract, including the lip and oral cavity, nasal cavity, paranasal sinuses, nasopharynx, 
oropharynx, larynx and hypopharynx (11, 15, 16, 17, 18). 
A large number of patients with head and neck cancer initially present with locally advanced, 
Stage III/IV disease that is initially treated with combinations of chemotherapy, radiation and/or 
surgery. This initial treatment is generally designated as “definitive” therapy, which typically 
combines chemoradiation and surgery and can result in DCR ranging between 33% and 86% of 
patients. Patients who progress after initial definitive therapy require subsequent treatment for 
recurrent (R) disease. Patients who initially present with metastatic (M) disease generally receive 
the same therapy as those with recurrent disease after definitive treatment. 
2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 and other combinations may be found in the 
Investigator’s Brochure (IB). 
2.3.1 Risk assessment 
Safety data from clinical studies conducted with SAR444245 in humans is currently limited to 
available data from the Phase 1/2 first-in-human (HAMMER) study. Consequently, the 
assessment of the risks associated with SAR444245 is based on existing preclinical data and takes 
into consideration the known safety profile of the structurally similar product aldesleukin 
(Proleukin®) as well as current knowledge of the new generation, investigational IL-2 analog 
NKTR-214 (bempegaldesleukin).  
VV-CLIN-0616194 4.0
34
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 35 
Table 8 summarizes potential risks for SAR444245 identified from preclinical experience and 
from the Phase 1/2 first-in-human (HAMMER) study. 
2.3.1.1 Aldesleukin experience 
There is currently one marketed IL-2 product, Proleukin (aldesleukin). It is an IL-2 therapeutic 
that is currently licensed in the US for the treatment of metastatic RCC and metastatic melanoma, 
and in several European countries for the treatment of metastatic RCC. 
Aldesleukin is a human recombinant interleukin-2 which has been shown to possess the biological 
activities of human native IL-2 mediated through its binding with the high-affinity IL-2Rαβγ and 
intermediate-affinity IL-2Rβγ receptors. The widespread use of aldesleukin has been limited by its 
low response rate, a short t1/2 that requires dosing three times per day, and toxicities (14), which 
include life-threatening and sometimes fatal VLS. Vascular leak syndrome is characterized by a 
loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. It 
results in hypotension and reduced organ perfusion which, if severe, can result in death. It may be 
associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial 
infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, edema, and mental status changes. 
Aldesleukin has been associated with exacerbation of pre-existing or initial presentation of 
auto-immune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, 
thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic 
IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous 
pemphigoid, have been reported following treatment with IL-2. 
It was recognized early in clinical studies that eosinophilia appeared to mark the onset of VLS, 
with several reports of fast, dose-dependent elevation in eosinophils. Additional publications 
suggested a causal connection between the increase in peripheral IL-5 levels and identified ILC-2 
as the source of this powerful chemoattractant and activator of eosinophils (15). Aldesleukin 
mediates activation of ILC-2s via interaction with the high affinity IL-2R⍺ chain that exists at low 
levels on ILC-2s. 
Treatment with aldesleukin is associated with impaired neutrophil function (reduced chemotaxis) 
and the resulting increase in the risk of disseminated infection, including sepsis and bacterial 
endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to 
initiation of Proleukin therapy. 
Proleukin toxicity threat mandates that it should be administered in a hospital setting under the 
supervision of a qualified physician experienced in the use of anticancer agents. An intensive care 
facility and cardiopulmonary or intensive care specialists must be available. 
Proleukin has been shown to have embryo lethal effects in rats but there are no adequate well-
controlled studies in pregnant women; this information can be extrapolated to SAR444245. Also, 
since it is not known whether SAR444245 is excreted in human breast milk, nursing mothers 
cannot participate in this study. 
VV-CLIN-0616194 4.0
35
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 36 
High doses of aldesleukin (IL-2) were associated with decreased expression of enzymes of hepatic 
metabolism (16). As SAR444245 also exercises IL-2 activity, the Investigator should monitor 
clinical effects of narrow therapeutic index drugs that are hepatically metabolized.  
2.3.1.2 SAR444245  
2.3.1.2.1 Preclinical data  
Among the potential risks, preclinical data for SAR444245 are lacking for IRRs, immunogenicity 
(anti-drug antibodies), hypersensitivity, and immune-mediated AEs. Those are, however, typical 
effects associated with the use of biologic drugs in oncology and should be considered for 
SAR444245. 
Further, preclinical data for SAR444245 do not indicate the potential for nephrotoxicity, 
neurotoxicity, or pulmonary toxicity, which are known adverse effects for aldesleukin. However, 
mitigation strategies for nephrotoxicity and neurotoxicity are also proposed in the protocol. 
Preclinical data for SAR444245 do not indicate higher risk for infections. However, infections are 
typically associated with the use of aldesleukin and are to be expected. 
There are no preclinical data for tumor lysis syndrome (TLS) associated with the use of 
SAR444245, but it is known to occur when aldesleukin is combined with cisplatinum, vinblastine 
and dacarbazine (refer to Proleukin US label) (14). The participants at greatest risk of TLS are 
those with high tumor burden prior to treatment, elevated uric acid level, poor hydration or tumor 
infiltration of the kidney, or receiving intensive cytoreductive therapy. 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been described 
in the setting of immunotherapy with T cell engagement. It is characterized by a variety of 
symptoms including high fevers, hypotension, rigors and malaise, and may progress to cytokine 
storm (uncontrolled immune hyperactivation involving myriad cytokines) with more severe and 
potentially life-threatening manifestations. As SAR444245 mediates immune activation, it may 
induce AEs related to cytokine release (eg, fatigue, fever, chills, muscle pain, rash, nausea, 
symptoms of autoimmune disease). Furthermore, SAR444245-related increases of plasma 
monocyte chemoattractant protein-1 (MCP-1), IL-2, and IL-1RA were observed in non-human 
primates, indicating that SAR444245 administration may be associated with CRS. 
No manifestations of VLS have been reported in pre-clinical toxicity studies with SAR444245. 
Although there is a theoretical risk of VLS occurring in an immunotherapy setting, it has not been 
observed for IL-2 variants with “non-alpha” profiles. Being a “non-alpha” IL-2, SAR444245 is 
not anticipated to cause VLS. 
No data pertaining to pregnancy and lactation exposure and outcomes are available for 
SAR444245. Due to the missing information for this important risk, detailed mitigation measures 
will be introduced. Conditions for eligibility of women of reproductive potential and male 
subjects with female partners of childbearing potential are detailed in Section 5.1 of the protocol. 
Also, since it is not known whether SAR444245 is excreted in human breast milk, nursing 
mothers cannot participate in this study. 
VV-CLIN-0616194 4.0
36
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 37 
2.3.1.2.2 Clinical studies  
A Phase 1/2 first-in-human study (HAMMER) is currently ongoing in adult patients with 
advanced or metastatic solid tumors. Available safety information from this study has informed 
the selection of the dose (see details in Section 4.3). 
For the most up-to-date safety information from this study please refer to SAR444245 IB. 
2.3.1.3 NKTR-214 (bempegaldesleukin) clinical data  
Useful insight can also be obtained from NKTR-214 (bempegaldesleukin), another new 
generation IL-2 derivative, with activity biased towards the IL-2Rβγ receptor.  
In the first-in-human Phase 1 study, NKTR-214 was administered as an outpatient regimen and 
was well tolerated. Twenty-eight patients with advanced or locally advanced solid tumor 
malignancies were enrolled in the study. Grade 3 treatment-related adverse events (TRAEs) were 
reported by 21.4% of patients; there were no Grade 4 TRAEs or any treatment related deaths. The 
most common TRAEs included fatigue (71%), flu-like symptoms (68%), pruritus (64%), 
hypotension (57%), rash (50%), decreased appetite (46%), arthralgia and cough (each 32%). The 
majority of these events coincided with the peak plasma concentrations of the active cytokine and 
resolved spontaneously or were mitigated by nonprescription oral or topical treatments. There was 
one reported immune-related adverse event (irAE) of hypothyroidism associated with NKTR-214, 
which was treated with replacement therapy. All Grade 3 hypotension events (18%) were rapidly 
reversed with IV fluid administration and did not require treatment discontinuation. 
NKTR-214-related hypotension was predictable, manageable, and reversible and the incidence of 
Grade 3 hypotension was reduced once hypotension risk mitigation strategies were implemented. 
The maximum tolerated dose (MTD) was determined to be 0.009 mg/kg Q3W. This new 
generation, IL-2Rβγ-biased IL2 could be safely administered as outpatient basis, and there was no 
report of capillary leak syndrome (CLS) or VLS (17). 
In PIVOT-02, a single-arm, Phase 1/2 study, NKTR-214 plus nivolumab was administered to 
38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, RCC, and 
non-small cell lung cancer [NSCLC]). Several treatment regimens were explored. The dose of 
0.009 mg/kg had excessive toxicity (2 of 3 patients with DLT: Grade 3 hypotension [n=1] & 
Grade 4 hyperglycemia + metabolic acidosis [n=1]) when combined with 360 mg of nivolumab. 
All 38 patients had TEAEs that were considered related to the study combination. The MTD of the 
combination was defined as NKTR-214 0.006 mg/kg + nivolumab 360 mg Q3W and this dose was 
selected as the recommended Phase 2 dose (RP2D). The most common TRAEs (≥30%) at the RP2D 
were flu-like symptoms (80%), rash (80%), fatigue (76%), pruritis (48%), arthralgia (44%), headache 
and diarrhea (40%), nausea (40%), decreased appetite (36%) and peripheral edema (36%), myalgia 
(32%), and nasal congestion (32%). Grade ≥3 TRAEs occurred in 16% of patients at the RP2D 
(hyperglycemia, lipase increase, rash, cerebrovascular accident, hyponatremia, infectious pleural 
effusion, syncope). Immune-mediated AEs were observed in 31.6% overall: hypothyroidism (11), 
hyperthyroidism (2), hyperglycemia (2). Cytokine-related symptoms were observed primarily in 
Cycles 1 & 2 and significantly reduced thereafter. There were no treatment-related deaths and 
generally, Grade ≥3 TRAEs were manageable using standard guidelines. Tumor responses were 
observed regardless of baseline PD-L1 status and baseline levels of tumor infiltrating lymphocytes 
VV-CLIN-0616194 4.0
37
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 38 
(TILs), suggesting therapeutic potential for patients with poor prognostic risk factors for response to 
PD-1/PD-L1 blockade. These data demonstrated that NKTR-214 can be safely combined with a 
checkpoint inhibitor as dual immunotherapy for the treatment of a range of advanced solid tumors 
(18). 
2.3.2 Benefit assessment  
The ability of IL-2 to expand T cells with maintenance of functional activity has been translated 
into the first reproducible effective human cancer immunotherapies. The first-generation IL-2 
(aldesleukin) was the first immunotherapy effective for human cancer. Aldesleukin is approved in 
metastatic RCC and metastatic melanoma and its use has resulted in durable, complete responses 
(CRs) in some patients with anti-tumor effects via elevations in CD8+ T cells (naïve, effector, and 
memory T cells). However, clinical benefit of aldesleukin requires high dose as the enhancement 
of the CD8+ T-cell population is mediated through the intermediate-affinity by IL-2Rβγ, the 
suppressor CD4+ Treg cells are preferentially enhanced at lower dose through the high-affinity 
IL-2Rαβγ which is probably responsible for the limited proportion of responding patients 
(ORR 16% in metastatic melanoma patients - US Label), and at the price of significant toxicities. 
Local interleukin-2 (IL-2) treatment was introduced as a neoadjuvant immunobiotherapy applied 
before the surgical resection of the oral squamous cell carcinoma. Early data demonstrated highly 
variable response rates for local rhIL-2 administrations (6% to 65%) (19). Phase III trials 
involving the local administration of rhIL-2 to oral squamous cell carcinoma patients resulted in a 
significant increase in disease-free survival as well as increased OS (20).  
SAR444245, as a “non-alpha” new generation IL-2 is expected to result in greater anti-tumor 
activity than aldesleukin that has already demonstrated clinical benefit. Furthermore, preliminary 
Phase 1 clinical data from another new generation IL-2, RO6874281, a fibroblast activation 
protein (FAP) targeting IL-2 variant, shows CR was achieved in a recurrent and heavily pretreated 
HNSCC patient, who discontinued from study treatment after 2 years on study (21). 
2.3.3 Overall benefit: risk conclusion  
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the IL-2 α receptor, while retaining stimulatory activity for cells expressing the moderate 
affinity IL-2 βγ receptor. These design features are anticipated to minimize safety liability 
associated with Proleukin by avoiding expansion of immunosuppressive immune cell populations 
(regulatory T cells) and off-target complications such as VLS, while still promoting expansion of 
immune populations that can support anti-tumor immune responses. 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with this new generation IL-2 SAR444245 combined with other 
anticancer treatments are justified by the anticipated benefits that may be afforded to participants 
with HNSCC. 
VV-CLIN-0616194 4.0
38
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 39 
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
2.3.4.1 Risks in the context of COVID-19 
2.3.4.1.1 Risks related to the patient population 
Head and neck squamous cell carcinoma (HNSCC) is unique in its location in the upper 
aerodigestive tract, a known location that harbors SARS-Cov2, the causative virus in COVID-19. 
Comorbidities coexist with head and neck cancers in 36.4%-88.9% and 65%-90% of cases 
diagnosed at an advanced stage. Being mostly heavy smokers, chronic obstructive pulmonary 
disease (COPD) is one of the most common comorbidities in this group of patients. All these 
factors significantly increase the risk of a severe outcome, including acute respiratory distress 
syndrome (ARDS), hospitalization in intensive care units (ICUs), mechanical ventilation, and 
even death. Sidaway et al. report 53.6% of cancer patients requiring mechanical ventilation and a 
28.6% death rate in this category of patients, with most fatalities due to ARDS. Another specific 
aspect of HNSCC is immunosuppressive treatment, an effect that is associated with a 
compromised immunity state generated by cancer, thus increasing the risk of a worse outcome in 
case of infection with the new coronavirus (22, 23). In a systematic review and meta-analysis that 
evaluated the effect of oncological therapies on the course of Covid-19 disease, Yekedüz et al. 
identified chemotherapy as a risk factor for severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection mortality without a consensus on safety in surgery, radiation therapy, 
target molecular therapy, and immunotherapy. A systematic review and meta-analysis by Wang et 
al. concluded that these therapies do not increase the risk of death in combination with Covid-19, 
chemotherapy being in this case also considered to be the only cancer therapy at risk. Cancer is 
considered due to its immunosuppressive status a risk factor in association with SARS-CoV-2 
infection, the rate of possible severe complications, not only ARDS, considered to be 33%. 
SARS-CoV-2 has had effects on HNSCC management in choosing optimal treatment, taking into 
account that resources available in each department involved are essential. The multidisciplinary 
team has an essential role in evaluating the optimal option and is also involved in patient 
evaluation and follow-up during this pandemic period (24, 25). 
In response to the pandemic, many institutions created consensus guidelines to aid in the 
management of patients. These include the European Society for Medical Oncology (ESMO) 
Guidelines (26) and the American Society of Clinical Oncology (ASCO) COVID-19 Patient Care 
Disease-specific Information (27). 
Head and neck cancer treatment remains a high priority during this pandemic and patients should 
undergo standard of care treatment as soon as possible when system resources are available, and 
the risk of collateral exposure can be controlled or prevented. 
Testing for SARS-CoV-2 infection during the screening phase should be at Investigator’s 
discretion and should also follow local/international guidelines (eg, asymptomatic but high risk of 
infection patients, patients with symptoms that could be associated with SARS-CoV-2 infection).  
VV-CLIN-0616194 4.0
39
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
During the study, if a participant is diagnosed with SARS-CoV-2, dose modification of study 
intervention should be based on the recommendations provided in Section 6.6. In addition, all 
Investigators are instructed to consult official COVID-19 clinical research guidance from their 
local hospital/institution along with other relevant resources, such as: 
• American society of clinical oncology (ASCO) (27). 
• European Society for Medical Oncology (ESMO) (26). 
2.3.4.1.2 Risks related to study treatment  
SAR444245 has the potential to induce CRS which could exacerbate the manifestations of 
COVID-19 infection. It is, however, worth noting that pegylated IL-2 bempegaldesleukin is 
currently being evaluated for the treatment of patients with mild COVID-19 in a Phase 1b study 
(NCT04646044). 
2.3.4.1.3 Risks related to study related activity  
It is important to minimize the risk of exposure of patients to COVID-19. In addition to the 
contingency measures described in Section 10.11, the following prevention and mitigation plans 
could be implemented at clinical sites: 
• All participating sites should have implemented measures according to regional/local 
Health Authorities, European Medicines Agency (EMA), ESMO, ASCO guidelines 
including but not limited to restrictions of access to the hospitals for visitors, physical 
distancing and personal protective equipment (PPE).  
• Study participants should be treated in a dedicated area that is separated from patients with 
COVID-19 infection. 
2.3.4.1.4 Conclusion on the benefit-risk assessment pertaining to COVID-19  
Overall, the benefit-risk ratio is deemed acceptable in patients with HNSCC during COVID-19 
pandemic. 
VV-CLIN-0616194 4.0
40
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of 
SAR444245 in combination with other anti-
cancer therapies in patients with HNSCC 
• 
Objective response rate (ORR) defined as proportion of 
participants who have a confirmed complete response 
(CR) or partial response (PR) determined by Investigator 
per Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 (1) 
Secondary 
 
• 
To assess the safety profile of SAR444245 
when combined with other anti-cancer 
therapies 
• 
Incidence of TEAEs, SAEs, laboratory abnormalities 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) 
V 5.0 and American Society for Transplantation and 
Cellular Therapy (ASTCT) consensus grading (2) 
• 
To assess other indicators of antitumor activity 
• 
Time to response (TTR) defined as the time from the 
first administration of investigational medicinal product 
(IMP) to the first tumor assessment at which the overall 
response was recorded as PR or CR that is 
subsequently confirmed and determined by Investigator 
per RECIST 1.1 
• 
Duration of Response (DoR), defined as the time from 
first tumor assessment at which the overall response 
was recorded as PR or CR that is subsequently 
confirmed until documented progressive disease (PD) 
determined by Investigator per RECIST 1.1 or death 
from any cause, whichever occurs first 
• 
Clinical benefit rate (CBR) including confirmed CR or PR 
at any time or stable disease (SD) of at least 6 months 
(determined by investigator per RECIST 1.1) 
• 
Progression free survival (PFS), defined as the time 
from the date of first IMP administration to the date of 
first documented disease progression determined by 
Investigator as per RECIST 1.1, or death due to any 
cause, whichever occurs first 
• 
To assess the concentrations of SAR444245 
• 
Plasma concentrations of SAR444245 
• 
To assess the immunogenicity of SAR444245 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245 
VV-CLIN-0616194 4.0
41
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 42 
Objectives 
Endpoints 
Exploratory 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in an oncology study setting.  
In addition, suitable steps have been built into each of these assessments to ensure their reliability 
and accuracy and to minimize any risks to participant safety. 
VV-CLIN-0616194 4.0
42
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 43 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with HNSCC. 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 in combination with various anticancer therapies by identifying early signals. This 
design is with the flexibility to open new treatment cohorts as new treatment combinations 
become available and close existing treatment arms that demonstrate minimal clinical activity or 
unacceptable toxicity. 
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
This study is designed with the flexibility to open new treatment arms or add new indications as 
permitted by scientific rationale.  
The study consists of a core phase for all cohorts, with a safety run-in and an expansion phase for 
specific cohorts (see Figure 1). The results of an interim analysis after the core phase will decide 
if the expansion phase will be opened. Further details on study design are provided in each 
substudy. An overview of the study intervention and disease being treated for each cohort is 
provided in Table 3.  
Table 3 - Overview of study cohorts 
Cohort 
Study intervention 
Disease 
A1 
SAR444245 + pembrolizumab 
R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1 
A2 
SAR444245 + cetuximab + pembrolizumab 
R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1 
B1 
SAR444245 + pembrolizumab 
R/M HNSCC treated with PD1/PD-L1-based regimen & platinum-
based regimen after failure of no more than 2 regimens for R/M 
disease 
B2 
SAR444245 + cetuximab 
R/M HNSCC treated with platinum-based regimen & cetuximab-naïve 
after failure of no more than 2 regimens for R/M disease 
CPS: combined positive score; HNSCC: Head and neck squamous cell carcinoma; PD1: Programmed cell death protein 1; 
PD-L1: programmed cell death-ligand 1; R/M: Recurrent/metastatic. 
Participants who are eligible for both Cohorts A1 (to receive SAR444245 and pembrolizumab) 
and A2 (to receive SAR444245, pembrolizumab and cetuximab) should be enrolled in Cohort A1 
until Cohort A1 enrollment is completed. Further details guiding the enrolment in each cohort are 
provided in the individual substudies. 
VV-CLIN-0616194 4.0
43
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 44 
Study Board 
The study Investigators (or designee) participating in the safety run-in part of applicable cohorts 
and the Sponsor clinical team members will constitute the Study Board (SB). The SB will review 
clinical data on a regular basis in order to decide dose confirmation or dose reduction on the basis 
of their knowledge of the safety data. Minutes of each meeting will be written by the Sponsor and 
distributed to all sites participating in the safety run-in part. Decisions regarding final dose 
selection will be made during one of the SB meeting and documented in the meeting minutes. 
See further details in substudies for cohorts with safety run-in. 
Special considerations pertaining to methodology 
Interactive Response Technology will be used to control recruitment assignment per site and 
facilitate drug supply.  
The duration of the study for a participant will include: 
•
Screening period: up to 28 days.
•
Treatment Period: enrolled participants will receive continuous treatment until PD,
unacceptable AE, other full permanent discontinuation criteria as described in Section 6, or
completion of Cycle 35.
•
End of Treatment and Follow-up. End of Treatment Visit will occur 30 days ±7 days
from last IMP administration or prior to initiation of further therapy. Participants will then
enter the Observation period and will be followed differently depending on the reason
leading to EOT:
1. Participants who discontinue study treatment without PD or who complete 35 cycles of
treatment without PD, will be followed for safety (as per Schedule of Activities [SoA])
and tumor imaging assessments every 3 months ±7 days from last IMP administration,
until PD, start of another anticancer therapy, final cohort cut-off, whichever comes first,
before moving to the Survival Phone Call Follow-Up Period.
2. Participants who discontinue study treatment with PD will be followed for safety in the
Follow-Up Visit 1 occurring 3 months ±7 days from last IMP administration, before
moving to the Survival Phone Call Follow-Up Period.
Participants who move into the Survival Phone Call Follow-Up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Information on the first 
subsequent anticancer treatment with best reported response, and date of progression will also be 
collected. Updated survival status may be requested by the Sponsor at any time during the course 
of the study. Survival Phone Call Follow-Up will continue until death, participant request to 
discontinue from follow-up, or final cohort cut-off, or upon cancellation of Survival follow-up at 
the discretion of the Sponsor at any prior timepoint.  
After the cohort cut-off date for the primary ORR analysis, participants can continue to receive 
IMP, if clinical benefit is observed, until permanent discontinuation criteria described in  
Section 7.1.1 are met and will continue to undergo all assessments as per the SoA. 
VV-CLIN-0616194 4.0
44
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 45 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of primary objective) will be 3 years from cohort LPI.  After this cut-off date for the final 
analysis, the participants still receiving study treatment in that specific cohort will be followed up 
as the cohorts after early termination described in Section 10.1.9. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with other anticancer therapies, will result in a significant increase in the percentage of trial 
participants with HNSCC experiencing an objective response. 
The design of the study is a non-randomized study where the experimental combinations will be 
assessed in separate cohorts, using historical data from agents combined with SAR444245 as a 
benchmark to show outstanding objective response rate. The ORR will be assessed using response 
evaluation criteria in solid tumors (RECIST) 1.1. The objective response will be assessed per 
Investigator as primary endpoint. Central imaging reading may be done retrospectively if 
significant activity is observed. 
4.2.1 Participant input into design  
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
Dose escalation for SAR444245 monotherapy and in combination with pembrolizumab or 
cetuximab is ongoing in the first-in-human HAMMER study. Data from a total of 68 patients who 
have received SAR444245 Q2W or Q3W in monotherapy, in a Q3W regimen in combination with 
pembrolizumab 200 mg Q3W, or with cetuximab 400/250 mg/m² QW is available as of 18 June 
2021. SAR444245 24 µg/kg Q3W pembrolizumab combination and cetuximab combination dose 
level have been cleared by Hammer Safety Review Committee based on this data cut-off. 
The dose levels tested to date for SAR444245 monotherapy administered using a Q3W schedule 
are 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=11), 32 µg/kg (n=6) and 40 µg/kg (n=2).  
In combination with pembrolizumab, SAR444245 has been administered Q3W at the doses of 
8 µg/kg (n=4), 16 µg/kg (n=9), 24 µg/kg (n=6), 32 µg/kg (n=1). In combination with cetuximab, 
SAR444245 has been administered Q3W at 16 µg/kg (n=5) or 24 µg/kg (n=5). 
For monotherapy cohort, the only DLT observed to date is a Grade 3 infusion reaction (occurred 
in C2D1 which resolved on the same day with supportive care) reported in a patient on 32 µg/kg 
Q3W monotherapy.  
For SAR444245 in combination with pembrolizumab 200 mg Q3W, 1 DLT (Grade 3 liver 
enzyme elevation with Grade 2 bilirubin elevation meeting drug-induced liver injury [DILI] 
criteria occurred in C1D1 which resolved after 7 days with steroids) was observed in a participant 
with SAR444245 24 µg/kg Q3W with pembrolizumab. 
VV-CLIN-0616194 4.0
45
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 46 
No DLTs were reported by SAR444245 cetuximab combination cohort (SAR444245 24 µg/kg 
Q3W). 
Grade 3/4 TEAEs commonly reported by participants who received SAR444245 24 µg/kg 
monotherapy (n=11) include in particular Grade 4 lymphocyte count decreased/lymphopenia 
(7 participants, 63.6%), Grade 3 anemia (3 participants, 27.3%), and Grade 3 dyspnea 
(2 participants, 18.2%). Of note, transient lymphocyte count decrease in the peripheral blood is an 
expected effect, consequence of T cell activation and temporary compartmental redistribution 
after IL-2 treatment. Nevertheless, this phenomenon can be reported as an adverse event (AE) in 
HAMMER study. 
Grade 3/4 TEAEs reported by participants who received SAR444245 24 µg/kg in combination 
with pembrolizumab (n=6) include Grade 4 lymphocyte count decreased (3 participants, 50.0%), 
Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT) & gamma-glutamyl 
transferase (GGT) increased (2 participants each for AST & ALT increased, 33.3%; 1 participant 
for GGT increased, 16.7%), Grade 3 blood phosphorus decreased & hypophosphatemia 
(1 participant each, 16.7%), and Grade 3 dyspnea (1 participant, 16.7%).  
Grade 3/4 TEAEs reported by participants who received SAR444245 24 µg/kg in combination 
with cetuximab (n=5) include Grade 3 chills (1 participant, 20.0%) and Grade 3 abdominal pain 
and vomiting (1 participant for each, 20.0%). 
Within the HAMMER study, all together there were 13 patients that experienced any grade of 
CRS (per CTCAE version 5). Only 1 Grade 4 CRS with Grade 3 hypertension, Grade 2 fever, and 
Grade 2/3 neurological symptoms (with 24 µg/kg Q3W, 2.6%) is reported among participants 
who received SAR444245 monotherapy (n=38). From participants who received SAR444245 
pembrolizumab combination (n=20), grade 3 CRS (with 16 µg/kg Q3W) is observed in 
1 participant (5.0%) with Grade 3 hypotension and Grade 2 fever. 
According to literature, prophylactic hydration on the dosing days could mitigate incidence and 
severity of hypotension as part of CRS. As HAMMER study was not mandating prophylactic 
hydration before January 2021, the participants who experienced CRS in HAMMER study did not 
always receive peri-infusion hydration. Based on this learning, hydration and CRS management 
guidelines have been included in the Phase 2 study protocols. 
With respect to PK, SAR444245 exposure increased in an approximately dose-proportional 
manner in the monotherapy cohorts, and no impact of anti-drug antibody (ADA) on SAR444245 
PK could be identified. Also, in the combination cohort, there was no apparent impact of 
pembrolizumab on the PK of SAR444245. 
Differently from native IL-2 and aldesleukin, SAR444245 does not have high potency at the 
IL-2Rα/β/γ receptor subunit expressed on T regulatory (Treg) cells because the site-specific 
pegylation blocks IL-2Rα engagement and demonstrates high potency at the IL2Rβ/γ receptor 
subunit expressed on CD8+ T and natural killer cells (NK). Due to this re-programmed receptor 
bias, SAR444245 induces proliferation of peripheral CD8+ T and NK cells and less impact on 
immunosuppressive Treg cells. Therefore, we closely monitored the pharmacodynamic (PDy) 
change of CD8+ T, NK and Treg cells in HAMMER study as supportive information for R2PD 
selection. 
VV-CLIN-0616194 4.0
46
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 47 
In the SAR444245 monotherapy dose levels (8 µg/kg, 16 µg/kg and 24 µg/kg and 32 µg/kg 
Q3W), the PDy data suggest that a trend for dose-dependent expansion of CD8+ T cells and NK 
cells has been achieved. In the 8 µg/kg dose levels, the average increase in peripheral blood CD8+ 
T cells over baseline at 72 hours post dose was 1.75-fold. For dose levels 16 µg/kg and 24 µg/kg, 
the peripheral blood CD8+ T cell expansion was 2.47 and 4.47-fold at the day 8 postdose peak of 
expansion. The day 8 sample timepoint was added after the first 3 participants in the 8 µg/kg 
cohort were dosed. 
In addition, the average increase in peripheral blood NK cells was 4.22-fold at 72 hours for 
8 µg/kg. The 16 µg/kg and 24 µg/kg dose levels resulted in 5.9 and 7.67-fold NK expansion, 
compared to baseline at the day 8 peak expansion. Among the dose levels tested to date for 
SAR444245 in combination with pembrolizumab administered using Q3W schedule, we have 
collected available PDy data for the 8 µg/kg (n=4) and 16 µg/kg cohort (n=6), in which the 
average increase in CD8+ T cells, compared to baseline, is 2.06-fold and 3.71-fold, respectively; 
and the average increase in NK cells, compared to baseline, is 6.73-fold and 13.43-fold, 
respectively at the peak expansion day 8. In addition, the comparison of T and NK cell expansion 
between 
 µg/kg and 
 µg/kg cohorts indicated that the anticipated maximum CD8+ T and NK 
cells expansion PDy effect may have been achieved at 
 µg/kg cohort. Based on these data, 
additional quantitative systems pharmacology (QSP) and population PK/PDy models were 
developed and indicated that the increase of CD8+ T and NK cells was less than proportional with 
increasing dose, suggesting a flattening of the dose-response curve. 
In addition, preclinical studies using human whole blood to assess the induction of cytokines 
showed no change in cytokine profiles when administering SAR444245 with and without 
pembrolizumab. This study used SAR444245 concentration ranges that went significantly higher 
than current clinical dosages (0.2-4.5 µg/mL) and showed that SAR444245-induced cytokine 
release in human whole blood was not affected in the presence of pembrolizumab at Q3W 
schedule. 
Considering below, Sponsor proposes to evaluate the clinical benefit of SAR444245 24 µg/kg in 
this Phase 2 study. 
1. SAR444245 monotherapy up to 32 µg/kg Q3W, pembrolizumab combination up to
32 µg/kg Q3W and cetuximab combination 24 µg/kg Q3W are all cleared in HAMMER
study.
2. Sustained relevant PDy effect in blood, higher at higher dose, was documented in
participants; and
3. Observed safety data from the Hammer study suggests the combination of SAR444245
combined with anti-PD1 (eg, pembrolizumab) may not lead to significant overlapping
toxicities.
4.4 
END OF STUDY DEFINITION 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the SoA for the last participant in the trial globally. 
VV-CLIN-0616194 4.0
47
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 48 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
The inclusion criteria listed in the master protocol are only those applicable to all the participants 
common to all substudies. For additional substudy specific criteria, refer to the particular 
substudy. 
 Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age (or country’s legal age of majority if >18 years), at 
the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Histologically or cytologically confirmed diagnosis of R/M HNSCC that is considered not 
amenable to further therapy with curative intent. The eligible primary tumor locations are 
oropharynx, oral cavity, hypopharynx, and larynx (nasopharynx is excluded). 
I 03. Measurable disease 
At least 1 measurable lesion (not biopsied at baseline) per RECIST 1.1 criteria. Target 
lesion(s) may be located in a previously irradiated field if there is documented radiographic 
disease progression of such lesion(s). 
I 04. Known HPV p16 status for oropharyngeal cancer. 
Weight (not applicable)  
I 05. Sex 
All (male and female)  
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a) Male participants
Male participants are eligible to participate if they agree to the following during the
intervention period and for at least 3 days [corresponding to time needed to eliminate
SAR444245] after the last dose of SAR444245:
-
Refrain from donating or cryopreserving sperm.
VV-CLIN-0616194 4.0
48
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
PLUS either: 
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR 
- 
Must agree to use contraception/barrier as detailed below 
- 
A male condom with female partner use of an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in Appendix 4 
(Section 10.4) of the protocol when having sexual intercourse with a woman of 
childbearing potential (WOCBP) who is not currently pregnant, or during homosexual 
intercourse 
b) Female participants 
- A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP) 
OR 
- 
Is a WOCBP and agrees to use a contraceptive method that is highly effective 
(with a failure rate of <1% per year), with low user dependency, as described in 
Appendix 4 (Section 10.4) during the intervention period (to be effective before 
starting the intervention) and for at least 120 days (for Cohorts A1, A2 and B1) or 
60 days (for Cohort B2) [corresponding to the time needed to eliminate any study 
intervention(s)] after the last dose of study intervention and agrees not to donate or 
cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this 
period. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (as required by 
local regulations) within 7 days before the first dose of study intervention.  
- 
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 4 (Section 10.4).  
- 
The Investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Appendix 1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
VV-CLIN-0616194 4.0
49
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 50 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. 
E 02. Predicted life expectancy ≤3 months. 
E 03.  Active brain metastases or leptomeningeal metastases.  
- 
Patients with previously treated brain metastases are eligible provided they are 
clinically stable for at least 4 weeks with no evidence of new or enlarging brain 
metastases and have not received corticosteroids at least 2 weeks prior to first IMP 
administration (Note: participants with brain involvement due to direct extension of 
invading tumor, rather than metastasis, may be allowed to enroll if they do not require 
greater than 10 mg prednisone daily, after discussion and approval from the Sponsor). 
- 
 Patients with asymptomatic brain metastases (ie, no neurological symptoms, no 
requirements for corticosteroids, and no lesion >1.5 cm) are eligible but will require 
regular imaging of the brain as a site of disease. 
E 04. History of allogenic tissue/solid organ transplant. 
E 05. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents and anti-cytotoxic 
T lymphocyte associated protein 4 monoclonal antibodies) that caused permanent 
discontinuation of the agent, or that were Grade 4 in severity. 
E 06. Last administration of prior antitumor therapy (chemotherapy, targeted agents, and 
immunotherapy) or any investigational treatment within 28 days or less than 5 times the 
half-life, whichever is shorter; major surgery or local intervention within 28 days prior to 
first IMP administration.  
E 07. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 2 weeks of IMP initiation. Inhaled or topical steroids are permitted, provided that 
they are not for treatment of an autoimmune disorder. Participants who require a brief 
course of steroids (eg, as prophylaxis for imaging studies due to hypersensitivity to 
contrast agents) are not excluded. 
E 08. Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP, or any 
serious systemic fungal, bacterial, viral (excluding viral infection settings as described in  
E 15), or other infection that is not controlled. 
E 09. Severe or unstable cardiac condition within 6 months prior to starting study treatment, such 
as congestive heart failure (New York Heart Association Class III or IV), cardiac bypass 
surgery or coronary artery stent placement, angioplasty, left ventricular ejection fraction 
(LVEF) below 50%, unstable angina, medically uncontrolled hypertension 
VV-CLIN-0616194 4.0
50
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 51 
(eg, ≥160 mmHg systolic or ≥100 mmHg diastolic), uncontrolled cardiac arrhythmia 
requiring medication (≥ Grade 2, according to NCI-CTCAE v5.0), or myocardial infarction. 
E 10. Ongoing AEs caused by any prior anticancer therapy ≥ Grade 2 (NCI-CTCAE 
Version 5.0). Participants with Grade 2 peripheral neuropathy, or Grade 2 alopecia, are 
permitted. Participants with endocrine-related AEs Grade ≤2 requiring treatment or 
hormone replacement may be eligible.  
Note: If the participant had major surgery, the participant must have recovered adequately 
from the procedure and/or any complications from the surgery prior to starting study 
intervention. 
E 11. Active, known, or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs), except controlled by replacement therapy (eg, thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc). The following are not exclusionary: vitiligo, childhood asthma that has 
resolved, psoriasis that does not require systemic treatment. 
E 12. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or 
has current (non-infectious) pneumonitis / interstitial lung disease.  
E 13. Participant who has received prior radiotherapy within 2 weeks of start of study 
intervention. Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
E 14. Receipt of a live or live-attenuated virus vaccine within 28 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted. 
E 15. Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi 
sarcoma and/or Multicentric Castleman Disease or known uncontrolled infection with 
HIV. HIV-infected participants must be on anti-retroviral therapy (ART) and have a well-
controlled HIV infection/disease defined as: 
-
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of
screening.
-
Participants on ART must have achieved and maintained virologic suppression defined
as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification
(below the limit of detection) using the locally available assay at the time of screening
and for at least 12 weeks prior to screening.
-
Participants on ART must have been on a stable regimen, without changes in drugs or
dose modification, for at least 4 weeks prior to study entry (Day 1).
-
Combination ART regimen must not contain any antiretroviral medications other than:
abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenoforvir.
HIV serology will be tested at screening for participants in Germany and Italy (see details 
and specific instructions in Section 10.2 and Section 10.8). 
VV-CLIN-0616194 4.0
51
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
E 16. Known uncontrolled hepatitis B infection, known untreated current hepatitis C infection, 
active tuberculosis, or severe infection requiring parenteral antibiotic treatment. 
- 
To control HBV infection, participants with positive HBsAg should have started 
anti-HBV therapy before initiation of IMP. Antiviral therapy for HBV must be given 
for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose 
of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL 
should stay on the same therapy throughout study treatment. 
- 
Participants who are positive for anti-hepatitis B core antibody HBc, negative for 
hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B 
surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not 
require HBV anti-viral prophylaxis. 
- 
Participants with past or ongoing hepatitis C virus (HCV) infection will be eligible for 
the study. The treated participants must have completed their treatment at least 
1 month prior to starting study intervention. Participants with positive HCV antibody 
and undetectable HCV RNA without anti-HCV therapy are eligible.  
Hepatitis B and C serology will be tested at screening for participants in Germany and 
Italy (see details and specific instructions in Section 10.2 and Section 10.8). 
E 17. Known second malignancy either progressing or requiring active treatment within the last 
3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded. 
E 18. Known severe hypersensitivity (≥ Grade 3) to or contraindication for the use of any study 
intervention or components thereof, including premedication to be administered in this study, 
as well as PEG or any pegylated drug and E. coli-derived protein. 
E 19. Participants with baseline oxygen saturation (SpO2) ≤92% (without oxygen therapy). 
Prior/concomitant therapy 
E 20. Has received prior IL2-based anti-cancer treatment. 
E 21. Is unable or unwilling to take premedication.  
E 22. Participants under anti-hypertensive treatment who cannot temporarily (for at least 
36 hours) withhold antihypertensive medications prior to each IMP dosing. 
Prior/concurrent clinical study experience 
E 23. Current enrollment or past participation in a study of an investigational treatment or has 
used an investigational device within 28 days prior to the first dose of study treatment.  
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 28 days after the last dose of the previous investigational 
treatment. 
VV-CLIN-0616194 4.0
52
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 53 
Diagnostic assessments 
Not applicable. 
Organ and bone marrow function 
E 24. Absolute neutrophil count <1500 /uL (1.5 × 109/L) (after at least one week off G-CSF). 
E 25. Platelets <100 × 10³ /µL (after at least 3 days without platelet transfusion). 
E 26. Hemoglobin <9 g/dL (without packed red blood cell [pRBC] transfusion within prior 
2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months). 
E 27. Total bilirubin >1.5 x upper limit of normal (ULN) unless direct bilirubin ≤ULN 
(participants with known Gilbert disease who have serum bilirubin level ≤3 × ULN may be 
enrolled) 
E 28. Aspartate aminotransferase and/or alanine aminotransferase >2.5 × ULN (or >5 × ULN for 
participants with liver metastases). 
E 29. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² (Modification of Diet in 
Renal Disease [MDRD] Formula, see Appendix 2). 
E 30. International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated Partial 
Thromboplastin Time (aPTT) >1.5 × ULN unless the participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants. 
Other exclusions 
E 31. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 32. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 (country-specific requirements). 
E 33. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 34. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the ICH-GCP Ordinance E6). 
E 35. Any specific situation during study implementation/course that may raise ethics considerations 
E 36. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject's participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating Investigator.  
 
VV-CLIN-0616194 4.0
53
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 54 
5.3 
LIFESTYLE CONSIDERATIONS 
5.3.1 Meals and dietary restrictions  
No food or drink restrictions are required. Guidelines on fluid intake are presented in Section 6.1.3. 
5.3.2 Caffeine, alcohol, and tobacco 
No restrictions are required. 
5.3.3 Activity 
Participants are advised to abstain from strenuous exercise and avoid long hot showers and saunas 
on Days 1 to 4 of every treatment cycle. 
5.3.4 Hydration 
Since SAR444245 may induce episodes of hypotension participants should be informed of the 
importance of being well hydrated and provided hydration instructions. Guidelines pertaining to 
fluid intake on the day of SAR444245 dosing and for the 3 days after administration are detailed 
in Section 6.1.3. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure reason may not be expected within a reasonable time 
frame, will be recorded as screen failures. In case the participant is a temporary screen failure 
(ie, prolonged screening), there is no need to have participant re-consent (ie, new ICF signed) if 
the participant finally participates in the trial. However, if the reason for temporary screen failure 
is a reason that might have altered the initial given agreement of the participant to participate, the 
Investigator should ensure the willingness of the participant to continue or redo some screening 
procedures and his/her participation to the trial. This oral agreement should be documented in the 
participant’s chart. All the tests out of protocol window should be repeated and entered to the 
additional pages.  
A participant who screen failed may be rescreened; in this situation, the rescreened participant 
should sign a new ICF. A participant may be rescreened only once. 
Rescreened participants should be assigned a different participant number as for the initial screening. 
VV-CLIN-0616194 4.0
54
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 55 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 10.11. 
VV-CLIN-0616194 4.0
55
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 56 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), intended 
to be administered to a study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Participants will receive study treatment until confirmed PD, unacceptable toxicity, other permanent 
discontinuation criteria as described in Section 6, or completion of Cycle 35 when applicable. 
If a participant has immune unconfirmed progression of disease (iUPD) and is clinically stable, it 
is at the discretion of the Investigator to continue treating the subject with the assigned treatment 
per protocol until progression of disease is confirmed (iCPD) at least 4 weeks, but no longer than 
8 weeks from the date of the scan suggesting progression of disease (Section 10.10).  
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in  
Section 10.11. 
6.1.1 Investigational medicinal products  
Details of SAR444245 are shown in Table 4.  
Preparation and administration of investigational medicinal product (IMP) are detailed in the 
pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3. 
Table 4 - Overview of IMP administered  
Intervention name 
SAR444245 
Type 
Biologic 
Dose formulation 
Concentrate for solution for infusion 
Unit dose strength(s) 
2.0 mg/mL 
Dosage level(s)a 
24 μg/kg  
Route of administration 
IV infusion 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and labeling 
Supplied in a single-dose vial in a treatment box. Each vial contains 
2 mg/mL with an extractable volume of 1 mL. Each vial and 
treatment box will be labeled as required per country requirement. 
Current/Former name(s) or alias(es) 
NA 
VV-CLIN-0616194 4.0
56
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 57 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the electronic 
case report form (e-CRF). Study sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted. 
6.1.2 Noninvestigational medicinal products 
6.1.2.1 Premedication for SAR444245 
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, 30 to 60 minutes prior to SAR444245 
infusion (no longer than 60 minutes) for the first 4 cycles: 
•
Acetaminophen (paracetamol) 650 to 1000 mg (IV or PO) (or equivalent), and then
optionally thereafter, as needed.
•
Diphenhydramine 25 to 50 mg IV or PO (or equivalent eg, cetirizine, promethazine,
dexchlorpheniramine, according to local approval and availability), and then optionally
thereafter, as needed.
SAR444245 premedication may be optional after 4 cycles 
•
For a participant who has no IRR during the first 4 cycles: Premedication for the
subsequent infusions is optional at the Investigator’s discretion. However, if during the
subsequent infusions without premedication the participant experiences an IRR (any
grade), premedication must be restarted for all subsequent infusions.
•
If a participant develops an IRR Grade <2 during their first cycle only and then
experiences no further IRRs during their next 3 cycles: The Investigator may consider
omitting premedication for the next cycle. If no IRR is observed during the next cycle
without premedication, premedication is optional for the subsequent cycles at the
Investigator’s discretion. However, if during the next cycle without premedication the
participant experiences an IRR (any grade), premedication must be restarted for all
subsequent cycles.
6.1.3 Hydration guidelines for SAR444245 administration 
VV-CLIN-0616194 4.0
57
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 58 
6.1.4 Readiness for treatment of severe cytokine release syndrome 
Doses of tocilizumab or alternative therapies per site practice in CRS management should be 
available at site at all times in the event that a participant requires rapid intervention for the 
treatment of severe CRS. Please refer to Section 6.5 of individual substudies protocols for detailed 
guidelines for the management of CRS. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
1. The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received and any discrepancies are
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorized
site staff may supply or administer study intervention. All study intervention must be
stored in a secure, environmentally controlled, and monitored (manual or automated) area
in accordance with the labeled storage conditions with access limited to the Investigator
and authorized site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is
responsible for study intervention accountability, reconciliation, and record maintenance
(ie, receipt, reconciliation, and final disposition records).
VV-CLIN-0616194 4.0
58
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
Treatment preparation and administration (including compatible materials) will be further detailed 
in the pharmacy manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Participants must be dosed at the site and will receive IMP directly from the Investigator or 
designee, under medical supervision. The person responsible for drug dispensing is required to 
maintain adequate records of the IMP administration. These records include the date the IMP 
components are received from the Sponsor, dispensed to the participant and destroyed or returned to 
the Sponsor. The packaging batch number and the treatment number on the vial must be recorded on 
the drug accountability form. The date and time of each dose administered in the clinic will be 
recorded in the source documents and recorded in the electronic case report form (e-CRF). 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.  
6.5 
DOSE MODIFICATION  
Please see respective substudies protocols.  
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There will be no intervention beyond the end of the study. 
6.7 
TREATMENT OF OVERDOSE  
There is no specific antidote for overdose with SAR444245.  
If overdose occurs (see Section 8.3.8  for definitions), symptomatic management is indicated.  
Treatment of overdose should consist of general supportive care with aggressive fluid management, 
if clinically indicated. 
VV-CLIN-0616194 4.0
59
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 60 
Procedures for treating symptoms and complications of immune-related adverse events are 
provided in Section 6.5 of individual substudies protocols. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 90 days). 
3. Obtain a plasma sample for PK analysis right after the overdose event is identified (only if 
an overdose is identified within 5 days from start of overdose infusion). 
4. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant. 
6.8 
CONCOMITANT THERAPY  
Any medication (including over-the-counter [OTC] or prescription medicines, vitamins, and/or 
herbal supplements) or vaccine that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior therapy. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from study intervention may be required. The 
Investigator is to discuss prohibited medication/vaccination with the Sponsor. The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the participant's 
primary physician. However, the decision to continue the participant on trial therapy schedule 
requires the mutual agreement of the Investigator, the Sponsor and the participant. 
6.8.1 Acceptable concomitant medications  
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the e-CRF including all 
prescription, OTC, herbal supplements, and IV medications and fluids. If changes occur during 
the trial period, documentation of route, and date will also be included on the e-CRF. 
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms. Surgery or radiotherapy for tumor control is not 
permitted during the study; however, radiotherapy or procedures for symptom management is 
allowed after discussion with and approval by the Sponsor. 
VV-CLIN-0616194 4.0
60
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 61 
All concomitant medications received within 28 days before the first dose of trial treatment 
through the Follow-up Visit should be recorded. 
Colony-Stimulating Factors 
Routine use of colony-stimulating factors (CSFs) is not permitted. American Society of Clinical 
Oncology guidelines for use of CSFs should be followed (28). 
6.8.2 Prohibited concomitant medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol.
•
Immunotherapy not specified in this protocol.
•
Investigational agents other than specified in this protocol.
•
Radiotherapy for tumor control (please refer to Section 6.8.1 for allowed radiotherapy).
•
Live or live-attenuated virus vaccines within 28 days prior to the first dose of trial
treatment and while participating in the trial. Examples of live-virus vaccines include, but
are not limited to, the following: measles, mumps, rubella, chickenpox, yellow fever,
seasonal flu (seasonal flu vaccines that do not contain live virus are permitted), nasal
H1N1 flu, rabies, Bacillus Calmette-Guérin (BCG), and typhoid.
•
Systemic glucocorticoids and other immunosuppressive therapies such as anti-TNF,
anti-IL6, etc, except for:
-
Treatment of immune-mediated AEs when indicated (IRR, CRS, irAE, and ICANS,
see individual substudies protocols in Section 6.5),
-
Treatment of any life-threatening emergency,
-
Physiologic replacement as long as they are not being administered for
immunosuppressive intent, and
-
A brief course (≤7 days) of systemic corticosteroid for prophylaxis (eg, contrast dye
allergy) or for the treatment of non-autoimmune conditions (eg, delayed-type
hypersensitivity reactions caused by contact allergen).
Participants who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Participants 
may receive other medications that the Investigator deems to be medically necessary. 
The exclusion criteria describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Observation and Survival Follow-up Periods. 
For withholding antihypertensive medications as part of hydration guidelines, please refer 
to Section 6.1.3. 
VV-CLIN-0616194 4.0
61
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 62 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
7.1.1 Permanent discontinuation  
Study intervention should be permanently discontinued in any of the following cases: 
•
At the participant’s request, at any time and irrespective of the reason (consent’s
withdrawal), or at the request of their legally authorized representative (if allowed by local
regulations). “Legally authorized representative” is considered to be an individual or
judicial or other body authorized under applicable law to consent on behalf of a
prospective participant to the patient’s participation in the procedure(s) involved in the
research.
•
If, in the Investigator’s opinion, continuation of the study treatment would be detrimental
to the participant’s wellbeing, such as:
-
Unacceptable AE.
-
Documented disease progression
-
Poor compliance to the study protocol.
-
Completion of 35 cycles when applicable
-
Other, such as concurrent illness, that prevents further administration of study
intervention, or that in the Investigator’s opinion, in the best interest of the participant
•
In case of pregnancy occurrence.
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for serial tumor assessment if permanent discontinuation is not due to PD, for safety 
assessment as per SoA (Section 1.3) and until resolution or stabilization of AE, and any other 
assessment as per SoA. Data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed are reported in the SoA. 
7.1.1.1 Unacceptable adverse events leading to permanent intervention discontinuation 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the dose modification and 
toxicity management guidelines (see individual substudies protocols) or if the Investigator 
believes that it is in best interest of the participant.  
If a clinically significant finding is identified after enrollment, the Investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the electrocardiogram (ECG) printed at the time 
of collection must be documented. Any new clinically relevant finding should be reported as an 
AE. 
VV-CLIN-0616194 4.0
62
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 63 
Any potentially clinically significant abnormal laboratory value or ECG parameter will be 
immediately rechecked for confirmation and repeated after 24 hours to document evolution before 
making a decision of permanent intervention discontinuation for the concerned participant. 
Decision criteria for discontinuation following immune-mediated AEs are described in Section 6.5 
of individual substudies protocols (Guidelines for the management of IRR, CRS, ICANS, VLS). 
If participants are clinically stable, and possibly deriving clinical benefit from therapy with 
minimal toxicity, they will be maintained on treatment.  
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed.  
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent intervention discontinuation, the participants will be assessed 
using the procedure normally planned for the last dosing day with the IMP including a 
pharmacokinetics sample, if appropriate. Tumor assessment should be repeated if not done at the 
last cycle. A biopsy (optional - special consent) may be performed if treatment is discontinued for 
disease progression following an initial response. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 10.11). For all temporary intervention discontinuations, 
duration should be recorded by the Investigator in the appropriate pages of the e-CRF.  
7.1.3 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
and if the selection criteria for the study are still met. 
Recommendations for rechallenge in the context of an epidemic/pandemic (eg, COVID-19), are 
included in the Contingency Measures for a regional or national emergency that is declared by a 
governmental agency (Section 10.11). 
VV-CLIN-0616194 4.0
63
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 64 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, see SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time.  
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-included in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
 A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
VV-CLIN-0616194 4.0
64
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 65 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
•
The site must attempt to contact the participant and reschedule the missed visit as soon as
possible and counsel the participant on the importance of maintaining the assigned visit
schedule and ascertain whether or not the participant wishes to and/or should continue in
the study.
•
Before a participant is deemed lost to follow-up, the Investigator or designee must make
every effort to regain contact with the participant (where possible, 3 telephone calls and, if
necessary, a certified letter to the participant’s last known mailing address or local
equivalent methods). These contact attempts should be documented in the participant’s
medical record.
•
Should the participant continue to be unreachable, he/she will be considered to have
withdrawn from the study.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
VV-CLIN-0616194 4.0
65
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 66 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures are summarized in this section and their timing is presented in the SoA. 
Protocol waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must 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 and to confirm eligibility or record reasons for 
screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• During the screening period, demography, medical/surgical, and disease history will be 
evaluated. Demography includes age, gender, race, and ethnicity. Medical/surgical history 
includes relevant history of previous pathologies and smoking status. Disease history includes 
stage at diagnosis and at study entry, and previous anti-tumor therapy (type, duration, reason 
for discontinuation and response to the therapy). In addition, results of driver gene mutation 
(such as BRAFV600E for participants with melanoma) are also to be collected. 
• A comprehensive medical history will be assessed for any cardiovascular signs or symptoms 
prior to treatment, along with a baseline ECG, echocardiogram and troponin level. 
• Regular blood samples will be collected from each participant throughout the duration of 
the study. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. Details on blood sampling, including the estimated volume 
collected for each analysis are provided in the laboratory manual. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Section 10.11. 
8.1 
EFFICACY ASSESSMENTS   
The assessment of anti-tumor activity documented by objective response to the IMP is the primary 
endpoint for this study and is conducted as per schedule provided in the SoA. All participants 
treated must have at least one measurable lesion for inclusion.  
Decision to pursue treatment will be based on the response evaluation made by the Investigator, 
however, measures of lesions will be collected in the e-CRF for a determination of response by 
the Sponsor. A partial or complete response must be confirmed on a second examination done at 
least 4 weeks apart, in order to be documented as a confirmed response to therapy. Confirmation 
of PD
may be done at the discretion of the Investigator when clinically indicated.  
Investigators will obtain copies of the images and will provide them to Sponsor or other 
repository facility identified by the Sponsor for potential central review. Study sites must retain 
VV-CLIN-0616194 4.0
66
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 67 
tumor assessment images, as Sponsor may decide to collect these images for possible Independent 
Central Review in the future. 
Assessment of tumor response will be conducted using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 (see Section 10.9 according to the nature of the measurable lesions, as 
described below). 
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s)  
For participants with disease that is measured radiologically according to RECIST 1.1 criteria 
(Section 10.9) a CT or magnetic resonance imaging (MRI) for tumor assessment will be 
performed as detailed in Section 1.3. The choice of whether the imaging is by CT (preferred) or 
MRI is an Investigator decision. Once the choice of CT scan or MRI has been made, the same 
imaging technique should be used in a participant throughout the trial. 
Baseline imaging should include all known target lesions. Baseline scans must evaluate extent of 
disease, including imaging of head, chest, abdomen (pelvis is optional) and any other locations 
with suspicion or evidence of disease involvement. This may be accomplished with CT chest, 
abdomen, and pelvis with contrast, or CT chest with contrast and MRI abdomen/pelvis with 
gadolinium.  
The initial CT/MRI tumor imaging will be performed within 28 days prior to C1D1. Scans 
performed as part of routine clinical management are acceptable for use as the screening scan if 
they are of diagnostic quality and performed within 28 days prior to the date of enrollment. 
On-study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP and if 
clinically indicated. Imaging studies should follow calendar days and should not be adjusted for 
delays in cycle starts or extension. After Week 45 tumor imaging should be performed every 
12 weeks (84 ±7 days). Per the primary tumor assessment criteria, after the first documentation of 
response or the first documentation of progression (if the participant is clinically stable), 
confirmatory imaging may be performed no fewer than 28 days later. Alternately, the scan 
performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. 
Tumor assessment is not needed for participants who start another anticancer therapy. 
At a minimum, all radiologically measurable target lesions (RECIST 1.1) should be imaged at 
each response assessment. The same radiologic imaging modality should be used at each response 
assessment. 
For participants with no previous history of brain metastases, screening brain imaging will need to 
be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Two additional imaging, obtained at least 4 weeks apart, should be 
obtained to document disease stability AFTER local treatment administration to the brain 
metastases has been completed. If participants receive therapy during these 4 weeks stabilization 
at the treating physician's discretion, it will be considered as prior anticancer therapy. Participants 
with previously treated brain metastases may participate provided they are stable, which is defined 
as lack of progression on two sets of imaging obtained at least 4 weeks apart. Stability as defined 
above should be documented prior to the first dose of trial treatment. In addition, any neurologic 
VV-CLIN-0616194 4.0
67
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 68 
symptoms must have returned to baseline or resolved, and the participant is not using steroids for 
at least 14 days prior to study treatment. The screening brain imaging may be collected up to 
42 days prior to enrollment. 
RECIST 1.1 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention).  
8.2 
SAFETY ASSESSMENTS 
The main anticipated adverse effect for the combination of SAR444245 with other anticancer 
therapies includes manifestations of cytokine release that can range from fever to hypoxia to 
hypotension, with or without manifestations that may include any of the organ systems. These 
mild events occur between around 12 to 18 hours after the first administration and a more 
intensive monitoring of vital signs is planned during that period. Targeted physical exams and 
standard laboratory tests will be conducted to monitor potential changes in the main body 
functions. Measurement of cytokines in plasma are planned at relevant timepoints. White blood 
cell differential count will be measured to monitor for transient lymphopenia which is commonly 
observed in the first few days following SAR444245 infusion. Eosinophilia that is surrogate to 
VLS will also be monitored. IL-5, which is also a marker of VLS, will be included in the PDy 
cytokine panel. Combining SAR444245 with other anticancer therapies may increase the 
frequency and severity of immune-related adverse events related to other anticancer therapies. 
Immune-mediated endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, 
and cortisol level will be monitored.  When clinically indicated, on-treatment ECG, LVEF and 
troponin will be assessed and compared to baseline. More details on the safety assessment are 
provided below. Planned time points for all safety assessments are provided in the SoA.  
8.2.1 Physical examinations 
•
A full physical examination will include, at a minimum, assessments of the cardiovascular,
respiratory, gastrointestinal, neurological and skin systems. Height and weight will also be
measured and recorded.
VV-CLIN-0616194 4.0
68
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 69 
•
A directed physical examination will include, at a minimum, assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).
•
Investigators should pay special attention to clinical signs related to previous serious
illnesses. Investigators should also pay attention to clinical signs suggestive of VLS, such
as peripheral edema, pericardial effusion and pleural effusion, as well as clinical signs
suggestive of immune-related adverse events, such as pneumonitis, colitis,
endocrinopathies, to name a few. Complementary assessments should be performed to
establish the diagnosis when clinically indicated. Early signs of CRS should also prompt a
thorough clinical assessment to identify the involvement of a specific organ system,
including neurological system.
8.2.2 Vital signs 
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest
for the participant in a quiet setting without distractions (eg, television, cell phones).
•
Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be
measured after 5 minutes rest.
•
At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;
-
Vital signs will be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5) hours
after start of SAR444245 dose.
-
At Investigator’s discretion, participants (not in the safety run-in) may have intensive vital
sign monitoring (to be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5),
8 (±0.5), 12 (±1), 16 (±1), 20 (±1), 24 (±1) hours after start of SAR444245 dose in an
in-patient setting).
•
For the core phase participants: from Cycle 2 to Cycle 4, study therapy will be
administered for all patients in out-patient clinic with vital signs taken prior to dosing, at
least 4 to 6 hours after the start of SAR444245 dosing, or for longer periods of time if
clinically indicated.
•
From Cycle 5 and beyond, vital signs will be collected prior to IMP administration.
8.2.3 Electrocardiograms and left ventricular ejection fraction (LVEF) 
•
Includes single 12-lead ECG, LVEF and troponin that will be performed at screening and
troponin at Cycle 4 Day 1, then, as clinically indicated.
•
At Cycle 1 Day 1, at pre-dose and at end of SAR444245 infusion, ECG will be obtained
using an ECG machine that automatically calculates the heart rate and measures PR, QRS,
QT, and QTcF intervals.
•
LVEF evaluation will be done by echocardiography or multigated acquisition (MUGA),
and any repeated assessment should be done with the same technology used at screening.
•
Additional evaluations such as ECG, LVEF, Holter monitoring, cardiac enzymes (such as
troponin) and consultation with a cardiologist should be done when clinically indicated.
VV-CLIN-0616194 4.0
69
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 70 
•
During treatment, or post treatment follow-up: Troponin will be performed at Cycle 4
Day 1. In case of a suspicion of a drug related cardiac event (eg, including signs/symptoms
of cardiac disease, ECG and/or echo changes, troponin elevation, etc.), Investigators are
encouraged to do ECG, echocardiography and/or cardiac biomarker tests, as medically
indicated, including cardiology consultation.
8.2.4 Clinical safety laboratory assessments 
•
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and
the SoA (Section 1.3) for the timing and frequency.
•
The clinical safety laboratory assessments will be done in the local laboratory.
•
The Investigator must review the laboratory report, document this review, and record any
clinically relevant changes occurring during the study. The laboratory reports must be filed
with the source documents. Abnormal laboratory findings associated with the underlying
disease are not considered clinically significant, unless judged by the Investigator to be
more severe than expected for the participant’s condition.
•
All laboratory tests with values considered clinically significantly abnormal during
participation in the study or within Follow-Up Visit 1 should be repeated until the values
return to normal or baseline or are no longer considered clinically significant by the
Investigator or Sponsor.
-
If such values do not return to normal/baseline within a period of time judged
reasonable by the Investigator, the etiology should be identified, and the Sponsor
notified.
-
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2) must be
conducted in accordance with the laboratory manual and the SoA.
-
If laboratory values from non-protocol specified laboratory tests performed at the
institution’s local laboratory require a change in participant management or are
considered clinically significant by the Investigator (eg, SAE or AE or dose
modification), then the results must be recorded.
8.2.5 Pregnancy testing 
•
Refer to Section 5.1 Inclusion criteria I 05 for pregnancy testing criteria; the Investigator is
responsible for review of medical history, menstrual history, and recent sexual activity to
decrease the risk for inclusion of a woman with an early undetected pregnancy
•
Women of childbearing potential must have a negative urine pregnancy test result within
72 hours prior to first IMP administration of each cycle, at EOT and every 30 (±7) days
until 60 days (for Cohort B2) or 120 days (for Cohorts A1, A2 and B1) after the last dose
of study treatment. If urine pregnancy results cannot be confirmed as negative, a serum
pregnancy test will be required. Pregnancy tests (serum and/or urine tests) should be
repeated if required by local guidelines.
VV-CLIN-0616194 4.0
70
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 71 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.8. AEs will be 
reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s 
legally authorized representative if allowed by local regulations).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs, including adverse events of new onset, as well as worsening of baseline signs and 
symptoms will be collected throughout study period, from the signing of the informed consent 
form (ICF) until 30 days following cessation of study treatment.  
All SAEs and AESIs will be collected throughout the study period, from the signing of the 
informed consent form (ICF) until 90 days following last administration of study treatment.  
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the 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 must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
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.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and AESIs 
(as defined in Section 8.3.8), 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). Stabilization is 
VV-CLIN-0616194 4.0
71
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 72 
defined as an AE ongoing without any change for at least 3 months. Participants with an AE of 
Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or starting of a new 
antineoplastic therapy, whichever occurs first. 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events (SAEs) that are considered expected will be specified in the 
reference safety information (IB for SAR444245). 
- 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, should be expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 60 days (for Cohort B2) or 
120 days (for Cohorts A1, A2 and B1) following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates another anticancer 
therapy.  
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
VV-CLIN-0616194 4.0
72
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 73 
•
Any post-study pregnancy-related SAE considered reasonably related to the study
intervention by the Investigator will be reported to the Sponsor as described in
Section 8.3.4. While the Investigator is not obligated to actively seek this information in
former study participants/pregnant female partner, 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.
8.3.6 Cardiovascular and death events 
Cardiovascular events that meet AESI criteria should be reported as such (see Section 8.3.8 for 
details). 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Adverse event of special interest 
An adverse event of special interest is an AE (serious or nonserious) of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
The following events need to be reported as AESIs: 
•
Pregnancy of a female participant entered in a study as well as pregnancy occurring in a
female partner of a male participant entered in a study with IMP/NIMP;
-
Pregnancy occurring in a female participant entered in the clinical trial or in a female
partner of a male participant entered in the clinical trial. It will be qualified as an SAE
only if it fulfills one of the seriousness criteria (see Section 10.3).
-
In the event of pregnancy in a female participant, IMP should be discontinued.
•
Follow-up of the pregnancy in a female participant or in a female partner of a male
participant is mandatory until the outcome has been determined (See Section 10.4).
Symptomatic overdose (serious or nonserious) with IMP/NIMP
-
An overdose of IMP is defined as: increase of at least 30% of the dose to be
administered in the specified duration or if the dose is administered in less than half
the recommended duration of administration.
-
An overdose (accidental or intentional) with the NIMP is an event suspected by the
Investigator or spontaneously notified by the participant (not based on systematic pills
count) and defined as at least twice the intended dose within the intended therapeutic
interval, adjusted according to the tested drug.
VV-CLIN-0616194 4.0
73
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 74 
• An elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) lab 
value that is greater than or equal to 3 times the ULN and an elevated total bilirubin lab 
value that is greater than or equal to 2 times the ULN and, at the same time, an alkaline 
phosphatase lab value that is less than 2 times the ULN, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing*. 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be made available. It may also be appropriate to conduct 
additional evaluation for an underlying etiology in the setting of abnormalities of liver 
blood tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the 
criteria noted above. In these cases, the decision to proceed with additional evaluation will 
be made through consultation between the study investigators and the Sponsor. 
• Other project-specific AESIs 
- 
IRR Grade ≥2  
- 
CRS Grade ≥2 
- 
ICANS of any grade 
- 
VLS of any grade 
- 
SARS-CoV-2 infection/COVID-19 disease 
- 
Any immune-related AE Grade ≥3 
- 
Arrhythmia Grade ≥3 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS  
The sampling time-points for PK and ADA for/against SAR444245 and/or other IMPs may be 
updated during the course of the study based on the updated knowledge of drug behavior upon 
notification from the Sponsor. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in the laboratory manual. The actual date and time (24-hour clock time) of each sample will be 
recorded while for samples to be collected at time of biomarker sampling, no specific time on the 
given day is necessary.  
VV-CLIN-0616194 4.0
74
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 75 
Instructions on the collection, processing, storage, and shipment of samples will be provided in the 
laboratory manual. Sample analysis will be performed at a laboratory designated by the Sponsor. 
Samples collected for analyses of SAR444245 concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS  
8.6 
BIOMARKERS  
 
VV-CLIN-0616194 4.0
75
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 76 
8.7 
IMMUNOGENICITY ASSESSMENTS 
The sampling time points for ADAs may be reduced or increased during the course of the study 
based on the updated knowledge of drug behavior and its immunogenicity, upon notification from 
the Sponsor. 
Samples for the immunogenicity assessment of SAR444245 will be collected according to the PK 
flowcharts. Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. Sample analysis will be performed at a laboratory designated by the Sponsor. 
Samples will be screened and then confirmed for anti-drug antibodies and the titer of confirmed 
positive samples will be reported. Additional analyses may be performed to further characterize 
the immunogenicity of SAR444245. 
Anti-drug antibody (ADA) samples remaining after determination of immunogenicity may be 
kept for possible exploratory analysis of biomarkers. The exploratory data will not be included in 
the study report but will be kept on file. 
8.8 
HEALTH ECONOMICS  
No health economics data will be collected. 
VV-CLIN-0616194 4.0
76
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 77 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
VV-CLIN-0616194 4.0
77
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 78 
9 
STATISTICAL CONSIDERATIONS  
Please refer to substudies protocols for additional statistical considerations. 
9.1 
 STATISTICAL HYPOTHESES  
All cohorts of the study are designed to obtain antitumor activity, safety, PK, and PDy data on 
SAR444245 administered in combination with other anticancer therapies.  
The study is designed to assess the clinical benefit of SAR444245 with other anticancer therapies 
in participants with HNSCC. As this study is not intended to explicitly test a hypothesis, 
calculations of power and Type I error were not considered in the study design. No formal testing 
procedure is planned. 
9.2 
SAMPLE SIZE DETERMINATION  
Overall, in the core phase, the plan is to treat approximately 40 participants per cohort.  
Core Phase 
Table 5 lists estimated ORR and the corresponding 90% exact CIs by number of responders in 
each cohort.  
Table 5 - Estimated objective response rate (ORR) and 90% CI for core phase  
Number of responders 
(N=40) 
ORR 
90% CI for ORR 
(Clopper-Pearson) 
6 
15.0% 
(6.7%, 27.5%) 
7 
17.5% 
(8.5%, 30.4%) 
8 
20.0% 
(10.4%, 33.2%) 
9 
22.5% 
(12.3%, 36.0%) 
10 
25.0% 
(14.2%, 38.7%) 
11 
27.5% 
(16.3%, 41.4%) 
13 
32.5% 
(20.4%, 46.6%) 
15 
37.5% 
(24.7%, 51.7%) 
17 
42.5% 
(29.2%, 56.7%) 
19 
47.5% 
(33.8%, 61.5%) 
24 
60.0% 
(45.8%, 73.1%) 
With a sample size of 40 study participants in each cohort in the core phase, the probability of 
observing 1 or more instances of a specific AE with a true incidence rate of 1%, 2%, or 5% is 
33.1%, 55.4%, or 87.1%, respectively. This provides reasonable assurance that events occurring 
at ≥5% frequency can be identified in this study. 
 
VV-CLIN-0616194 4.0
78
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 79 
9.3 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined: 
Table 6 - Populations for analyses 
Population 
Description 
Exposed 
Exposed population will include all participants who have given their informed consent and received 
at least one dose (even incomplete) of IMP (SAR444245 or other anticancer therapies).
Efficacy 
Efficacy population will include all participants from the exposed population with at least one 
evaluable post-baseline tumor assessment or who permanently discontinued study treatment. 
PK 
The PK population will include all participants from the exposed population with at least 1 PK 
concentration available after the first dose of study intervention. 
PDy 
The PDy population will include all participants from the exposed population with at least 1 PDy 
parameter assessed after the first dose of study intervention. 
9.4 
STATISTICAL ANALYSES 
The statistical analysis plan (SAP) will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary, key secondary endpoints and 
exploratory endpoints. 
9.4.1 General considerations 
This study is not intended to explicitly test a hypothesis, and 90% CI will be provided for primary 
and secondary efficacy endpoints for descriptive purpose only. 
All efficacy analyses will be performed on the efficacy population and analyzed by cohort. Some 
cross-cohort summaries will be presented too. Results will be presented by core phase and overall 
phase (combining core phase and expansion phase, if expansion phase applies). Objective 
response rate, as well as PFS, DOR, and CBR will be derived using the local 
radiologist’s/Investigator’s assessment for all cohorts. Central imaging may be done 
retrospectively if significant activity is observed. The assessments for all cohorts will use 
RECIST 1.1. 
All safety analyses will be performed on the exposed population by cohort, by dose 
(if applicable), and overall (if applicable). Baseline value will be defined as the latest value or 
measurement taken up to the first administration of the IMP.  
The analysis period will be divided into 3 segments: 
•
The pre-treatment period is defined as the time from when the participants give informed
consent to the first administration of the IMP.
•
The on-treatment period (ie, treatment-emergent period) is defined as the time from the
first administration of IMP up to 30 days after the last administration of IMP.
VV-CLIN-0616194 4.0
79
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 80 
• The post-treatment period is defined as the time from the 31 days after the last 
administration of IMP. 
9.4.2 Primary endpoint(s)  
The BOR is the best overall response observed from the date of first IMP until disease 
progression, death, cut-off date or initiation of post-treatment anti-cancer therapy, whichever 
occurs first. The BOR will be summarized with descriptive statistics. The ORR is the primary 
endpoint defined as the percentage of participants from the analysis population with BOR is either 
CR or PR, assessed per Investigator. The ORR and the corresponding 90% confidence intervals 
calculated from Clopper-Pearson exact method will be also presented. All objective responses 
need to be confirmed by a subsequent assessment performed at least 4 weeks apart from the initial 
response observation.   
9.4.3 Secondary endpoint(s)  
The secondary endpoints include efficacy (TTR, DOR, CBR, PFS), safety, immunogenicity, and 
PK. 
9.4.3.1 Time to response  
Time to response will be defined as the time from the first administration of IMP to the first tumor 
assessment at which the overall response was recorded as PR or CR that is subsequently 
confirmed.  
Time to response will be descriptively summarized on the subgroup of participants who have 
achieved confirmed objective response in the efficacy population. 
9.4.3.2 Duration of response  
The DoR will only be summarized on the subgroup of participants who have achieved confirmed 
objective response in the efficacy population.  
The DoR will be defined as the time from the date of first tumor assessment at which the overall 
response was recorded as PR or CR that is subsequently confirmed to the date of first 
documentation of objective PD before the initiation of any post-treatment anti-cancer therapy or 
death due to any cause, whichever occurs first.  
Duration of response will be summarized with descriptive statistics using Kaplan-Meier methods. 
The median DoR and associated 90% CI will be provided. 
9.4.3.3 Clinical benefit rate  
The CBR will be defined as the proportion of participants with clinical benefit (confirmed CR or 
PR as BOR, or stable disease (SD) lasting at least 6 months). Specifically, participants will be 
considered as clinical benefit responders if they achieve a CR or PR as BOR, or have an overall 
VV-CLIN-0616194 4.0
80
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 81 
response recorded as SD at 6 months (ie, 26 weeks or later from first IMP intake, allowing for the 
±7 days visit window for tumor assessment scheduled at 27 weeks).  
9.4.3.4 
 Progression-free survival   
Progression-free survival is defined as the time from the date of first IMP to the date of the first 
documentation of objective progressive disease when relevant or death due to any cause, 
whichever occurs first.  
The analysis of PFS will be based on the following censoring rules: 
• If progression or death is not observed before the cohort cut-off date and prior to the 
initiation of a further anticancer therapy, then PFS will be censored at the date of the last 
valid tumor assessment performed before the cohort cut-off date or date of initiation of a 
further anticancer therapy, whichever is earlier. 
• A participant without event (death or disease progression) and without any valid 
post‑baseline tumor assessment will be censored at the day of first IMP (Day 1). 
Progression-free survival will be summarized on the efficacy population using Kaplan-Meier 
methods. The median PFS times and associated 90% CI will be provided. 
9.4.3.5 Adverse events  
All AEs will be categorized according to NCI-CTCAE v 5.0 and classified by SOC and Preferred 
Term (PT) according to the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Immune Cell-Associated Neurotoxicity Syndrome and CRS events will be 
graded using ASTCT Consensus Grading and will be summarized separately. 
• Pre-treatment AEs are defined as any AEs occurring during the pre-treatment period. 
• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the 
Investigator’s opinion), or become serious during the on-treatment period.  
• Post-treatment AEs are defined as AEs that are reported during the post-treatment period.  
For participants with multiple occurrences of the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
Treatment-emergent adverse events: 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• TEAEs. 
• TEAEs of Grade ≥3 
• Grade 5 TEAE (any TEAE with a fatal outcome during the on-treatment period) 
VV-CLIN-0616194 4.0
81
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 82 
•
Serious TEAEs
•
Serious treatment-related TEAEs
•
TEAE leading to partial intervention discontinuation
•
TEAE leading to full intervention discontinuation
•
Treatment-related TEAEs
•
Treatment-related TEAEs of Grade ≥3
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v 5.0 grade (all grades and Grade ≥3). Missing grades, if any, will 
be included in the “all grades” category. Similar summaries will be prepared for treatment-related 
TEAEs, TEAEs leading to partial intervention discontinuation, TEAEs leading to full intervention 
discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, 
AESIs, and AEs/SAEs occurring during the post-treatment period. In addition, the number (%) of 
participants with any Grade 5 AE (TEAE and post-treatment) will be summarized.  
The following deaths summaries will be generated: 
•
Number and percentage of participants who died by study period (treatment-emergent period,
post-treatment period) and reasons for death (disease progression, AE, or other reason).
•
All TEAEs leading to death by primary SOC and PT showing number and percentage (%)
of participants.
9.4.3.6 
  Clinical laboratory evaluations 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
When relevant, for laboratory variables, descriptive statistics for results and changes from 
baseline will be provided for the last value and the worst value (minimum and/or maximum value 
depending on the parameter) during the on-treatment period.  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v 5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (all grades 
and by grade) using the worst grade during the treatment period will be provided. 
When the NCI-CTCAE v 5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
For laboratory variables graded by NCI-CTCAE: 
•
The number (%) of participants with abnormal laboratory tests at baseline will be
presented by grade.
•
The number (%) of participants with abnormal laboratory tests during the treatment-emergent
period will be summarized by grade.  When appropriate, the number (%) of participants with
abnormality of any grade and with Grade 3-4 abnormalities will be provided.
VV-CLIN-0616194 4.0
82
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 83 
9.4.3.7 
  Other secondary endpoints 
Immunogenicity analyses will be described in the SAP finalized before database lock. The PK 
analysis and pharmacodynamic analyses will be presented separately from the main clinical study 
report (CSR).  
Plasma concentrations of SAR444245 will be summarized with descriptive statistics by each cohort. 
9.4.4 Tertiary/exploratory endpoint(s) 
9.4.4.1 Exploratory antitumor indicators 
9.4.4.2 Biomarker endpoints 
9.4.5 Other safety analyse(s) 
All safety analyses will be made on the exposed population. When relevant, the summary 
statistics (including mean, median, standard error, minimum and maximum) of all vital signs (raw 
data and changes from baseline) will be calculated for baseline, last on treatment value and/or 
worst value. 
9.4.6 Other analysis 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.11.  
VV-CLIN-0616194 4.0
83
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 84 
9.5 
INTERIM ANALYSES   
During the core phase, no formal interim analyses are planned. However, the cumulative safety 
data for each study intervention across cohorts will be reviewed periodically by the Data Monitoring 
Committee (DMC). The enrollment will not be paused or stopped during the safety monitoring 
unless severe safety concern arises.  
In addition, in order to support project strategic planning and design of future studies, informal 
interim analysis(es) may be conducted during the study, eg, in each cohort, after 20 participants 
have undergone two post-baseline tumor assessments (approximately 18 weeks from the 
20 participants are first treated) or have discontinued study treatment whichever is earlier.  
For each cohort, the cut-off date for the final analysis will be 3 years from cohort last patient-in 
(LPI).   
VV-CLIN-0616194 4.0
84
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 85 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines, 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• 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 in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
VV-CLIN-0616194 4.0
85
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 86 
-
The participant in a clinical study has the right to opt out of being notified by the
Investigator of such incidental findings. In the event that the participant has opted
out of being notified and the finding has consequences for other individuals, eg, the
finding relates to a communicable disease, Investigators should seek independent
ethical advice before determining next steps.
-
In case the participant has decided to opt out, the Investigator must record in the
site medical files that she/he does not want to know about such findings.
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by
IRB/IEC procedures.
-
Providing oversight of the conduct of the study 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.
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process 
•
The Investigator or his/her representative will explain the nature of the study to the
participants or their legally authorized representative (if allowed by local regulations), and
answer all questions regarding the study, including what happens to the participant when
his/her participation ends (post-trial access strategy for the study).
•
Participants must be informed that their participation is voluntary. Participants or their
legally authorized representative will be required to sign a statement of informed consent
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and
Data Protection requirements including those of the Global Data Protection Regulation
(GDPR) and of the French law, Health Insurance Portability and Accountability Act
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.
•
The medical record must include a statement that written informed consent was obtained
before the participant was enrolled in the study and the date the written consent was
obtained. The authorized person obtaining the informed consent must also sign the ICF.
VV-CLIN-0616194 4.0
86
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 87 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable.  
 Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.11). 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
VV-CLIN-0616194 4.0
87
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 88 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study, 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
VV-CLIN-0616194 4.0
88
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 89 
-
Sanofi’s Binding Corporate Rules for intra-group transfers.
•
Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with
any competent local regulatory authority.
•
Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless
further retention is required by applicable regulations.
•
In order to facilitate the maintenance of Investigators personal data, especially if they
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates
in the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/).
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical
company members of the Transcelerate project. This sharing allows Investigators to keep
their data up-to-date once for all across pharmaceutical companies participating in the
project, with the right to object to the transfer of the data to the Transcelerate project.
•
Professionals have the right to request the access to and the rectification of their personal
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact).
10.1.5 Committees structure 
Data Monitoring Committee 
Independent from the Sponsor and Investigators, the DMC role will be to monitor the safety of the 
participants enrolled in the study (ie, exposed to study treatment and/or to study procedures) and 
to provide the Sponsor with appropriate recommendations in due time to ensure the safety of the 
participants. 
10.1.6 Dissemination of clinical study data 
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites for each 
completed substudy and final study results. This is based on company commitments, international 
and local legal and regulatory requirements, and other clinical trial disclosure commitments 
established by pharmaceutical industry associations.  These websites include clinicaltrials.gov, 
EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
VV-CLIN-0616194 4.0
89
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 90 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.  
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance 
•
All participant data relating to the study will be recorded on printed or e-CRF unless
transmitted to the Sponsor or designee electronically (eg, laboratory data). The
Investigator is responsible for verifying that data entries are accurate and correct by
physically or electronically signing the e-CRF.
•
Guidance on completion of CRFs will be provided in the relevant sponsor data
management study document.
•
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and
regulatory agency inspections and provide direct access to source data documents.
•
Monitoring details describing strategy (eg, 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 provided in separate study documents.
•
The Sponsor or designee is responsible for the data management of this study including
quality checking of the data.
•
The Sponsor assumes accountability for actions delegated to other individuals
(eg, Contract Research Organizations).
•
Records and documents, including signed ICFs, pertaining to the conduct of this study
must be retained by the Investigator for 25 years after the signature of the final study
report unless local regulations or institutional policies require a longer retention period.
No records may be destroyed during the retention period without the written approval of
the Sponsor. No records may be transferred to another location or party without written
notification to the Sponsor.
10.1.8 Source documents 
•
Source documents provide evidence for the existence of the participant and substantiate
the integrity of the data collected. Source documents are filed at the Investigator’s site.
VV-CLIN-0616194 4.0
90
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 91 
• Data reported on the CRF or entered in the e-CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study or one or 
more cohorts at any time for any reason at the sole discretion of the Sponsor. 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 study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study or cohort termination by the Sponsor, as well as reasons for the early closure of 
a study site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention development. 
• For cohort termination 
- 
Early evidence of lack of benefit. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines, 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
- 
Total number of participants included earlier than expected. 
VV-CLIN-0616194 4.0
91
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 92 
If the study or cohort is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. He/she should also stop all 
screening activities pertaining to the study or the relevant cohort(s). Should the Sponsor decide to 
pause recruitment in a cohort to allow decision making, the Investigator should pause all 
screening activities until further notice. 
If the study is terminated early participants who are receiving and benefitting from study 
treatment as per Investigator judgment may continue study treatment provided by the Sponsor 
until protocol defined treatment discontinuation criteria are met. The patients who continue study 
treatment after early study termination should be followed for safety (ie, study treatment 
administrations, ongoing SAE/related AE, new related AE, AESI or SAE and their associated 
concomitant medications and lab if any) and end of treatment reason during this time period. 
10.1.10 
Publication policy  
• 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 the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with 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 mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 7 will be performed by local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.  
VV-CLIN-0616194 4.0
92
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 93 
Table 7 - Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Hematologya 
Platelet count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistrya 
Urea or Urea nitrogen 
Creatinine and eGFR (MDRD formulab) 
Glucose  
Potassium 
Sodium 
Corrected Calcium 
Phosphate 
Chloride 
Magnesium 
Bicarbonatec 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
Alkaline phosphatase 
Total and direct bilirubin 
Total protein 
Lactate dehydrogenase (LDH) 
Albumin 
Amylase  
Lipase 
Coagulation 
International normalized ratio (INR) or Prothrombin Time (PT) (or Activated Partial 
Thromboplastin Time [aPTT]) 
Routine urinalysisd 
•
Specific gravity, pH, glucose, protein, blood, ketones, and leukocytes by
dipstick.
•
Microscopic examination (if blood or protein is abnormal).
VV-CLIN-0616194 4.0
93
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 94 
Laboratory assessments 
Parameters 
Other screening tests 
•
Follicle-stimulating hormone and estradiol may be used to confirm a
postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT).
•
Highly sensitive serum or urine human chorionic gonadotropin (hCG)
pregnancy test (as needed for women of childbearing potential)e.
•
Serology (hepatitis B surface antigen [HBsAg], hepatitis C virus antibody),
Hepatitis B viral load, HCV RNA level, CD4 counts & HIV viral Loadf.
•
Troponin
•
The results of each test must be entered into the e-CRF.
NOTES: 
a Blood Chemistry/hematology should be done with an overnight fasting if possible (should not interfere with hydration requirements). It will 
be performed weekly on D1 pre-dose, D8 and D15 during Cycle 1, then on Day 1 of every cycle up to Cycle 12, then every other cycle 
during Treatment Phase. During the Observation Period, it will be performed at Follow-Up Visit 1. It can also be performed as clinically 
indicated. In case of Grade ≥3 liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline 
value. 
b Modification of Diet in Renal Disease (MDRD) equation: Glomerular filtration rate (mL/min/1.73 m2) = 175 × (Serum Creatinine)-1.154 × (Age)-0.203 
× (0.742 if Female) × (1.212 if African American) 
c Bicarbonate or carbon dioxide (venous) (if bicarbonate or carbon dioxide are assessed only on arterial blood at site level, to be done only 
if clinically indicated). 
d Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) 
will be performed every 4 cycles during the Treatment period and as clinically indicated. 
e Pregnancy Test: Women of childbearing potential must have a negative urine pregnancy test result within 72 hours prior to first IMP 
administration of each cycle, at EOT and every 30 (±7) days until 60 days (for Cohort B2) or 120 days (for Cohorts A1, A2 and B1) after 
the last dose of study treatment. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
f 
Participants with known HIV infection under antiretroviral treatment should have HIV viral load & CD4+ count done at screening to confirm 
controlled infection. Participants with known HBV hepatitis under treatment must have viral load determined at baseline to document 
controlled infection. Participants with positive serology against HCV must have determination of HCV RNA levels. The need for additional 
testing due to positive test results will be at the discretion of the Investigator. HIV, hepatitis B and C serology will be tested at screening 
for participants in Germany and Italy (see Section 10.8). 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
10.3.1 Definition of AE 
AE definition 
•
An AE is any untoward medical occurrence in a patient or clinical study participant,
temporally associated with the use of study intervention, whether or not considered related
to the study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally
associated with the use of study intervention.
VV-CLIN-0616194 4.0
94
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 95 
Definition of unsolicited and solicited AE 
•
An unsolicited adverse event is an adverse event that was not solicited using a participant
diary and that is communicated by a participant who has signed the informed consent.
Unsolicited AEs include serious and non-serious AEs.
•
Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a
hospitalisation, or emergency room visit, or visit to/by a health care provider). The
participant will be instructed to contact the site as soon as possible to report medically
attended event(s), as well as any events that, though not medically attended, are of
participant concern. Detailed information about reported unsolicited AEs will be collected
by qualified site personnel and documented in the participant’s records.
•
Unsolicited AEs that are not medically attended nor perceived as a concern by participant
will be collected during interview with the participant and by review of available medical
records at the next visit.
•
Solicited AEs are predefined local and systemic events for which the participant is
specifically questioned, and which are noted by the participants in their diary.
Events meeting the AE definition 
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or
other safety assessments (eg, ECG, radiological scans, vital signs measurements),
including those that worsen from baseline, considered clinically significant in the medical
and scientific judgment of the Investigator (ie, not related to progression of underlying
disease), eg:
-
Leading to IMP discontinuation or modification of dosing, and/or
-
Fulfilling a seriousness criterion, and/or
-
Defined as an AESI.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though
it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study
intervention or a concomitant medication.
•
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be
reported as an AE or SAE. Such instances will be captured in the efficacy assessments.
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.
•
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE.
VV-CLIN-0616194 4.0
95
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 96 
Events NOT meeting the AE definition 
•
Any clinically significant abnormal laboratory findings or other abnormal safety
assessments which are associated with the underlying disease, unless judged by the
Investigator to be more severe than expected for the participant’s condition.
•
The disease/disorder being studied or expected progression, signs, or symptoms of the
disease/disorder being studied, unless more severe than expected for the participant’s
condition.
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or
detected at the start of the study that do not worsen.
10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
A) Results in death.
B) Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the
participant was at risk of death at the time of the event. It does not refer to an event, which
hypothetically might have caused death, if it were more severe.
C) Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually
involving at least an overnight stay) at the hospital or emergency ward for observation
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a
complication prolongs hospitalization or fulfills any other serious criteria, the event is
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from
baseline is not considered an AE.
D) Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza,
and accidental trauma (eg, sprained ankle) which may interfere with or prevent
everyday life functions but do not constitute a substantial disruption.
VV-CLIN-0616194 4.0
96
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 97 
E) Is a congenital anomaly/birth defect. 
F) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm,  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc), 
- 
Development of drug dependence or drug abuse,  
- 
Suicide attempt or any event suggestive of suicidality,  
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
- 
Bullous cutaneous eruptions.   
The purpose of the seriousness criteria listed above is to guide regulatory reporting obligations by 
the Sponsor. The Sponsor is required to expedite serious unexpected adverse reactions to 
regulatory health authorities and Investigators. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the e-CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE e-CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
VV-CLIN-0616194 4.0
97
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 98 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories, as per NCI CTCAE V5.0 definitions (except 
for ICANS and CRS that will be graded using ASTCT criteria): 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)*. 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
VV-CLIN-0616194 4.0
98
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 99 
•
There may be situations in which an SAE has occurred and the Investigator has minimal
information to include in the initial report to the Sponsor’s representative. However, it is
very important that the Investigator always make an assessment of causality for
every event before the initial transmission of the SAE data to the Sponsor’s
representative.
•
The Investigator may change his/her opinion of causality in light of follow-up information
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting
requirements.
Follow-up of AEs and SAEs 
•
The Investigator is obligated to perform or arrange for the conduct of supplemental
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s
representative to elucidate the nature and/or causality of the AE or SAE as fully as
possible. This may include additional laboratory tests or investigations, histopathological
examinations, or consultation with other health care professionals.
•
If a participant dies during participation in the study or during a recognized follow-up
period, the Investigator will provide the Sponsor’s representative with a copy of any
post-mortem findings including histopathology.
•
New or updated information will be recorded in the originally submitted documents.
•
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of
receipt of the information.
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
•
The primary mechanism for reporting an SAE to the Sponsor’s representative will be the
electronic data collection tool.
•
If the electronic system is unavailable, then the site will use the paper SAE data collection
tool (see next section) to report the event within 24 hours.
•
The site will enter the SAE data into the electronic system as soon as it becomes available.
•
After the study is completed at a given site, the electronic data collection tool will be taken
off-line to prevent the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to
the Sponsor’s representative by telephone.
•
Contacts for SAE reporting can be found in the Investigator study file.
VV-CLIN-0616194 4.0
99
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 100 
SAE reporting to the Sponsor via paper data collection tool 
•
Facsimile transmission of the SAE paper data collection tool is the preferred method to
transmit this information to the Sponsor’s representative.
•
In rare circumstances and in the absence of facsimile equipment, notification by telephone
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier
service.
•
Initial notification via telephone does not replace the need for the Investigator to complete
and sign the SAE data collection tool within the designated reporting time frames.
•
Contacts for SAE reporting can be found in the Investigator study file.
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
10.4.1 Definitions 
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). A postmenopausal state is 
defined as the period of time after a woman has experienced no menses for 12 consecutive months 
without an alternative medical cause. 
•
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used
to confirm a postmenopausal state in women not using hormonal contraception or
hormonal replacement therapy (HRT).
•
Females 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 they wish to continue
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation
of postmenopausal status before study enrollment.
Permanent sterilization methods include: 
•
Documented hysterectomy.
•
Documented bilateral salpingectomy.
•
Documented bilateral oophorectomy.
•
For individuals with permanent infertility due to an alternate medical cause other than the
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator
discretion should be applied to determining study entry eligibility.
Note: Documentation can come from the site personnel’s review of the participant’s
medical records, medical examination, or medical history interview.
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
VV-CLIN-0616194 4.0
100
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 101 
10.4.2 Contraception guidance  
Participants should be given advice about donation and cryopreservation of germ cells prior to the 
start of the study intervention, in line with the fact that study intervention may affect ova and 
sperm for up to the number of days specified respectively for each cohort in the inclusion criteria. 
 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be used together (due 
to risk of failure with friction). 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 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 and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
VV-CLIN-0616194 4.0
101
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 102 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s 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. 
• 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 still birth (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 described 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. 
10.5 
APPENDIX 5: GENETICS  
VV-CLIN-0616194 4.0
102
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 103 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS 
10.8.1 Amendment for Germany 
Section 1.3 Schedule of Activities (SoA) (Section 1.3), Section 5.2 Exclusion Criteria 
(Section 5.2) and Section 10.2 Clinical Laboratory tests (Section 10.2)  
In Germany, serology for HIV, hepatitis B and C will be tested at screening. 
10.8.2 Amendment for Italy 
Section 1.3 Schedule of Activities (SoA) (Section 1.3), Section 5.2 Exclusion Criteria 
(Section 5.2) and Section 10.2 Clinical Laboratory tests (Section 10.2)  
In Italy, serology for HIV, hepatitis B and C will be tested at screening. 
VV-CLIN-0616194 4.0
103
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 104 
10.9 
APPENDIX 9: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1  
Confirmatory scans should be obtained at least 4 weeks following initial documentation of 
objective response. 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline Version 1.1 (1). 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
Selection of Lesions 
• Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest X-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in 
follow-up, only the short axis will be measured and followed. 
• Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm 
[≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
• Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
VV-CLIN-0616194 4.0
104
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 105 
• Non-target lesions: All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as close as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
• Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (eg, skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as 
assessed using calipers (eg, skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
• Chest X-ray. Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
• Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans 
have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situation. 
• PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed. 
• Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
VV-CLIN-0616194 4.0
105
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 106 
•
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor
evaluation is not advised. However, such techniques may be useful to confirm complete
pathological response when biopsies are obtained or to determine relapse in trials where
recurrence following complete response (CR) or surgical resection is an endpoint.
•
Tumor markers. Tumor markers alone cannot be used to assess response. If markers are
initially above the upper normal limit, they must normalize for a patient to be considered
in complete clinical response.
•
Cytology, Histology. These techniques can be used to differentiate between partial
responses (PR) and complete responses (CR) in rare cases (eg, residual lesions in tumor
types, such as germ cell tumors, where known residual benign tumors can remain).The
cytological confirmation of the neoplastic origin of any effusion that appears or worsens
during treatment when the measurable tumor has met criteria for response or stable disease
is mandatory to differentiate between response or stable disease (an effusion may be a side
effect of the treatment) and progressive disease.
•
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis
of FDG-PET imaging can be identified according to the following algorithm:
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of
PD based on a new lesion.
b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET
at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional
follow-up CT scans are needed to determine if there is truly progression occurring at that
site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the
positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is
not progressing on the basis of the anatomic images, this is not PD.
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy
in cases where a residual radiographic abnormality is thought to represent fibrosis or
scarring. The use of FDG-PET in this circumstance should be prospectively described
in the protocol and supported by disease-specific medical literature for the indication.
However, it must be acknowledged that both approaches may lead to false positive CR
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
Response Criteria 
Evaluation of Target Lesions 
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm).
VV-CLIN-0616194 4.0
106
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 107 
• Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
• Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm (0.5 cm). (Note: the appearance of one 
or more new lesions is also considered progressions). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
Evaluation of Non-Target Lesions 
• Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm [<1 cm] 
short axis). Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
• Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Overall Response Criteria 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). The patient’s best response assignment will depend on the 
achievement of both measurement and confirmation criteria. Revised Response Evaluation 
Criteria in Solid Tumors (RECIST) Version 1.1 (1) are summarized in the table: 
Response According to Revised Response Evaluation Criteria in Solid Tumors (Version 1.1) 
 
Target lesions 
Non-target lesions New lesions 
Overall response 
Best overall response 
when confirmation is 
requireda 
CR 
CR 
No 
CR 
>4 weeks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not 
evaluated 
No 
PR 
VV-CLIN-0616194 4.0
107
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 108 
Target lesions 
Non-target lesions New lesions 
Overall response 
Best overall response 
when confirmation is 
requireda 
SD 
Non-CR/Non-PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete response; PD = Progressive disease; PR = Partial response; SD = Stable disease. 
a In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
10.10 APPENDIX 10:
 
VV-CLIN-0616194 4.0
108
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 109 
VV-CLIN-0616194 4.0
109
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 110 
10.10.1 
Response and stable disease duration (RECIST 1.1 
)  
Response duration will be measured from the time measurement criteria for CR/PR
 
(whichever is first recorded) are first met until the first date that recurrent or PD is objectively 
documented, taking as reference the smallest measurements recorded on study (including 
baseline).  
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
10.10.2 
Methods of measurement  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Assessments should be identified on 
a calendar schedule and should not be affected by delays in therapy. While on study, all lesions 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (eg, 2 mm). If it is the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned. For lesions 
which fragment/split add together the longest diameters of the fragmented portions; for lesions 
which coalesce, measure the maximal longest diameter for the “merged lesion.” 
VV-CLIN-0616194 4.0
110
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 111 
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. If feasible, imaging is preferred. 
Chest X-Ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions.  
However, lesions ≥20 mm on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). Other specialized imaging or 
other techniques may also be appropriate for individual case (1). For example, while PET scans 
are not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is advised to differentiate between response or SD and PD.  
10.11 APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
VV-CLIN-0616194 4.0
111
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 112 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening and enrollment of participants and administration of study intervention may 
be temporarily delayed (see also Section 7.1.2). 
10.11.1 
Informed consent  
The participant or their legally authorized representative (if allowed by local regulations) should 
be verbally informed prior to initiating any changes that are to be implemented for the duration of 
the emergency (eg, study visit delays/treatment extension, use of local labs). 
10.11.2 
Study procedures  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  If onsite visits are possible and there is a need to reduce the time spent on site 
to a minimum, the focus should be on IMP infusion/administration, collection of safety 
information (vital signs, adverse events) and safety blood collection (mainly biochemistry, 
hematology and ADA, if planned for the visit). However, all efforts should be made to perform 
the measurements of key parameters for efficacy endpoints, namely CT/MRI scan and tumor 
tissue collection for this study. 
If onsite visits are not possible due to a temporary disruption caused by an emergency, focus 
should be given to assessments necessary to ensure the safety of participants and those important 
to preserving the main scientific value of the study. 
• Remote visits (eg, with home nurses, home health vendor, etc) may be planned for the 
collection of possible safety and/or efficacy data. 
• Visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely.   
• Use of local clinic or laboratory locations may be allowed. 
10.11.3 
Statistical analysis  
The impact of any regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
VV-CLIN-0616194 4.0
112
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 113 
10.11.4 
Temporary discontinuation 
Study intervention must be administered intravenously and at study site under the responsibility of 
the Investigator. Consequently, for participants who have started treatment but are unable to come 
to the site, administration of study intervention must be paused until regular study visits can be 
safely resumed at the study site.   
In the event of disruption of the clinical trial due to an epidemic/pandemic (eg, COVID-19), 
reinitiation of IMP can only occur once the Investigator has determined, according to his/her best 
judgement, that the contribution of the IMP(s) to the occurrence of the epidemic event 
(eg, COVID-19) was unlikely. 
Contingencies implemented due to emergency will be documented. 
10.12 APPENDIX 12: RISK ASSESSMENT 
The information shown in Table 8 reflects the clinical safety data available at the time of 
Edition 3 of the SAR444245 IB. Please always refer to the latest version of the IB for the most up-
to-date safety data. 
Table 8 - Risk assessment 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s)
Infusion-associated reactions 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
A minority of patients in the 
THOR-707-101/HAMMER study have 
reported such AE as detailed in the IB. 
SAR444245 
Standard pre-medication 
Dose modification and treatment 
guidelines for SAR444245 
infusion-associated reactions are 
provided in individual substudies. 
Hypersensitivity, including 
anaphylaxis
SAR444245 
Not observed in non-clinical toxicology 
studies. 
No reports of anaphylaxis in the HAMMER 
study to date. 
Exclusion of participants with known 
hypersensitivity to or contraindication 
any components of SAR444245, PEG, 
or pegylated drugs.  
Infections
SAR444245 
Nonclinical data do not indicate higher risk 
for infections. 
Adverse events of infections have been 
reported in the HAMMER study and are 
presented in the SAR444245 IB. 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function 
to be included. 
During treatment, regular hematology 
and biochemistry is examined. 
Signs and symptoms of infection are 
monitored as part of TEAE. 
VV-CLIN-0616194 4.0
113
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 114 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Cytokine release syndrome 
SAR444245 
No major increases in cytokines have been 
reported in non-clinical toxicology studies. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
Study to be conducted at sites 
experienced with CRS management, 
with bed available in ICU. 
Premedication with paracetamol, 
diphenhydramine (or equivalent 
medications). 
Hydration guidelines, including 
management of anti-hypertensive 
treatment around the time of infusion, 
are provided. 
Extensive post-dosing monitoring will be 
performed. 
Dose modification and treatment 
guidelines are provided in individual 
substudies. 
Capillary leak syndrome (CLS) / 
Vascular leak syndrome (VLS) 
 SAR444245 
Not observed in non-clinical toxicology 
studies. 
None reported in the HAMMER study. 
Intensive monitoring in C1D1 and 
beyond in the first cycle.  
Participants are monitored for signs and 
symptoms of VLS. 
Dose modification and treatment 
guidelines are provided in individual 
substudies. 
Hematological/bone marrow toxicity 
SAR444245 
In 28-day repeat-dose study of 
IV SAR444245 in non-human primates, 
SAR444245-related changes in clinical 
pathology parameters were observed at all 
doses and were generally most prominent 
3 days following each dose. Changes in 
hematology parameters included decreased 
or attenuated reticulocytes followed by 
decreases in red blood cell (RBC) mass at 
 mg/kg/dose, and increased WBCs 
(lymphocytes and monocytes) and 
transiently mildly decreased platelets at 
 mg/kg/dose. The increases in 
lymphocytes were attributed to the expected 
pharmacology of SAR444245 and correlated 
with the gross and microscopic findings of 
splenic and lymph node enlargement and 
increased lymphoid cellularity; there were no 
microscopic or clinical correlates for the 
decreases in platelets. 
Adverse events of bone marrow toxicity 
have been reported in the HAMMER study 
and are presented in the SAR444245 IB. 
Transient lymphopenia has also been 
observed. 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function 
to be included. 
During treatment, regular hematology 
and biochemistry is examined. 
Dose modification/discontinuation of 
IMP for Grade 3/4 anemia, 
thrombocytopenia and/or neutropenia 
as per general guidelines for the 
management of TRAEs (see individual 
substudies). 
VV-CLIN-0616194 4.0
114
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 115 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Hepatotoxicity 
SAR444245  
In 28-day repeat-dose study of IV 
SAR444245 in mice, males at
mg/kg/dose 
and females at  and  mg/kg/dose also had 
mild increases in AST and ALT activity that 
corresponded to a spectrum of microscopic 
findings in the liver including mononuclear 
cell infiltration, apoptosis, necrosis, mixed 
leukocyte inflammation, oval cell 
hyperplasia, and Kupffer cell hypertrophy. 
No such data are reported in 28-day 
Repeat-Dose Study of IV SAR444245 in 
non-human primates. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB.  
Patients with significant impaired liver 
functions are excluded. 
Monitor clinical signs and symptoms of 
hepatic impairment as part of TEAE. 
Monitor liver function parameters (AST, 
ALT, bilirubin & ALP) regularly from 
screening and throughout the study. 
Dose modification and treatment 
guidelines for liver enzyme increase are 
provide under immune-related reactions 
in individual substudies. 
Nephrotoxicity 
SAR444245 
There are no non-clinical data indicating a 
potential for nephrotoxicity. 
One relevant serious adverse event (SAE) 
considered related to SAR444245 (Acute 
Kidney Injury) has been reported in the 
HAMMER study within a monotherapy 
cohort. 
Participants must have appropriate 
eGFR to be included. 
Monitor renal function parameters 
(BUN/urea & creatinine) regularly from 
screening and throughout the study. 
Dose modification and treatment 
guidelines for nephrotoxicity are provide 
under immune-related reactions 
in individual substudies. 
 
Investigator’s assessment is that it is related 
to the CRS occurring in the same patient. 
Sponsor's assessment was that the kidney 
injury was related to increased fluid losses 
from persistent fever. 
 
Neurological AEs, including ICANS 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
One SAE of CRS (Grade 4 with 24 ug/kg 
monotherapy) associated with neurological 
manifestations [hypertension, chills/rigors, 
flushing, fever (maximum 
temperature: 102.8°F), as well as 
neurological symptomatology (loss of ability 
to follow commands, confusion, aphasia, 
and involuntary fist clinching)] was reported 
in the HAMMER study. The event resolved 
completely within 30 to 60 minutes after 
treatment with tocilizumab and steroid. This 
patient later discontinued the study. 
Exclusion of participants with 
lymphomatous involvement of the 
central nervous system.  
Guidelines for the management of 
ICANS are provided in Table 10. 
VV-CLIN-0616194 4.0
115
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 116 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Cardiovascular effects, including 
QT interval prolongation 
SAR444245 
In 28-day repeat-dose study of 
IV SAR444245 in non-human primates, 
there were no SAR444245-related changes 
to the PR or QRS intervals or the heart rate 
(HR) corrected QTca interval. There was a 
SAR444245-related, dose dependent, 
non-adverse higher HR at doses of 
 mg/kg/dose beginning on Day 1 
compared to the control dose group and 
persisting through each respective dose 
following applicable telemetry recording 
sessions, with recovery. There was also an 
expected physiologic inverse relationship in 
the respiration rate (RR) intervals as well as 
the raw QT intervals, which correlated to the 
changes in HR, and were also considered to 
be non-adverse. There were increases in 
individual females of troponin I minimal post 
first dose. There were marked decreases in 
females and males.  
These changes correlated with findings of 
mononuclear cell infiltrates and/or 
myocardial degeneration. All changes 
however, recovered by the end of a 28 day 
or 42/44 day treatment free period. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB.  
Routine mitigation:  
Selection of qualified investigative 
centers with availability of intensive 
critical care/equipment. 
Exclusion of patients with severe or 
unstable cardiac condition within 
6 months prior to starting study 
treatment.  
ECG, LVEF, and vital sign monitoring 
and coagulation tests performed at 
screening and thereafter as clinically 
indicated. 
Monitoring will depend on site 
assessment of participant’s symptoms. 
Immune-mediated Adverse Events 
SAR444245 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
Exclusion of participants with: 
Active, known, or suspected 
autoimmune disease that has required 
systemic treatment in the past 2 years 
(ie, with use of disease modifying 
agents, corticosteroids or 
immunosuppressive drugs), except 
controlled by replacement therapy 
(eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc). 
Close monitoring for endocrine 
abnormalities and other potentially 
autoimmune phenomena will be 
performed.  
Dose modification and treatment 
guidelines for under immune-related 
reactions are provided in individual 
substudies. 
VV-CLIN-0616194 4.0
116
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 117 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Risks related to special 
populations 
Pregnancy and lactation exposure 
and outcomes
SAR444245 
No studies have been conducted with 
SAR444245 on fertility or general 
reproductive performance. 
Exclusion of participants who are 
pregnant or breastfeeding or expecting 
to conceive or father children within the 
projected duration of the trial as per 
inclusion criterion I05. 
Guidance on highly effective 
contraceptive methods is provided in the 
protocol. Pregnancy tests are to be 
performed regularly as described 
in Section 8.2.5. 
Use in children 
The safety and efficacy of the study 
interventions in children below 18 years of 
age have not yet been established. 
Participants over 75 years of age 
SAR444245 
At this stage of development, no safety data 
are available for this population. 
No specific mitigation strategy for this 
population. 
Clinically significant medication 
errors 
With the increased complexity of the design 
of oncology clinical trials, medication errors 
need to be considered. Although their 
occurrence is estimated to be low (eg, 
chemotherapy errors occur at a rate of about 
one to four per 1000 orders), their impact 
may be high. According to the report on 
medication safety in cancer clinical trials, the 
processes in which the errors originated 
were prescribing (47%), administering 
(10%), dispensing (6%), and monitoring 
(5%). Prescribing errors typically arise from 
not following an institutional procedure or the 
protocol (39%, most likely due to the 
protocol procedures differing from existing 
standards of care), followed by the written 
order (30%), and poor communication 
involving both the healthcare team and the 
patient (26%) (29, 30, 31).
Strict adherence to the protocol. 
Adequate and verified training of staff at 
investigational sites. 
Overdose and its treatment 
There is no specific antidote for overdose 
with SAR444245. 
Strict adherence to the protocol; 
Adequate and verified training of staff at 
investigational sites. 
See Section 6.7.
Study procedures 
Biopsies of tumor tissue are 
expected during the trial. 
Strict adherence to the guidance in the 
protocol 
VV-CLIN-0616194 4.0
117
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 118 
10.13 APPENDIX 13: ASTCT ASSESSMENT FOR ICANS AND CRS 
Table 9 - Encephalopathy assessment ICE tool for ICANS Grading 
Immune Effector Cell-Associated Encephalopathy (ICE) Assessment 
Number of points 
Orientation: Orientation to year, month, city, hospital 
4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button) 
3 points 
Ability to follow simple commands: (eg, “Show me 2 fingers” or “Close your eyes and stick 
out your tongue”) 
1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”) 
1 point 
Attention: ability to count backwards from 100 by 10  
1 point 
Source: (2). 
Table 10 - ASTCT ICANS consensus grading for adults 
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7-9
3-6
0-2
0 (participant is unrousable and unable 
to perform ICE). 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to tactile 
stimulus 
Participant is unarousable or requires 
vigorous or repetitive tactile stimuli to 
arouse. Stupor or coma. 
Seizure 
N/A 
N/A 
Any clinical seizure focal or 
generalized that resolves 
rapidly or nonconvulsive 
seizures on EEG that 
resolve with intervention. 
Life-threatening prolonged seizure 
(>5 min); or Repetitive clinical or 
electrical seizures without return to 
baseline in between. 
Motor findingsc 
N/A 
N/A 
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis. 
Elevated ICP cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimagingd
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or 
Cranial nerve VI palsy; or Papilledema; or 
Cushing’s triad. 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) 
not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may 
be classified as Grade 4 ICANS if unrousable. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medications). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE V5.0, but they do not influence 
ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It 
may be graded according to CTCAE V5.0.  
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CTCAE = Common Terminology Criteria for Adverse Events; 
EEG = Electroencephalogram; ICANS = Immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy; ICP = Intracranial pressure;  
N/A = Not applicable. 
Source: (2). 
VV-CLIN-0616194 4.0
118
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 119 
Table 11 - ASTCT CRS consensus grading  
CRS parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature ≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
With 
Hypotensionb 
None 
Not requiring 
vasopressors 
Requiring a vasopressor 
with or without 
vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow nasal 
cannulac, facemask, 
nonrebreather mask, or 
Venturi mask 
Requiring positive pressure 
(eg, CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.  
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or alternative therapies per site practice in CRS management or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5° C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.  
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP=Bi-level positive airway pressure CPAP= Continuous 
Positive Airway Pressure; CRS=Cytokine release syndrome. 
Source: (2) 
 
10.14 APPENDIX 14: ABBREVIATIONS  
 
ADA: 
Anti-drug antibody 
ADCC: 
antibody-dependent cellular-mediated cytotoxicity 
ADL: 
activities of daily living 
AE: 
adverse events 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase 
ASTCT: 
American Society for Transplantation and Cellular Therapy  
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CI: 
confidence interval 
CLS: 
capillary leak syndrome 
CR: 
complete response 
CRF: 
case report form 
CRS: 
cytokine release syndrome 
CSFs: 
colony-stimulating factors 
 
 
VV-CLIN-0616194 4.0
119
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 120 
DMC: 
Data Monitoring Committee 
DoR: 
duration of response 
EBV: 
Epstein Barr Virus 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
e-CRF: 
electronic case report form 
EGFR: 
epidermal growth factor receptor 
EOT: 
end of treatment 
ESMO: 
European Society for Medical Oncology 
FDA: 
Food and Drug Administration 
HCV: 
hepatitis C virus 
HIV: 
Human immunodeficiency virus 
HNSCC: 
head and neck squamous cell carcinoma 
HPV: 
Human Papilloma virus 
IAR: 
infusion-associated reaction 
IB: 
Investigator’s Brochure 
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICF: 
informed consent form 
IFNγ: 
interferon gamma 
IL: 
interleukin 
ILC: 
innate lymphoid cell 
IMP: 
investigational medicinal product 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
LPI: 
last patient-in, last patient-in 
LVEF: 
left ventricular ejection fraction 
MCP-1: 
monocyte chemoattractant protein-1 
MRI: 
magnetic resonance imaging 
MTD: 
 Maximum Tolerated Dose  
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP: 
non-human primates 
NK: 
natural killer 
ORR: 
objective response rate 
OTC: 
over-the-counter 
PD: 
progressive disease 
PD-L1: 
programmed death-ligand 1 
PDy: 
pharmacodynamic 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PO: 
oral route 
PR: 
partial response 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
QoL: 
quality of life 
VV-CLIN-0616194 4.0
120
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 121 
RCC: 
renal cell carcinoma 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse events 
SAP: 
statistical analysis plan 
SARS-CoV-2: 
severe acute respiratory syndrome coronavirus 2 
SB: 
Study Board 
SD: 
stable disease 
SoA: 
Schedule of Activities 
SpO2: 
oxygen saturation 
TCR: 
T cell receptor 
TEAEs: 
treatment-emergent adverse events 
TLS: 
tumor lysis syndrome 
TTR: 
time to response 
ULN: 
upper limit of normal 
US: 
United States 
VLS: 
vascular leak syndrome 
WOCBP: 
woman of childbearing potential 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amended protocol 01 (26 July 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth 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 overall rationale for the amendment is to respond to the Health Authorities (Food and Drug 
Administration, [FDA]) requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Updated to mark ECG at C1D1. 
Regulatory Authority (FDA) request 
Section 1.5.1 All Cohorts 
The frequency of sampling for PK and ADA 
has been increased to obtain data every cycle 
for the first 3 cycles, every other cycle for 
4 samples, then every 4th cycle. 
Regulatory Authority (FDA) request 
VV-CLIN-0616194 4.0
121
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 122 
Section # and Name 
Description of Change 
Brief Rationale 
Section 4.3 Justification for 
Dose 
Updated based on most recent data. 
Regulatory Authority (FDA) request 
Section 8.2.3 
Electrocardiograms 
The following text has been added: “At Cycle 
Day 1, at pre-dose and at end of SAR444245 
infusion, ECG will be obtained using an ECG 
machine that automatically calculates the 
heart rate and measures PR, QRS, QT, and 
QTcF intervals.”  
Regulatory Authority (FDA) request 
Amended protocol 02 (19 August 2021) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth 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 main rationale for this amendment is the decision to add a new study cohort (Cohort A2, 
Substudy protocol 02) to explore the triplet combination of SAR444245 + cetuximab + 
pembrolizumab in R/M HNSCC treatment-naïve participants for R/M disease. A new substudy 
protocol (Substudy 02) has been therefore created. Other changes have been made for 
clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
In the rationale, the following text “for non-alpha 
IL-2 SAR444245 combined with other anticancer 
therapies” has been deleted. 
For correction and readability 
Section 1.1 Synopsis 
and Section 4.1 Overall 
Design  
A brief description of study phases has been 
added. Table 1 and Table 3 have been newly 
added. Subsequent tables have been 
renumbered. 
The priority of recruitment for participants eligible 
to both Cohort A1 and Cohort A2 has been also 
specified. 
To ensure clarity on study conduct and 
participants recruitment 
Section 1.2 Schema 
and Section 4.1 Overall 
Design 
The name “Study Committee” has been changed 
to “Study Board”. Details describing its 
composition and role have been provided. 
To ensure clarity and avoid confusion with any 
Independent Committee 
VV-CLIN-0616194 4.0
122
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 123 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA), Section 
5.2 Exclusion Criteria, 
Section 10.2 Clinical 
laboratory tests, and 
Section 10.8 Country-
Specific Requirements 
Requirement for human immunodeficiency virus 
(HIV), hepatitis B and C serologies has been 
added at screening for participants in Germany 
and specified in exclusion criteria E15 and E16, 
SoA in a new footnote “f” (subsequent footnotes 
have been resequenced), laboratory tests and 
country-specific requirements sections. The 
following text “in any countries where mandatory 
as per local requirements” has been removed 
from footnote “e” of Section 10.2. 
To align with standard German Health 
Authorities requirements 
Section 5.2 Exclusion 
Criteria 
The E04 “History of allogenic or solid organ 
transplant” has been revised to “History of 
allogenic tissue/solid organ transplant”. 
For clarification 
Section 8.2.3 
Electrocardiograms and 
left ventricular ejection 
fraction (LVEF) 
The following text: “and left ventricular ejection 
fraction (LVEF)” has been added to the naming of 
the section. 
Regarding ECG measurement, “At Cycle Day 1” 
was changed to “At Cycle 1 Day 1”. 
For correction and clarification 
Throughout the 
document 
Minor editorial corrections have been made. 
For consistency 
 
VV-CLIN-0616194 4.0
123
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 124 
11 
REFERENCES  
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47. 
2. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
 
4. Cohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The 
Society for Immunotherapy of Cancer consensus statement on immunotherapy for the 
treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer. 
2019;7(1):184.  
5. Salmaninejad A, Valilou SF,  Shabgah AG, Aslani S, Alimardani M, Pasdar A, et al. PD-
1/PD-L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol 
2019;234(10):16824-37. 
6. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond. Adv Exp 
Med Biol. 2020;1248:33-59. 
7. Mendelsohn J and Baselga J. Status of epidermal growth factor receptor antagonists in the 
biology and treatment of cancer. J Clin Oncol. 2003;21(14):2787-99. 
8. Miyauchi S, Kim SS, Pang J, Gold KA, Gutkind JS, Califano JA, et al. Immune modulation of 
head and neck squamous cell carcinoma and the tumor microenvironment by conventional 
therapeutics. Clin Cancer Res. 2019;25(14):4211-23. 
9. Pinette A, McMichael E, Courtney NB, Duggan M, Benner BN, Choueiry F, et al. An IL-15-
based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous 
cell carcinoma of the head and neck. Cancer Immunol Immunother. 2019;68(8):1379-89. 
10. Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Castro AF, et al. Evidence-based 
treatment options in recurrent and/or metastatic squamous cell carcinoma of the head and 
neck. Front Oncol. 2017;7:72. 
11. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, 
uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a 
single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head 
and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171-7. 
12. Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn M-J, et al. Pembrolizumab 
versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck 
VV-CLIN-0616194 4.0
124
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 125 
squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 
2019;393(10167):156-67. 
13. Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab 
for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 
2016;375(19):1856-67. 
14. Prescribing Information. Proleukin® (Aldesleukin). Revised July 2012. [Online]. Accessed 03 
July 2020. Available form: 
URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf 
15. Van Gool F, Molofsky AB, Morar MM, Rosenzwajg M, Liang HE, Klatzmann D, et al. 
Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by 
interleukin-2 therapy. Blood. 2014;124(24):3572-6. 
16. Elkahwaji J, Robin MA, Berson A, Tinel M, Lettéron P, Labbe G, et al. Decrease in hepatic 
cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999;57(8):951-4. 
17. Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A 
First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased 
Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discov. 
2019;9(6):711-21. 
18. Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. 
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: 
Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). 
Cancer Discov. 2020;10(8):1158-73. 
19. Tímár J, Ladányi A, Forster-Horváth C, Lukits J, Döme B, Remenár E, et al. Neoadjuvant 
immunotherapy of oral squamous cell carcinoma modulates intratumoral CD4/CD8 ratio and 
tumor microenvironment: a multicenter phase II clinical trial. J Clin Oncol. 2005;23(15):3421-
32. 
20. De Stefani A, Forni G, Ragona R, Cavallo G, Bussi M, Usai A, et al. Improved survival with 
perilymphatic interleukin 2 in patients with resectable squamous cell carcinoma of the oral 
cavity and oropharynx. Cancer. 2002;95(1):90-7. 
21. Melero I, Alvarez EC, Mau-Sorensen M, Lassen UN, Lolkema MP, Robbrecht DG, et al. 
Clinical activity, safety, and PK/PD from a phase I study of RO6874281, a fibroblast 
activation protein (FAP) targeted interleukin-2 variant (IL-2v). Ann Oncol. 2018;29(suppl 
8):VIII134-5. 
22. Paleri V, Wight RG, Silver CE, Haigentz MJr, Takes RP, Bradley PJ, et al. Comorbidity in 
head and neck cancer: A critical appraisal and recommendations for practice. Oral Oncol. 
2010;46(10):712-9. 
23. Sidaway P. COVID-19 and cancer: What we know so far. Nat. Rev. Clin. Oncol. 
2020;17(6):336. 
VV-CLIN-0616194 4.0
125
VV-CLIN-0701966 1.0

Amended Clinical Trial Master Protocol 03 
SAR444245-ACT16903 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 126 
24. Kulcsar MA, Montenegro FL, Arap SS, Tavares MR, Kowalski LP. High Risk of COVID-19 
Infection for Head and Neck Surgeons. Int. Arch. Otorhinolaryngol. 2020;24(2):e129-30. 
25. COVID Surg Collaborative. Mortality and pulmonary complications in patients undergoing 
surgery with perioperative SARS-CoV2 infection: An international cohort study. Lancet. 
2020;396(10243):27-38. 
26. ESMO management and treatment adapted recommendations in the covid-19 era: head and 
neck cancers. [Online]. [cited 2021 Jun 03]. Available from: 
URL:https://www.esmo.org/guidelines/cancer-patient-management-during-the-covid-19-
pandemic/head-and-neck-cancers-in-the-covid-19-era 
27. ASCO. COVID-19 Disease-Specific Information. [Online]. [cited 2021 Jun 03]. Available 
from: URL:https://www.asco.org/asco-coronavirus-resources/care-individuals-cancer-during-
covid-19/disease-specific-information 
28. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations 
for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol. 2015;33(28):3199-212. 
29. Moon JY, Lee Y, Han JM, Lee MH, Yee J, Song MK, et al. Effects of pharmacist 
interventions on reducing prescribing errors of investigational drugs in oncology clinical trials. 
J Oncol Pharm Pract. 2020;26(1):29-35. 
30. Weingart SN, Zhang L, Sweeney M, Hassett M. Chemotherapy medication errors. Lancet 
Oncol. 2018;19(4):e191-9. 
31. Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. American society 
of clinical oncology 2007 clinical practice guideline update on the role of bisphosphonates in 
multiple myeloma. J Clin Oncol. 2007;25(17):2464-72. 
 
   
 
VV-CLIN-0616194 4.0
126
VV-CLIN-0701966 1.0

Signature Page for VV-CLIN-0616194 v4.0
act16903-16-1-1-amended-protocol03-master
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0616194 4.0
127
VV-CLIN-0701966 1.0

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 01) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab for 
the treatment of recurrent/metastatic (R/M) head and neck 
squamous cell carcinoma (HNSCC) treatment-naïve 
participants for R/M disease, programmed cell death-
ligand 1 (PD-L1) combined positive score (CPS) ≥1 
Protocol number: 
ACT16903-S01 
Amendment number: 03 
Compound number 
(INN/Trademark): 
SAR444245  
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab for 
the treatment of R/M HNSCC treatment-naïve participants 
for R/M disease, PD-L1 CPS ≥1  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name 
and contact 
information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
IND156423 
2021-002105-99 
NCT05061420
U1111-1251-5073 
Date: 
22-Dec-2021
Total number of pages: 64 
VV-CLIN-0616195 4.0
128
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 (Substudy 01)  
All 
22 December 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 (Substudy 01)  
All 
19 August 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 (Substudy 01)  
All 
26 July 2021, version 1 (electronic 2.0) 
Clinical Trial Protocol (Substudy 01) 
All 
11 June 2021, version 1 (electronic 1.0) 
Amended protocol 03 (22 December 2021) 
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Spanish (Agency for Medicine and 
Health Products [AEMPS]), Italian (Medicines Agency [AIFA]) and German (Federal Institute for 
Drugs and Medical Devices [BfArM]) Health Authorities after initial review. Other changes have 
been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SoA) 
A complete Table of SoA applicable for this substudy has been 
provided with procedures taken from the master protocol. 
For clarity and consistency 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up 
visit 1. 
To allow assessments of any 
potential cardiotoxicity 
1.4 Biomarker flow-chart 
and 1.5 Pharmacokinetic 
flow-chart 
Complete biomarker and pharmacokinetic flow-charts 
applicable for this substudy have been provided with 
procedures taken from the master protocol. 
For clarity and consistency 
6.5.3 General guidelines 
for the management of 
treatment-related adverse 
events 
As the Study Board does not intervene for this substudy, any 
reference to it has been removed. 
For consistency 
VV-CLIN-0616195 4.0
129
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome (CRS) 
and 6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
The following statement “or alternative therapies per site 
practice in CRS management” has been added to 
“tocilizumab”. 
For flexibility following an issue 
with tocilizumab availability 
6.5.4.5 Immune Cell-
Associated Neurotoxicity 
Syndrome (ICANS)  
In Table 6 under Grade 4, “signs of” has been removed before 
“diffuse cerebral edema on neuroimaging”.
Change made for consistency 
with the American Society for 
Transplantation and Cellular 
Therapy (ASTCT) Consensus 
and correction 
10.1 Appendix 1: 
Regulatory, ethical, and 
study oversight 
considerations  
A new subsection 10.1.6 entitled “Dissemination of clinical 
study data” has been added with the following text: “Study 
participants results summaries will be provided in any one of 
the clinical trial portals after completion of the substudy, until 
the end of study”. 
Per CTFG guidance 2019: 
Recommendation Paper on the 
Initiation and Conduct of 
Complex Clinical Trials 
10.11 Appendix 11: 
Abbreviations 
List of abbreviations has been revised. 
For consistency 
11 References 
List of references has been updated. 
For consistency 
Throughout the document 
Minor editorial corrections were made. 
For consistency 
VV-CLIN-0616195 4.0
130
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 4 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 01) .................................................................. 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2
TABLE OF CONTENTS .................................................................................................................................. 4
LIST OF TABLES ........................................................................................................................................... 8
LIST OF FIGURES .......................................................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................................................. 9
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 13 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 21 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 22 
2
INTRODUCTION ............................................................................................................................ 23
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.2.1 
Pembrolizumab .............................................................................................................................. 23 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 23 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 24 
2.2.2 
Rationale for HNSCC and selected participant population ............................................................ 24 
2.2.3 
Current standard of care in HNSCC .............................................................................................. 25 
2.2.3.1 
PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as first line therapy ...... 25 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 26 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 26 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 27 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 27 
3
OBJECTIVES AND ENDPOINTS ................................................................................................. 28
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 28 
4
STUDY DESIGN ............................................................................................................................ 29
VV-CLIN-0616195 4.0
131
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 5 
4.1 
OVERALL DESIGN ........................................................................................................................ 29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 29 
4.2.1 
Participant input into design ........................................................................................................... 29 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 29 
4.3.1 
SAR444245 dose ........................................................................................................................... 29 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 29 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 30 
5
STUDY POPULATION .................................................................................................................. 31
5.1 
INCLUSION CRITERIA .................................................................................................................. 31 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 31 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 32 
5.4 
SCREEN FAILURES...................................................................................................................... 32 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION] ....................................................................................................................... 32 
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 33
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 33 
6.1.1 
Investigational medicinal product ................................................................................................... 33 
6.1.2 
Non-investigational medicinal product ........................................................................................... 34 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 34 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 34 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 34 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 34 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 34 
6.5 
DOSE MODIFICATION .................................................................................................................. 34 
6.5.1 
General rules .................................................................................................................................. 34 
6.5.2 
Cycle delay ..................................................................................................................................... 35 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 36 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 36 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 36 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 39 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 39 
6.5.4.4 
Immune-related adverse events .................................................................................................... 41 
VV-CLIN-0616195 4.0
132
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 6 
6.5.4.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 44 
6.5.4.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 46 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY ............................... 47 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 47 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 47 
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 48
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 48 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 48 
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 49
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 49 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 49 
8.2.1 
Physical examinations ................................................................................................................... 49 
8.2.2 
Vital signs ....................................................................................................................................... 49 
8.2.3 
Electrocardiograms and left ventricular ejection fraction (LVEF) ................................................... 49 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 49 
8.2.5 
Pregnancy testing .......................................................................................................................... 50 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 50 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 50 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 50 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 50 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 50 
8.3.5 
Pregnancy ...................................................................................................................................... 50 
8.3.6 
Cardiovascular and death events .................................................................................................. 50 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 50 
8.3.8 
Adverse event of special interest ................................................................................................... 50 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 51 
8.4 
PHARMACOKINETICS .................................................................................................................. 51 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 51 
8.6 
BIOMARKERS ............................................................................................................................... 51 
VV-CLIN-0616195 4.0
133
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 7 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 51 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 51 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 51 
9
STATISTICAL CONSIDERATIONS .............................................................................................. 52
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 52 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 52 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 52 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 52 
9.5 
INTERIM ANALYSES .................................................................................................................... 52 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 53
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 53 
10.1.6 
Dissemination of clinical study data ............................................................................................... 53 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 53 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 53 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 53 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 53 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 54 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 54 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 54 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 54 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 54 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 55 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 56 
11
REFERENCES ............................................................................................................................... 60
VV-CLIN-0616195 4.0
134
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 8 
LIST OF TABLES 
Table 1 - Overview of IMP administered ....................................................................................................... 33 
Table 2 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 37 
Table 3 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 38 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 40 
Table 5 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 42 
Table 6 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) ... 45 
Table 7 - Guidelines for the management of Vascular Leak Syndrome (VLS) ............................................. 46 
Table 8 - Protocol-required laboratory assessments .................................................................................... 53 
Table 9 - Risk assessment ............................................................................................................................ 54 
LIST OF FIGURES 
Figure 1 - Overall substudy schema .............................................................................................................. 12 
VV-CLIN-0616195 4.0
135
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. 
Substudy A1-specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of 
recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) treatment-naïve 
participants for R/M disease, PD-L1 CPS ≥1 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of R/M 
HNSCC treatment-naïve participants for R/M disease, PD-L1 CPS ≥1 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 1 
(PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in 
the syngeneic murine colon cancer CT-26 model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with pembrolizumab will result in a significant increase in the percentage of patients with HNSCC 
experiencing an objective response.
Objectives and endpoints 
Please refer to the master protocol for description of objectives and endpoints. 
Overall design: 
Please refer to the master protocol. 
Brief summary:  
Cohort A1: This substudy will include participants with HNSCC who are treatment-naïve for 
R/M disease, PD-L1 Combined Positive Score (CPS) ≥1 and will assess SAR444245 combined 
with pembrolizumab. 
A graphical presentation of the study schema is shown in Figure 1. 
VV-CLIN-0616195 4.0
136
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 10 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in Cohort A1.  
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration. 
Study intervention(s) 
Cohort A1: R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1, SAR444245 
+ pembrolizumab
Dosing sequence:
Investigational medicinal product(s) 
Pembrolizumab 
•
Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in single-
dose vials.
•
Route of administration: intravenous (IV) infusion.
•
Dose regimen: Pembrolizumab will be administered at a dose of 200 mg using a 30-minute
IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles.
Study sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window between -5 minutes and 
+10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min).
SAR444245 
•
Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion
in a single-dose vial with an extractable volume of 1 mL.
•
Route of administration: intravenous (IV) infusion.
•
Dose regimen: 24 μg/kg administered as an IV infusion over 30 mins every 3 weeks on
Day 1 of each cycle (21 days per cycle) for up to 35 cycles.
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
Non-investigational medicinal products 
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
137
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 11 
Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. 
For Cohort A1, the cohort cut-off for the primary objective response rate (ORR) endpoint 
analyses is estimated to be approximately 9 months from the date of the last participant’s first 
infusion in the core phase (to document that last participant response is maintained for 6 months 
in the core phase). 
Data Monitoring: Yes 
VV-CLIN-0616195 4.0
138
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 12
1.2 
SCHEMA 
Figure 1 - Overall substudy schema 
CPS: Combined Positive Score; HNSCC: head and neck squamous cell carcinoma; PD-L1: programmed death ligand 1; pembro: pembrolizumab; Tx: treatment; R/M: recurrent/metastatic. 
VV-CLIN-0616195 4.0
139
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Elements of the schedule of activities (SoA) common to all cohorts are detailed in the master protocol. Cohort A1-specific evaluations are 
presented in this table.  
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Informed consent 
Inclusion/Exclusion 
criteria 
X 
IRT contact 
X 
X 
X 
X 
X 
Demography, 
medical/surgical and 
disease history 
X 
See Section 8 
of master 
protocol 
Full physical examination 
X 
X 
Directed physical 
examination 
X 
X 
X 
X 
X 
X 
See 
 Section 8.2.1 
of master 
protocol 
VV-CLIN-0616195 4.0
140
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 14 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Body weight/Heighte
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
See 
 Section 8.2.2 
& Section 
8.2.2 of 
master 
protocol 
SpO2 
X 
As clinically indicated 
Performance status 
(ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
As clinically indicated 
See 
 Section 8.2.3 
of master 
protocol 
LVEF 
X 
As clinically indicated 
See 
 Section 8.2.3 
of master 
protocol 
VV-CLIN-0616195 4.0
141
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 15 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1
D1 
D8 
(±1) 
D15 
(±1) 
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Laboratory assessments 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically indicated 
See 
Section 8.2.3 
& Section 10.2 
of master 
protocol 
Pregnancy test 
X 
X 
X 
X 
X 
X 
X 
See 
Section 8.2.5, 
Section 8.3.5 
& Section 10.2 
of master 
protocol 
Blood 
chemistry/hematology 
X 
X 
X 
X 
X 
X 
X 
X 
See 
 Section 10.2 
and Section 
10.2 of master 
protocol 
VV-CLIN-0616195 4.0
142
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 16 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
T3, FT4, TSH, and 
cortisol 
X 
 
 
 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 
Coagulation 
X 
As clinically indicated 
  
  
  
See  
Section 10.2 
of master 
protocol  
Urinalysisk 
X 
X 
 
 
 
X 
X 
X 
 
 
 
See  
Section 10.2 
of master 
protocol 
Hepatitis serology 
CD4 counts & Viral Load 
 Xf 
As clinically indicated 
  
  
  
See  
Section 10.2 
of master 
protocol 
HPV p16 status for 
participants with 
oropharyngeal cancer 
X 
   
  
 
  
  
  
  
  
  
  
 
VV-CLIN-0616195 4.0
143
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 17 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
PK 
See PK Flow-Chart in Section 1.5 
 
ADA 
See PK Flow-Chart in Section 1.5 
 
Exploratory biomarkers 
 
PDy - Blood and tumor 
tissue collectiong 
See Biomarkers Flow-Chart in Section 1.4 
 
Disease assessment 
 
CT/MRIh 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
See 
 Section 8.1 of 
master 
protocol 
Brain imagingi 
X 
 
 
 
 
 
 
 
 
 
 
See  
Section 8.1 of 
master 
protocol 
VV-CLIN-0616195 4.0
144
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 18 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
IMP Administration 
(SAR444245 
administration) 
 
X 
 
 
X 
X 
 
 
 
 
 
 
Pembrolizumab 
Administration 
 
X 
 
 
X 
X 
 
 
 
 
 
 
AE/SAE assessmentj 
X 
Continuously throughout treatment period 
X 
 
 
 
See 
 Section 8.3 of 
master 
protocol 
Prior medication 
(within 28 days 
prior to first 
dose) 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
Continuously throughout treatment period 
 
 
 
 
See  
Section 6.8 of 
master 
protocol 
VV-CLIN-0616195 4.0
145
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 19 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
First subsequent 
anticancer therapy 
  
   
  
 
  
   
X 
X  
 X 
X  
X 
 
Survival status 
  
  
  
 
  
  
  
  
  
  
X 
 
a Evaluation: There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as part of screening within 3 days prior to first IMP administration. During the study treatment period, all 
assessments must be performed, and results should be reviewed by the investigator prior to IMP administration at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be 
collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are performed and can be signed more than 28 days prior to first IMP administration. Screening time 
indicates the maximum time frame relative to the first IMP administration in which assessments used to support eligibility are done. 
b Cycle: A treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the Cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation Period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1 of master protocol. For 
participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessments are performed. 
d Survival Phone Call Follow-Up Period: Participant who moves into the Survival Follow-up Period should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. 
Information on the first subsequent anticancer treatment, best reported response, and date of progression will also be collected. Updated survival status may be requested by the Sponsor at any time during the 
study. 
e Weight/Height: Height is required at baseline only. Weight is required at Screening and prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most 
recent weight assuming it was assessed in a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible 
considering the variability of local process from site to site.  If the infusion is prepared with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each 
cycle. 
f 
For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.8 of master protocol). 
VV-CLIN-0616195 4.0
146
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 20 
g If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
h CT/MRI: The initial tumor imaging will be performed within 28 days prior to the C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP or more frequently if clinically indicated in the first 
45 weeks. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging technique should be used in a participant throughout the trial. After 
Week 45 tumor imaging should be performed every 12 weeks (84 ±7 days). CT scan of the head, neck, chest and abdomen (pelvis is optional) and any other locations with suspicion or evidence of disease 
involvement is required for the baseline assessment and during treatment period until PD. After the first documentation of response or the first documentation of progression (if the participant is clinically stable) per 
RECIST 1.1, confirmatory imaging should be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor 
assessment is not needed for participants who start another anti-cancer therapy.  
i 
Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of 
the brain as a site of disease as per protocol tumor assessment schedule. In all other cases, the lesions must be treated. Two additional scans obtained at least 4 weeks apart, should be obtained to document 
disease stability AFTER local treatment administration to the brain metastases has been completed. If participants receive systemic therapy during these 4 weeks stabilization at the treating physician's discretion, 
this systemic therapy will be considered as part of prior anti-cancer therapy. Participants with previously treated brain metastases may participate provided they are stable, which is defined as lack of progression 
on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to 
baseline or resolved, and the participant is not using steroids for at least 14 days prior to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment. 
j 
AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5.0, ICANS and cytokine release syndrome (CRS) will be graded using ASTCT criteria integrated with central laboratory cytokine results 
(1). 
k Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) will be performed every 4 cycles during the Treatment period and as 
clinically indicated. 
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; ASTCT: American Society for Transplantation and Cellular Therapy; C: Cycle; CT: computed tomography; D: Day; ECG: electrocardiogram; ECOG: 
Eastern Cooperative Oncology Group; EOT: end-of-treatment; FT4: free thyroxine; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; HIV: human immunodeficiency virus; HPV: Human Papilloma virus; 
ICANS: Immune effector cell-associated neurotoxicity syndrome; ICF: informed consent form; IMP: investigational medicinal product; IRT: Interactive Response Technology; LVEF: left ventricular ejection fraction; 
MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer Institute-Common terminology criteria for adverse events; PD: progressive disease; PDy: pharmacodynamic; PK: pharmacokinetic; RECIST: 
Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SpO2: oxygen saturation; T3: triiodothyronine; TSH: thyroid stimulating hormone.  
VV-CLIN-0616195 4.0
147
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 21 
1.4 
BIOMARKER FLOWCHART 
VV-CLIN-0616195 4.0
148
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 22 
1.5 
PHARMACOKINETIC FLOWCHART 
Cycle 
Treatment Cycle 1 
Treatment Cycles 2, 
3, 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
30 (±7) days after last IMP 
admin
Day
D1 
D2 
D8 
D1
Time after start of 
SAR444245 dosing 
SOI 
EOI 
Any 
time 
Any time 
SOI 
EOI 
SAR444245 PK 
sample 
P00b 
P01 
P00b 
SAR444245 ADA 
sample 
AB00a 
AB01 
AB00a 
ABF00 
aa Samples collected strictly before start of infusion (SOI). 
b EOI samples must be taken at end of infusion (EOI) precisely ±5 minutes. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOI: end of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: start of infusion. 
VV-CLIN-0616195 4.0
149
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 23 
2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 in combination with various anticancer therapies by identifying early signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to Cohort A1 (participants with HNSCC who are treatment-naïve for 
R/M disease, PD-L1 CPS ≥1), for the combination of SAR444245 with pembrolizumab. 
Please refer to the master protocol for an introduction for ACT16903 study. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models while anti-PD-1 antibody prevents T cell suppression 
through the PD-1/PD-L1 pathway. The combination of anti-PD-1 treatment with SAR444245 was 
tested in a syngeneic mouse Ct-26 colon cancer model and demonstrated enhanced anti-tumor 
activity and prolonged survival compared to each monotherapy. These data support evaluation of 
SAR444245 in combination with pembrolizumab. 
2.2 
BACKGROUND  
2.2.1 Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across a 
number of indications.  
Refer to the approved local labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and renal cell carcinoma (RCC). Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses 
in cancers such as melanoma (3, 4). 
VV-CLIN-0616195 4.0
150
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 24 
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell
signaling cascade (6, 8, 9, 10). The mechanism by which PD1 down-modulates T cell responses is
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set
of signaling proteins (11, 12).
2.2.1.2 Pre-clinical trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(13, 14, 15, 16, 17, 18, 19). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (7, 16, 18, 19, 20). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo. Experiments 
have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see pembrolizumab 
Investigator’s brochure [IB]). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
2.2.2 Rationale for HNSCC and selected participant population 
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
151
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 25 
2.2.3 Current standard of care in HNSCC 
2.2.3.1 PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as first 
line therapy 
Anti-PD-1 therapy has recently been approved in the first line R/M setting. The Phase 3 
KEYNOTE-048 trial investigated pembrolizumab as 1st line therapy for the treatment of patients 
with R/M HNSCC (21, 22). This study randomized 882 patients to receive treatment in one of 
three arms: pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin or 
carboplatin and 5-FU) or the EXTREME regimen (cetuximab plus cisplatin or carboplatin and 
5-FU).
Pembrolizumab monotherapy significantly prolonged OS in patients with a CPS ≥1 (12.3 versus 
10.3 months, respectively; HR 0.78 with 95% confidence interval [CI] 0.64-0.96), and, in all 
patients irrespective of CPS, was non-inferior to standard of care (SOC) chemotherapy plus 
cetuximab with a non-inferiority boundary of 1.2. Although patients treated with pembrolizumab 
monotherapy had a lower ORR compared to patients treated with SOC (23% versus 36% for 
CPS ≥20, 19% versus 35% for CPS ≥1), duration of response (DOR) in patients treated with 
pembrolizumab monotherapy was longer compared to SOC for patients with CPS ≥1 (20.9 versus 
4.5 months). Overall, treatment with pembrolizumab monotherapy demonstrated a favorable 
safety profile with lower incidence of any grade, Grade 3-4, and Grade 5 treatment-related 
adverse events (TRAEs). Moreover, pembrolizumab plus platinum-based chemotherapy versus 
EXTREME significantly prolonged OS in the total patient population (13.0 versus 10.7 months, 
respectively; HR 0.77 [95% CI: 0.63-0.93]). There was a similar incidence of TRAEs and no 
unexpected toxicity due to addition of chemotherapy to checkpoint blockade. 
2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SAR444245 and other combinations may be found in the 
Investigator’s Brochure. 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with pembrolizumab results from anticipated risks for 
SAR444245 and from the label information for pembrolizumab, taking into account potential 
overlapping risks. The available safety data for pembrolizumab, along with proposed mitigation 
strategies are summarized below and also provided in Table 9. 
VV-CLIN-0616195 4.0
152
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 26 
2.3.1.1 Pembrolizumab 
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment. 
The use of pembrolizumab may cause infusion-related reactions (IRRs) (drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, hypersensitivity and cytokine release syndrome 
[CRS]). Pembrolizumab use may be associated with infections (pneumonia), bone marrow 
suppression (anemia, thrombocytopenia, leukopenia), increase in the level of hepatic enzymes 
(alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase), kidney damage 
(nephritis, acute kidney injury), as well as adverse effects on the functioning of nervous system 
(dizziness, headache, peripheral neuropathy, dysgeusia (very common) and lethargy). In 
combination therapy with other chemotherapeutic drugs, pembrolizumab administration is 
commonly associated with hypertension and cardiac arrhythmia (including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risk for pembrolizumab 
(23). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in post 
marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis. 
Please refer to pembrolizumab country-approved product labeling (eg, United States Package 
Insert [USPI], Summary of Product Characteristics [SmPC]) for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab 
Due to synergistic action of SAR444245 and pembrolizumab, combining these two substances 
may lead to an increased frequency and/or severity of adverse events (AEs) related to immune 
activation for each substance individually or may cause occurrences of qualitatively different 
AEs. Serious adverse drug reactions reported with agents known to increase immune activation 
include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction (see Section 2.3.1.1). 
VV-CLIN-0616195 4.0
153
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 27 
The maximum tolerated dose of SAR444245 combined with the approved dosing of the anti-PD1 
pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. Safety data 
generated from the combination of SAR444245 and pembrolizumab have informed the selection 
of the combination dose in this study. 
2.3.2 Benefit assessment  
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of CRs and prolonged survival 
which was durable as demonstrated by the failure of the tumor to grow upon re-engraftment on 
the tumor free animals, indicating the establishment of a durable memory T-cell population in 
response to the initial treatment (see SAR444245 IB).  
2.3.3 Overall benefit: risk conclusion  
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. Overall, the potential risks identified in association with this new generation IL-2 
SAR444245 combined with the anti PD1 inhibitor pembrolizumab are justified by the anticipated 
benefits that may be afforded to participants with HNSCC. 
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity.  
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was explored by 2 groups who did not find a clinically meaningful signal (24, 25). 
VV-CLIN-0616195 4.0
154
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 28 
3 
OBJECTIVES AND ENDPOINTS  
Please refer to the master protocol for description of objectives and endpoints.  
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
155
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 29 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This substudy will include participants with HNSCC who are treatment-naïve for R/M disease, 
PD-L1 CPS ≥1 and will assess SAR444245 combined with pembrolizumab. 
Overall, approximately 40 participants will be enrolled and treated in Cohort A1. 
The maximum number of cycles allowed in this Cohort A1 substudy is 35 cycles.  
Please refer to the master protocol for a full description of the study design and for therapy details 
applicable to all cohorts. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The proposed substudy aims to establish proof-of-concept that non-alpha IL-2 SAR444245 
combined with the anti-PD1 antibody pembrolizumab, will result in a significant increase in the 
percentage of trial participants with HNSCC experiencing an objective response. 
This regimen has been already tested and dose confirmed in first in human HAMMER 
study, therefore this substudy is designed to treat participants only in a core phase. 
Please refer to the master protocol for more information. 
4.2.1 Participant input into design  
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE  
4.3.1 SAR444245 dose  
Please refer to the master protocol. 
4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of data 
generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type. As outlined below, 
this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer 
(NSCLC) indications demonstrating flat dose- and exposure-efficacy relationships from 
2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 
7.5-fold exposure range (refer to the pembrolizumab IB) (23). 
VV-CLIN-0616195 4.0
156
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 30 
• Population pharmacokinetic (PK) analysis showing that both fixed dosing and weight-
based dosing provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W. 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications.  
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION  
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
157
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 31 
5 
STUDY POPULATION  
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort A1-specific criteria. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. PD-L1 expression CPS as determined preferably using a locally approved assay (with an 
absolute value provided to Sponsor) at local laboratory (for details on PD-L1 assay, please 
refer to lab manual) 
- 
PD-L1 expression CPS ≥1 (with an absolute value provided to Sponsor).  
I 02. Provision of tumor tissue: 
- 
Mandatory baseline biopsy in Core Phase (minimum 5 slides with 4-5 micron 
thickness for the first 20 participants who have signed ICF, excluding screening 
failure participants, minimum 10 slides with 4-5 micron thickness for subsequent 
participants). Archival tumor tissue samples should be obtained from biopsies done 
within 6 months, and there should be no systemic anti-cancer therapy between 
collection of biopsy and enrollment. Slides specifications are detailed in Lab Manual. 
- 
The Sponsor may approve the written request to enroll, on a case-by-case basis, 
participants with: 
- 
location of the tumor not amenable to biopsy due to significant risk, OR 
- 
less than required number of slides or archival tumor tissue sample collected 
more than 6 months prior to enrollment. 
I 03. Prior anticancer therapy 
- 
Have not received prior systemic therapy for R/M disease. Participants who received 
systemic therapy as part of multimodal treatment for locally advanced disease are 
eligible if the systemic therapy was completed at least 6 months prior to enrollment. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
Prior/concomitant therapy 
E 01. Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1 
pathway (participants who joined a study with an anti-PD-1/PD-L1 in the experimental 
arm but have written confirmation they have not received anti-PD-1/PD-L1 are allowed). 
VV-CLIN-0616195 4.0
158
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 32 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES  
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION]  
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
159
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 33 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
The maximum number of cycles allowed in this Cohort A1 substudy is 35 cycles. 
Dosing sequence: 
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245, and pembrolizumab 
administered as described in Section 4.1. Details of each IMP component to be administered are 
shown in Table 1.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.
Table 1 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
25 mg/mL 
Dosage level(s)a 
24 μg/kg Q3W 
200 mg Q3W 
Route of 
administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
IMP 
IMP 
Packaging and 
labeling 
See master protocol 
Supplied in single-dose vials containing 
100 mg/4 mL pembrolizumab labelled with a 
multilingual booklet. 1 vial per treatment box. 
Current/Former 
name(s) or alias(es) 
NA 
Keytruda 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the electronic 
case report form (e-CRF). Study sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min).
VV-CLIN-0616195 4.0
160
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 34 
6.1.2 Non-investigational medicinal product  
Please refer to the master protocol. 
6.1.3 Hydration guidelines for SAR444245 administration 
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome 
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules 
Dose modifications for SAR444245 is permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed. 
Once a dose has been decreased, intra-patient re-escalation back to the previous dose level is not 
permitted. 
VV-CLIN-0616195 4.0
161
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 35 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case, it is partial permanent discontinuation, and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued, it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay 
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administered ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3. After cycle delayed, such participants may be considered for treatment 
resumption once the toxicity resolves or improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
•
For Q3W IMP administration: If toxicity occurs and the participant does not recover on the
day of planned administration, the cycle will be delayed; restart of study IMPs could occur
only on the initiation of the subsequent cycle.
•
In case of cycle delay for the recovery of toxicity, the following rules should be followed
for restart or discontinuation of the treatment:
-
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the
study treatment.
-
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to restart
the study treatment, if a clear benefit from treatment is observed and after consultation
with the Sponsor.
-
The study treatment must be permanently discontinued if the cycle delay is longer than
84 days.
•
Cycle may be delayed for situations other than TEAEs such as medical/surgical events or
logistical reasons not related to study therapy. Participants should be placed back on study
therapy within 21 days of the scheduled delay, unless otherwise discussed with the Sponsor
(for example for national or regional emergencies). The reason for this delay should be
documented in the participant’s study record.
VV-CLIN-0616195 4.0
162
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 36 
6.5.3 General guidelines for the management of treatment-related adverse events 
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
will be required to temporarily cycle delay the IMP, unless specified otherwise in the protocol, 
and with the exception of the TRAEs resolving within 5 days. After cycle delay, such participants 
may be considered for treatment resumption once the TRAE resolves or improves to Grade 1 or 
baseline. Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to 
be in the best interest of the participant, except when specified otherwise in this protocol, or if the 
event has required the IMP temporary interruption for more than 84 days from the last scheduled 
dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
µg/kg to 
 µg/kg or another lower dose may be decided 
when specified in the protocol or following discussions with the Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific AEs including irAE, CRS, Vascular 
Leak Syndrome (VLS) and IRRs are presented in Section 6.5.4. 
6.5.4 Guidelines for the management of specific adverse events 
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF.
6.5.4.1 Infusion-related reactions (IRR) 
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An IRR in this study is defined as any signs or symptoms which develop during the infusion or up 
to 24 hours after the completion of the infusion. The term IRR indicates only a specific temporal 
relationship with the infusion and does not specify a particular mechanism underlying the signs or 
symptoms.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
VV-CLIN-0616195 4.0
163
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 37 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 2. 
After an IRR due to pembrolizumab infusion (Grade 3 or Grade 4), the SAR444245 infusion will 
be delayed and can be administered after resolution of symptoms. The Investigator should discuss 
with the Sponsor’s Medical Monitor if the SAR444245 infusion needs to be delayed more than 
1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 3. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
Table 2 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, 
IV fluids); prophylactic 
medications indicated for 
≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
•
IV fluids,
•
Antihistamines,
•
NSAIDs,
•
Acetaminophen,
•
Narcotics.
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr. to 50 mL/hr.). Otherwise dosing 
will be held until symptoms resolve and the participant 
should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
VV-CLIN-0616195 4.0
164
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 38 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; urgent 
intervention  indicated 
•
Stop Infusion.
Additional appropriate medical therapy may include but is 
not limited to: 
•
Epinephrine*,
•
IV fluids,
•
Antihistamines,
•
NSAIDs,
•
Acetaminophen,
•
Narcotics,
•
Oxygen,
•
Pressors,
•
Corticosteroids.
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
•
Hospitalization may be indicated.
*In cases of anaphylaxis, epinephrine should be used
immediately.
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration. 
Table 3 - SAR444245 Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary. 
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs 
as medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
Interrupt SAR444245 infusion. 
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion 
may be restarted at 50% of the original infusion rate. Otherwise dosing will be 
held until symptoms resolve and the participant will be premedicated for the 
next scheduled dose according to Section 6.1.2.1 of the master protocol. 
Give the next infusion at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics. 
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
VV-CLIN-0616195 4.0
165
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 39 
NCI CTCAE Grade 
Treatment 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae 
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination 
During or after completion of infusion, additional appropriate medical therapy may 
include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
Grade 4 
Life-threatening; urgent intervention indicated 
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, 
NSAIDs, acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
a Information for preparation and storage of SAR444245 are provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
6.5.4.2 Anaphylaxis 
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of SAR444245 being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines) 
(26, 27, 28). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS) 
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Monitoring of vital signs is detailed in Safety Assessments (Section 8.2.2). 
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 4. If any grade of CRS is suspected, sites should make every effort 
to draw an additional blood sample for cytokines levels (by central laboratory) prior to the 
administration of tocilizumab or alternative therapies per site practice in CRS management, as well as 
C-reactive protein (CRP) and ferritin (by local laboratory). 
Sites should have at least 2 full doses of tocilizumab or alternative therapies per site practice in 
CRS management available and access to an intensive care unit (ICU), in case participants 
develop CRS. 
VV-CLIN-0616195 4.0
166
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
Guidelines for management of CRS according to severity grading are provided in Table 4. 
ASTCT CRS consensus grading scale is provided in Section 10.13 of the master protocol. 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS)  
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less 
frequently as the participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Increase monitoring of vital signs, cardiac and other organ functions 
closely as medically indicated until the participant recovers. Transfer to 
ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, 
hypotension, or participants in whom symptoms (eg, high grade fever) that 
do not respond to antipyretics within 72 hours treatment with 
corticosteroids and/or tocilizumab or alternative therapies per site practice 
in CRS management should be considered, as per guidance for Grade 3 
events.  
IMP may be resumed when clinical symptoms have resolved or improved 
to Grade 1 and corticosteroid taper. No dose modification is required but 
decreasing to half the infusion rate can be considered. 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a vasopressor 
with or without vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
If CRS grade 3, temporarily cycle delay SAR444245, and resume subsequent 
treatment only when symptoms have resolved or improved to Grade 1. 
 SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated. 
 
 
 
If CRS Grade 4, permanently discontinue SAR444245. 
If CRS Grade 3 or Grade 4, initiate IV corticosteroids (outside of the 
context of CAR-T cells, corticosteroids alone maybe initiated in first 
intention) and tocilizumab or alternative therapies per site practice in CRS 
management considered, and/or epinephrine and/or other vasopressors 
should be administered as needed. Participants with severe CRS may 
require management in intensive care setting, with monitoring of clinical 
status and laboratory tests performed at least daily. 
As the participant improves, the intensity of the monitoring and setting can 
be decreased, but the participant should not be discharged from the 
hospital until clinically stable. Corticosteroids can then be administered 
IV or orally every 8 hours for up to 3 days, then tapered over 4 days. In 
VV-CLIN-0616195 4.0
167
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
general, tapering of steroids can start when vasopressors and high-flow 
oxygen are no longer needed.  
CRS is considered resolved when there is sustained resolution of fever 
and there is no longer a need for oxygen supplementation to relieve 
hypoxia nor vasopressors to maintain blood pressure; however, 
normalization of temperature alone does not define resolution of CRS. 
 
If no clinical improvement in oxygenation, hypotension, fever, and other 
CRS manifestations is observed within 24 to 72 hours, initiate 
management for persistent or worsening CRS. Re-evaluation for other 
contributing conditions will be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous Tocilizumab at 
8 mg/kg (for participants weighing ≥30 kg) or alternative therapies per site 
practice in CRS management should be administered, and steroids should 
be administered concurrently. If still no improvement in oxygenation, 
hypotension fever and other manifestations is observed after the first dose 
of tocilizumab, it may be repeated after an interval of at least 8 hours and 
should not exceed 4 doses in total. 
For participants with severe CRS who fail to improve after repetitive 
treatment with both tocilizumab or alternative therapies per site practice in 
CRS management and steroids, alternative options will be discussed with 
clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or alternative therapies per site practice in CRS management or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Immune-
related AEs (irAEs) are thought to be caused by unrestrained cellular immune responses directed 
at the normal host tissues. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing pembrolizumab clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of irAEs 
because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected irAEs, 
adequate evaluation should be performed to confirm etiology or exclude neoplastic, infectious, 
metabolic, toxin, or other etiologic causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and/or SAR444245 and administer corticosteroids. 
VV-CLIN-0616195 4.0
168
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 42 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 5. Of 
note, if the AE is considered immune-related, both drugs in the combination should be held 
according to recommended dose modifications. If a participant experiences several irAEs, the 
most conservative recommendation should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 5 the 
combination of SAR444245 and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered 
after communication with the Sponsor. 
Table 5 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245   
General instructions: 
1. 
Treat severe and life-threatening irAEs with IV corticosteroids followed by oral steroids. Begin other 
immunosuppressive treatment if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
Begin the corticosteroid taper when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the 
irAE decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Pneumonitis  
Grade 2 
Withholda  
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Add prophylactic antibiotics 
for opportunistic infections. 
Monitor participants for signs and 
symptoms of pneumonitis. 
Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment. 
Recurrent 
Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb  
VV-CLIN-0616195 4.0
169
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 43 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Monitor participants for signs and 
symptoms of enterocolitis (ie, diarrhea, 
abdominal pain, blood or mucus in 
stool with or without fever) and of 
bowel perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy 
to rule out colitis. 
Participants with diarrhea/colitis should 
be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake 
is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinueb 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb  
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Type 1 Diabetes 
Mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withholda,f 
Initiate insulin 
replacement therapy for 
participants with T1DM. 
Administer antihyperglycemic 
in participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
Hyperthyroidism  
Grade 2 
Continue 
Treat with nonselective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
Hypothyroidism 
Grade 2, 3, or 
4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per standard 
of care. 
Monitor for signs and symptoms of 
thyroid disorders. 
VV-CLIN-0616195 4.0
170
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 44 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg 
or equivalent) followed by 
taper. 
Monitor changes of renal function. 
Grade 3 or 4 
Permanently 
discontinueb  
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinueb  
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinueb 
All Other irAEs 
Persistent 
Grade 2 
Withholda 
Based on severity of AE 
administer 
corticosteroids. 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg 
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinueb 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x ULN if baseline normal;  
>1.5 to 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-
Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
6.5.4.5 Immune Cell-Associated Neurotoxicity Syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment of 
cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
VV-CLIN-0616195 4.0
171
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 45 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.13 of 
the master protocol). Recommendations for ICANS management mainly include the use of steroids, 
whereas tocilizumab or alternative therapies per site practice in CRS management should only be 
used in the context of CRS, as outlined in Table 6. The proposed management should be considered 
only as recommendations and in light of recommendations from site specialist. 
Table 6 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
Delay SAR444245a. 
Initiate treatment with IV corticosteroids as needed.  
SAR444245 may be resumed only after participant recovery or improvement 
to Grade 1 after corticosteroid taper. Consideration for reduction of 
SAR444245 dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 3 ICANS, delay SAR444245. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Section 6.5.4.3. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days. 
 
If Grade 4 ICANS, permanently discontinue SAR444245.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Section 6.5.4.3. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days.  
 
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) or alternative therapies per site practice in 
CRS management should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
VV-CLIN-0616195 4.0
172
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 46 
6.5.4.6 Vascular Leak Syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic, shock 
with multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a 
balance between maintaining the intravascular volume to ensure organ perfusion to prevent organ 
failure, while avoiding volume overload. The management of VLS according to severity grading 
is described in Table 7. These guidelines are not comprehensive and the Investigator should 
exercise clinical judgment based on the symptoms and condition of the individual participant and 
refer to current guidelines to the topic (29).  
Table 7 - Guidelines for the management of Vascular Leak Syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245   
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
Delay SAR444245. Upon resolution of VLS or improvement to Grade 1, 
SAR444245a can be resumed at the reduced dose of
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
If Grade 3 or Grade 4 VLS, permanently discontinue SAR444245.  
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. Supportive 
care with invasive and noninvasive ventilation as well as renal replacement 
may be necessary in severe cases. When available, disease-specific therapy 
should be initiated as soon as possible to facilitate recovery.  
During the recovery phase from severe capillary leak, the endothelial 
injury resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
VV-CLIN-0616195 4.0
173
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 47 
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245   
dose modification and supportive care guidelines 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY  
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE  
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
There is no specific antidote for overdose with pembrolizumab. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
6.8 
CONCOMITANT THERAPY  
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
174
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 48 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Please refer to the master protocol. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol. 
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
175
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 49 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol. 
8.1 
EFFICACY ASSESSMENTS 
Please refer to the master protocol.  
8.2 
SAFETY ASSESSMENTS 
8.2.1 Physical examinations  
Please refer to the master protocol. 
8.2.2 Vital signs 
•
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest
for the participant in a quiet setting without distractions (eg, television, cell phones).
•
Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be
measured after 5 minutes rest.
•
At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;
-
Vital signs will be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5)
hours after start of SAR444245 dose.
-
At Investigator’s discretion, participants (not in the safety run-in) may have intensive
vital sign monitoring (to be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5),
4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 20 (±1), 24 (±1) hours after start of SAR444245
dose in an in-patient setting).
•
For the core phase participants: from Cycle 2 to Cycle 4 study therapy will be
administered for all patients in out-patient clinic with vital signs taken at baseline, at least
4 to 6 hours after the start of SAR444245 dosing, or for longer periods of time if clinically
indicated.
8.2.3 Electrocardiograms and left ventricular ejection fraction (LVEF) 
Please refer to the master protocol.  
8.2.4 Clinical safety laboratory assessments 
Please refer to the master protocol.  
VV-CLIN-0616195 4.0
176
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 50 
8.2.5 Pregnancy testing  
Please refer to the master protocol. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort A1 irAEs will be collected until 90 days following last administration of 
study treatment regardless of whether or not another anticancer therapy is initiated.  
8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, serious adverse events (SAEs) that are considered expected will be specified 
in the reference safety information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy  
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
177
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 51 
In addition, symptomatic or asymptomatic overdose with pembrolizumab is described as below: 
•
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
178
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 52 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION 
Sample size: 
The plan is to treat a total of 40 participants in Cohort A1. Please refer to the master protocol for 
details on sample size. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol.  
9.5 
INTERIM ANALYSES 
In the core phase, periodic Data Monitoring Committees (DMCs) are planned (details are in the 
master protocol). 
The cohort cut-off for the primary ORR endpoint analysis corresponds to approximately 9 months 
from the date of the last participant’s first infusion (to document that last participant response is 
maintained for 6 months).  
VV-CLIN-0616195 4.0
179
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 53 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. 
Cohort A1-specific evaluations are presented in Table 8. 
Table 8 - Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
Tri-iodothyronine (T3) 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS  
Please refer to the master protocol. 
VV-CLIN-0616195 4.0
180
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 54 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS 
Please refer to the master protocol. 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Please refer to the master protocol. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Please refer to the master protocol. 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 9. 
Table 9 - Risk assessment 
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s)
Infusion-related 
reactions 
Pembrolizumab 
Common, but infusion-related reactions in labeling include drug 
hypersensitivity, anaphylactic reaction, anaphylactoid reaction, 
hypersensitivity and CRS. 
Pembrolizumab 
Dose modification and treatment 
guidelines for pembrolizumab 
infusion associated reactions are 
provided in Table 2. 
Hypersensitivity, 
including 
anaphylaxis
Pembrolizumab 
Not specifically reported but included among infusion-related 
reactions in label. 
Exclusion of participants with 
known hypersensitivity to any 
components of pembrolizumab. 
Infections
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master 
protocol. 
Hepatotoxicity
Pembrolizumab 
Pembrolizumab can cause immune-mediated hepatitis. Immune-
mediated hepatitis occurred in 0.7% (19/2799) of patients 
receiving pembrolizumab, including Grade 4 (<0.1%), Grade 3 
(0.4%), and Grade 2 (0.1%) adverse reactions. Systemic 
corticosteroids were required in 68% (13/19) of patients with 
hepatitis. Eleven percent of these patients required additional 
immunosuppressant therapy. Hepatitis led to permanent 
Dose modification and treatment 
guidelines for liver enzyme 
increase are provided under 
immune-related reactions in 
Table 5. 
VV-CLIN-0616195 4.0
181
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 55 
Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
discontinuation of KEYTRUDA in 0.2% (6) of patients and 
withholding of pembrolizumab in 0.3% (9) of patients. All patients 
who were withheld reinitiated pembrolizumab after symptom 
improvement; of these, none had recurrence of hepatitis. 
Hepatitis resolved in 79% of the 19 patients. 
Nephrotoxicity
Pembrolizumab 
Common: nephritis, acute kidney injury 
Dose modification and treatment 
guidelines for nephrotoxicity are 
provided under immune-related 
reactions in Table 5. 
Neurological AEs
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, dysgeusia (very 
common) and lethargy (common) for pembrolizumab in 
combination with chemotherapy  
Uncommon: epilepsy.  
Dose modification and treatment 
guidelines for neurological AEs are 
provided under immune-related 
reactions in Table 5. 
Immune-mediated 
Adverse Events
Pembrolizumab 
Immune-mediated adverse events are designated as important 
identified risk for pembrolizumab. 
Dose modification and treatment 
guidelines for immune-related 
reactions are provided in Table 5. 
Risks related 
to special 
populations 
Pregnancy and 
lactation exposure 
and outcomes
Pembrolizumab 
Pembrolizumab should not be used during pregnancy unless the 
clinical condition of the woman requires treatment with 
pembrolizumab. 
See master protocol for exclusion 
of participants, guidance on highly 
effective contraceptive methods, 
and pregnancy tests to be 
performed regularly. 
Drug-drug 
interactions
No data available. 
Overdose and its 
treatment 
No specific information is available on the treatment of overdose 
of pembrolizumab. 
See Section 6.7. 
10.11 APPENDIX 11: ABBREVIATIONS 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CI: 
confidence interval 
COVID-19: 
Coronavirus disease 2019 
CPS: 
Combined Positive Score 
CR: 
complete response 
CRS: 
cytokine release syndrome 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
e-CRF:
electronic case report form 
EOT:
end of treatment 
FDA:
Food and Drug Administration 
VV-CLIN-0616195 4.0
182
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 56 
HNSCC: 
head and neck squamous cell carcinoma 
IB: 
Investigator's brochure 
ICANS: 
Immune cell-associated neurotoxicity syndrome 
ICU: 
intensive care unit 
Ig: 
immunoglobulin 
IMP: 
investigational medicinal product 
irAEs: 
immune-related AEs 
IRR: 
infusion-related reactions  
IV: 
intravenous 
LVEF: 
left ventricular ejection fraction 
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NSCLC: 
non-small cell lung cancer 
PBPK: 
physiologically-based PK 
PD1: 
programmed cell death-1 
PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death ligand 2 
PK: 
pharmacokinetic 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
R/M: 
recurrent and/or metastatic 
SAEs: 
serious adverse events 
SoA: 
schedule of activities 
SOC: 
standard of care 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
TRAEs: 
treatment-related adverse events 
VLS: 
Vascular Leak Syndrome 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).  
Amended protocol 01 (26 July 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth 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 overall rationale for the amendment is to respond to the Health Authorities (Food and Drug 
Administration, [FDA]) requests. 
VV-CLIN-0616195 4.0
183
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 57 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.4 Guidelines 
for the management of 
specific adverse events 
For clarity and brevity, command language has 
been used in the toxicity management sections. 
Regulatory Authorities (FDA) request 
Section 6.5.4.1 Infusion-
related reactions (IRR)  
In Table 3 the following text has been revised: 
Under Grade 3 and Grade 4:  
- “prematurely” deleted from “prematurely
permanently discontinued”.
- “clearly attributable” deleted from “If IRR is clearly
attributable to SAR444245” as the table title
already indicates treatment with regards to
SAR444245 IRRs.
Under Grade 2, Grade 3 and Grade 4: “if 
applicable” deleted in the sentence that reads 
“SAR444245 infusion should be interrupted if 
applicable”. 
Regulatory Authorities (FDA) request 
In Table 2 and Table 3, the following text “requires 
therapy or infusion interruption” has changed to 
“Therapy or infusion interruption indicated', and 
“pressor or ventilator support indicated” has been 
changed to “urgent intervention indicated''.  
For consistency with Common terminology 
criteria for adverse events (CTCAE) 
guidelines (version 5) 
Section 6.5.4.1 Infusion-
related reactions (IRR) 
and Section 10.10 Risk 
assessment (Table 9) 
The text “SAR444245 infusion-associated reaction” 
was changed to “SAR444245 infusion-related 
reaction”. 
For consistency 
Section 6.5.4.3 Fever, flu-
like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 4 the following text “If subsequent 
administration is tolerated, increasing the 
SAR444245 dose to 
 µg/kg at subsequent 
administration can be considered based on the 
clinical judgement of the Investigator with the 
Sponsor” has been removed for Grade 3.  
Regulatory Authorities (FDA) request 
For Grade 3, the following sentence has been 
changed from “If CRS grade 3, temporarily cycle 
delay SAR444245, and resume subsequent 
treatment only when symptoms have resolved or 
improved to Grade 1 at 
 µg/kg or permanently 
discontinued, as clinically indicated” to “If CRS 
grade 3, temporarily cycle delay SAR444245, and 
resume subsequent treatment only when 
symptoms have resolved or improved to Grade 1. 
SAR444245 can be either restarted at 
 µg/kg or 
permanently discontinued, as clinically indicated”. 
For Grade 4 “as clinically indicated” has been 
removed from the subtitle. 
The following sentence has been added: 
“Monitoring of vital signs is detailed in 
Section 8.2.2” for clarity. 
For consistency and clarity 
VV-CLIN-0616195 4.0
184
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 58 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
In Table 6 the following text has been added under 
Grade 3 ICANS: “Treatment with IV corticosteroids 
should be initiated. Concomitant CRS may require 
tocilizumab and should be handled as described in 
Section 6.5.4.3. Corticosteroids can then be 
administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days.” 
Regulatory Authorities (FDA) request 
The following text “diffuse cerebral edema” has 
been revised to “signs of diffuse cerebral edema”. 
For consistency with the American Society 
for Transplantation and Cellular Therapy 
(ASTCT) Consensus 
Sections 8.2.1 Physical 
examinations, Section 
8.2.2 Vital signs, Section 
8.2.3 Electrocardiograms, 
Section 8.2.4 Clinical 
safety laboratory 
assessments, and 
Section 8.2.5 Pregnancy 
testing 
Sections newly inserted. 
For clarity 
Section 8.2.2 Vital signs 
Details regarding monitoring of vital signs provided 
in the Master protocol have been added. 
Regulatory Authorities (FDA) request 
Section 10.10: Appendix 
10: Risk assessment 
In Table 9 assessment under hepatoxicity for 
pembrolizumab was revised to be aligned with the 
last version of USPI warnings and precautions for 
pembrolizumab. 
Regulatory Authorities (FDA) request 
Throughout the document 
Minor editorial corrections were made. 
Changes made for consistency 
VV-CLIN-0616195 4.0
185
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 59 
Amended protocol 02 (19 August 2021) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to add a new study cohort (Cohort A2, substudy 
protocol 02) and clarify the priority of recruitment of participants between Cohorts A1 and A2 
(see Master protocol). Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Columns indicating D8 (±1) and D15 (±1) for treatment cycle 2 
and treatment cycle 3 and beyond were removed.
Change made for correction 
“IMP Administration (SAR444245 Administration)” has been 
changed to “SAR444245 Administration” with a reference to 
the master protocol. 
Change made for clarification 
Section 5.1 Inclusion 
criteria 
In I06 “participants with less than required number of slides or 
archival tumor tissue sample collected more than 6 months 
prior to screening” has been revised to “participants with less 
than required number of slides or archival tumor tissue sample 
collected more than 6 months prior to enrollment”   
Harmonization per program 
level approach 
Section 6.5.2 Cycle delay, 
and Section 6.5.3 General 
guidelines for the 
management of treatment-
related adverse events 
The following text regarding the treatment resumption after 
cycle delay has been deleted: “or is stable and manageable 
through supportive/medical therapy”.
Change made for correction 
Section 6.5.3 General 
guidelines for the 
management of treatment-
related adverse events 
The name “Study Committee” has been changed to “Study 
Board”.
Change made to ensure clarity 
and avoid confusion with any 
Independent Committee 
Section 6.5.4.1 Infusion-
related reactions (IRR) 
In Table 3 under Grade 3 and Grade 4, the following text 
“Interrupt SAR444245 infusion” has been removed. 
Change made for clarification 
Section 8.2.3 
Electrocardiograms and 
left ventricular ejection 
fraction (LVEF) 
The following text: “and left ventricular ejection fraction (LVEF)” 
has been added to the naming of the section. 
Change made for clarification 
Throughout the document 
Minor editorial corrections were made. 
Changes made for consistency 
VV-CLIN-0616195 4.0
186
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 60 
11 
REFERENCES 
1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT
consensus grading for cytokine release syndrome and neurologic toxicity associated with
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38
2. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531-8.
3. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol.
2005;23(10):2346-57.
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med.
2008;358(25):2698-703.
5. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol.
2005;23:515-48.
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71.
7. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47.
8. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol.
2004;173(2):945-54.
9. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooter J, et al. PD-1 inhibits T-cell
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41.
10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25.
11. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al.
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol.
2005;25(21):9543-53.
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.
Immunol Rev. 2010;236:219-42.
13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res.
2005;65(3):1089-96.
VV-CLIN-0616195 4.0
187
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 61 
14. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the 
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
15. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9. 
16. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade 
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 
2003;63(19):6501-5. 
17. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2:3. 
18. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
19. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
20. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7. 
21. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al. KEYNOTE-
048: phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck 
squamous cell carcinoma (R/M HNSCC) (abstract). Oncology Pro. 2018. 
22. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al. 
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for 
recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a 
randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-28. 
23. Keytruda® European Public Assessment Report, Risk Management Plan Summary , last 
updated 18 June 2020. [Online]. [Cited 01 Jun 2021]. Available from: 
URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda 
24. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al. 
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, 
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 
2021;2(1):100124. 
VV-CLIN-0616195 4.0
188
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 62 
25. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov.
2020;10(8):1121-8.
26. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
27. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol.
2017;28(suppl 4):iv100-18.
28. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014;69(8):1026-45.
29. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology,
and management. Kidney Int. 2017;92(1):37-46.
30. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol.
2005;23(10):2346-57.
31. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med.
2008;358(25):2698-703.
32. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol.
2005;23:515-48.
33. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71.
34. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47.
35. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol.
2004;173(2):945-54.
36. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooter J, et al. PD-1 inhibits T-cell
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41.
VV-CLIN-0616195 4.0
189
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 63 
37. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25.
38. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al.
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol.
2005;25(21):9543-53.
39. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.
Immunol Rev. 2010;236:219-42.
40. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res.
2005;65(3):1089-96.
41. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer
Res. 2004;64(3):1140-5.
42. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9.
43. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res.
2003;63(19):6501-5.
44. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored
IL-2 production and proliferation of CD8(+) T cells directly within the tumor
microenvironment. J Immunother Cancer. 2014;2:3.
45. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80.
46. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J
Immunol. 2010;184(7):3442-9.
47. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7.
48. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al. KEYNOTE-
048: phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck
squamous cell carcinoma (R/M HNSCC) (abstract). Oncology Pro. 2018.
49. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al.
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for
VV-CLIN-0616195 4.0
190
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 01) 
SAR444245-ACT16903-S01  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 64 
recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a 
randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-28. 
50. Keytruda® European Public Assessment Report, Risk Management Plan Summary , last
updated 18 June 2020. [Online]. [Cited 01 Jun 2021]. Available from:
URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
51. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al.
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence,
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep.
2021;2(1):100124.
52. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov.
2020;10(8):1121-8.
53. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7.
54. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol.
2017;28(suppl 4):iv100-18.
55. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014;69(8):1026-45.
56. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology,
and management. Kidney Int. 2017;92(1):37-46.
VV-CLIN-0616195 4.0
191
VV-CLIN-0701966 1.0

Signature Page for VV-CLIN-0616195 v4.0
act16903-16-1-1-amended-protocol03-substudy01
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0616195 4.0
192
VV-CLIN-0701966 1.0

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 02) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab and 
cetuximab for the treatment of recurrent/metastatic (R/M) 
head and neck squamous cell carcinoma (HNSCC) 
treatment-naïve participants for R/M disease, programmed 
cell death-ligand 1 (PD-L1) combined positive score (CPS) 
≥1 
Protocol number: 
ACT16903-S02 
Amendment number: 01 
Compound number 
(INN/Trademark): 
SAR444245  
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab and 
cetuximab for the treatment of R/M HNSCC treatment-naïve 
participants for R/M disease, PD-L1 CPS ≥1 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin, 
France 
Monitoring team’s 
representative name 
and contact 
information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
IND156423 
2021-002105-99 
NCT05061420
U1111-1251-5073 
Date: 
22-Dec-2021
Total number of pages: 74 
VV-CLIN-0624549 1.0
193
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01 (Substudy 02)  
All 
22 December 2021, version 1 (electronic 1.0) 
Clinical Trial Protocol (Substudy 02)  
All 
19 August 2021, version 1 (electronic 1.0) 
Amended protocol 01 (22 December 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Spanish (Agency for Medicine and 
Health Products [AEMPS]), Italian (Medicines Agency [AIFA]) and German (Federal Institute for 
Drugs and Medical Devices [BfArM]) Health Authorities after initial review. Other changes have 
been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 4.1 Overall 
Design, and 9.3 
Populations for Analyses 
The definition of DLT-evaluable participants has been updated 
to “all participants in the safety run-in part who have been 
treated and observed for at least 21 days. Any participant who 
experienced a DLT at any time during the first 21 days will also 
be DLT-evaluable.” 
Per harmonization across 
program 
1.3 Schedule of activities 
(SoA) 
Table of SoA for this substudy has been updated with 
procedures taken from the master protocol. Footnotes have 
been added and abbreviation list has been updated. 
For clarity and consistency 
For electrolytes, “weekly under treatment and then at the EOT, 
at FU visit 1” has been removed, and a cross has been 
presented for appropriate times instead. 
For clarification 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up visit 1. 
To allow assessments of any 
potential cardiotoxicity 
VV-CLIN-0624549 1.0
194
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
1.4 Biomarker flow-chart 
and 1.5 Pharmacokinetic 
flow-chart 
Complete biomarker and pharmacokinetic flow-charts applicable 
for this substudy have been provided with procedures taken 
from the master protocol. 
For clarity and consistency 
1.4 Biomarker flowchart: 
footnote c, 6.5.4.3 Fever, 
flu-like symptoms and 
cytokine-release 
syndrome (CRS) and 
6.5.4.6 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
1.5.1 A2 Cohort 
The cetuximab PK sample identification labelling has been 
changed from “P00” to “SC00” at start of infusion (SOI) and from 
“P01” to “SC01” at end of infusion (EOI). The cetuximab PK 
sample identification labelling “SC02” has been provided at D3 
of cycle 1 for participants in the safety run-in who have a Day 3 
visit. 
Change made for correction and 
clarity 
1.3 Schedule of activities 
(SoA): footnote f, 
5.1 Inclusion Criteria: I03 
and 10.7.1 Amendment for 
Germany 
The following country-specific requirement has been added: 
“German participants will not be enrolled in Cohort A2 substudy 
02”. 
To specify that German 
participants cannot be included 
in this substudy  
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome (CRS) 
Information on cytokine-release syndrome (CRS) reported with 
cetuximab and recommended guidelines for management have 
been added. A column mentioning "Recommended Cetuximab 
dose modifications and supportive care guidelines" has been 
added to Table 9. 
To add recommended 
guidelines for management of 
CRS reported with cetuximab  
6.5.4.6 Immune Cell-
Associated Neurotoxicity 
Syndrome  
In Table 12 under Grade 4, “signs of” has been removed before 
“diffuse cerebral edema on neuroimaging”.
Change made for consistency 
with the American Society for 
Transplantation and Cellular 
Therapy (ASTCT) Consensus 
and correction 
10.1 Appendix 1: 
Regulatory, ethical, and 
study oversight 
considerations  
A new subsection 10.1.6 entitled “Dissemination of clinical study 
data” has been added with the following text: “Study participants 
results summaries will be provided in any one of the clinical trial 
portals after completion of the substudy, until the end of study”.  
Per CTFG guidance 2019: 
Recommendation Paper on the 
Initiation and Conduct of 
Complex Clinical Trials 
10.10 Appendix 10: Risk 
assessment 
The following wording has been added: “For pembrolizumab and 
cetuximab, the information below is per currently available USPI 
and EU SmPC. Please always refer to the latest version of the 
SAR444245 IB and pembrolizumab and/or cetuximab local label 
for the most up-to-date safety data”. 
To refer to the latest version of 
IB or local label for the safety 
data 
10.11 Appendix 11: 
Abbreviations 
List of abbreviations has been revised. 
For consistency 
11 References 
List of references has been updated. 
For consistency 
Throughout the document 
Minor editorial corrections were made. 
For consistency 
VV-CLIN-0624549 1.0
195
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 4 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 02) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 8 
1 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 14 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 15 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 20 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 21 
1.5.1 
A2 Cohort ....................................................................................................................................... 21 
2 
INTRODUCTION ............................................................................................................................ 22 
2.1 
STUDY RATIONALE...................................................................................................................... 22 
2.1.1 
Cohort A2: triplet combination of SAR444245, pembrolizumab and cetuximab ............................ 22 
2.2 
BACKGROUND ............................................................................................................................. 22 
2.2.1 
Pembrolizumab .............................................................................................................................. 22 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 23 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 23 
2.2.2 
Cetuximab ...................................................................................................................................... 24 
2.2.3 
Rationale for HNSCC and selected participant population ............................................................ 24 
2.2.4 
Current standard of care in HNSCC .............................................................................................. 24 
2.2.4.1 
PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as first line therapy ...... 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 25 
2.3.1.2 
Cetuximab ...................................................................................................................................... 26 
2.3.1.3 
SAR444245 combined with pembrolizumab and cetuximab ......................................................... 27 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
VV-CLIN-0624549 1.0
196
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 5 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 28 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 33 
4.2.1 
Participant input into design ........................................................................................................... 33 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 33 
4.3.1 
SAR444245 dose ........................................................................................................................... 33 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 33 
4.3.3 
Cetuximab dose ............................................................................................................................. 34 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 34 
5 
STUDY POPULATION .................................................................................................................. 35 
5.1 
INCLUSION CRITERIA .................................................................................................................. 35 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 35 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 36 
5.4 
SCREEN FAILURES...................................................................................................................... 36 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION] ....................................................................................................................... 36 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 37 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 37 
6.1.1 
Investigational medicinal product ................................................................................................... 37 
6.1.2 
Non-investigational medicinal product ........................................................................................... 38 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 38 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 38 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 38 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 39 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 39 
6.5 
DOSE MODIFICATION .................................................................................................................. 39 
VV-CLIN-0624549 1.0
197
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 6 
6.5.1 
General rules .................................................................................................................................. 39 
6.5.2 
Cycle delay and dose omission ..................................................................................................... 39 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 41 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 41 
6.5.4.1 
Infusion-related reactions ............................................................................................................... 41 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 44 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 45 
6.5.4.4 
Immune-related adverse events .................................................................................................... 49 
6.5.4.5 
Dermatologic toxicity ...................................................................................................................... 52 
6.5.4.6 
Immune Cell-Associated Neurotoxicity Syndrome ......................................................................... 53 
6.5.4.7 
Vascular Leak Syndrome (VLS) ..................................................................................................... 54 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY ............................... 55 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 55 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 56 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 57 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 57 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 57 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 57 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 58 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 58 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 58 
8.2.1 
Physical examinations ................................................................................................................... 58 
8.2.2 
Vital signs ....................................................................................................................................... 58 
8.2.3 
Electrocardiograms and left ventricular ejection fraction (LVEF) ................................................... 58 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 58 
8.2.5 
Pregnancy testing .......................................................................................................................... 58 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 59 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 59 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 59 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 59 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 59 
8.3.5 
Pregnancy ...................................................................................................................................... 59 
8.3.6 
Cardiovascular and death events .................................................................................................. 59 
VV-CLIN-0624549 1.0
198
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 7 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 59 
8.3.8 
Adverse event of special interest ................................................................................................... 59 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 60 
8.4 
PHARMACOKINETICS .................................................................................................................. 60 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 60 
8.6 
BIOMARKERS ............................................................................................................................... 60 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 60 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 60 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 60 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 61 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 61 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 61 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 61 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 61 
9.4.1 
General considerations .................................................................................................................. 61 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 61 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 62 
9.4.3.1 
Adverse events .............................................................................................................................. 62 
9.4.3.2 
Other secondary endpoints ............................................................................................................ 62 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 62 
9.5 
INTERIM ANALYSES .................................................................................................................... 62 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 63 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 63 
10.1.6 
Dissemination of clinical study data ............................................................................................... 63 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 63 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 63 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 63 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 64 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 64 
VV-CLIN-0624549 1.0
199
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 8 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 64 
10.7.1 
Amendment for Germany ............................................................................................................... 64 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 64 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 64 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 64 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 69 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 71 
11 
REFERENCES ............................................................................................................................... 72 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 10 
Table 2 - Objectives and endpoints ............................................................................................................... 29 
Table 3 - Dose escalation rule of the modified toxicity probability interval-2 method ................................... 31 
Table 4 - Overview of IMP administered ....................................................................................................... 37 
Table 5 - Dose levels for cetuximab dose reduction ..................................................................................... 40 
Table 6 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 42 
Table 7 - Cetuximab Infusion-related reaction dose modification and treatment guidelines ........................ 43 
Table 8 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 44 
Table 9 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 46 
Table 10 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 50 
Table 11 - Cetuximab dose modification for dermatologic toxicities ............................................................. 53 
Table 12 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) . 53 
Table 13 - Guidelines for the management of Vascular Leak Syndrome (VLS) ........................................... 55 
Table 14 - Populations for analyses .............................................................................................................. 61 
Table 15 - Protocol-required laboratory assessments .................................................................................. 63 
Table 16 - Risk assessment .......................................................................................................................... 65 
 
LIST OF FIGURES 
Figure 1 - Overall Substudy schema ............................................................................................................. 14 
 
VV-CLIN-0624549 1.0
200
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Substudy A2-
specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab and cetuximab for the 
treatment of recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) 
treatment-naïve participants for R/M disease, programmed cell death-ligand 1 (PD-L1) combined 
positive score (CPS) ≥1 
Brief title: 
A study of SAR444245 combined with pembrolizumab and cetuximab for the 
treatment of R/M HNSCC treatment-naïve participants for R/M disease, PD-L1 
CPS ≥1 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 1 
(PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in 
the syngeneic murine colon cancer CT-26 model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
Collectively, the combination of SAR444245 with pembrolizumab and cetuximab is supported by: 
a) increase in natural killers (NK) cells by SAR444245 b) the ability of cytokines such as IL-2 to 
improve the antibody-dependent cellular cytotoxicity (ADCC) response of cetuximab and c) 
addition of an anti-PD-1 to prevent PD-1/L-1 inhibition of infiltrating cytotoxic immune cells. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with pembrolizumab and cetuximab will result in a significant increase in the percentage of 
patients with HNSCC experiencing an objective response. 
VV-CLIN-0624549 1.0
201
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 10 
Objectives and endpoints 
Please refer to the master protocol for description of objectives and endpoints common to all 
study cohorts. Substudy-specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Secondary 
 
To confirm the dose of SAR444245 when combined with 
cetuximab and pembrolizumab 
Incidence of dose-limiting toxicities (DLT) 
To assess the concentrations of cetuximab  
Concentrations of cetuximab 
Overall design: 
Please refer to the master protocol. 
Brief summary:  
Cohort A2: This substudy will include participants with HNSCC who are treatment-naïve for 
R/M disease, PD-L1 CPS ≥1 and will assess SAR444245 combined with pembrolizumab and 
cetuximab. 
A safety run-in will confirm the dose of SAR444245 when combined with pembrolizumab and 
cetuximab in a sample of at least 6 participants. After recruitment of the first 10 participants, 
enrollment will be paused if a total of at least 6 participants are evaluable for dose-limiting 
toxicities (DLT). Safety data for these participants will be reviewed by the Study Board (SB) 
comprising the Investigators or designees participating in the safety run-in part of the trial and the 
Sponsor clinical team members. DLT-evaluable participants include all participants in the safety 
run-in part who have been treated and observed for at least 21 days. Any participant who 
experienced a DLT during the first 21 days will also be DLT-evaluable. If no safety concerns are 
identified by the SB, participant enrollment will continue. 
If after recruiting the first 10 participants there are fewer than 6 participants evaluable for DLT, 
more participants will be enrolled to ensure at least 6 DLT evaluable participants after agreement 
from Study Board. Participants who are enrolled in the safety run-in and treated at the confirmed 
safe dose will be included in the total number of participants. 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an IV infusion over 
30 minutes every 3 weeks (Q3W) on Day 1 of each cycle (21 days per cycle). Overall safety 
monitoring will be performed throughout the study. If recommended by the SB, SAR444245 dose 
may be reduced to 
μg/kg or another lower dose level which will be explored following the 
same process described in the safety run-in for 24 μg/kg dose level. 
The dose confirmation will follow modified toxicity probability interval 2 (mTPI2) design. 
VV-CLIN-0624549 1.0
202
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 11 
Dose limiting toxicity: Selected events occurring during the DLT observation period (21 days of 
first cycle) are considered as DLT unless due to disease progression or to a cause obviously 
unrelated to study drugs. Please refer to the full list of events in Section 4.1. Based on the 
occurrence of DLT and overall assessment of safety data supplemented with data from other 
SAR444245 studies, the Study Board will determine if the dose of SAR444245 needs to be 
reduced to 
 μg/kg or another lower dose level, in agreement with the Sponsor. 
A graphical presentation of the study schema is shown in Figure 1. 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated at the confirmed safe dose in 
Cohort A2.  
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration. 
Study intervention(s) 
Cohort A2: R/M HNSCC treatment-naïve for R/M disease, PD-L1 CPS ≥1, SAR444245 
+ pembrolizumab + cetuximab
Dosing sequence: 
Investigational medicinal product(s) 
Pembrolizumab 
•
Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in single-
dose vials.
•
Route of administration: intravenous (IV) infusion.
•
Dose regimen: Pembrolizumab will be administered at a dose of 200 mg using a 30-minute
IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles.
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window between 
-5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min).
VV-CLIN-0624549 1.0
203
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 12 
Cetuximab 
• Formulation:  
- 
a clear, colorless solution for injection provided as 100 mg/50 mL (2 mg/mL) or 
200 mg/100 mL in a single-dose vial 
or 
- 
100 mg/20 mL or 500 mg/100 mL 
or 
- 
any other cetuximab formulation approved locally. 
• Route of administration: IV infusion.  
• Dose regimen: cetuximab will be given on Cycle 1 Day 1 as an initial loading dose of 
400 mg/m2 infused over 120 minutes (maximum infusion rate 10 mg/min or as per local 
practice and labels) followed by weekly 250 mg/m2 infused over 60 minutes (maximum 
infusion rate 10 mg/min) for all subsequent doses starting with the Cycle 1 Day 8 
administration, until progressive disease (PD). 
SAR444245 
• Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion 
in a single-dose vial with an extractable volume of 1 mL. 
• Route of administration: IV infusion.  
• Dose regimen: 24 μg/kg (or reduced to 
μg/kg Q3W or another lower dose level 
recommended by Study Board) administered as an IV infusion over 30 mins every 
3 weeks on Day 1 of each cycle (21 days per cycle) for up to 35 cycles.  
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
Non-investigational medicinal products 
Please refer to the master protocol for SAR444245 premedication. 
Premedication for cetuximab 
All participants who will receive cetuximab should be pre-medicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab, or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior infusion reactions (IR). 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication.  
VV-CLIN-0624549 1.0
204
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 13 
Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. Cohort A2 
specific analysis: 
• Analysis of other secondary endpoints: 
Plasma concentrations of cetuximab will be summarized with descriptive statistics. 
For Cohort A2, the cohort cut-off for the primary objective response rate (ORR) endpoint 
analyses is estimated to be approximately 9 months from the date of the last participant’s first 
infusion in the core phase (to document that last participant response is maintained for 6 months 
in the core phase). 
Data Monitoring Committee: Yes 
VV-CLIN-0624549 1.0
205
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 14
1.2 
SCHEMA 
Figure 1 - Overall Substudy schema 
CPS: Combined Positive Score; HNSCC: head and neck squamous cell carcinoma; N: number of participants; PD-L1: programmed death ligand 1; pembro: pembrolizumab; Tx: treatment; R/M: recurrent/metastatic.
VV-CLIN-0624549 1.0
206
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Elements of the schedule of activities (SoA) common to all cohorts are detailed in the master protocol. Cohort A2-specific evaluations are 
presented in this table.  
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to 
D-1 
D1  D2 D3l D8 
(±1) 
D15 
(±1)  
D1 
(±3) 
D8 
(±1)  
D15 
(±1) 
D1 
(±3) 
D8 
(±1)  
D15 
(±1)  
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin  
±7 days 
Every 
3 months 
±7 days 
Every 
3 months  
±14 days 
 
Informed consent 
Inclusion/Exclusion 
criteria 
X 
   
 
 
  
 
  
 
 
   
 
 
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Demography, 
medical/surgical 
and disease history 
X 
   
 
 
  
 
  
 
 
    
 
 
  
  
  
  
 
See Section 8 of 
master protocol  
Full physical 
examination 
X 
  
 
 
  
 
  
 
 
 
 
 
X 
  
 
  
  
 
Directed physical 
examination 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
See Section 8.2.1 
of master 
protocol  
Body 
weight/Heighte 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
 
 
 
VV-CLIN-0624549 1.0
207
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 16 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1 D2 D3l D8 
(±1) 
D15 
(±1)  
D1 
(±3) 
D8 
(±1)  
D15 
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See 
Section 8.2.2 of 
master protocol & 
Section 8.2.2 
SpO2 
X 
As clinically indicated 
Hospitalizationm 
X 
Performance status 
(ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
As clinically indicated 
See Section 8.2.3 
of master protocol 
LVEF 
X 
As clinically indicated 
See Section 8.2.3 
of master protocol 
Laboratory assessments 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically indicated 
See Section 8.2.3 
& Section 10.2 of 
master protocol 
Pregnancy test 
X 
X 
X 
X 
X 
X 
X 
See Section 8.2.5, 
Section 8.3.5 & 
Section 10.2 of 
master protocol 
Blood chemistry/ 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 10.2 
of master protocol 
Electrolytes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
as clinically indicated 
VV-CLIN-0624549 1.0
208
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 17 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1 D2 D3l D8 
(±1) 
D15 
(±1)  
D1 
(±3) 
D8 
(±1)  
D15 
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
T3, FT4, TSH, and 
cortisol 
X 
X 
X 
X 
X 
See Section 10.2 
Coagulation 
X 
As clinically indicated 
See Section 10.2 
of master protocol 
Urinalysisk 
X 
X 
X 
X 
X 
See Section 10.2 
of master protocol 
Hepatitis serology 
CD4 counts & Viral 
Load 
 Xf 
As clinically indicated 
See Section 10.2 
of master protocol 
HPV p16 status for 
participants with 
oropharyngeal 
cancer 
X 
PK 
See PK Flow-Chart in Section 1.5 
ADA 
See PK Flow-Chart in Section 1.5 
Exploratory biomarkers 
PDy - Blood and 
tumor tissue 
collectiong
See Section 1.4 
VV-CLIN-0624549 1.0
209
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 18 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1 D2 D3l D8 
(±1) 
D15 
(±1)  
D1 
(±3) 
D8 
(±1)  
D15 
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Disease assessment 
CT/MRIh 
X 
X 
X 
X 
X 
X 
See Section 8.1 
of master protocol 
Brain imagingi 
X 
See Section 8.1 
of master protocol 
SAR444245 
administration 
X 
X 
X 
Cetuximab 
administration 
X 
Xn 
Xn 
X 
Xn 
Xn 
X 
Xn 
Xn 
Pembrolizumab 
administration 
X 
X 
X 
AE/SAE 
assessmentj 
X 
Continuously throughout treatment period 
X 
See Section 8.3 
of master protocol 
Prior medication 
X (within 
28 days 
prior to first 
dose) 
Concomitant 
medication 
Continuously throughout treatment period 
See Section 6.8 
of master protocol 
First subsequent 
anticancer therapy 
X 
X 
 X 
X 
X 
Survival status 
X 
VV-CLIN-0624549 1.0
210
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 19 
a Evaluation: There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as part of screening within 3 days prior to first IMP administration. During the study treatment period, all 
assessments must be performed, and results should be reviewed by the investigator prior to IMP administration at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be 
collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are performed and can be signed more than 28 days prior to first IMP administration. Screening time 
indicates the maximum time frame relative to the first IMP administration in which assessments used to support eligibility are done. 
b Cycle: A treatment cycle is 21 days. See details in Section 6.1 of master protocol for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed 
according to the Cycle number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation Period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1 of master protocol. For 
participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessments are performed. 
d Survival Phone Call Follow-Up Period: Participant who moves into the Survival Follow-up Period should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. Information on the 
first subsequent anticancer treatment, best reported response, and date of progression will also be collected. Updated survival status may be requested by the Sponsor at any time during the study. 
e Weight/Height: Height is required at baseline only. Weight is required at Screening and prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most recent 
weight assuming it was assessed in a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible considering the 
variability of local process from site to site.  If the infusion is prepared with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each cycle. 
f 
For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany (See wording specific to Germany in Section 10.7.1) 
and Italy (see details and specific instructions in Section 10.2 and Section 10.8 of master protocol). 
g If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. 
h CT/MRI: The initial tumor imaging will be performed within 28 days prior to the C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP or more frequently if clinically indicated in the first 
45 weeks. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging technique should be used in a participant throughout the trial. After 
Week 45 tumor imaging should be performed every 12 weeks (84 ±7 days). CT scan of the head, neck, chest and abdomen (pelvis is optional) and any other locations with suspicion or evidence of disease 
involvement is required for the baseline assessment and during treatment period until PD. After the first documentation of response or the first documentation of progression (if the participant is clinically stable) per 
RECIST 1.1, confirmatory imaging should be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor 
assessment is not needed for participants who start another anti-cancer therapy.  
i 
Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of 
the brain as a site of disease as per protocol tumor assessment schedule. In all other cases, the lesions must be treated. Two additional scans obtained at least 4 weeks apart, should be obtained to document 
disease stability AFTER local treatment administration to the brain metastases has been completed. If participants receive systemic therapy during these 4 weeks stabilization at the treating physician's discretion, 
this systemic therapy will be considered as part of prior anti-cancer therapy. Participants with previously treated brain metastases may participate provided they are stable, which is defined as lack of progression 
on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to 
baseline or resolved, and the participant is not using steroids for at least 14 days prior to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment. 
j 
AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5.0, ICANS and cytokine release syndrome (CRS) will be graded using ASTCT criteria integrated with central laboratory cytokine results 
(1). 
k Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) will be performed every 4 cycles during the Treatment period and as 
clinically indicated. 
l
Visit and assessments on C1D3 are only for participants in the safety run-in.
m Only for safety run-in participants.
n Cetuximab dosing only.
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; ASTCT: American Society for Transplantation and Cellular Therapy; C: Cycle; CT: computed tomography; D: Day; ECG: electrocardiogram; 
ECOG: Eastern Cooperative Oncology Group; EOT: end-of-treatment; FT4: free thyroxine; FU: follow-up; HPV: Human Papilloma virus; ICANS: Immune effector cell-associated neurotoxicity syndrome; ICF: informed 
consent form; IMP: investigational medicinal product; IRT: Interactive Response Technology; LVEF; MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer Institute-Common terminology criteria for adverse 
events; PD: progressive disease; PDy:  pharmacodynamic; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SpO2: oxygen saturation; T3: triiodothyronine; 
TSH: thyroid stimulating hormone. 
VV-CLIN-0624549 1.0
211
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 20 
1.4 
BIOMARKER FLOWCHART 
Cohort A2-specific samplings are presented in the table below: 
VV-CLIN-0624549 1.0
212
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 21 
1.5 
PHARMACOKINETIC FLOWCHART 
1.5.1 A2 Cohort 
Cycle 
Treatment Cycle 1 
Treatment Cycles 2, 
3, 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
30 (±7) days 
after last IMP 
admin
Day
D1 
D2 
D3c
D8 
D1 
Time after start of SAR444245 
dosing 
SOI 
EOI 
Any 
time 
Any 
time 
Any time 
SOI 
EOI 
SAR444245 PK sample 
P00b 
P01 
P00b 
SAR444245 ADA sample 
AB00a 
AB01 
AB00a 
ABF00 
Time after start of dosing 
cetuximab  
SOI 
EOI 
D2 
D3c
D8
SOI 
EOI 
Cetuximab PK sample 
SC00a SC01b 
SC02a 
SC00a 
SC01b 
a Samples collected strictly before start of infusion (SOI). 
b EOI samples must be taken at end of infusion (EOI) precisely ±5 minutes. 
c Day 3 sampling only for participants in the safety run-in who have a Day 3 visit. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOI: end of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: start of infusion. 
VV-CLIN-0624549 1.0
213
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 22 
2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of SAR444245 
in combination with various anticancer therapies by identifying early signals. The information that 
is common to all cohorts is included in the master protocol, and this substudy provides details 
specific to Cohort A2 (participants with HNSCC who are treatment-naïve for R/M disease, PD-L1 
CPS ≥1), for the combination of SAR444245 with pembrolizumab and cetuximab. 
Please refer to the master protocol for an introduction for ACT16903 study. 
2.1 
STUDY RATIONALE 
2.1.1 Cohort A2: triplet combination of SAR444245, pembrolizumab and cetuximab 
Clinical data from the on-going monotherapy dose escalation of SAR444245 has indicated a 
peripheral increase in the number of NK cells. NK cells are an important effector cells which 
mediate ADCC for immunoglobulin G1 (IgG1) antibodies such as cetuximab. Furthermore, in 
vitro data have shown that NK-cell-mediated lysis of head and neck tumor cells is significantly 
enhanced by the combination of cetuximab therapy with immune stimulatory cytokines, including 
IL-2 (2). This was demonstrated in SAR444245 in vitro studies, where NK cells pretreated with 
SAR444245 and then co-cultured with the Epithelial Growth Factor Receptor (EGFR)-expressing 
CAL27 cancer cells improved the ADCC function of cetuximab in a dose-dependent fashion. 
Cetuximab can prime the immune system for anti-PD-1 therapy by recruiting cytotoxic cell 
effectors of both the innate and adaptive immune systems to the intratumoral space (3). 
Additionally, associated negative feedback loops lead to upregulation of PD-1/PD-L1-mediated 
immunosuppression of active cytotoxic cell types, an issue that could be overcome successfully 
via combination therapy with anti-PD-1. Collectively, the combination of SAR444245 with 
pembrolizumab and cetuximab is supported by: a) increase in NK cells by SAR444245 b) the 
ability of cytokines such as IL-2 to improve the ADCC response of cetuximab and c) addition of 
an anti-PD-1 to prevent PD-1/L-1 inhibition of infiltrating cytotoxic immune cells. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across a 
number of indications.  
Refer to the approved local labeling for detailed background information on pembrolizumab. 
VV-CLIN-0624549 1.0
214
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 23 
2.2.1.1 Pharmaceutical and therapeutic background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (4). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and RCC. Tumor-infiltrating lymphocytes can be expanded 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
(5, 6). 
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (7, 8) 
The structure of murine PD1 has been resolved (9). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell
signaling cascade (8, 10, 11, 12). The mechanism by which PD1 down-modulates T cell responses
is similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping
set of signaling proteins (13, 14).
2.2.1.2 Pre-clinical trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(15, 16, 17, 18, 19, 20, 21). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (9, 18, 20, 21, 22). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo (20). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see pembrolizumab Investigator’s brochure [IB]). 
VV-CLIN-0624549 1.0
215
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 24 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
2.2.2 Cetuximab 
Cetuximab is an IgG1 monoclonal antibody against the ligand binding domain of EGFR, which is 
abnormally activated in many epithelial cancers including colorectal cancer (23). The mechanism 
of action of cetuximab appears to include antibody dependent cell mediated cytotoxicity (24) in 
addition to EGFR blockade, which may contribute to its efficacy and may be further exploited. 
Erbitux (Cetuximab) is indicated for the treatment of locally or regionally advanced squamous 
cell carcinoma of the head and neck in combination with radiation therapy; recurrent locoregional 
disease or metastatic squamous cell carcinoma of the head and neck in combination with 
platinum-based therapy with fluorouracil. It is also indicated for the treatment of R/M squamous 
cell carcinoma of the head and neck. 
2.2.3 Rationale for HNSCC and selected participant population 
Please refer to the master protocol. 
2.2.4 Current standard of care in HNSCC 
2.2.4.1 PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as first 
line therapy 
Anti-PD-1 therapy has recently been approved in the first line R/M setting. The Phase 3 
KEYNOTE-048 trial investigated pembrolizumab as 1st line therapy for the treatment of patients 
with R/M HNSCC (25, 26). This study randomized 882 patients to receive treatment in one of 
three arms: pembrolizumab monotherapy, pembrolizumab plus chemotherapy (cisplatin or 
carboplatin and 5-FU) or the EXTREME regimen (cetuximab plus cisplatin or carboplatin and 
5-FU).
Pembrolizumab monotherapy significantly prolonged OS in patients with a CPS ≥1 (12.3 versus 
10.3 months, respectively; HR 0.78 with 95% confidence interval [CI] 0.64-0.96), and, in all 
patients irrespective of CPS, was non-inferior to standard of care (SOC) chemotherapy plus 
cetuximab with a non-inferiority boundary of 1.2. Although patients treated with pembrolizumab 
monotherapy had a lower ORR compared to patients treated with SOC (23% versus 36% for CPS 
≥20, 19% versus 35% for CPS ≥1), duration of response (DOR) in patients treated with 
pembrolizumab monotherapy was longer compared to SOC for patients with CPS ≥1 (20.9 versus 
4.5 months). Overall, treatment with pembrolizumab monotherapy demonstrated a favorable 
safety profile with lower incidence of any grade, Grade 3-4, and Grade 5 treatment-related 
adverse events (TRAEs). Moreover, pembrolizumab plus platinum-based chemotherapy versus 
EXTREME significantly prolonged OS in the total patient population (13.0 versus 10.7 months, 
respectively; HR 0.77 [95% CI: 0.63-0.93]). There was a similar incidence of TRAEs and no 
unexpected toxicity due to addition of chemotherapy to checkpoint blockade. 
VV-CLIN-0624549 1.0
216
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 25 
2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 and other combinations may be found in the IB. 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with pembrolizumab and cetuximab results from 
anticipated risks for SAR444245 and from the label information for Keytruda® (pembrolizumab) 
and Erbitux® (cetuximab), taking into account potential overlapping risks. The available safety 
data for pembrolizumab and cetuximab, along with proposed mitigation strategies are summarized 
below and also provided in Table 16. 
2.3.1.1 Pembrolizumab 
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment. 
The use of pembrolizumab may cause infusion-related reactions (IRRs) (drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, hypersensitivity and cytokine release syndrome 
[CRS]). Pembrolizumab use may be associated with infections (pneumonia), bone marrow 
suppression (anemia, thrombocytopenia, leukopenia), increase in the level of hepatic enzymes 
(alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase), kidney damage 
(nephritis, acute kidney injury), as well as adverse effects on the functioning of nervous system 
(dizziness, headache, peripheral neuropathy, dysgeusia (very common) and lethargy (common). In 
combination therapy with other chemotherapeutic drugs, pembrolizumab administration is 
commonly associated with hypertension and cardiac arrhythmia (including atrial fibrillation). 
Immune-mediated AEs are designated as important identified risk for pembrolizumab (27). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in post 
marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
VV-CLIN-0624549 1.0
217
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 26 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis. 
Please refer to pembrolizumab country-approved product labeling (eg, United States Package 
Insert [USPI], Summary of Product Characteristics [SmPC]) for more detailed information. 
2.3.1.2 Cetuximab 
The important identified risks for cetuximab include, but are not limited to: IRs (including 
anaphylaxis on the first dose); interstitial lung disease (ILD), severe adverse skin reactions (with 
increased risk of secondary bacterial infection), electrolyte disturbances (hypomagnesemia, 
hypokalemia, hypocalcemia) cardiac AEs (including cardiopulmonary arrest/sudden death), and 
eye disorders (including ulcerative keratitis).  
The most common adverse reactions (incidence ≥25%) are: cutaneous adverse reactions 
(including rash, pruritus, and nail changes), headache, diarrhea, and infection.  
The following precautions and warnings are to be acknowledged: 
Cetuximab can cause serious and fatal IRs. Infusion reactions (IRs) of any grade occurred in 8.4% 
of patients who received cetuximab across clinical trials. Grades 3 and 4 IRs occurred in 2.2% of 
patients. Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, 
hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac 
arrest. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, 
red meat allergy, or in the presence of immunoglobulin E (IgE) antibodies directed against 
galactose-α-1,3-galactose (alpha-gal). Approximately 90% of severe IRs occurred with the first 
infusion despite premedication with antihistamines. Infusion reactions (IRs) may occur during or 
several hours following completion of the infusion. Premedication with a histamine-1 (H1) 
receptor antagonist is recommended together with monitor patients for at least 1 hour following 
each infusion.  
Cardiopulmonary arrest or sudden death have occurred in 2%-3% patients with squamous cell 
carcinoma of the head and neck receiving cetuximab with radiation therapy or a cetuximab 
product with platinum-based therapy and fluorouracil cetuximab. A history of coronary artery 
disease, congestive heart failure, or arrhythmias and abnormal serum electrolytes may be 
predisposing factors.  
Interstitial lung disease that may be fatal has occurred in <0.5% of patients receiving cetuximab in 
clinical trials.  
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. Acneiform rash occurred in 82% of patients across clinical trials. 
Grades 3 or 4 acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed 
within the first two weeks of therapy; the rash lasted more than 28 days after stopping treatment in 
VV-CLIN-0624549 1.0
218
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 27 
most patients. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, 
and skin sloughing, has been observed. It could not be determined whether these mucocutaneous 
adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related 
effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).  
Cetuximab can cause hypomagnesemia which occurred in 55% patients in various clinical trials, 
including Grades 3 and 4 in 6% to 17%. Hypomagnesemia and accompanying electrolyte 
abnormalities can occur days to months after initiating treatment. It is recommended to monitor 
patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for 
at least 8 weeks following the completion of treatment and to replete electrolytes as necessary. 
Based on animal data and its mechanism of action, cetuximab can cause fetal harm when 
administered to a pregnant woman. There are no available data for cetuximab exposure in 
pregnant women. In an animal reproduction study, intravenous administration of cetuximab once 
weekly to pregnant cynomolgus monkeys resulted in an increased incidence of embryo-lethality 
and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-
fetal development including effects on placental, lung, cardiac, skin, and neural development. 
Please refer to the country-approved cetuximab labeling (eg, USPI, SmPC) for more detailed 
prescribing information. 
2.3.1.3 SAR444245 combined with pembrolizumab and cetuximab 
Due to synergistic action of SAR444245 and pembrolizumab, combining these two substances 
may lead to an increased frequency and/or severity of AEs related to immune activation for each 
substance individually or may cause occurrences of qualitatively different AEs. Serious adverse 
drug reactions reported with agents known to increase immune activation include pneumonitis, 
hepatitis, nephritis, colitis, and hormonal dysfunction (see Section 2.3.1.1). SAR444245 could 
also increase the incidence of cetuximab-induced cutaneous toxicities. 
As all three substances are biologic agents, they may have the propensity to induce IRR that may 
have higher rate of occurrence and severity when SAR444245 with pembrolizumab or cetuximab 
are used in combination. 
The maximum tolerated dose of SAR444245 combined with the approved dosing of the anti-PD1 
pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. Safety data 
generated from the combination of SAR444245 and pembrolizumab have informed the selection 
of the combination dose in this study. 
Data from the combination in Phase 2 study pembrolizumab plus cetuximab in R/M HNSCC are 
very promising, with a manageable safety profile and encouraging ORR (28). 
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245, pembrolizumab and cetuximab are provided below. 
VV-CLIN-0624549 1.0
219
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 28 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of CRs and prolonged survival 
which was durable as demonstrated by the failure of the tumor to grow upon re-engraftment on 
the tumor free animals, indicating the establishment of a durable memory T-cell population in 
response to the initial treatment (see SAR444245 IB).  
Preclinical and preliminary clinical data indicates that SAR444245 expands NK cells which are 
important effector cells mediating ADCC for IgG1 antibodies such as cetuximab. In vitro 
experiments show that SAR444245 improved the ADCC function of cetuximab in a dose-
dependent fashion. 
Head and neck squamous cell carcinoma is a tumor type that benefits from immune checkpoint 
inhibitor (ICI) and cetuximab treatment. The companion ICI (anti-PD1) pembrolizumab and 
cetuximab to be combined with SAR444245 in this study is approved to treat various disease 
settings of HNSCC either as a monotherapy or in combination with chemotherapy. 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. Overall, the potential risks identified in association with this new generation IL-2 
SAR444245 combined with the anti PD1 inhibitor pembrolizumab and cetuximab are justified by 
the anticipated benefits that may be afforded to participants with HNSCC.  
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity.  
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was explored by 2 groups who did not find a clinically meaningful signal (29, 30). 
VV-CLIN-0624549 1.0
220
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 29 
3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of objectives and endpoints common to all 
study cohorts. Substudy-specific objectives and endpoints are summarized below. 
Table 2 - Objectives and endpoints 
Objectives 
Endpoints 
Secondary 
To confirm the dose of SAR444245 when combined with 
cetuximab and pembrolizumab 
Incidence of dose-limiting toxicities (DLT) 
To assess the concentrations of cetuximab 
Concentrations of cetuximab 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
221
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 30 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This substudy will include participants with HNSCC who are treatment-naïve for R/M disease, 
PD-L1 CPS ≥1 and will assess SAR444245 combined with pembrolizumab and cetuximab. 
Overall, approximately 40 participants will be enrolled and treated at the confirmed safe dose in 
Cohort A2. 
The maximum number of cycles allowed in this Cohort A2 substudy is 35 cycles for SAR444245 
and pembrolizumab, and until PD for cetuximab.  
A safety run-in will confirm the dose of SAR444245 when combined with pembrolizumab and 
cetuximab in a sample of at least 6 participants. After recruitment of the first 10 participants, 
enrollment will be paused if a total of at least 6 participants are evaluable for DLT. Safety data for 
these participants will be reviewed by the Study Board comprising the Investigators or designees 
participating in the safety run-in part of the trial and the Sponsor clinical team members DLT-
evaluable participants include all participants in the safety run-in part who have been treated and 
observed for at least 21 days. Any participant who experienced a DLT during the first 21 days will 
also be DLT-evaluable. If no safety concerns are identified by the Study Board, participant 
enrollment will continue. 
If after recruiting the first 10 participants there are fewer than 6 participants evaluable for DLT, 
more participants will be enrolled to ensure at least 6 DLT evaluable participants after agreement 
from Study Board. Participants who are enrolled in the safety run-in and treated at the confirmed 
safe dose will be included in the total number of participants. 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an IV infusion over 
30 minutes every 3 weeks on Day 1 of each cycle (21 days per cycle). Overall safety monitoring 
will be performed throughout the study.  If recommended by the Study Board, SAR444245 dose 
may be reduced to 
 μg/kg or another lower dose level which will be explored following the 
same process described in the safety run-in for 24 μg/kg dose level. 
The Modified Toxicity Probability Interval 2 design will be used in the safety run-in part. The 
mTPI2 design is a Bayesian interval design that can be implemented in a simple fashion as the 
traditional 3+3 design, but it is more flexible and possesses superior operating characteristics. The 
target toxicity rate for the Maximum Tolerated Dose (MTD) is 0.3, with the acceptable toxicity 
probability interval of (0.25,0.35). The dose decision (stay at 24 µg/kg dose or reduce the dose) 
will be made by the Study Board and will be guided by the decision rules from the mTPI2 design. 
The mTPI2 decision rules are based on calculating the unit probability mass (UPM) of intervals as 
follows: (0, 0.05), (0.05, 0.15), (0.15, 0.25), (0.25, 0.35), (0.35, 0.45) …… (0.85, 0.95), (0.95, 1). 
In the mTPI2 method, intervals that are lower than 0.25 indicate dose escalation, equivalence 
interval (0.25,0.35) indicates staying at the current dose level, and intervals that are higher than 
VV-CLIN-0624549 1.0
222
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 31 
0.35 indicate dose de-escalation. The interval with the largest UPM is the winning interval and 
implies the corresponding dose escalation/de-escalation decision. For the safety run-in part of the 
study, mTPI2 rules (see Table 3) will be applied as follows, unless decided otherwise by the Study 
Board: 
•
If the dose recommendation from mTPI2 is “E” (Escalate to the next higher dose) or “S”
(Stay at the same dose), the cohort will continue with the SAR444245 24 µg/kg dose
•
If the dose recommendation from mTPI2 is to de-escalate to a lower dose (either “D”
[De-escalate to the previous lower dose] or “DU” [De-escalate to the previous lower dose
and the current dose will never be used again in the cohort]), a dose lower than 24 µg/kg
will be tested and assessed with the same methodology.
Table 3 - Dose escalation rule of the modified toxicity probability interval-2 method
Number of DLT-evaluable participants 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of dose limiting toxicities 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
2 
DU 
D
D 
D 
S 
S 
S 
E 
E 
3 
DU 
DU 
D 
D 
D 
D 
S 
S 
4 
DU 
DU 
DU 
D 
D 
D 
D 
5 
DU 
DU 
DU 
DU 
DU 
D 
6 
DU 
DU 
DU 
DU 
DU 
7 
DU 
DU 
DU 
DU 
8 
DU 
DU 
DU 
9 
DU 
DU 
10 
DU 
E: Escalate to the next higher dose, S: Stay at the current dose, D: De-escalate to the next lower dose, DU: De-escalate to the next 
lower dose and the current dose will never be used again because unacceptable high toxicity. 
Dose limiting toxicity: The following events occurring during the DLT observation period 
(21 days of first cycle) are considered as DLT unless due to disease progression or to a cause 
obviously unrelated to study drugs. Please refer to the list of events as below. Based on the 
occurrence of DLT and overall assessment of safety data supplemented with data from other 
SAR444245 studies, the Study Board will determine if the dose of SAR444245 needs to be 
reduced to 
 μg/kg Q3W or another lower dose level, in agreement with the Sponsor.  
Hematologic abnormalities: 
•
Grade 4 neutropenia for ≥7 consecutive days
•
Grade 3 or 4 neutropenia complicated by fever (temperature of >38.3°C [101°F] or a
sustained temperature of ≥38.0°C [100.4°F] for more than 1 hour) or microbiologically or
radiographically documented infection.
•
Grade 3 or 4 thrombocytopenia associated with clinically significant bleeding requiring
clinical intervention.
VV-CLIN-0624549 1.0
223
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 32 
Non-hematologic abnormalities: 
•
Grade 3 or above alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in
combination with a bilirubin >2 times upper limit of normal (ULN) with no evidence of
cholestasis or another cause such as viral infection or other drugs
•
Grade 3 or above Vascular Leak Syndrome (VLS)
•
Grade 3 or above hypotension
•
Grade 3 or above cytokine release syndrome
•
Other Grade 3 or above AE except:
-
Grade 3 fatigue that resolves within 1 week
-
Grade 3 nausea, vomiting, or diarrhea that resolves within 72 hours with antiemetics
and standard supportive care measures
•
Any Grade 3 non-hematologic laboratory value
Exceptions:
-
Grade 3 electrolyte abnormalities that are not clinically complicated and resolve within
72 hours with conventional medical interventions.
-
Grade 3 amylase or lipase that is not associated with symptoms or clinical
manifestations of pancreatitis.
•
Any Grade 4 non-hematologic laboratory value.
Other abnormalities: 
•
Any death not clearly due to the underlying disease or extraneous causes.
•
Any toxicity requiring permanent discontinuation of the study drug(s).
•
More than 1 missing dose of cetuximab due to toxicity.
Participants who are treated at the confirmed safe dose in the safety run-in of Cohort A2 will be 
included in the total number of participants for Cohort A2. 
Please refer to the master protocol for a full description of the study design and for therapy details 
applicable to all cohorts. 
Study Board 
The study Investigators (or designee) participating in the safety run-in part and the Sponsor 
clinical team members will constitute the Study Board (SB). The SB will review clinical data on a 
regular basis in order to decide dose confirmation or dose reduction on the basis of their 
knowledge of the safety data. Minutes of each meeting will be written by the Sponsor and 
distributed to all sites participating in the safety run-in part. Decisions regarding final dose 
selection will be made during one of the SB meeting and documented in the meeting minutes. 
VV-CLIN-0624549 1.0
224
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 33 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that non-alpha IL-2 SAR444245 
combined with pembrolizumab and cetuximab, will result in a significant increase in the 
percentage of trial participants with HNSCC experiencing an objective response. 
A safety run-in on the first 6-10 participants being enrolled has been embedded in the substudy to 
confirm the absence of safety issues before launching enrollment of the remaining participants. 
The design of the study is an open-label study where the experimental combination will be 
assessed in a single cohort to show outstanding ORR. The ORR will be assessed using RECIST 
1.1 for participants with R/M HNSCC. 
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol.  
4.3.2 Pembrolizumab dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 
•
Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer
(NSCLC) indications demonstrating flat dose- and exposure-efficacy relationships from
2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to
7.5-fold exposure range (refer to the pembrolizumab IB)
•
Population pharmacokinetic (PK) analysis showing that both fixed dosing and weight-
based dosing provides similar control of PK variability with considerable overlap in the
distributions of exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall survival
at 200 mg Q3W across multiple indications.
•
Pharmacology data showing full target saturation in both systemic circulation (inferred
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at
200 mg Q3W.
VV-CLIN-0624549 1.0
225
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 34 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.3.3 Cetuximab dose 
This study proposes to evaluate the clinical benefit of 24 µg/kg SAR444245 Q3W combined with 
pembrolizumab at the dose of 200 mg every 3 weeks (Q3W) and the approved dose of 400 mg/m² 
cetuximab as an IV infusion on day 1 of the study followed by subsequent doses of 250 mg/m² 
cetuximab IV QW. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
226
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 35 
5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort A2-specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. PD-L1 expression CPS as determined (with an absolute value provided to Sponsor) at local 
laboratory (for details on PD-L1 assay, please refer to lab manual) 
- 
PD-L1 expression CPS ≥1 (with an absolute value provided to Sponsor).  
I 02. Provision of tumor tissue: 
- 
Mandatory baseline biopsy in Core Phase (minimum 5 slides with 4-5 micron 
thickness for the first 20 participants who have signed ICF (excluding screening 
failure participants), minimum 10 slides with 4-5 micron thickness for subsequent 
participants). Archival tumor tissue samples should be obtained from biopsies done 
within 6 months, and there should be no systemic anti-cancer therapy between 
collection of biopsy and enrollment. Slides specifications are detailed in Lab Manual. 
- 
The Sponsor may approve the written request to enroll, on a case-by-case basis, 
participants with: 
- 
location of the tumor not amenable to biopsy due to significant risk, OR 
- 
less than required number of slides or archival tumor tissue sample collected 
more than 6 months prior to enrollment. 
I 03. Prior anticancer therapy 
- 
Have not received prior systemic therapy for R/M disease. Participants who received 
systemic therapy as part of multimodal treatment for locally advanced disease are 
eligible if the systemic therapy was completed at least 6 months prior to enrollment 
(See wording specific to Germany in Section 10.7.1). 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
E 01. Electrolytes (magnesium, calcium, and potassium) outside the normal ranges. 
VV-CLIN-0624549 1.0
227
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 36 
Prior/concomitant therapy 
E 02. Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1 
pathway (participants who joined a study with an anti-PD-1/PD-L1 in the experimental 
arm but have written confirmation they have not received anti-PD-1/PD-L1 are allowed). 
E 03. Prior treatment with cetuximab (prior cetuximab allowed if used for the treatment of 
locally advanced disease, with no PD for at least 4 months from completion of prior 
cetuximab therapy). 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION] 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
228
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 37 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
The maximum number of cycles allowed in this Cohort A2 substudy is 35 cycles for SAR444245 
and pembrolizumab, and until PD for cetuximab. 
Dosing sequence: 
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245, cetuximab and 
pembrolizumab administered as described in Section 4.1. Details of each IMP component to be 
administered are shown in Table 4.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.
Table 4 - Overview of IMP administered 
Intervention 
name 
SAR444245 
Pembrolizumab 
Cetuximab 
Type 
See master protocol 
Biologic 
Biologic 
Dose 
formulation 
See master protocol 
Solution for infusion 
Solution for infusion 
Unit dose 
strength(s) 
See master protocol 
25 mg/mL 
100 mg/ 50 mL (2 mg/mL) 
Dosage 
level(s)a 
24 μg/kg Q3W (or reduced to 
 μg/kg Q3W or another lower 
dose level recommended by 
Study Board) 
200 mg Q3W 
400 mg/m2 C1D1 and QW 
250 mg/m2 at C1D8 and 
subsequent administrations 
Route of 
administration 
See master protocol 
IV infusion 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
Treatment of cancer (combination) 
IMP or NIMP 
IMP 
IMP 
IMP 
VV-CLIN-0624549 1.0
229
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 38 
Intervention 
name 
SAR444245 
Pembrolizumab 
Cetuximab 
Packaging and 
labeling 
See master protocol 
Supplied in single-dose vials 
containing 100 mg/4 mL 
pembrolizumab labelled with a 
multilingual booklet. 1 vial per 
treatment box. 
Supplied as 100 mg/50 mL 
(2 mg/mL) or 200 mg/100 mL in a 
single-dose vial or 100 mg/20 mL 
or 500 mg/100 mL or any other 
formulation approved locally. 
Current/Former 
name(s) or 
alias(es) 
NA 
Keytruda 
Erbitux 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the electronic 
case report form (e-CRF). For SAR444245 and pembrolizumab, study sites should make every effort to target infusion timing to be as close 
to 30 minutes as possible. However, given the variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is 
permitted (ie, infusion time is 30 minutes -5 min/+10 min). 
6.1.2 Non-investigational medicinal product 
Please refer to the master protocol for SAR444245 premedication. 
Premedication for cetuximab 
All participants who will receive cetuximab should be pre-medicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab, or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior IRs. 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication 
6.1.3 Hydration guidelines for SAR444245 administration 
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome 
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
230
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 39 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules 
Dose modifications for SAR444245 is permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. Dose modifications for cetuximab are permitted, and 
modification of dose levels in case of dose reduction is described in Table 5. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) or dose omission (ie, omission of any 
component of the IMP within a cycle) are permitted in case of treatment-emergent adverse event 
(TEAE). Dose modification will be made according to the worst grade of toxicity observed within 
a cycle. If a participant experiences several toxicities and there are conflicting recommendations, 
the most conservative recommended dose adjustment should be followed. Once a dose has been 
decreased, intra-patient re-escalation back to the previous dose level is not permitted. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case it is partial permanent discontinuation and the end-of-treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining 
IMP(s). When all IMP components are permanently discontinued it is full permanent 
discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay and dose omission 
The treatment window is ±3 days for each of the Q3W IMP administrations. The treatment 
window is ±1 day for cetuximab administration on Day 8 and Day 15 of each cycle.  
VV-CLIN-0624549 1.0
231
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 40 
A cycle is deemed to have been delayed if the treatment is administered ≥4 days beyond the 
theoretical day of Q3W IMP administration. The participant may receive the next dose after 
recovery from the toxicity as described in Section 6.5.3. After cycle delayed, such participants 
may be considered for treatment resumption once the toxicity resolves or improves to Grade 1 or 
baseline.  
Participants may have cycle delay, or dose omission if toxicity occurs and the participant does not 
recover according to following rules: 
•
For Q3W IMP administration: If toxicity occurs and the participant does not recover on the
day of planned administration; restart of study IMPs could occur only on the initiation of
the subsequent cycle.
•
For cetuximab Day 8 and Day 15 administration in each cycle: if toxicity occurs and the
patient does not recover on the day of planned infusion or within the following 3 days,
infusion may be omitted.
•
In case of cycle delay or dose omissions for the recovery of toxicity, the following rules
should be followed for restart or discontinuation of the treatment:
-
In case of a cycle delay up to 14 days or a dose omission, it is per Investigator’s
decision to restart the study treatment.
-
After a cycle delay of >14 days and ≤84 days, or 2 to 4 consecutive dose omissions, it
is per Investigator’s decision to restart the study treatment or the IMP that is omitted, if
a clear benefit from treatment is observed and after consultation with the Sponsor.
-
The study treatment must be permanently discontinued if the cycle delay is longer than
84 days.
-
For any delayed cetuximab treatment, do not repeat the initial dose of 400 mg/m². At
the restart of cetuximab treatment, all subsequent infusions will be at the appropriate
dose level according to Table 5.
•
Cycle delay or dose omission may be considered may be interrupted for situations other
than TEAEs such as medical/surgical events or logistical reasons not related to study
therapy. Participants should be placed back on study therapy within 21 days of the
scheduled delay or dose omission, unless otherwise discussed with the Sponsor (for
example for national or regional emergencies). The reason for this delay or dose omission
should be documented in the participant’s study record.
Modification of dose levels in case of dose reduction 
Dose reduction steps for cetuximab are shown in Table 5. One or several doses of cetuximab can 
be omitted. 
Table 5 - Dose levels for cetuximab dose reduction 
Starting dose 
Dose level 1 
Dose level 2 
400 mg/m2 then 
250 mg/m2 
200 mg/m2 
(20% decrease) 
150 mg/m2 
(20% decrease) 
VV-CLIN-0624549 1.0
232
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 41 
6.5.3 General guidelines for the management of treatment-related adverse events 
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
will be required to delay or omit the IMP, unless specified otherwise in the protocol, and with the 
exception of the TRAEs resolving within 5 days. After cycle delay, such participants may be 
considered for treatment resumption once the TRAE resolves or improves to Grade 1 or baseline. 
Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to be in the 
best interest of the participant, except when specified otherwise in this protocol, or if the event has 
required the IMP temporary interruption for more than 84 days from the last scheduled dose.  
The delay or omission of treatment for Grade 2 events is left at the discretion of the Investigator 
unless otherwise specified in this protocol.  
No delay/omission of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
 µg/kg to
 µg/kg (or another lower dose recommended 
by Study Board) may be decided when specified in the protocol or following discussions with the 
Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific AEs including irAE, CRS, VLS and 
IRR are presented in Section 6.5.4. 
6.5.4 Guidelines for the management of specific adverse events 
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF.
6.5.4.1 Infusion-related reactions 
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An IRR in this study is defined as any signs or symptoms which develop during the infusion or up 
to 24 hours after the completion of the infusion. The term IRR indicates only a specific temporal 
relationship with the infusion and does not specify a particular mechanism underlying the signs or 
symptoms.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-related infusion reaction are 
provided in Table 6. 
VV-CLIN-0624549 1.0
233
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 42 
Table 6 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
•
Increase monitoring of vital signs as medically indicated
until the participant is deemed medically stable in the
opinion of the investigator.
None 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
•
Stop Infusion.
•
Additional appropriate medical therapy may include but
is not limited to:
-
IV fluids,
-
Antihistamines,
-
NSAIDs,
-
Acetaminophen,
-
Narcotics.
•
Increase monitoring of vital signs as medically indicated
until the participant is deemed medically stable in the
opinion of the investigator.
•
If symptoms resolve within 1 hour of stopping drug
infusion, the infusion may be restarted at 50% of the
original infusion rate (eg, from 100 mL/hr. to 50 mL/hr.).
Otherwise dosing will be held until symptoms resolve
and the participant should be premedicated for the next
scheduled dose.
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from 
further study drug treatment 
Participant may be 
premedicated 1.5 h 
(±30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; urgent 
intervention indicated 
•
Stop Infusion
•
Additional appropriate medical therapy may include but
is not limited to:
-
Epinephrine*,
-
IV fluids,
-
Antihistamines,
-
NSAIDs,
-
Acetaminophen,
-
Narcotics,
-
Oxygen,
-
Pressors,
-
Corticosteroids.
•
Increase monitoring of vital signs as medically indicated
until the participant is deemed medically stable in the
opinion of the investigator.
•
Hospitalization may be indicated.
*In cases of anaphylaxis, epinephrine should be used
immediately.
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v 5.0 (CTCAE) at http://ctep.cancer.gov. 
VV-CLIN-0624549 1.0
234
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 43 
Participants who experience cetuximab-related infusion reactions should have cetuximab reduced 
according to Table 7 and continue to receive antihistamine premedication prior to administration. 
Once the cetuximab infusion rate has been decreased due to an allergic/hypersensitivity reaction, 
it should remain decreased for all subsequent infusions. If the participant experiences a second 
infusion reaction at the decreased rate, cetuximab should be permanently discontinued. If any 
Grade 3-4 infusion reaction occurs, cetuximab treatment should be discontinued immediately and 
permanently. 
Severe infusion-related reactions, including anaphylactic reactions, may commonly occur, in 
some cases with fatal outcome. Occurrence of a severe infusion-related reaction requires 
immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency 
treatment. Some of these reactions may be anaphylactic or anaphylactoid in nature or represent a 
CRS. Symptoms may occur during the first infusion and for up to several hours afterwards or with 
subsequent infusions. 
Table 7 - Cetuximab Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Dose modification 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Decrease the cetuximab infusion rate by 50% and monitor closely for any 
worsening. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications indicated for 
≤24 hrs. 
Stop cetuximab infusion and administer bronchodilators, oxygen, etc. as 
medically indicated. 
Resume infusion at 50% of previous rate once allergic/hypersensitivity reaction 
has resolved or decreased to Grade 1 in severity, and monitor closely for any 
worsening 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae (eg, renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; urgent intervention indicated 
Stop the cetuximab infusion immediately, administer epinephrine, 
bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc, as medically indicated. 
Permanently discontinue Cetuximab. The participant can continue treatment 
with pembrolizumab or SAR444245. 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion related reaction; NCI = National Cancer Institute. 
Guidelines for the management of SAR444245 IRR events are provided in Table 8. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
VV-CLIN-0624549 1.0
235
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 44 
Table 8 - SAR444245 Infusion-related reaction dose modification and treatment guidelines
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary. 
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
Interrupt SAR444245 infusion. 
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise, dosing will be held 
until symptoms resolve and the participant will be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
Give the next infusion at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics. 
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae 
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; urgent intervention indicated 
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
6.5.4.2 Anaphylaxis 
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of pembrolizumab and cetuximab being administered.  
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines in 
(14, 31, 32). 
VV-CLIN-0624549 1.0
236
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 45 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Monitoring of vital signs is detailed in Safety Assessments (Section 8.2.2). 
Cetuximab may be associated with CRS. Cytokine-release syndrome typically occurs within 
one hour after infusion and is less commonly associated with bronchospasm and urticaria. 
Cytokine-release syndrome is normally most severe in relation to the first infusion of cetuximab. 
Cetuximab related IRRs, including CRS, are discussed in Section 6.5.4.1 of the protocol. Please 
refer to Table 7 for Cetuximab IRR dose modifications and treatment guidelines. 
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 9. If any grade of CRS is suspected, sites should make every 
effort to draw an additional blood sample for cytokines levels (by central laboratory) prior to the 
administration of tocilizumab or alternative therapies per site practice in CRS management, as 
well as C-reactive protein (CRP) and ferritin (by local laboratory). 
Sites should have at least 2 full doses of tocilizumab or alternative therapies per site practice in 
CRS management available and access to an intensive care unit (ICU), in case participants 
develop CRS. 
Guidelines for management of CRS according to severity grading are provided in Table 9. 
ASTCT CRS consensus grading scale is provided in Section 10.13 of the master protocol. 
 
VV-CLIN-0624549 1.0
237
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 46 
Table 9 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
Grade 1 
•
Fever (Temperature ≥38°C)b
•
No hypotension
•
No hypoxia
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV fluids (care should be 
taken to not excessively hydrate if evidence of vascular leak), antihistamines, NSAIDs and 
acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and laboratory monitoring 
should initially be performed daily, then less frequently as the participant improves. 
Decrease the cetuximab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 
•
Feverb (Temperature ≥38°C)
•
Hypotension not requiring
vasopressors
•
and/orc hypoxia requiring low-
flow nasal cannulad or blow-by.
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to IV fluids (care should 
be taken to not excessively hydrate if evidence of vascular leak), antihistamines, NSAIDs and 
acetaminophen. 
Increase monitoring of vital signs, cardiac and other organ functions closely as medically 
indicated until the participant recovers. Transfer to ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, hypotension, or 
participants in whom symptoms (eg, high grade fever) that do not respond to antipyretics within 
72 hours treatment with corticosteroids and/or tocilizumab or alternative therapies per site 
practice in CRS management should be considered, as per guidance for Grade 3 events.  
IMP may be resumed when clinical symptoms have resolved or improved to Grade 1 and 
corticosteroid taper. No dose modification is required but decreasing to half the infusion rate 
can be considered. 
Stop cetuximab infusion and administer 
intravenous fluids, bronchodilators, oxygen, etc. 
as medically indicated. Resume infusion at 50% of 
previous rate once the event has resolved or 
decreased to Grade 1 in severity, and monitor 
closely for any worsening. 
VV-CLIN-0624549 1.0
238
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 47 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
Grade 3 
•
Feverb (Temperature ≥38°C)
•
Hypotension requiring a
vasopressor with or without
vasopressin
•
And/orc hypoxia requiring high-
flow nasal cannulad, face mask,
nonrebreather mask, or Venturi
mask
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
•
Feverb (Temperature ≥38°C)
•
Hypotension requiring multiple
vasopressors (excluding
vasopressin)
•
And/orc hypoxia requiring
positive pressure (eg, CPAP,
BiPAP, intubation and
mechanical ventilation)
If CRS grade 3, temporarily cycle delay SAR444245, and resume subsequent treatment only 
when symptoms have resolved or improved to Grade 1.  
SAR444245 can be either restarted at 
 µg/kg or permanently discontinued, as clinically 
indicated. 
If CRS Grade 4, permanently discontinue SAR444245. 
If CRS Grade 3 or Grade 4, initiate IV corticosteroids (outside of the context of CAR-T cells, 
corticosteroids alone maybe initiated in first intention) and tocilizumab or alternative therapies 
per site practice in CRS management considered, and/or epinephrine and/or other 
vasopressors should be administered as needed. Participants with severe CRS may require 
management in intensive care setting, with monitoring of clinical status and laboratory tests 
performed at least daily. 
As the participant improves, the intensity of the monitoring and setting can be decreased, but 
the participant should not be discharged from the hospital until clinically stable. Corticosteroids 
can then be administered IV or orally every 8 hours for up to 3 days, then tapered over 4 days. 
In general, tapering of steroids can start when vasopressors and high-flow oxygen are no 
longer needed.  
CRS is considered resolved when there is sustained resolution of fever and there is no longer 
a need for oxygen supplementation to relieve hypoxia nor vasopressors to maintain blood 
pressure; however, normalization of temperature alone does not define resolution of CRS. 
Stop the cetuximab infusion immediately, 
administer epinephrine, bronchodilators, 
antihistamines, glucocorticoids, intravenous fluids, 
vasopressor agents, oxygen, etc., as medically 
indicated. Cetuximab should be permanently 
discontinued. The participant can continue 
treatment with SAR444245. 
VV-CLIN-0624549 1.0
239
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 48 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
 
If no clinical improvement in oxygenation, hypotension, fever, and other CRS manifestations is 
observed within 24 to 72 hours, initiate management for persistent or worsening CRS. Re-
evaluation for other contributing conditions will be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous Tocilizumab at 8 mg/kg (for participants 
weighing ≥30 kg) or alternative therapies per site practice in CRS management should be 
administered, and steroids should be administered concurrently. If still no improvement in 
oxygenation, hypotension, fever and other manifestations is observed after the first dose of 
tocilizumab, it may be repeated after an interval of at least 8 hours and should not exceed 
4 doses in total. 
For participants with severe CRS who fail to improve after repetitive treatment with both 
tocilizumab or alternative therapies per site practice in CRS management and steroids, 
alternative options will be discussed with clinical site specialists. 
 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or alternative therapies per site practice in 
CRS management or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and 
hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at 
>6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = Bilevel Positive Airway Pressure; CPAP = Continuous Positive Airway Pressure; CRS = cytokine 
release syndrome; ICU = intensive care unit; IL = Interleukin; IMP = investigational medicinal product; IV = Intravenous; NSAIDs = Non-steroidal anti-inflammatory drugs. 
 
VV-CLIN-0624549 1.0
240
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. Immune-
related AEs are thought to be caused by unrestrained cellular immune responses directed at the 
normal host tissues. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing pembrolizumab clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and/or 
cetuximab and administer corticosteroids. 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 10. Of 
note, if the AE is considered immune-related, both drugs in the combination should be held 
according to recommended dose modifications.  If a participant experiences several irAEs, the 
most conservative recommendation should be followed.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 10,  the 
combination of SAR444245, pembrolizumab and cetuximab may be restarted at the 
discretion of the Investigator. In these cases where the toxicity is attributed to the 
combination or to SAR444245 alone, re-initiation of pembrolizumab as a monotherapy 
may be considered after communication with the Sponsor. 
VV-CLIN-0624549 1.0
241
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 50 
Table 10 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245  
General instructions: 
1.
Treat severe and life-threatening irAEs with IV corticosteroids followed by oral steroids. Begin other immunosuppressive
treatment if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.
3.
Begin the corticosteroid taper when the irAE is ≤Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE
decreased to ≤ Grade 1 after corticosteroid taper.
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Pneumonitis 
Grade 2 
Withholda 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Monitor participants for signs and 
symptoms of pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment. 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently discontinueb 
Diarrhea/Colitis 
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Monitor participants for signs and 
symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis. 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently discontinueb 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper. 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable). 
Grade 3d or 4e 
Permanently discontinueb  Administer corticosteroids
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
VV-CLIN-0624549 1.0
242
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 51 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Type 1 Diabetes 
Mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell failure 
Withholda,f
Initiate insulin 
replacement therapy for 
participants with T1DM. 
Administer 
antihyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
Withholda or permanently 
discontinueb,f  
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective 
beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate. 
Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
Withholda or permanently 
discontinueb,f 
Hypothyroidism 
Grade 2, 3, or 
4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per SOC 
Monitor for signs and symptoms 
of thyroid disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinueb 
Myocarditis 
Grade 2, 3 or 
4 
Permanently discontinueb  Based on severity of AE
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently discontinueb 
VV-CLIN-0624549 1.0
243
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
All Other irAEs 
Persistent 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes. 
Grade 3 
Withholda  or discontinue 
based on the eventg 
Recurrent 
Grade 3 or 
Grade 4  
Permanently discontinueb  
a SAR444245 to be withheld plus pembrolizumab: to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x ULN if baseline normal;  
>1.5 to 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse 
Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; 
IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of 
normal. Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
6.5.4.5 Dermatologic toxicity 
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. 
The dosing of cetuximab will be omitted 1 to 2 weeks in the case of severe (Grade 3 or 4) 
acneiform rash. If acneiform rash improves during this time, then the dose of cetuximab should be 
reduced as indicated in Table 11. The dose modification guidelines in Table 5 should be followed 
for dermatologic toxicities other than acneiform rash.  
If acneiform rash does not improve during this time, cetuximab will be permanently discontinued.  
Participants who have omitted cetuximab therapy for more than 2 consecutive infusions due to 
acneiform rash, and upon resolution of the toxicity are still felt to be benefiting from cetuximab 
treatment may resume cetuximab with Sponsor approval. 
VV-CLIN-0624549 1.0
244
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 53 
Table 11 - Cetuximab dose modification for dermatologic toxicities 
Dermatologic toxicities and infectious 
sequelae (eg, acneiform rash, 
mucocutaneous disease) 
Recommended IMP 
dose modification 
1st occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, continue at 
the same dose of 250 mg/m2. If no improvement, discontinue cetuximab. 
2nd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently 
reduce at dose level 1. If no improvement, discontinue cetuximab. 
3rd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently 
reduce at dose level 2. If no improvement, discontinue cetuximab. 
4th occurrence; Grade 3 or 4 
Permanently discontinue cetuximab. 
6.5.4.6 Immune Cell-Associated Neurotoxicity Syndrome 
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which is 
frequently associated with CRS; however, it is specifically excluded from the definition of CRS and 
can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment of 
cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.13 of 
the master protocol). Recommendations for ICANS management mainly include the use of steroids, 
whereas tocilizumab or alternative therapies per site practice in CRS management should only be 
used in the context of CRS, as outlined in Table 12. The proposed management should be considered 
only as recommendations and in light of recommendations from site specialist. 
Table 12 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS) 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring. 
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
Delay SAR444245a. 
Initiate treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement to 
Grade 1 after corticosteroid taper. Consideration for reduction of SAR444245 
dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus. 
Any clinical seizure focal or generalized that 
If Grade 3 ICANS, delay SAR444245. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor. 
VV-CLIN-0624549 1.0
245
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 54 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
resolves rapidly or nonconvulsive seizures on EEG 
that resolve with intervention. 
Grade 4 
ICE score: 0 (participant is unarousable and unable 
to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Table 9. 
Corticosteroids can then be administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days.   
If Grade 4 ICANS, permanently discontinue SAR444245. 
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Table 9. 
Corticosteroids can then be administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) should be considered or alternative therapies 
per site practice in CRS management, and steroids should be administered 
concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.5.4.7 Vascular Leak Syndrome (VLS) 
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic, shock with 
multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a balance 
between maintaining the intravascular volume to ensure organ perfusion to prevent organ failure, 
while avoiding volume overload. The management of VLS according to severity grading is 
described in Table 13. These guidelines are not comprehensive, and the Investigator should 
exercise clinical judgment based on the symptoms and condition of the individual participant and 
refer to current guidelines to the topic (13). 
VV-CLIN-0624549 1.0
246
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 55 
Table 13 - Guidelines for the management of Vascular Leak Syndrome (VLS) 
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
Delay SAR444245 .Upon resolution of VLS or improvement to Grade 1, 
SAR444245a can be resumed at the reduced dose of 
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, permanently discontinue SAR444245. 
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
Definition of pembrolizumab overdose is provided in Section 8.3.8. 
VV-CLIN-0624549 1.0
247
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 56 
There is no specific antidote for overdose with pembrolizumab. No specific information is 
available on the treatment of overdose of pembrolizumab or cetuximab. In the event of overdose, 
the participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
248
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol.  
VV-CLIN-0624549 1.0
249
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 58 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol.  
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.2 
SAFETY ASSESSMENTS  
8.2.1 Physical examinations 
Please refer to the master protocol. 
8.2.2 Vital signs 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be 
measured after 5 minutes rest. 
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively: 
- 
For the safety run-in participants vital signs will be measured at Pre-dose, 
0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 20 (±1), 
24 (±1) hours after start of SAR444245 dose. 
• For the core phase participants: from Cycle 2 to Cycle 4 study therapy will be 
administered for all patients in out-patient clinic with vital signs taken at baseline, at least 
4 to 6 hours after the start of SAR444245 dosing, or for longer periods of time if clinically 
indicated. 
8.2.3 Electrocardiograms and left ventricular ejection fraction (LVEF) 
Please refer to the master protocol. 
8.2.4 Clinical safety laboratory assessments 
Please refer to the master protocol. 
8.2.5 Pregnancy testing 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
250
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information 
Please refer to the master protocol. For participants in Cohort A2 irAEs will be collected until 
90 days following last administration of study treatment regardless of whether or not another 
anticancer therapy is initiated. 
8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab and cetuximab, serious adverse events (SAEs) that are considered expected 
will be specified in the reference safety information (country-approved product labeling for 
pembrolizumab and cetuximab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
In addition, symptomatic or asymptomatic overdose with pembrolizumab is described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
VV-CLIN-0624549 1.0
251
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 60 
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol for description of common PK evaluations, substudy specific 
evaluations are summarized below. 
Samples collected for analyses of cetuximab concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant.  
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
252
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 61 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION  
Sample size: 
For Cohort A2 the study will start with a safety run-in to confirm the dose of SAR444245 when 
combined with pembrolizumab and cetuximab in a sample of at least 6 participants.  
The plan is to treat a total of 40 participants at the confirmed safe dose in Cohort A2. Participants 
who are enrolled in the safety run-in and treated at the confirmed safe dose will be included in the 
total number of participants for this cohort.  
Please refer to the master protocol for details on sample size. 
9.3 
POPULATIONS FOR ANALYSES 
The following additional population for analyses is defined for Cohort A2. Please refer to the 
master protocol for populations common to all cohorts. 
Table 14 - Populations for analyses 
Population 
Description 
DLT-evaluable 
DLT-evaluable population include all participants in safety run-in part who have been treated and 
observed for least 21 days. Any participants who have experienced a DLT during DLT observation period 
will also be DLT-evaluable. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol.  
9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
253
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 62 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below. 
9.4.3.1 Adverse events 
Incidence of DLTs will be summarized by dose levels (if applicable) for DLT-evaluable 
population in the safety run-in part. 
9.4.3.2 Other secondary endpoints 
Plasma concentrations of cetuximab will be summarized with descriptive statistics.
9.4.4 Tertiary/exploratory endpoint(s) 
Please refer to the master protocol. 
9.5 
INTERIM ANALYSES  
No formal interim analyses are planned. However, the following analyses will be performed: 
•
At the end of the safety run-in for Cohort A2 regimen, the occurrence of DLT and other
safety data will be reviewed by the Study Board to decide about continuation of the dose
of SAR444245 of 24 µg/kg or dose reduction.
•
After the dose is confirmed by the Study Board, the cumulative safety data for each study
intervention across cohorts will be reviewed periodically by the Data Monitoring
Committee. The enrollment will not be paused or stopped during the safety monitoring
unless severe safety concern arises.
Further details on Data Monitoring Committee are provided in the master protocol. 
The cohort cut-off for the primary ORR endpoint analysis corresponds to approximately 9 months 
from the date of the last participant’s first infusion (to document that last participant response is 
maintained for 6 months).  
VV-CLIN-0624549 1.0
254
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 63 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. Cohort 
A2-specific evaluations are presented in Table 15. 
Table 15 - Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Clinical chemistrya 
See master protocol 
Endocrine function testsb 
Thyroid-stimulating hormone (TSH) 
Tri-iodothyronine (T3) 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
a For participants in Cohorts A2 electrolytes to be done weekly under treatment and then at the end of treatment, at FU visit 1 and as clinically 
indicated. Additional electrolytes monitoring for Cohort A2, outside the visits, maybe done according the local standard institutional care. 
b Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
VV-CLIN-0624549 1.0
255
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 64 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS 
Please refer to the master protocol. 
10.7.1 Amendment for Germany 
Section 5.1 Inclusion Criteria (Section 5.1) 
German participants will not be enrolled in Cohort A2 substudy 02. 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Please refer to the master protocol. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol for detailed information about SAR444245. Available 
information about pembrolizumab and cetuximab is shown in Table 16. For pembrolizumab and 
cetuximab, the information below is per currently available USPI and EU SmPC.  
Please always refer to the latest version of the SAR444245 IB and pembrolizumab and/or 
cetuximab local label for the most up-to-date safety data. 
VV-CLIN-0624549 1.0
256
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 65 
Table 16 - Risk assessment 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
Pembrolizumab 
Common, but infusion-related reactions in 
labeling include drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, 
hypersensitivity and cytokine release 
syndrome. 
Cetuximab 
Cetuximab can cause serious and fatal infusion 
reactions. Infusion reactions of any grade 
occurred in 8.4% of 1373 patients who received 
cetuximab across clinical trials. Severe (Grades 
3 and 4) infusion reactions occurred in 2.2% of 
patients. Signs and symptoms included rapid 
onset of airway obstruction (bronchospasm, 
stridor, hoarseness), hypotension, shock, loss 
of consciousness, myocardial infarction, and/or 
cardiac arrest. The risk of anaphylactic 
reactions may be increased in patients with a 
history of tick bites, red meat allergy, or in the 
presence of IgE antibodies directed against 
galactose-α-1,3-galactose (alpha-gal). 
Consider testing patients for alpha-gal IgE 
antibodies using FDA-cleared methods prior to 
initiating cetuximab. Negative results for alpha-
gal antibodies do not rule out the risk of severe 
infusion reactions. Approximately 90% of 
severe infusion reactions occurred with the first 
infusion despite premedication with 
antihistamines. Infusion reactions may occur 
during or several hours following completion of 
the infusion. 
Pembrolizumab 
Dose modification and treatment guidelines 
for pembrolizumab infusion associated 
reactions are provided in Table 6. 
Cetuximab 
Premedicate with a histamine-1(H1) receptor 
antagonist as recommended. Monitor 
patients for at least 1 hour following each 
cetuximab infusion, in a setting with 
resuscitation equipment and other agents 
necessary to treat anaphylaxis. In patients 
requiring treatment for infusion reactions, 
monitor for more than 1 hour to confirm 
resolution of the reaction. Interrupt the 
infusion and upon recovery, resume the 
infusion at a slower rate or permanently 
discontinue cetuximab based on severity. 
Immediately interrupt cetuximab and 
permanently discontinue cetuximab for 
serious IRRs. 
Advise patients that the risk of serious 
infusion reactions may be increased in 
patients who have had a tick bite or red meat 
allergy. Advise patients to contact their 
healthcare provider and to report signs and 
symptoms of infusion reactions, including 
late onset infusion reactions, such as fever, 
chills, or breathing problems. 
Hypersensitivity, including 
anaphylaxis 
Pembrolizumab 
Not specifically reported but included among 
infusion-related reactions in label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
Also, see specific instructions for cetuximab. 
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master protocol. 
Cytokine release syndrome 
Pembrolizumab 
Not specifically reported. 
Dose modification and treatment guidelines 
are provided in Section 6.5.4.3. 
VV-CLIN-0624549 1.0
257
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 66 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Hepatotoxicity 
Pembrolizumab 
Pembrolizumab can cause immune-mediated 
hepatitis. Immune-mediated hepatitis occurred 
in 0.7% (19/2799) of patients receiving 
pembrolizumab, including Grade 4 (<0.1%), 
Grade 3 (0.4%), and Grade 2 (0.1%) adverse 
reactions. Systemic corticosteroids were 
required in 68% (13/19) of patients with 
hepatitis. Eleven percent of these patients 
required additional immunosuppressant 
therapy. Hepatitis led to permanent 
discontinuation of KEYTRUDA in 0.2% (6) of 
patients and withholding of pembrolizumab in 
0.3% (9) of patients. All patients who were 
withheld reinitiated pembrolizumab after 
symptom improvement; of these, none had 
recurrence of hepatitis. Hepatitis resolved in 
79% of the 19 patients. 
Cetuximab 
Increase in liver enzymes is very common. 
Exclusion of participants with impaired liver 
functions: 
Aspartate aminotransferase and/or alanine 
aminotransferase >2.5 × ULN (or >5 × ULN 
for participants with liver metastases). 
Monitor clinical signs and symptoms of 
hepatic impairment as part of TEAE. Monitor 
liver function parameters (AST, ALT, 
bilirubin, & alkaline phosphatase [ALP]) 
regularly from screening and throughout the 
study. 
Pembrolizumab dose modification and 
treatment guidelines for liver enzyme 
increase are provided under immune-related 
reactions in Table 10. 
 Electrolyte abnormalities 
(including Hypomagnesemia)  
Cetuximab 
Cetuximab can cause hypomagnesemia. 
Hypomagnesemia occurred in 55% of 365 
patients receiving cetuximab in Study CA225-
025 and two other clinical trials in patients with 
colorectal cancer (CRC) or head and neck 
cancer, including Grades 3 and 4 in 6% to 17%. 
In EXTREME, where a cetuximab product was 
administered in combination with platinum-
based therapy, the addition of cetuximab to 
cisplatin and fluorouracil resulted in an 
increased incidence of hypomagnesemia of any 
grade (14%) and of Grade 3 or 4 
hypomagnesemia (7%). Hypomagnesemia of 
any grade occurred in 4% of patients who 
received cetuximab, carboplatin, and 
fluorouracil. No Electrolyte abnormalities 
(including Hypomagnesemia) and 
accompanying electrolyte abnormalities can 
occur days to months after initiating cetuximab. 
Monitor patients weekly during treatment for 
hypomagnesemia, hypocalcemia, and 
hypokalemia, and for at least 8 weeks 
following the completion of cetuximab. 
Replete electrolytes as necessary. 
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury. 
Dose modification and treatment guidelines 
for nephrotoxicity are provided under 
immune-related reactions in Table 10. 
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy 
(common) for pembrolizumab in combination 
with chemotherapy  
Uncommon: epilepsy.  
Dose modification and treatment guidelines 
for neurological AEs are provided under 
immune-related reactions in Table 10. 
VV-CLIN-0624549 1.0
258
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 67 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Cardiovascular effects, 
including QT interval 
prolongation & 
cardiopulmonary arrest 
Pembrolizumab 
Combination with chemotherapy, common: 
hypertension, cardiac arrhythmia (including 
atrial fibrillation) 
Cetuximab 
Cetuximab can cause cardiopulmonary arrest. 
Cardiopulmonary arrest or sudden death 
occurred in 2% of 208 patients treated with 
radiation therapy and cetuximab in BONNER. 
BONNER (NCT00004227) was a randomized, 
multicenter, controlled trial of 424 patients with 
locally or regionally advanced HNSCC being 
treated with cetuximab in combination with 
radiation therapy. Three patients with prior 
history of coronary artery disease died at home, 
with myocardial infarction as the presumed 
cause of death. One of these patients had 
arrhythmia and one had congestive heart 
failure. Death occurred 27, 32, and 43 days 
after the last dose of cetuximab. One patient 
with no prior history of coronary artery disease 
died one day after the last dose of cetuximab. 
In EXTREME, fatal cardiac disorders and/or 
sudden death occurred in 3% of 219 patients 
treated with a cetuximab product in 
combination with platinum-based therapy and 
fluorouracil. 
 
 
 
 
 
Carefully consider use of cetuximab with 
radiation therapy or platinum-based therapy 
with fluorouracil in patients with SCCHN with 
a history of coronary artery disease, 
congestive heart failure, or arrhythmias. 
Monitor serum electrolytes, including serum 
magnesium, potassium, and calcium, during 
and after cetuximab administration (see 
Hypomagnesemia and Accompanying 
Electrolyte Abnormalities). 
Advise patients of the risk of 
cardiopulmonary arrest or sudden death and 
to report any history of coronary artery 
disease, congestive heart failure, or 
arrhythmias. 
Immune-mediated Adverse 
Events 
Pembrolizumab 
Immune-mediated adverse events are 
designated as important identified risk for 
pembrolizumab. 
Dose modification and treatment guidelines 
for immune-related reactions are provided in 
Table 10. 
Pulmonary effects 
Cetuximab 
Cetuximab can cause interstitial lung disease 
(ILD). ILD, including 1 fatality, occurred in less 
than 0.5% of 1570 patients receiving cetuximab 
in clinical trials. 
Monitor patients for signs and symptoms of 
pulmonary toxicity. Interrupt or permanently 
discontinue cetuximab for acute onset or 
worsening of pulmonary symptoms. 
Permanently discontinue cetuximab for 
confirmed ILD. 
Advise patients to contact their healthcare 
provider immediately for new or worsening 
cough, chest pain, or shortness of breath. 
VV-CLIN-0624549 1.0
259
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 68 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Dermatological effects 
Cetuximab: 
Cetuximab can cause dermatologic toxicities, 
including acneiform rash, skin drying and 
fissuring, paronychial inflammation, infectious 
sequelae (for example, S. aureus sepsis, 
abscess formation, cellulitis, blepharitis, 
conjunctivitis, keratitis/ulcerative keratitis with 
decreased visual acuity, cheilitis), and 
hypertrichosis. Acneiform rash occurred in 82% 
of the 1373 patients who received cetuximab 
across clinical trials. Severe (Grades 3 or 4) 
acneiform rash occurred in 9.7% of patients. 
Acneiform rash usually developed within the 
first two weeks of therapy; the rash lasted more 
than 28 days after stopping cetuximab in most 
patients. Life-threatening and fatal bullous 
mucocutaneous disease with blisters, erosions, 
and skin sloughing, has been observed in 
patients who received cetuximab. It could not 
be determined whether these mucocutaneous 
adverse reactions were directly related to 
EGFR inhibition or to idiosyncratic immune-
related effects (eg, Stevens-Johnson syndrome 
or toxic epidermal necrolysis). Cutaneous 
adverse reactions (including rash, pruritus and 
nail changes) are the most common adverse 
reaction (incidence greater than 25%).  
Pembrolizumab: 
Refer to immune-related adverse events. 
Cetuximab: 
Monitor patients receiving cetuximab for 
dermatologic toxicities and infectious 
sequelae. Instruct patients to limit sun 
exposure during cetuximab therapy. 
Withhold, reduce dose or permanently 
discontinue cetuximab based on severity of 
acneiform rash or mucocutaneous disease. 
Advise patients to limit sun exposure during 
cetuximab treatment and for 2 months after 
the last dose of cetuximab. Advise patients 
to notify their healthcare provider of any sign 
of acne-like rash, (which can include itchy, 
dry, scaly, or cracking skin and inflammation, 
infection or swelling at the base of the nails 
or loss of the nails), conjunctivitis, 
blepharitis, or decreased vision. 
Risks related to special 
populations
Reproductive toxicity
Pembrolizumab 
Pembrolizumab should not be used during 
pregnancy unless the clinical condition of the 
woman requires treatment with pembrolizumab. 
Cetuximab 
Based on animal data and its mechanism of 
action, cetuximab can cause fetal harm when 
administered to a pregnant woman. There are 
no available data for cetuximab exposure in 
pregnant women. In an animal reproduction 
study, intravenous administration of cetuximab 
once weekly to pregnant cynomolgus monkeys 
during the period of organogenesis resulted in 
an increased incidence of embryolethality and 
abortion. Disruption or depletion of EGFR in 
animal models results in impairment of embryo-
fetal development including effects on 
placental, lung, cardiac, skin, and neural 
development. Human IgG is known to cross the 
placental barrier; therefore, cetuximab may be 
transmitted from the mother to the developing 
fetus. Advise pregnant women of the potential 
Advise pregnant women of the potential risk 
to a fetus. Advise females of reproductive 
potential to use effective contraception 
during treatment with cetuximab and for 
2 months after the last dose of cetuximab. 
Verify pregnancy status in females of 
reproductive potential prior to initiating 
cetuximab. 
VV-CLIN-0624549 1.0
260
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 69 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
risk to a fetus. In the U.S. general population, 
the estimated background risk of major birth 
defects and miscarriage in clinically recognized 
pregnancies is 2 to 4% and 15-20% 
respectively.  
Pregnant cynomolgus monkeys were 
administered cetuximab intravenously once 
weekly during the period of organogenesis 
(gestation day [GD] 20-48) at dose levels 0.4 to 
4 times the recommended dose of cetuximab 
based on body surface area (BSA). Cetuximab 
was detected in the amniotic fluid and in the 
serum of embryos from treated dams on GD 
49. While no fetal malformations occurred in 
offspring, there was an increased incidence of 
embryolethality and abortions at doses 
approximately 1 to 4 times the recommended 
dose of cetuximab based on BSA. In mice, 
EGFR is critically important in reproductive and 
developmental processes including blastocyst 
implantation, placental development, and 
embryo-fetal/postnatal survival and 
development. Reduction or elimination of 
embryo-fetal or maternal EGFR signaling can 
prevent implantation, can cause embryo-fetal 
loss during various stages of gestation (through 
effects on placental development), and can 
cause developmental anomalies and early 
death in surviving fetuses. Adverse 
developmental outcomes were observed in 
multiple organs in embryos/neonates of mice 
with disrupted EGFR signaling. 
Drug-drug interactions 
No data available.  
Overdose and its treatment 
No specific information is available on the 
treatment of overdose of pembrolizumab. 
See Section 6.7  
 
10.11 APPENDIX 11: ABBREVIATIONS 
 
ADCC: 
antibody-dependent cellular cytotoxicity 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CI: 
confidence interval 
COVID-19: 
Coronavirus disease 2019 
CPS: 
Combined Positive Score 
CR: 
complete response 
VV-CLIN-0624549 1.0
261
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 70 
CRS: 
cytokine release syndrome 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
DLT: 
dose-limiting toxicities 
e-CRF: 
electronic case report form 
EGFR: 
Epithelial Growth Factor Receptor 
EOT: 
end-of-treatment 
HNSCC: 
head and neck squamous cell carcinoma 
IB: 
Investigator's brochure 
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICU: 
intensive care unit 
Ig: 
immunoglobulin 
IgE: 
immunoglobulin E 
IgG1: 
immunoglobulin G1 
ILD: 
interstitial lung disease 
IMP: 
investigational medicinal product  
IR: 
infusion reaction 
irAEs: 
immune-related AEs 
IRR: 
infusion-related reactions  
IV: 
intravenous 
LVEF: 
left ventricular ejection fraction 
mTPI2: 
modified toxicity probability interval 2 
NCI-CTCAE: 
National Cancer Institute-Common Terminology Criteria for Adverse Events  
NK: 
natural killers 
NSCLC: 
non-small cell lung cancer 
ORR: 
objective response rate 
PBPK: 
physiologically-based PK 
PD: 
progressive disease 
PD1: 
programmed cell death-1 
PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death ligand 2 
PK: 
pharmacokinetic 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
R/M: 
recurrent/metastatic 
SAEs: 
serious adverse events 
SB: 
Study Board 
SmPC: 
Summary of Product Characteristics 
SoA: 
schedule of activities 
SOC: 
standard of care 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
TRAEs: 
treatment-related adverse events 
ULN: 
upper limit of normal 
USPI: 
United States Package Insert 
VLS: 
Vascular Leak Syndrome 
 
VV-CLIN-0624549 1.0
262
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 71 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
before the Table of Contents. 
VV-CLIN-0624549 1.0
263
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 72 
11 
REFERENCES 
1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
2. Luedke E, Jaime-Ramirez AC, Bhave N, Roda J, Choudhary MM, Kumar B, et al. Cetuximab 
therapy in head and neck cancer: immune modulation with interleukin-12 and other natural 
killer cell-activating cytokines. Surgery. 2012;152(3):431-40. 
3. Ferris RL, Lenz HJ, Trotta AM, García-Foncillas J, Schulten J, Audhuy F, et al. Rationale for 
combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors: 
Harnessing innate and adaptive immunity through IgG1 isotype immune effector stimulation. 
Cancer Treat Rev. 2018;63:48-60. 
4. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8. 
5. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for 
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol. 
2005;23(10):2346-57. 
6. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
2008;358(25):2698-703. 
7. Greenwald RJ, Freeman GJ,  Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
8. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
9. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
10. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol. 
2004;173 (2):945-54. 
11. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George, JA, Wooter, J, et al. PD-1 inhibits T-
cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41. 
12. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
VV-CLIN-0624549 1.0
264
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 73 
13. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein, I, Kobayashi, SV, et al.
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol.
2005;25(21):9543-53.
14. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.
Immunol Rev. 2010;236:219-42.
15. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res.
2005;65(3):1089-96.
16. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer
Res. 2004;64(3):1140-5.
17. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9.
18. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res.
2003;63(19):6501-5.
19. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored
IL-2 production and proliferation of CD8(+) T cells directly within the tumor
microenvironment. J Immunother Cancer. 2014;2:3.
20. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80.
21. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J
Immunol. 2010;184(7):3442-9.
22. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7.
23. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology
and treatment of cancer. J Clin Oncol. 2003;21(14):2787-99.
24. Iannello A, Ahmad A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy
of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 2005;24(4):487-99.
25. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al. KEYNOTE-
048: phase 3 study of first-line pembrolizumab (P) for recurrent/metastatic head and neck
squamous cell carcinoma (R/M HNSCC) (abstract). Oncology Pro. 2018.
VV-CLIN-0624549 1.0
265
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 01 (Substudy 02) 
SAR444245-ACT16903-S02  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 74 
26. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, De Castro G, et al.
Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for
recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a
randomised, open-label, phase 3 study. Lancet. 2019;394(10212):1915-28.
27. Keytruda® European Public Assessment Report, Risk Management Plan Summary [Internet].
[updated 2020 Jun 18; cited 2020 Oct 07]. Available from:
https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
28. Sacco AG, Chen R, Worden FP, Wong DJL, Adkins D, Swiecicki P, et al. Pembrolizumab
plus cetuximab in patients with recurrent or metastatic head and neck squamous cell
carcinoma: an open-label, multi-arm, non-randomised, multicentre, phase 2 trial. Lancet
Oncol. 2021;22(6):883-92.
29. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al.
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence,
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep.
2020;2(1):100124.
30. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov.
2020;10(8):1121-8.
31. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol.
2017;28(suppl 4):iv100-18.
32. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014;69(8):1026-45.
VV-CLIN-0624549 1.0
266
VV-CLIN-0701966 1.0

Signature Page for VV-CLIN-0624549 v1.0
act16903-16-1-1-amended-protocol01-substudy02
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0624549 1.0
267
VV-CLIN-0701966 1.0

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 04) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab for 
the treatment of participants in 2nd/3rd line 
recurrent/metastatic (R/M) head and neck squamous cell 
carcinoma (HNSCC) 
Protocol number: 
ACT16903-S04 
Amendment number: 03 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab for 
the treatment of participants in 2nd/3rd line R/M HNSCC  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name 
and contact 
information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
IND156423 
2021-002105-99 
NCT05061420 
U1111-1251-5073 
Date: 
22-Dec-2021
Total number of pages: 62 
VV-CLIN-0616196 4.0
268
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 (Substudy 04)   
All 
22 December 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 (Substudy 04)   
All 
19 August 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 (Substudy 04)   
All 
26 July 2021, version 1 (electronic 2.0) 
Clinical Trial Protocol (Substudy 04) 
All 
11 June 2021, version 1 (electronic 1.0) 
Amended protocol 03 (22 December 2021) 
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Spanish (Agency for Medicine and 
Health Products [AEMPS]), Italian (Medicines Agency [AIFA]) and German (Federal Institute for 
Drugs and Medical Devices [BfArM]) Health Authorities after initial review. Other changes have 
been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SoA) 
A complete Table of SoA is provided for this substudy with 
procedures taken from the master protocol. 
For clarity and consistency 
 
The row indicating “electrolytes” has been removed.  
For clarity and consistency 
 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up visit 1. 
To allow assessments of any 
potential cardiotoxicity 
1.4 Biomarker flow-chart 
and 1.5 Pharmacokinetic 
flow-chart 
Complete biomarker and pharmacokinetic flow-charts applicable 
for this substudy have been provided with procedures taken 
from the master protocol. 
For clarity and consistency 
6.5.3 General guidelines 
for the management of 
treatment-related adverse 
events 
As the Study Board does not intervene for this substudy, any 
reference to it has been removed. 
For consistency 
VV-CLIN-0616196 4.0
269
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
6.5.4.3 Fever, flu-like 
symptoms and 
cytokine-release 
syndrome (CRS) and 
6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS)  
The following statement “or alternative therapies per site 
practice in CRS management” has been added to “tocilizumab”. 
For flexibility following an issue 
with tocilizumab availability 
6.5.4.5 Immune Cell-
Associated Neurotoxicity 
Syndrome (ICANS)  
In Table 6 under Grade 4, “signs of” has been removed before 
“diffuse cerebral edema on neuroimaging”. 
Change made for consistency 
with the American Society for 
Transplantation and Cellular 
Therapy (ASTCT) Consensus 
and correction 
10.1 Appendix 1: 
Regulatory, ethical, and 
study oversight 
considerations  
A new subsection 10.1.6 entitled “Dissemination of clinical study 
data” has been added with the following text: “Study participants 
results summaries will be provided in any one of the clinical trial 
portals after completion of the substudy, until the end of study”. 
Per CTFG guidance 2019: 
Recommendation Paper on the 
Initiation and Conduct of 
Complex Clinical Trials 
10.11 Appendix 11: 
Abbreviations 
List of abbreviations has been revised.  
For consistency  
11 References 
List of references has been updated. 
For consistency 
Throughout the document 
Minor editorial corrections were made. 
For consistency  
VV-CLIN-0616196 4.0
270
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 4 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 04) .................................................................. 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2
TABLE OF CONTENTS .................................................................................................................................. 4
LIST OF TABLES ........................................................................................................................................... 8
LIST OF FIGURES .......................................................................................................................................... 8
1
PROTOCOL SUMMARY ................................................................................................................. 9
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 13 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 20 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 21 
2
INTRODUCTION ............................................................................................................................ 22
2.1 
STUDY RATIONALE...................................................................................................................... 22 
2.2 
BACKGROUND ............................................................................................................................. 22 
2.2.1 
Pembrolizumab .............................................................................................................................. 22 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 22 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 23 
2.2.2 
Rationale for HNSCC and selected participant population ............................................................ 23 
2.2.3 
Current standard of care in HNSCC .............................................................................................. 24 
2.2.3.1 
PD1/PD-L1 inhibitor monotherapy as second line therapy ............................................................ 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 24 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 25 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 26 
2.3.2 
Benefit assessment ........................................................................................................................ 26 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 26 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 26 
3
OBJECTIVES AND ENDPOINTS ................................................................................................. 27
VV-CLIN-0616196 4.0
271
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 5 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 27 
4
STUDY DESIGN ............................................................................................................................ 28
4.1 
OVERALL DESIGN ........................................................................................................................ 28 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 28 
4.2.1 
Participant input into design ........................................................................................................... 28 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 28 
4.3.1 
SAR444245 dose ........................................................................................................................... 28 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 28 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 29 
5
STUDY POPULATION .................................................................................................................. 30
5.1 
INCLUSION CRITERIA .................................................................................................................. 30 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 31 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 31 
5.4 
SCREEN FAILURES...................................................................................................................... 31 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
(ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION) ....................................................................................................................... 31 
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 32
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 32 
6.1.1 
Investigational medicinal product ................................................................................................... 32 
6.1.2 
Non-investigational medicinal product ........................................................................................... 33 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 33 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 33 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 33 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 33 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 33 
6.5 
DOSE MODIFICATION .................................................................................................................. 33 
6.5.1 
General rules .................................................................................................................................. 33 
6.5.2 
Cycle delay ..................................................................................................................................... 34 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 35 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 35 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 35 
VV-CLIN-0616196 4.0
272
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 6 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 38 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 38 
6.5.4.4 
Immune-related adverse events .................................................................................................... 40 
6.5.4.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 44 
6.5.4.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 45 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 46 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 46 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 46 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 47 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 47 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 47 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 47 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 48 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 48 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 48 
8.2.1 
Physical examinations ................................................................................................................... 48 
8.2.2 
Vital signs ....................................................................................................................................... 48 
8.2.3 
Electrocardiograms and left ventricular ejection fraction (LVEF) ................................................... 48 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 48 
8.2.5 
Pregnancy testing .......................................................................................................................... 49 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 49 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 49 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 49 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 49 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 49 
8.3.5 
Pregnancy ...................................................................................................................................... 49 
8.3.6 
Cardiovascular and death events .................................................................................................. 49 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 49 
8.3.8 
Adverse event of special interest ................................................................................................... 49 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 50 
8.4 
PHARMACOKINETICS .................................................................................................................. 50 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 50 
VV-CLIN-0616196 4.0
273
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 7 
8.6 
BIOMARKERS ............................................................................................................................... 50 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 50 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 50 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 50 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 51 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 51 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 51 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 52 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 52 
9.5 
INTERIM ANALYSES .................................................................................................................... 52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 53 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 53 
10.1.6 
Dissemination of clinical study data ............................................................................................... 53 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 53 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 53 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 53 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 53 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 54 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 54 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 54 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 54 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 54 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 56 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 57 
11 
REFERENCES ............................................................................................................................... 60 
 
VV-CLIN-0616196 4.0
274
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 8 
LIST OF TABLES 
Table 1 - Overview of IMP administered ....................................................................................................... 32 
Table 2 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 36 
Table 3 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 37 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 39 
Table 5 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 41 
Table 6 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) ... 44 
Table 7 - Guidelines for the management of Vascular Leak Syndrome (VLS) ............................................. 45 
Table 8 - Estimated objective response rate (ORR) and 95% CI for Cohort B1 (combining core and 
expansion phases) ........................................................................................................................................ 51 
Table 9 - Protocol-required laboratory assessments .................................................................................... 53 
Table 10 - Risk assessment .......................................................................................................................... 54 
LIST OF FIGURES 
Figure 1 - Overall substudy schema .............................................................................................................. 12 
VV-CLIN-0616196 4.0
275
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Substudy B1-
specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of 
participants in 2nd/3rd line recurrent/metastatic (R/M) head and neck squamous cell carcinoma 
(HNSCC) 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of 
participants in 2nd/3rd line R/M HNSCC 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 1 
(PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in 
the syngeneic murine colon cancer CT-26 model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with pembrolizumab will result in a significant increase in the percentage of participants with 
R/M HNSCC previously treated with PD1/PD-L1-based regimen & platinum-based regimen 
experiencing an objective response. 
Objectives and endpoints 
Please refer to the master protocol.  
Overall design:  
Please refer to the master protocol.  
Brief summary:  
Cohort B1: This substudy will include participants with R/M HNSCC previously treated with 
PD1/PD-L1-based regimen & platinum-based regimen after failure of no more than 2 regimens for 
recurrent and/or metastatic (R/M) disease and will assess SAR444245 combined with pembrolizumab. 
VV-CLIN-0616196 4.0
276
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 10 
A graphical presentation of the study schema is shown in Figure 1. 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in the core phase of Cohort B1.  
In the expansion phase, approximately 56 participants will be enrolled. 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration. 
Study intervention(s) 
Cohort B1: PD1/PD-L1-based regimen & platinum-based regimen treated R/M HNSCC 
after failure of no more than 2 regimens for R/M disease, SAR444245 + pembrolizumab 
Dosing sequence: 
Investigational medicinal product(s) 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in 
single-dose vials. 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered at a dose of 200 mg using a 30-minute 
IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min). 
SAR444245 
• Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion 
in a single-dose vial with an extractable volume of 1 mL. 
• Route of administration: intravenous (IV) infusion.  
• Dose regimen: 24 μg/kg administered as an IV infusion over 30 mins every 3 weeks 
(Q3W) on Day 1 of each cycle (21 days per cycle) for up to 35 cycles.  
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
VV-CLIN-0616196 4.0
277
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 11 
Non-investigational medicinal products 
Please refer to the master protocol. 
Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. 
For Cohort B1, the cohort cut-offs for the analyses are as follows: 
• Interim analysis cut-off: the date on which all participants in the core phase have at least 
2 post-baseline tumor assessments or discontinue study treatment (whichever occurs first).  
• The cohort cut-off for the primary objective response rate (ORR) endpoint analysis 
corresponds to approximately 9 months from last participant’s first infusion in the 
expansion phase (to document that last participant response is maintained for 6 months in 
the expansion phase). 
Data Monitoring Committee: Yes 
 
VV-CLIN-0616196 4.0
278
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 12
1.2 
SCHEMA 
Figure 1 - Overall substudy schema 
CPS: Combined Positive Score; HNSCC: head and neck squamous cell carcinoma; PD1: programmed death 1; PD-L1: programmed death ligand 1; pembro: pembrolizumab; Tx: treatment; R/M: recurrent/metastatic. 
VV-CLIN-0616196 4.0
279
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Elements of the schedule of activities (SoA) common to all cohorts are detailed in the master protocol. Cohort B1-specific evaluations are 
presented in this table.  
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Informed consent 
Inclusion/Exclusion criteria 
X 
   
  
 
  
   
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical and 
disease history 
X 
   
  
 
  
   
  
  
  
  
 
See Section 8 
of master 
protocol 
Full physical examination 
X 
  
  
 
  
 
X 
  
 
  
  
 
Directed physical 
examination 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
See 
 Section 8.2.1 
of master 
protocol 
Body weight/Heighte 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
VV-CLIN-0616196 4.0
280
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 14 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 8.2.2 
& Section 
8.2.2 of 
master 
protocol 
SpO2 
X 
As clinically indicated 
 
 
 
 
 
 
Performance status 
(ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
12-lead ECG 
X 
X 
As clinically indicated 
 
 
 
See 
 Section 8.2.3 
of master 
protocol 
LVEF 
X 
As clinically indicated 
 
 
 
See 
 Section 8.2.3 
of master 
protocol 
VV-CLIN-0616196 4.0
281
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 15 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Laboratory assessments 
 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically 
indicated 
 
 
 
 
See Section 
Section 8.2.3 
& Section 10.2 
Pregnancy test 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
See 
Section 8.2.5, 
Section 8.3.5 
& Section 10.2 
of master 
protocol 
Blood 
chemistry/hematology 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 & 
Section 10.2 
of master 
protocol  
T3, FT4, TSH, and cortisol 
X 
 
 
 
X 
X 
X 
X 
 
 
 
See  
Section 10.2 
VV-CLIN-0616196 4.0
282
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 16 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Coagulation 
X 
As clinically indicated 
  
  
  
See  
Section 10.2 
of master 
protocol  
Urinalysisk 
X 
X 
 
 
 
X 
X 
X 
 
 
 
See  
Section 10.2 
of master 
protocol 
Hepatitis serology 
CD4 counts & Viral Load 
 Xf 
As clinically indicated 
  
  
  
See  
Section 10.2 
of master 
protocol 
HPV p16 status for 
participants with 
oropharyngeal cancer 
X 
  
  
  
 
  
  
  
  
  
  
  
 
PK 
See PK Flow-Chart in Section 1.5 
 
ADA 
See PK Flow-Chart in Section 1.5 
 
VV-CLIN-0616196 4.0
283
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 17 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Exploratory biomarkers 
 
PDy - Blood and tumor 
tissue collectiong 
See Biomarkers Flow-Chart in Section 1.4 
 
Disease assessment 
 
CT/MRIh 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
See 
 Section 8.1 of 
master 
protocol 
Brain imagingi 
X 
 
 
 
 
 
 
 
 
 
 
See  
Section 8.1 of 
master 
protocol 
SAR444245 
Administration 
 
X 
 
 
X 
X 
 
 
 
 
 
 
Pembrolizumab 
 
X 
 
 
X 
X 
 
 
 
 
 
 
VV-CLIN-0616196 4.0
284
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 18 
Evaluationa 
Screening/ 
baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
 
  
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 
and 
beyond 
EOT Visit 
Follow 
up Visit 1 
Follow up 
Visit 2 
Follow 
up 
Visit 3 
and 
beyond 
Phone call 
follow-up 
Cycle day (Visit 
window in Days) 
D-28 to D-1 
D1  
D8 
(±1)  
D15 
(±1)  
D1 (±3) 
D1 (±3) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Administration 
AE/SAE assessmentj 
X 
Continuously throughout treatment period 
X 
 
 
 
See 
 Section 8.3 of 
master 
protocol 
Prior medication 
(within 28 days 
prior to first 
dose) 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
Continuously throughout treatment period 
 
 
 
 
See  
Section 6.8 of 
master 
protocol 
First subsequent anticancer 
therapy 
  
   
  
 
  
   
X 
X  
 X 
X  
X 
 
Survival status 
  
   
  
 
  
  
  
  
  
  
X 
 
 
VV-CLIN-0616196 4.0
285
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 19 
a Evaluation: There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as part of screening within 3 days prior to first IMP administration. During the study treatment period, all 
assessments must be performed, and results should be reviewed by the investigator prior to IMP administration at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be 
collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are performed and can be signed more than 28 days prior to first IMP administration. Screening time 
indicates the maximum time frame relative to the first IMP administration in which assessments used to support eligibility are done. 
b Cycle: A treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the Cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation Period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1 of master protocol. For 
participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessments are performed. 
d Survival Phone Call Follow-Up Period: Participant who moves into the Survival Follow-up Period should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. 
Information on the first subsequent anticancer treatment, best reported response, and date of progression will also be collected. Updated survival status may be requested by the Sponsor at any time during the 
study. 
e Weight/Height: Height is required at baseline only. Weight is required at Screening and prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most 
recent weight assuming it was assessed in a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible 
considering the variability of local process from site to site.  If the infusion is prepared with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each 
cycle. 
f 
For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.8 of master protocol). 
g If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
h CT/MRI: The initial tumor imaging will be performed within 28 days prior to the C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP or more frequently if clinically indicated in the first 
45 weeks. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging technique should be used in a participant throughout the trial. After 
Week 45 tumor imaging should be performed every 12 weeks (84 ±7 days). CT scan of the head, neck, chest and abdomen (pelvis is optional) and any other locations with suspicion or evidence of disease 
involvement is required for the baseline assessment and during treatment period until PD. After the first documentation of response or the first documentation of progression (if the participant is clinically stable) per 
RECIST 1.1, confirmatory imaging should be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor 
assessment is not needed for participants who start another anti-cancer therapy.  
i 
Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of 
the brain as a site of disease as per protocol tumor assessment schedule. In all other cases, the lesions must be treated. Two additional scans obtained at least 4 weeks apart, should be obtained to document 
disease stability AFTER local treatment administration to the brain metastases has been completed. If participants receive systemic therapy during these 4 weeks stabilization at the treating physician's discretion, 
this systemic therapy will be considered as part of prior anti-cancer therapy. Participants with previously treated brain metastases may participate provided they are stable, which is defined as lack of progression 
on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to 
baseline or resolved, and the participant is not using steroids for at least 14 days prior to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment. 
j 
AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5.0, ICANS and cytokine release syndrome (CRS) will be graded using ASTCT criteria integrated with central laboratory cytokine results 
(1). 
k Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) will be performed every 4 cycles during the Treatment period and as 
clinically indicated. 
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; ASTCT: American Society for Transplantation and Cellular Therapy; C: Cycle; CT: computed tomography; D: Day; ECG: electrocardiogram; ECOG: 
Eastern Cooperative Oncology Group; EOT: end-of-treatment; FT4: free thyroxine; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; HIV: human immunodeficiency virus; HPV: Human Papilloma virus; 
ICANS: Immune effector cell-associated neurotoxicity syndrome; ICF: informed consent form; IMP: investigational medicinal product; IRT: Interactive Response Technology; LVEF; MRI: magnetic resonance imaging; 
NCI-CTCAE: National Cancer Institute-Common terminology criteria for adverse events; PDprogressive disease; PDy: pharmacodynamic; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; 
SAE: serious adverse event; SpO2: oxygen saturation; T3: triiodothyronine; TSH: thyroid stimulating hormone.  
VV-CLIN-0616196 4.0
286
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 20 
1.4 
BIOMARKER FLOWCHART 
VV-CLIN-0616196 4.0
287
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 21 
1.5 
PHARMACOKINETIC FLOWCHART 
Cycle 
Treatment Cycle 1 
Treatment Cycles 2, 
3, 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
30 (±7) days after last IMP 
admin
Day
D1 
D2 
D8 
D1
Time after start of 
SAR444245 dosing 
SOI 
EOI 
Any 
time 
Any time 
SOI 
EOI 
SAR444245 PK 
sample 
P00b 
P01 
P00b 
SAR444245 ADA 
sample 
AB00a 
AB01 
AB00a 
ABF00 
aa Samples collected strictly before start of infusion (SOI). 
b EOI samples must be taken at end of infusion (EOI) precisely ±5 minutes.  
Abbreviations: ADA: anti-drug antibodies; D: day; EOI: end of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: start of infusion. 
VV-CLIN-0616196 4.0
288
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 22 
2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 in combination with various anticancer therapies by identifying early signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to Cohort B1 (R/M HNSCC participants previously treated with 
PD1/PD-L1-based regimen & platinum-based regimen after failure of no more than 2 regimens 
for R/M disease), for the combination of SAR444245 with pembrolizumab. 
Please refer to the master protocol for an introduction for ACT16903 study. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+T cells in murine and NHP models while anti-PD-1 antibody prevents T cell suppression 
through the PD-1/PD-L1 pathway. The combination of anti-PD-1 treatment with SAR444245 was 
tested in a syngeneic mouse Ct-26 colon cancer model and demonstrated enhanced anti-tumor 
activity and prolonged survival compared to each monotherapy. These data support evaluation of 
SAR444245 in combination with pembrolizumab. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across a 
number of indications.  
Refer to the approved local labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and RCC. Tumor-infiltrating lymphocytes can be expanded ex vivo 
and reinfused, inducing durable objective tumor responses in cancers such as melanoma (3, 4). 
VV-CLIN-0616196 4.0
289
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 23 
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7, 8). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (3, 4, 5, 9). The mechanism by which PD1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins (6, 10). 
2.2.1.2 Pre-clinical trials 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(7, 11, 12, 13, 8, 14, 15). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (2, 8, 14, 15, 16). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo. Experiments 
have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, as well as in 
combination with chemotherapy, in syngeneic mouse tumor models (see pembrolizumab 
Investigator’s brochure [IB]). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
2.2.2 Rationale for HNSCC and selected participant population 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
290
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 24 
2.2.3 Current standard of care in HNSCC 
2.2.3.1 PD1/PD-L1 inhibitor monotherapy as second line therapy 
Previously, R/M HNSCC patients in need of second-line treatment (eg, fit patients who progress 
on platinum-based first-line therapy in the R/M setting) primarily received either single-agent 
chemotherapy, targeted therapy with cetuximab, best supportive care, or entered into clinical trials 
(17, 18, 19). 
KEYNOTE-040 was a randomized, Phase 3 study evaluating the efficacy of 2nd line 
pembrolizumab. This multicenter, open-label study compared OS post-treatment with 
pembrolizumab to investigator’s choice (IC) of standard systemic therapy (weekly methotrexate, 
weekly cetuximab or, Q3W docetaxel). In the intention-to-treat (ITT) population, irrespective of 
PD-L1 status, median OS was 8.4 months (95% CI 6.4-9.4) with pembrolizumab versus 
6.9 months (5.9-8.0) with standard of care (SOC) (hazard ratio 0.80, 0.65-0.98; p = 0.0161) (20). 
Among patients with a CPS; the number of PD-L1 positive cells (including tumor, lymphocytes 
and macrophages, in relation to total tumor cells) for tumor and immune cell PD-L1-expression of 
at least 1, median OS was 8.7 months (95% CI 6.9-11.4) with pembrolizumab versus 7.1 months 
(5.7-8.3) with standard treatments (HR 0.74; 95% CI: 0.58-0.93, p = 0.0049). Among patients 
with a Combined Positive Score (CPS) score of less than 1, median OS was 6.3 months (3.9-8.9) 
with pembrolizumab compared to 7.0 months (5.1-9.0) with SOC (HR 1.28; 95% CI: 0.8-2.07, 
p = 0.8476).  
Additionally, incidence of Grade 3-5 treatment-related adverse events (TRAEs) was significantly 
lower in the pembrolizumab cohort (13.0%) compared to the SOC cohort (36.0%), with 2 and 1%, 
respectively, reporting deaths due to TRAEs (20). Thus, while pembrolizumab increased median 
OS compared with standard chemotherapy irrespective of PD-L1 status, the benefit of 
pembrolizumab was greater in patients with PD-L1 CPS ≥1 and TPS ≥50% (20). 
CheckMate 141 was a randomized, Phase 3 study of a PD-1 inhibitor in HNSCC and enrolled 
361 patients regardless of tumor PD-L1 status. In this trial, patients received either 3 mg/kg 
nivolumab every 2 weeks (Q2W)or investigator’s choice of weekly systemic standard therapy 
(methotrexate, weekly docetaxel, or cetuximab). Patients who received nivolumab demonstrated 
increased median OS (7.5 months versus 5.1 months, respectively) and an increased overall 
response rate (ORR; 13.3% versus 5.8%, respectively) compared to patients who received 
chemotherapy. At the first interim analysis, estimated one-year OS was 36% with nivolumab 
compared to 16.6% with standard therapy (9). Furthermore, only 13.1% of patients treated with 
nivolumab experienced grade 3-4 TRAEs compared to 35.1% of patients treated with standard 
therapy. 
2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 and other combinations may be found in the IB. 
VV-CLIN-0616196 4.0
291
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 25 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the 
new-generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with pembrolizumab results from anticipated risks for 
SAR444245 and from the label information for pembrolizumab, taking into account potential 
overlapping risks. The available safety data for pembrolizumab, along with proposed mitigation 
strategies are summarized below and also provided in Table 10. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment. 
The use of pembrolizumab may cause infusion-related reactions (IRR) (drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, hypersensitivity and cytokine release syndrome 
[CRS]); Pembrolizumab use may be associated with infections (pneumonia), bone marrow 
suppression (anemia, thrombocytopenia, leukopenia), increase in the level of hepatic enzymes 
(alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase), kidney damage 
(nephritis, acute kidney injury), as well as adverse effects on the functioning of nervous system 
(dizziness, headache, peripheral neuropathy, dysgeusia (very common) and lethargy (common). In 
combination therapy with other chemotherapeutic drugs, pembrolizumab administration is 
commonly associated with hypertension and cardiac arrhythmia (including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risk for pembrolizumab 
(21). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in post 
marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis. 
VV-CLIN-0616196 4.0
292
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 26 
Please refer to the country-approved product labeling (eg, United States Package Insert [USPI], 
Summary of Product Characteristics [SmPC]) for pembrolizumab for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab 
Due to synergistic action of SAR444245 and pembrolizumab, combining these two substances 
may lead to an increased frequency and/or severity of adverse events (AEs) related to immune 
activation for each substance individually or may cause occurrences of qualitatively different 
AEs. Serious adverse drug reactions reported with agents known to increase immune activation 
include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction (see Section 2.3.1.1). 
The maximum tolerated dose of SAR444245 combined with the approved dosing of the anti-PD1 
pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. Safety data 
generated from the combination of SAR444245 and pembrolizumab have informed the selection 
of the combination dose in this study. 
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of CRs and prolonged survival 
which was durable as demonstrated by the failure of the tumor to grow upon re-engraftment on 
the tumor free animals, indicating the establishment of a durable memory T-cell population in 
response to the initial treatment (see SAR444245 IB).  
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. Overall, the potential risks identified in association with this new generation IL-2 
SAR444245 combined with the anti PD1 inhibitor pembrolizumab are justified by the anticipated 
benefits that may be afforded to participants with HNSCC. 
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity.  
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was explored by 2 groups who did not find a clinically meaningful signal (22, 23). 
VV-CLIN-0616196 4.0
293
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 27 
3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of objectives and endpoints.  
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
294
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 28 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This substudy will include participants with R/M HNSCC previously treated with PD1/PD-L1-
based regimen & platinum-based regimen, after failure of no more than 2 regimens for R/M 
disease and will assess SAR444245 combined with pembrolizumab. 
Overall, approximately 40 participants will be enrolled and treated in the core phase of Cohort B1.
In the expansion phase, approximately 56 participants will be enrolled. 
The maximum number of cycles allowed in this Cohort B1 substudy is 35 cycles. 
Please refer to the master protocol for a full description of the study design and for therapy details 
applicable to all cohorts. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that non-alpha IL-2 SAR444245 
combined with the anti-PD1 antibody pembrolizumab, will result in a significant increase in the 
percentage of trial participants with HNSCC experiencing an objective response. 
After the core phase to gather more safety data with the confirmed dose, the substudy may be 
expanded to enroll more participants and accumulate evidence of clinical activity. 
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol. 
4.3.2 Pembrolizumab dose 
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of data 
generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications and regardless of tumor type. As outlined below, 
this dose is justified by: 
VV-CLIN-0616196 4.0
295
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 29 
• Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer 
(NSCLC) indications demonstrating flat dose- and exposure-efficacy relationships from 
2 mg/kg Q3W to 10 mg/kg Q2W representing an approximate 5 to 7.5 fold exposure range 
(refer to the pembrolizumab IB). 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications.  
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
296
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 30 
5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort B1-specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply 
(in addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Provision of tumor tissue: 
- 
Optional baseline biopsy for participants in Core Phase. 
- 
Mandatory baseline biopsy for all participant in Expansion Phase (minimum 
10 slides with 4-5 micron thickness). Archival tumor tissue samples should be 
obtained from biopsies done within 6 months, and there should be no systemic 
anti-cancer therapy between collection of biopsy and enrollment. Slides specifications 
are detailed in Lab Manual. 
- 
The Sponsor may approve the written request to enroll, on a case-by-case basis, 
participants with: 
- 
Location of the tumor not amenable to biopsy due to significant risk, OR 
- 
Less than required number of slides or archival tumor tissue sample collected 
more than 6 months prior to enrollment. 
I 02. Prior anticancer therapy 
Have failed no more than 2 systemic anti-cancer regimens (a platinum-containing regimen, 
AND an anti-PD-1/PD-L1 based regimen, administered either sequentially or concurrently, 
unless these regimens are already given in locally advanced disease) in R/M disease: 
- 
One previous anti-PD-1/PDL1 based regimen (may include chemotherapy agents as 
part of the regimen) failure defined as disease progressed (when participants are 
still receiving) but after documented benefit, on an anti-PD1/PDL-1 based 
regimen per RECIST 1.1. Documentation of benefit defined as stable disease [SD] at 
≥1 radiographic imaging scan, CR, or PR from anti-PD1/PDL-1 based regimen. An 
anti PD-1/PD-L1 containing regimen is defined as either an anti PD-1/PD-L1 
monotherapy, or an anti-PD-1/PD-L1 agent administered in the same cycle as another 
systemic anti-cancer therapy. If an anti-PD-1/PDL-1 agent was used beyond initial 
radiological progression (without change the anti-PD-1/PDL-1 agent used before 
progressive disease), it's still considered as the same regimen. The site’s study team 
must have reviewed previous tumor assessments (including screening tumor imaging) 
to determine that radiographic progression has occurred per RECIST 1.1 following 
initiation of the anti PD-1/PD-L1 containing regimen. 
VV-CLIN-0616196 4.0
297
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 31 
AND 
-
One previous platinum-containing regimen failure defined as either disease
progression on or after treatment with a platinum-containing regimen.
5.2 
EXCLUSION CRITERIA 
Please refer to master protocol. 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
(ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION) 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
298
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 32 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
The maximum number of cycles allowed in this Cohort B1 substudy is 35 cycles. 
Dosing sequence:
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245, and pembrolizumab 
administered as described in Section 4.1. Details of each IMP component to be administered are 
shown in Table 1.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.  
Table 1 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
25 mg/mL 
Dosage level(s)a 
24 μg/kg Q3W  
200 mg Q3W 
Route of administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
IMP 
IMP 
Packaging and labeling 
See master protocol 
Supplied in single-dose vials containing 
100 mg/4 mL pembrolizumab labelled with a 
multilingual booklet. 1 vial per treatment box. 
Current/Former name(s) 
or alias(es) 
NA 
Keytruda 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the e-CRF. Study 
sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min).
VV-CLIN-0616196 4.0
299
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 33 
6.1.2 Non-investigational medicinal product 
Please refer to the master protocol. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modifications for SAR444245 are permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed. 
Once a dose has been decreased, intra-patient re-escalation back to the previous dose level is not 
permitted. 
VV-CLIN-0616196 4.0
300
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 34 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If a toxicity leads to SAR444245 discontinuation, pembrolizumab must be discontinued unless the 
TEAE leading to permanent IMP discontinuation is clearly attributable only to SAR444245, and 
patients have clinical benefit as determined by the treating physician. 
Participants who continue pembrolizumab in this scenario are informed as part of the initial 
consent process that pembrolizumab monotherapy is not a standard of care. In this case it is partial 
permanent discontinuation and the end of treatment (EOT) assessment will be 30 days after the 
date of the last administration of the remaining IMP. When all IMP components are permanently 
discontinued it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay  
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administered ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3. After cycle delayed, such participants may be considered for treatment 
resumption once the toxicity resolves or improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on 
the day of planned administration, the cycle will be delayed; restart of study IMPs could 
occur only on the initiation of the subsequent cycle. 
• In case of cycle delay for the recovery of toxicity, the following rules should be followed 
for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to restart 
the study treatment, if a clear benefit from treatment is observed and after consultation 
with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer than 
84 days. 
• Cycle may be delayed for situations other than TEAEs such as medical/surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study 
therapy within 21 days of the scheduled delay, unless otherwise discussed with the 
Sponsor (for example for national or regional emergencies). The reason for this delay 
should be documented in the participant’s study record. 
VV-CLIN-0616196 4.0
301
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 35 
6.5.3 General guidelines for the management of treatment-related adverse events 
Participants who experience Grade ≥3 treatment-related adverse events (TRAEs) at any time of 
the study (including clinically significant Grade 3 laboratory abnormalities as defined in 
Section 10.3.1 of the master protocol) will be required to temporarily delay the IMP, unless 
specified otherwise in the protocol, and with the exception of the TRAEs resolving within 5 days. 
After cycle delay, such participants may be considered for treatment resumption once the TRAE 
resolves or improves to Grade 1 or baseline. Treatment resumption is at the discretion of the 
Investigator and Sponsor, if thought to be in the best interest of the participant, except when 
specified otherwise in this protocol, or if the event has required the IMP temporary interruption 
for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
 µg/kg to 
 µg/kg or another lower dose may be decided 
when specified in the protocol or following discussions with the Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific AEs including irAE, CRS, vascular leak 
syndrome (VLS) and IRRs are presented in Section 6.5.4. 
6.5.4 Guidelines for the management of specific adverse events 
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute-Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF. 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
infusion-related reactions (IRR). 
An IRR in this study is defined as any signs or symptoms which develop during the infusion or up 
to 24 hours after the completion of the infusion. The term IRR indicates only a specific temporal 
relationship with the infusion and does not specify a particular mechanism underlying the signs or 
symptoms.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
VV-CLIN-0616196 4.0
302
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 36 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 2. 
After an infusion-related reaction due to pembrolizumab infusion, the SAR444245 infusion will 
be delayed and can be administered after resolution of symptoms. The Investigator should discuss 
with the Sponsor’s Medical Monitor if the SAR444245 infusion needs to be delayed more than 
1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 3. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
Table 2 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator. 
None 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
•
IV fluids,
•
Antihistamines,
•
NSAIDs,
•
Acetaminophen,
•
Narcotics.
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, 
the infusion may be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr. to 50 mL/hr.). Otherwise dosing will 
be held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
VV-CLIN-0616196 4.0
303
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 37 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; urgent 
intervention indicated 
Stop Infusion 
Additional appropriate medical therapy may include but is 
not limited to: 
•
Epinephrine*,
•
IV fluids,
•
Antihistamines,
•
NSAIDs,
•
Acetaminophen,
•
Narcotics,
•
Oxygen,
•
Pressors,
•
Corticosteroids.
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of 
the investigator. 
Hospitalization may be indicated. 
*In cases of anaphylaxis, epinephrine should be used
immediately.
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
Table 3 - SAR444245 Infusion-related reaction dose modification and treatment guidelines
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary. 
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
Interrupt SAR444245 infusion. 
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise dosing will be held 
until symptoms resolve and the participant will be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
Give the next infusion at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics. 
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
VV-CLIN-0616196 4.0
304
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 38 
NCI CTCAE Grade 
Treatment 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
Grade 4 
Life-threatening; urgent intervention indicated 
Permanently discontinue SAR444245. The participant can continue treatment 
with the other anti-cancer therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately. 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of SAR444245 being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines) 
(24, 25, 26). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Monitoring of vital signs is detailed in Section 8.2.2. 
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 4. If any grade of CRS is suspected, sites should make every effort 
to draw an additional blood sample for cytokines levels (by central laboratory) prior to the 
administration of tocilizumab or alternative therapies per site practice in CRS management, as well 
as C-reactive protein (CRP) and ferritin (by local laboratory). 
Sites should have at least 2 full doses of tocilizumab or alternative therapies per site practice in 
CRS management available and access to an intensive care unit (ICU), in case participants 
develop CRS. 
VV-CLIN-0616196 4.0
305
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 39 
Guidelines for management of CRS according to severity grading are provided in Table 4. 
ASTCT CRS consensus grading scale is provided in Section 10.13 of the master protocol. 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
•
Fever (Temperature ≥38°C)b
•
No hypotension
•
No hypoxia
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV fluids 
(care should be taken to not excessively hydrate if evidence of vascular 
leak), antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less frequently 
as the participant improves. 
Grade 2 
•
Feverb (Temperature ≥38°C)
•
Hypotension not requiring vasopressors
•
and/orc hypoxia requiring low-flow nasal
cannulad or blow-by.
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Increase monitoring of vital signs, cardiac and other organ functions closely 
as medically indicated until the participant recovers. Transfer to ICU may be 
required. 
For participants with comorbidities, older age, or with oxygen requirement, 
hypotension, or participants in whom symptoms (eg, high grade fever) that 
do not respond to antipyretics within 72 hours treatment with corticosteroids 
and/or tocilizumab or alternative therapies per site practice in CRS 
management should be considered, as per guidance for Grade 3 events.  
IMP may be resumed when clinical symptoms have resolved or improved to 
Grade 1 and corticosteroid taper. No dose modification is required but 
decreasing to half the infusion rate can be considered. 
Grade 3 
•
Feverb (Temperature ≥38°C)
•
Hypotension requiring a vasopressor
with or without vasopressin
•
And/orc hypoxia requiring high-flow nasal
cannulad, face mask, nonrebreather
mask, or Venturi mask
Grade 4 
Life-threatening consequences; urgent intervention 
indicated 
•
Feverb (Temperature ≥38°C)
•
Hypotension requiring multiple
vasopressors (excluding vasopressin)
•
And/orc hypoxia requiring positive
pressure (eg, CPAP, BiPAP, intubation
and mechanical ventilation)
If CRS grade 3, temporarily cycle delay SAR444245 and resume subsequent 
treatment only when symptoms have resolved or improved to Grade 1. 
SAR444245 can be either restarted at 
 µg/kg or permanently discontinued, as 
clinically indicated.  
If CRS Grade 4, permanently discontinue SAR444245. 
If CRS Grade 3 or Grade 4, initiate IV corticosteroids (outside of the context 
of CAR-T cells, corticosteroids alone maybe initiated in first intention) and 
tocilizumab or alternative therapies per site practice in CRS management 
considered, and/or epinephrine and/or other vasopressors should be 
administered as needed. Participants with severe CRS may require 
management in intensive care setting, with monitoring of clinical status and 
laboratory tests performed at least daily. 
As the participant improves, the intensity of the monitoring and setting can 
be decreased, but the participant should not be discharged from the hospital 
until clinically stable. Corticosteroids can then be administered IV or orally 
every 8 hours for up to 3 days, then tapered over 4 days. In general, 
tapering of steroids can start when vasopressors and high-flow oxygen are 
no longer needed.  
VV-CLIN-0616196 4.0
306
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 40 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
CRS is considered resolved when there is sustained resolution of fever and 
there is no longer a need for oxygen supplementation to relieve hypoxia nor 
vasopressors to maintain blood pressure; however, normalization of 
temperature alone does not define resolution of CRS. 
If no clinical improvement in oxygenation, hypotension, fever, and other 
CRS manifestations is observed within 24 to 72 hours, initiate management 
for persistent or worsening CRS. Re-evaluation for other contributing 
conditions will be done, such as infection, cardiac, thromboembolic and 
other complications. Intravenous Tocilizumab at 8 mg/kg (for participants
weighing ≥30 kg) or alternative therapies per site practice in CRS 
management should be administered, and steroids should be administered 
concurrently. If still no improvement in oxygenation, hypotension, fever and 
other manifestations, is observed after the first dose of tocilizumab, it may 
be repeated after an interval of at least 8 hours and should not exceed 
4 doses in total. 
For participants with severe CRS who fail to improve after repetitive 
treatment with both tocilizumab or alternative therapies per site practice in 
CRS management and steroids, alternative options will be discussed with 
clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or alternative therapies per site practice in CRS management or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.5.4.4 Immune-related adverse events 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Immune-related AEs (irAEs) are thought to be caused by unrestrained cellular immune responses 
directed at the normal host tissues. Therefore, early recognition and initiation of treatment is 
critical to reduce complications. Based on existing pembrolizumab clinical study data, most irAEs 
were reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and 
administer corticosteroids. 
VV-CLIN-0616196 4.0
307
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 41 
SAR444245 may increase the incidence and severity of these events. 
Dose modification and toxicity management guidelines for irAEs are provided in Table 5. Of 
note, if the AE is considered immune-related, both drugs in the combination should be held 
according to recommended dose modifications. If a participant experiences several irAEs, the 
most conservative recommendation should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs. 
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
•
If the toxicity does not resolve or the criteria for resuming treatment are not met, the
participant must be discontinued from all study drugs.
•
If the toxicities do resolve and conditions are aligned with what is defined in Table 5, the
combination of SAR444245 and pembrolizumab may be restarted at the discretion of the
investigator. In these cases where the toxicity is attributed to the combination or to
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered
after communication with the Sponsor.
Table 5 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245
General instructions: 
1.
Treat severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Begin other
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment.
3.
Begin the corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE
decreased to ≤ Grade 1 after corticosteroid taper.
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Pneumonitis 
Grade 2 
Withholda 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Monitor participants for signs and 
symptoms of pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment. 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently discontinueb 
VV-CLIN-0616196 4.0
308
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 42 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Diarrhea/Colitis 
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper. 
Monitor participants for signs and 
symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥ Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis. 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently discontinueb 
AST or ALT 
elevation or 
Increased 
Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper. 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable). 
Grade 3d or 4e 
Permanently discontinueb  Administer corticosteroids
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Type 1 Diabetes 
Mellitus (T1DM) 
or 
Hyperglycemia 
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withholda,f 
Initiate insulin 
replacement therapy for 
participants with T1DM. 
Administer 
antihyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and symptoms 
of hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
Withholda or permanently 
discontinueb, f 
Hyperthyroidism 
Grade 2 
Continue 
Treat with nonselective 
beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate. 
Monitor for signs and symptoms 
of thyroid disorders. 
Grade 3 or 4 
Withholda or permanently 
discontinueb, f 
VV-CLIN-0616196 4.0
309
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 43 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Hypothyroidism 
Grade 2, 3, or 
4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per standard 
of care. 
Monitor for signs and symptoms 
of thyroid disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently discontinueb 
Myocarditis 
Grade 2, 3 or 4 
Permanently discontinueb 
Based on severity of AE
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, or 
DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently discontinueb 
All Other irAEs 
Persistent 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes. 
Grade 3 
Withholda or discontinue 
based on the eventg 
Recurrent 
Grade 3 or 
Grade 4 
Permanently discontinueb 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 to 5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 to 3.0 x ULN if baseline normal; 
>1.5 to 3.0 x baseline if baseline abnormal.
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline 
normal; >3.0 to 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal.
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse 
Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; 
IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of 
normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
VV-CLIN-0616196 4.0
310
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 44 
6.5.4.5 Immune Cell-Associated Neurotoxicity Syndrome (ICANS) 
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment 
of cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment 
(Section 10.13 of the master protocol). Recommendations for ICANS management mainly include 
the use of steroids, whereas tocilizumab or alternative therapies per site practice in CRS 
management should only be used in the context of CRS, as outlined in Table 6. The proposed 
management should be considered only as recommendations and in light of recommendations 
from site specialist. 
Table 6 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS) 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring. 
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
Delay SAR444245a. 
Initiate treatment with IV corticosteroids as needed.  
SAR444245 may be resumed only after participant recovery or improvement to 
Grade 1 after corticosteroid taper. Consideration for reduction of SAR444245 
dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on EEG 
that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and unable 
to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
If Grade 3 ICANS, delay SAR444245. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Section 6.5.4.3 
Corticosteroids can then be administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days. 
If Grade 4 ICANS, permanently discontinue SAR444245. 
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Section 6.5.4.3. 
Corticosteroids can then be administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) or alternative therapies per site practice in CRS 
VV-CLIN-0616196 4.0
311
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 45 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
management should be considered, and steroids should be administered 
concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.5.4.6 Vascular Leak Syndrome (VLS) 
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions,
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic, shock 
with multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a 
balance between maintaining the intravascular volume to ensure organ perfusion to prevent organ 
failure, while avoiding volume overload. The management of VLS according to severity grading 
is described in Table 7. These guidelines are not comprehensive and the Investigator should 
exercise clinical judgment based on the symptoms and condition of the individual participant and 
refer to current guidelines to the topic (27).  
Table 7 - Guidelines for the management of Vascular Leak Syndrome (VLS) 
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
Delay SAR444245. Upon resolution of VLS or improvement to Grade 1, 
SAR444245a can be resumed at the reduced dose of 
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
VV-CLIN-0616196 4.0
312
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 46 
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, permanently discontinue SAR444245. 
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, 
disease-specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
Definition of pembrolizumab overdose is provided in Section 8.3.8. 
There is no specific antidote for overdose with pembrolizumab. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
313
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 47 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol.  
VV-CLIN-0616196 4.0
314
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 48 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol.  
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.2 
SAFETY ASSESSMENTS  
8.2.1 Physical examinations 
Please refer to the master protocol.  
8.2.2 Vital signs 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be 
measured after 5 minutes rest.  
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;  
- 
Vital signs will be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5),  
4 (±0.5) hours after start of SAR444245 dose.  
- 
At Investigator’s discretion, participants (not in the safety run-in) may have intensive 
vital sign monitoring (to be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5),  
4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 20 (±1), 24 (±1) hours after start of SAR444245 
dose in an in-patient setting).  
• For the core phase participants: from Cycle 2 to Cycle 4 study therapy will be 
administered for all patients in out-patient clinic with vital signs taken at baseline, at least 
4 to 6 hours after the start of SAR444245 dosing, or for longer periods of time if clinically 
indicated.   
8.2.3 Electrocardiograms and left ventricular ejection fraction (LVEF) 
Please refer to the master protocol.  
8.2.4 Clinical safety laboratory assessments 
Please refer to the master protocol.  
VV-CLIN-0616196 4.0
315
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 49 
8.2.5 Pregnancy testing 
Please refer to the master protocol.  
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort B1 irAEs will be collected until 90 days following last administration of 
study treatment regardless of whether or not another anticancer therapy is initiated.  
8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, SAEs that are considered expected will be specified in the reference safety 
information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
316
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 50 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
•
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
317
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 51 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION  
Sample size: 
The plan is to treat a total of 40 participants in core phase of Cohort B1. In the expansion phase, 
approximately 56 participants will be enrolled and treated. 
Core Phase 
Please refer to the master protocol. 
Expansion Phase 
At the end of the core phase of Cohort B1, the overall antitumor activity and safety will be 
assessed. The sponsor may decide to open a 56-participant expansion part based on the totality of 
data if the posterior probability that the true ORR is greater than 9%, which is considered minimal 
efficacious signal of interest, is greater than 80% with durable response. Based on a conjugate 
non-informative prior of beta (0.5, 0.5) at the time of the design of the study, at least 6 responders 
out of 40 exposed participants at the confirmed dose (confirmed ORR=15%) need to be observed 
in the core phase. However, emerging data generated from outside of the study may warrant a 
different prior to be considered before the formal IA. Analyses based on the total 96 participants 
by combining core phase and expansion phase will be performed. Table 8 lists estimated ORR and 
the corresponding 95% exact CIs by number of responders from a sample size of 96 participants 
evaluable for activity in each cohort.  
Table 8 - Estimated objective response rate (ORR) and 95% CI for Cohort B1 (combining core and 
expansion phases)  
Number of responders 
(N=96) 
ORR 
95% CI for ORR 
(Clopper-Pearson) 
10 
10.4% 
(5.1%, 18.3%) 
12 
12.5% 
(6%, 20.8.5%) 
14 
14.6% 
(8.2%, 23.3%) 
15 
15.6% 
(9%, 24.3%) 
VV-CLIN-0616196 4.0
318
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 52 
With a sample size of 40 study participants in the core phase, the probability of observing 1 or 
more instances of an AE with a true incidence rate of 1%, 2%, or 5% is 33.1%, 55.4%, or 87.1%, 
respectively. With a sample size of 96 study participants in total, the probability of observing 1 or 
more instances of an AE with a true incidence rate of 1%, 2%, or 5% is 61.9%, 85.6%, or >99%, 
respectively. This provides reasonable assurance that events occurring at ≥5% frequency can be 
identified in this study. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
9.5 
INTERIM ANALYSES  
Periodic Data Monitoring Committees (DMCs) are planned (details are in the master protocol). 
At the end of the core phase, Cohorts B1 will have one formal interim analysis when all 
participants in the core phase have at least 2 post‑baseline tumor assessments or discontinued 
study treatment (whichever occurs first). The sponsor will decide if the expansion will be initiated 
based on totality of the data observed. 
The cohort cut-off for the primary ORR endpoint analysis corresponds to approximately 9 months 
from the date of the last participant’s first infusion in the expansion phase (to document that last 
participant response is maintained for 6 months).  
VV-CLIN-0616196 4.0
319
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 53 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. 
Cohort B1-specific evaluations are presented in Table 9. 
Table 9 - Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
Tri-iodothyronine (T3) 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
VV-CLIN-0616196 4.0
320
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 54 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol. 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Please refer to the master protocol. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 10. 
Table 10 - Risk assessment 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
Pembrolizumab 
Common, but infusion-related reactions in 
labeling include drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, 
hypersensitivity and cytokine release syndrome.  
Pembrolizumab 
Dose modification and treatment 
guidelines for pembrolizumab 
infusion-related reactions are provided  
in Section 6.5.4.1. 
Hypersensitivity, including 
anaphylaxis 
Pembrolizumab 
Not specifically reported, but included among 
infusion-related reactions in label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master 
protocol. 
VV-CLIN-0616196 4.0
321
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 55 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Hepatotoxicity 
Pembrolizumab 
Pembrolizumab can cause immune-mediated 
hepatitis. Immune-mediated hepatitis occurred in 
0.7% (19/2799) of patients receiving 
pembrolizumab, including Grade 4 (<0.1%), 
Grade 3 (0.4%), and Grade 2 (0.1%) adverse 
reactions. Systemic corticosteroids were required 
in 68% (13/19) of patients with hepatitis. Eleven 
percent of these patients required additional 
immunosuppressant therapy. Hepatitis led to 
permanent discontinuation of KEYTRUDA in 
0.2% (6) of patients and withholding of 
pembrolizumab in 0.3% (9) of patients. All 
patients who were withheld reinitiated 
pembrolizumab after symptom improvement; of 
these, none had recurrence of hepatitis. Hepatitis 
resolved in 79% of the 19 patients. 
Dose modification and treatment 
guidelines for liver enzyme increase are 
provided under immune-related reactions 
in Section 6.5.4.4. 
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury. 
Dose modification and treatment 
guidelines for nephrotoxicity are provided 
under immune-related reactions 
in Section 6.5.4.4.  
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy (common) 
for pembrolizumab in combination with 
chemotherapy.  
Uncommon: epilepsy. 
Dose modification and treatment 
guidelines for neurological AEs are 
provided under immune-related reactions 
in Section 6.5.4.4. 
Immune-mediated Adverse 
Events 
Pembrolizumab 
Immune-mediated adverse events are designated 
as important identified risk for pembrolizumab. 
Dose modification and treatment 
guidelines for immune-related reactions 
are provided in Section 6.5.4.4. 
Risks related to special 
populations 
 
 
Pregnancy and lactation 
exposure and outcomes 
Pembrolizumab 
Pembrolizumab should not be used during 
pregnancy unless the clinical condition of the 
woman requires treatment with pembrolizumab. 
See master protocol for exclusion of 
participants, guidance on highly effective 
contraceptive methods, and pregnancy 
tests to be performed regularly. 
Drug-drug interactions 
No data available. 
 
Overdose and its treatment 
No specific information is available on the 
treatment of overdose of pembrolizumab. 
See Section 6.7 
VV-CLIN-0616196 4.0
322
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 56 
10.11 APPENDIX 11: ABBREVIATIONS 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
COVID-19: 
Coronavirus disease 2019 
CPS: 
Combined Positive Score 
CR: 
complete response 
CRS: 
cytokine release syndrome 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4  
e-CRF:
electronic case report form 
EOT:
end of treatment 
FDA:
Food and Drug Administration 
HNSCC:
head and neck squamous cell carcinoma 
IB:
Investigator's brochure 
ICANS:
Immune cell-associated neurotoxicity syndrome 
ICU:
intensive care unit 
Ig:
immunoglobulin 
IMP:
investigational medicinal product 
irAEs:
immune-related AEs 
IRR:
infusion-related reactions 
IV:
intravenous 
LVEF:
left ventricular ejection fraction
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NSCLC: 
non-small cell lung cancer 
ORR: 
objective response rate 
PBPK: 
physiologically-based PK 
PD1: 
programmed cell death-1 
PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death ligand 2 
PK: 
pharmacokinetic 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
R/M: 
recurrent and/or metastatic 
SAEs: 
serious adverse events 
SoA: 
schedule of activities 
SOC: 
standard of care 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
TRAEs: 
treatment-related adverse events 
VLS: 
vascular leak syndrome 
VV-CLIN-0616196 4.0
323
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 57 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amended protocol 01 (26 July 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth 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 overall rationale for the amendment is to respond to the Health Authorities (Food and Drug 
Administration, [FDA]) requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.4 Guidelines 
for the management of 
specific adverse events 
For clarity and brevity, command language has 
been used in the toxicity management sections. 
Regulatory Authority (FDA) request 
Section 6.5.4.1 
Infusion-related reactions 
(IRR)  
In Table 3 the following text has been revised:  
Under Grade 3 and Grade 4:  
- “prematurely” deleted from “prematurely 
permanently discontinued”. 
- “clearly attributable” deleted from “If IRR is 
clearly attributable to SAR444245”as the table 
title already indicates treatment with regards to 
SAR444245 IRRs.  
Under Grade 2, Grade 3 and Grade 4: “if 
applicable” deleted in the sentence that reads 
“SAR444245 infusion should be interrupted if 
applicable”. 
Regulatory Authority (FDA) request 
 
In Table 2 and Table 3, the following text 
“requires therapy or infusion interruption” has 
changed to “Therapy or infusion interruption 
indicated', and “pressor or ventilator support 
indicated” has been changed to “urgent 
intervention indicated''. 
For consistency with Common terminology 
criteria for adverse events (CTCAE) guidelines 
(version 5) 
Section 6.5.4.1 
Infusion-related reactions 
(IRR) and Section 10.10 
Risk assessment 
(Table10) 
The text “SAR444245 infusion-associated 
reaction” was changed to “SAR444245 
infusion-related reaction”. 
For consistency 
VV-CLIN-0616196 4.0
324
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 58 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.4.3 Fever, 
flu-like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 4 the following text “If subsequent 
administration is tolerated, increasing the 
SAR444245 dose to 
 µg/kg at subsequent 
administration can be considered based on the 
clinical judgement of the Investigator with the 
Sponsor” has been removed for Grade 3.  
For Grade 3, the following sentence has been 
changed from “If CRS grade 3, temporarily cycle 
delay SAR444245, and resume subsequent 
treatment only when symptoms have resolved or 
improved to Grade 1 at 
µg/kg or permanently 
discontinued, as clinically indicated” to “If CRS 
grade 3, temporarily cycle delay SAR444245, 
and resume subsequent treatment only when 
symptoms have resolved or improved to Grade 1. 
SAR444245 can be either restarted at 
 µg/kg 
or permanently discontinued, as clinically 
indicated”. 
For Grade 4 “as clinically indicated” has been 
removed from the subtitle. 
The following sentence has been added: 
“Monitoring of vital signs is detailed in 
Section 8.2.2” for clarity. 
Regulatory Authority (FDA) request 
For consistency and clarity 
Section 6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
In Table 6 the following text has been added 
under Grade 3 ICANS: “Treatment with IV 
corticosteroids should be initiated. Concomitant 
CRS may require tocilizumab and should be 
handled as described in Section 6.5.4.3. 
Corticosteroids can then be administered IV or 
orally every 8 hours for up to 3 days, then 
tapered over 4 days.” 
Regulatory Authority (FDA) request 
 
The following text “diffuse cerebral edema” has 
been revised to “signs of diffuse cerebral edema”. 
For consistency with the American Society for 
Transplantation and Cellular Therapy (ASTCT) 
Consensus 
Sections 8.2.1 Physical 
examinations, Section 
8.2.2 Vital signs, Section 
8.2.3 Electrocardiograms, 
Section 8.2.4 Clinical 
safety laboratory 
assessments, and Section 
8.2.5 Pregnancy testing 
Sections newly inserted. 
For clarity 
Section 8.2.2 Vital signs 
Details regarding monitoring of vital signs  
provided in the Master protocol have been added. 
Regulatory Authority (FDA) request 
Section 10.10: Appendix 
10: Risk assessment 
In Table 10 assessment under hepatoxicity for 
pembrolizumab was revised to be aligned with 
the last version of USPI warnings and 
precautions for pembrolizumab. 
Regulatory Authority (FDA) request 
Throughout the document 
Minor editorial corrections were made. 
Changes made for consistency  
VV-CLIN-0616196 4.0
325
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 59 
Amended protocol 02 (19 August 2021) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to add a new study cohort (Cohort A2, substudy 
protocol 02) and clarify the priority of recruitment of participants between Cohorts A1 and A2 
(see Master protocol). Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Columns indicating D8 (±1) and D15 (±1) for treatment Cycle 2 
and treatment Cycle 3 and beyond were removed.  
Change made for correction 
 
“IMP Administration (SAR444245 Administration)” has been 
changed to “SAR444245 Administration” with a reference to the 
master protocol. 
Change made for clarification 
Section 5.1 Inclusion 
criteria 
In I06 “participants with less than required number of slides or 
archival tumor tissue sample collected more than 6 months prior 
to screening” has been revised to “participants with less than 
required number of slides or archival tumor tissue sample 
collected more than 6 months prior to enrollment”   
Harmonization per program level 
approach 
Section 6.5.2 Cycle delay, 
and Section 6.5.3 General 
guidelines for the 
management of treatment-
related adverse events 
The following text regarding the treatment resumption after 
Cycle delay has been deleted: “or is stable and manageable 
through supportive/medical therapy”. 
Change made for correction 
Section 6.5.3 General 
guidelines for the 
management of treatment-
related adverse events 
The name “Study Committee” has been changed to “Study 
Board”. 
Change made to ensure clarity 
and avoid confusion with any 
Independent Committee 
Section 6.5.4.1 
Infusion-related reactions 
(IRR) 
In Table 3 under Grade 3 and Grade 4, the following text 
“Interrupt SAR444245 infusion” has been removed. 
Change made for clarification 
Section 8.2.3 
Electrocardiograms and 
left ventricular ejection 
fraction (LVEF) 
The following text: “and left ventricular ejection fraction (LVEF)” 
has been added to the naming of the section. 
Change made for clarification 
Throughout the document 
Minor editorial corrections were made. 
Changes made for consistency  
 
VV-CLIN-0616196 4.0
326
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021 
Version number: 1  
 
Property of the Sanofi Group - strictly confidential 
Page 60 
11 
REFERENCES 
1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
2. Disis ML. Immune regulation of cancer. J Clin Oncol. 2010;28(29):4531-8. 
3. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
cell transfer therapy following non-Myeloablative but lymphodepleting chemotherapy for the 
treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-
57. 
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
2008;358(25):2698-703. 
5. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
7. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
8. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
2005;25(21):9543-53. 
9. Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for 
recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):1856-
67. 
10. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
11. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol. 
2004,173 (2):945-54. 
12. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George, JA, Wooter, J, et al. PD-1 inhibits T-
cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574(1-3)37-41. 
VV-CLIN-0616196 4.0
327
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 61 
13. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25.
14. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res.
2005;65(3):1089-96.
15. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer
Res. 2004;64(3):1140-5.
16. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9.
17. Adelstein D, Gillison ML, Pfister DG, Spencer S, Adkins D, Brizel DM, et al. NCCN
guidelines insights: head and neck cancers, version 2.2017. J Natl Compr Cancer Netw.
2017;15(6):761-70.
18. Gregoire V, Lefebvre JL, Licitra L, Felip E, EHNS-ESMO-ESTRO Guidelines Working
Group. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO clinical
practice guidelines for diagnosis, treatment and followup. Ann Oncol. 2010;21(Suppl 5):v184-
6.
19. Argiris A, Harrington KJ, Tahara M, Schulten J, Chomette P, Castro AF, et al. Evidence-based
treatment options in recurrent and/or metastatic squamous cell carcinoma of the head and
neck. Front Oncol. 2017;7:72.
20. Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn M-J, et al. Pembrolizumab
versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck
squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet.
2019;393(10167):156-67.
21. Keytruda® European Public Assessment Report, Risk Management Plan Summary, last
updated 18 June 2020. [Online]. [Cited 01 Jun 2021]. Available from:
URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
22. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al.
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence,
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep.
2021;2(1):100124.
23. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov.
2020;10(8):1121-8.
24. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
VV-CLIN-0616196 4.0
328
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 04) 
SAR444245-ACT16903-S04 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 62 
25. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol.
2017;28(suppl 4):iv100-18.
26. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014;69(8):1026-45.
27. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology,
and management. Kidney Int. 2017;92(1):37-46.
VV-CLIN-0616196 4.0
329
VV-CLIN-0701966 1.0

Signature Page for VV-CLIN-0616196 v4.0
act16903-16-1-1-amended-protocol03-substudy04
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0616196 4.0
330
VV-CLIN-0701966 1.0

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 05) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with cetuximab for the 
treatment of cetuximab-naïve participants in 2nd/3rd line 
recurrent/metastatic (R/M) head and neck squamous cell 
carcinoma (HNSCC)  
Protocol number: 
ACT16903-S05 
Amendment number: 03 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with cetuximab for the 
treatment of cetuximab-naïve participants in 2nd/3rd line 
R/M HNSCC  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name 
and contact 
information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
IND156423 
2021-002105-99 
NCT05061420 
U1111-1251-5073 
Date: 
22-Dec-2021
Total number of pages: 59 
VV-CLIN-0616197 4.0
331
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 (Substudy 05)  
All 
22 December 2021, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 (Substudy 05)  
All 
19 August 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 (Substudy 05)  
All 
26 July 2021, version 1 (electronic 2.0) 
Clinical Trial Protocol (Substudy 05) 
All 
11 June 2021, version 1 (electronic 1.0) 
Amended protocol 03 (22 December 2021) 
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Spanish (Agency for Medicine and 
Health Products [AEMPS]), Italian (Medicines Agency [AIFA]) and German (Federal Institute for 
Drugs and Medical Devices [BfArM]) Health Authorities after initial review. Other changes have 
been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SoA) 
A complete Table of SoA is provided for this substudy with 
procedures taken from the master protocol. 
For clarity and consistency 
For electrolytes, “weekly under treatment and then at the EOT, 
at FU visit 1” has been removed, and a cross has been 
presented for appropriate times instead. 
For clarification 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up 
visit 1. 
To allow assessments of any 
potential cardiotoxicity 
1.4 Biomarker flow-chart 
and 1.5 Pharmacokinetic 
flow-chart 
Complete biomarker and pharmacokinetic flow-charts 
applicable for this substudy have been provided with 
procedures taken from the master protocol. 
For clarity and consistency 
VV-CLIN-0616197 4.0
332
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 3 
Section # and Name 
Description of Change 
Brief Rationale 
1.5.1 B2 Cohort 
The cetuximab PK sample labelling has been changed from 
“P00” to “SC00” at start of infusion (SOI) and from “P01” to 
“SC01” at end of infusion (EOI).  
For correction and clarity 
6.5.3 General guidelines 
for the management of 
treatment-related adverse 
events 
As the Study Board does not intervene for this substudy, any 
reference to it has been removed. 
For consistency 
6.5.4.3 Fever, flu-like 
symptoms and 
cytokine-release 
syndrome (CRS) 
Information on cytokine-release syndrome (CRS) reported with 
cetuximab and recommended guidelines for management have 
been added. A column mentioning "Recommended Cetuximab 
dose modifications and supportive care guidelines" has been 
added to Table 7. 
To add recommended 
guidelines for management of 
CRS reported with cetuximab 
6.5.4.3 Fever, flu-like 
symptoms and 
cytokine-release 
syndrome (CRS) and 
6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
The following statement “or alternative therapies per site 
practice in CRS management” has been added to 
“tocilizumab”. 
For flexibility following an issue 
with tocilizumab availability 
6.5.4.5 Immune Cell-
Associated Neurotoxicity 
Syndrome (ICANS)  
In Table 8 under Grade 4, “signs of” has been removed before 
“diffuse cerebral edema on neuroimaging”. 
Change made for consistency 
with the American Society for 
Transplantation and Cellular 
Therapy (ASTCT) Consensus 
and correction 
10.1 Appendix 1: 
Regulatory, ethical, and 
study oversight 
considerations  
A new subsection 10.1.6 entitled “Dissemination of clinical 
study data” has been added with the following text: “Study 
participants results summaries will be provided in any one of 
the clinical trial portals after completion of the substudy, until 
the end of study”. 
Per CTFG guidance 2019: 
Recommendation Paper on the 
Initiation and Conduct of 
Complex Clinical Trials 
10.10 Appendix 10: Risk 
assessment 
The following wording has been added: “The information below 
is per currently available USPI and EU SmPC. Please always 
refer to the latest version of the SAR444245 IB and cetuximab 
local label for the most up-to-date safety data”. 
To refer to the latest version of 
IB or local label for the safety 
data 
10.11 Appendix 11: 
Abbreviations 
List of abbreviations has been revised. 
For consistency 
11 References 
List of references has been updated. 
For consistency 
Throughout the document 
Minor editorial corrections were made. 
For consistency 
VV-CLIN-0616197 4.0
333
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 4 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 03 (SUBSTUDY 05) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 8 
1 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 13 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 18 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 19 
1.5.1 
B2 Cohort ....................................................................................................................................... 19 
2 
INTRODUCTION ............................................................................................................................ 20 
2.1 
STUDY RATIONALE...................................................................................................................... 20 
2.1.1 
Cohort B2: SAR444245 combined with cetuximab ........................................................................ 20 
2.2 
BACKGROUND ............................................................................................................................. 20 
2.2.1 
Cetuximab ...................................................................................................................................... 20 
2.2.2 
Rationale for HNSCC and selected participant population ............................................................ 20 
2.2.3 
Current standard of care in HNSCC .............................................................................................. 21 
2.2.3.1 
Cetuximab monotherapy as second line therapy ........................................................................... 21 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 21 
2.3.1 
Risk assessment ............................................................................................................................ 21 
2.3.1.1 
Cetuximab ...................................................................................................................................... 21 
2.3.1.2 
SAR444245 combined with cetuximab .......................................................................................... 22 
2.3.2 
Benefit assessment ........................................................................................................................ 23 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 23 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 23 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 24 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 24 
VV-CLIN-0616197 4.0
334
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 5 
4 
STUDY DESIGN ............................................................................................................................ 25 
4.1 
OVERALL DESIGN ........................................................................................................................ 25 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 25 
4.2.1 
Participant input into design ........................................................................................................... 25 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 25 
4.3.1 
SAR444245 dose ........................................................................................................................... 25 
4.3.2 
Cetuximab dose ............................................................................................................................. 25 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 25 
5 
STUDY POPULATION .................................................................................................................. 26 
5.1 
INCLUSION CRITERIA .................................................................................................................. 26 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 26 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 27 
5.4 
SCREEN FAILURES...................................................................................................................... 27 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION] ....................................................................................................................... 27 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 28 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 28 
6.1.1 
Investigational medicinal product ................................................................................................... 28 
6.1.2 
Non-investigational medicinal product ........................................................................................... 29 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 29 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 29 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 29 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 29 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 29 
6.5 
DOSE MODIFICATION .................................................................................................................. 29 
6.5.1 
General rules .................................................................................................................................. 29 
6.5.2 
Cycle delay and dose omission ..................................................................................................... 30 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 31 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 32 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 32 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 34 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 34 
VV-CLIN-0616197 4.0
335
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 6 
6.5.4.4 
Immune-related adverse events .................................................................................................... 39 
6.5.4.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 39 
6.5.4.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 40 
6.5.4.7 
Dermatologic Toxicity ..................................................................................................................... 41 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY ............................... 42 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 42 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 42 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 43 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 43 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 43 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 43 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 44 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 44 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 44 
8.2.1 
Physical examinations ................................................................................................................... 44 
8.2.2 
Vital signs ....................................................................................................................................... 44 
8.2.3 
Electrocardiograms and left ventricular ejection fraction (LVEF) ................................................... 44 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 44 
8.2.5 
Pregnancy testing .......................................................................................................................... 45 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 45 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 45 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 45 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 45 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 45 
8.3.5 
Pregnancy ...................................................................................................................................... 45 
8.3.6 
Cardiovascular and death events .................................................................................................. 45 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 45 
8.3.8 
Adverse event of special interest ................................................................................................... 45 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 46 
8.4 
PHARMACOKINETICS .................................................................................................................. 46 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 46 
VV-CLIN-0616197 4.0
336
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 7 
8.6 
BIOMARKERS ............................................................................................................................... 46 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 46 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 46 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 46 
9
STATISTICAL CONSIDERATIONS .............................................................................................. 47
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 47 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 47 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 48 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 48 
9.4.1 
General considerations .................................................................................................................. 48 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 48 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 48 
9.4.3.1 
Other secondary endpoints ............................................................................................................ 48 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 48 
9.5 
INTERIM ANALYSES .................................................................................................................... 48 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 49
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 49 
10.1.6 
Dissemination of clinical study data ............................................................................................... 49 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 49 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 49 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 49 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 49 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 49 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 50 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 50 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 50 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 50 
VV-CLIN-0616197 4.0
337
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 8 
10.11 
APPENDIX 11: ABBREVIATIONS ................................................................................................. 54 
10.12 
APPENDIX 12: PROTOCOL AMENDMENT HISTORY ................................................................ 55 
11
REFERENCES ............................................................................................................................... 59
LIST OF TABLES 
Table 1 - Objectives and endpoints ................................................................................................................. 9 
Table 2 - Objectives and endpoints ............................................................................................................... 24 
Table 3 - Overview of IMP administered ....................................................................................................... 28 
Table 4 - Dose levels for cetuximab dose reduction ..................................................................................... 31 
Table 5 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 32 
Table 6 - Cetuximab Infusion-related reaction dose modification and treatment guidelines ........................ 34 
Table 7 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 36 
Table 8 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) ... 39 
Table 9 - Guidelines for the management of Vascular Leak Syndrome (VLS) ............................................. 41 
Table 10 - Cetuximab dose Modification for dermatologic toxicities ............................................................. 42 
Table 11 - Estimated objective response rate (ORR) and 95% CI for Cohort B2 (combining core and 
expansion phases) ........................................................................................................................................ 47 
Table 12 - Protocol-required laboratory assessments .................................................................................. 49 
Table 13 - Risk assessment .......................................................................................................................... 50 
LIST OF FIGURES 
Figure 1 - Overall substudy schema .............................................................................................................. 12 
VV-CLIN-0616197 4.0
338
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Substudy B2-
specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with cetuximab for the treatment of cetuximab-
naïve participants in 2nd/3rd line recurrent/metastatic (R/M) head and neck squamous cell 
carcinoma (HNSCC) 
Brief title:
A study of SAR444245 combined with cetuximab for the treatment of cetuximab-
naïve participants in 2nd/3rd line R/M HNSCC 
Rationale: 
Clinical data from the on-going monotherapy dose escalation of SAR444245 has indicated a 
peripheral increase in the number of NK cells. NK cells are important effector cells which mediate 
antibody-dependent cellular cytotoxicity (ADCC) for IgG1 antibodies such as cetuximab. 
Furthermore, in vitro data have shown that NK-cell–mediated lysis of head and neck tumor cells 
is significantly enhanced by the combination of cetuximab therapy with immune stimulatory 
cytokines, including IL-2. This was demonstrated in SAR444245 in vitro studies, where NK cells 
pretreated with SAR444245 and then co-cultured with the epidermal growth factor receptor 
(EGFR)-expressing CAL27 cancer cells improved the ADCC function of cetuximab in a dose-
dependent fashion. Cetuximab can prime the immune system for anti-PD-1 therapy by recruiting 
cytotoxic cell effectors of both the innate and adaptive immune systems to the intra tumoral space. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with cetuximab will result in a significant increase in the percentage of participants with HNSCC 
previously treated with platinum-based regimen & cetuximab-naïve after failure of no more than 
2 regimens for R/M disease experiencing an objective response. 
Objectives and endpoints 
Please refer to the master protocol for description of objectives and endpoints common to all 
study cohorts. Substudy-specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Secondary 
To assess the concentrations of cetuximab 
Concentrations of cetuximab 
VV-CLIN-0616197 4.0
339
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 10 
Overall design: 
Please refer to the master protocol. 
Brief summary:  
Cohort B2: This substudy will include participants with R/M HNSCC previously treated with 
platinum-based regimen & cetuximab-naïve after failure of no more than 2 regimens for R/M 
disease and will assess SAR444245 combined with cetuximab. 
A graphical presentation of the study schema is shown in Figure 1. 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in the core phase of Cohort B2.
In the expansion phase, approximately 56 participants will be enrolled. 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration. 
Study intervention(s) 
Cohort B2: cetuximab-naïve & platinum-based regimen treated R/M HNSCC after failure 
of no more than 2 regimens for R/M disease, SAR444245 + cetuximab 
Dosing sequence: 
Investigational medicinal product(s) 
Cetuximab 
•
Formulation:
-
a clear, colorless solution for injection provided as 100 mg/50 mL (2 mg/mL) or
200 mg/100 mL in a single-dose vial
or 
-
100 mg/20 mL or 500 mg/100 mL
or 
-
any other cetuximab formulation approved locally.
•
Route of administration: IV infusion.
•
Dose regimen: cetuximab will be given on Cycle 1 Day 1 as an initial loading dose of
400 mg/m2 infused over 120 minutes (maximum infusion rate 10 mg/min or as per local
practice and labels) followed by weekly 250 mg/m2 infused over 60 minutes (maximum
infusion rate 10 mg/min) for all subsequent doses starting with the Cycle 1 Day 8
administration until progressive disease (PD).
VV-CLIN-0616197 4.0
340
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 11 
SAR444245 
•
Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion
in a single-dose vial with an extractable volume of 1 mL.
•
Route of administration: intravenous (IV) infusion.
•
Dose regimen: 24 μg/kg administered as an IV infusion over 30 mins every 3 weeks
(Q3W) on Day 1 of each cycle (21 days per cycle) until PD.
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
Non-investigational medicinal products 
Please refer to the master protocol for SAR444245 premedication. 
Premedication for cetuximab 
All participants who will receive cetuximab should be pre-medicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab, or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior infusion reactions (IR). 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication.  
Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. 
Cohort B2-specific analysis: 
•
Analysis of other secondary endpoints:
Plasma concentrations of cetuximab will be summarized with descriptive statistics. 
For Cohort B2, the cohort cut-offs for the analyses are as follows: 
•
Interim analysis cut-off: the date on which all participants in the core phase have at least
2 post-baseline tumor assessments or discontinue study treatment (whichever occurs first).
•
Primary analysis cut-off: the date on which the last participants response is maintained for
6 months in the expansion phase (approximately 9 months from last participant’s first
infusion in the expansion phase).
Data Monitoring Committee: Yes 
VV-CLIN-0616197 4.0
341
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 12
1.2 
SCHEMA 
Figure 1 - Overall substudy schema 
HNSCC: head and neck squamous cell carcinoma; R/M: recurrent/metastatic. 
VV-CLIN-0616197 4.0
342
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Elements of the schedule of activities (SoA) common to all cohorts are detailed in the master protocol. Cohort B2-specific evaluations are 
presented in this table.  
 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1  
D8 
(±1) 
D15 
(±1) 
D1 
(±3) 
D8 
(±1)  
D15 
(±1)  
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Informed consent 
Inclusion/Exclusio
n criteria 
X 
IRT contact 
X 
X 
X 
X 
X 
Demography, 
medical/surgical 
and disease 
history 
X 
See Section 8 of 
master protocol  
Full physical 
examination 
X 
X 
Directed physical 
examination 
X 
X 
X 
X 
X 
X 
See Section 8.2.1 
of master protocol  
Body 
weight/Heighte 
X 
X 
X 
X 
X 
X 
VV-CLIN-0616197 4.0
343
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 14 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1  
D8 
(±1) 
D15 
(±1) 
D1 
(±3) 
D8 
(±1)  
D15 
(±1)  
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 8.2.2 
of master protocol & 
Section 8.2.2 
SpO2 
X 
As clinically indicated 
Performance 
status (ECOG) 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG
X 
X 
As clinically indicated 
See Section 8.2.3 
of master protocol 
LVEF 
X 
As clinically indicated 
See Section 8.2.3 
of master protocol 
Laboratory assessments 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically indicated 
See 
 Section 8.2.3 & 
Section 10.2 of 
master protocol 
Pregnancy test 
X 
X 
X 
X 
X 
X 
X 
See Sections 8.2.5, 
8.3.5 & 10.2 of 
master protocol 
Blood chemistry/ 
hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
See Section 10.2 & 
Section 10.2 of 
master protocol 
Electrolytes 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
as clinically indicated 
VV-CLIN-0616197 4.0
344
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 15 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1  
D8 
(±1) 
D15 
(±1) 
D1 
(±3) 
D8 
(±1)  
D15 
(±1)  
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
Coagulation 
X 
As clinically indicated 
See Section 10.2 of 
master protocol 
Urinalysisk 
X 
X 
X 
X 
X 
See Section 10.2 of 
master protocol 
Hepatitis serology 
CD4 counts & 
Viral Load 
Xf 
As clinically indicated 
See Section 10.2 of 
master protocol 
HPV p16 status 
for participants 
with 
oropharyngeal 
cancer 
X 
PK 
See PK Flow-Chart in Section 1.5 
ADA 
See PK Flow-Chart in Section 1.5 
Exploratory biomarkers 
PDy - Blood and 
tumor tissue 
collectiong
See Biomarkers Flow-Chart in Section 1.4 
Disease assessment 
CT/MRIh 
X 
X 
X 
X 
X 
X 
See Section 8.1 of 
master protocol 
Brain imagingi 
X 
See Section 8.1 of 
master protocol 
VV-CLIN-0616197 4.0
345
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 16 
Evaluationa 
Screening 
/baseline 
Treatment periodb 
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Treatment 
Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 3 and 
beyond 
EOT Visit 
Follow 
up 
Visit 1 
Follow 
up 
Visit 2 
Follow up 
Visit 3 and 
beyond 
Phone call 
follow-up 
Cycle day 
(Visit window 
in Days) 
D-28 to
D-1
D1  
D8 
(±1) 
D15 
(±1) 
D1 
(±3) 
D8 
(±1)  
D15 
(±1)  
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 (±7) days 
after last 
IMP or prior 
to initiation 
of further 
therapy 
3 months 
from last 
IMP admin 
±7 days 
6 months 
from last 
IMP 
admin 
±7 days 
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
SAR444245 
administration 
X 
X 
X 
Cetuximab 
administration 
X 
Xl 
Xl 
X 
Xl 
Xl 
X 
Xl 
Xl 
AE/SAE 
assessmentj 
X 
Continuously throughout treatment period 
X 
See Section 8.3 of 
master protocol 
Prior medication 
X (within 
28 days 
prior to first 
dose) 
Concomitant 
medication 
Continuously throughout treatment period 
See Section 6.8 of 
master protocol 
First subsequent 
anticancer therapy 
X 
X 
 X 
X 
X 
Survival status 
X 
a Evaluation: There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as part of screening within 3 days prior to first IMP administration. During the study treatment period, all 
assessments must be performed, and results should be reviewed by the investigator prior to IMP administration at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be 
collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are performed and can be signed more than 28 days prior to first IMP administration. Screening time 
indicates the maximum time frame relative to the first IMP administration in which assessments used to support eligibility are done. 
b Cycle: A treatment cycle is 21 days. See details in Section 6.1 of master protocol for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed 
according to the Cycle number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation Period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1 of master protocol. For 
participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessments are performed. 
d Survival Phone Call Follow-Up Period: Participant who moves into the Survival Follow-up Period should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. Information on 
the first subsequent anticancer treatment, best reported response, and date of progression will also be collected. Updated survival status may be requested by the Sponsor at any time during the study. 
VV-CLIN-0616197 4.0
346
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05  
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 17 
e Weight/Height: Height is required at baseline only. Weight is required at Screening and prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most 
recent weight assuming it was assessed in a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible 
considering the variability of local process from site to site.  If the infusion is prepared with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each 
cycle. 
f 
For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.8 of master protocol). 
g If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
h CT/MRI: The initial tumor imaging will be performed within 28 days prior to the C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP or more frequently if clinically indicated in the first 
45 weeks. Imaging studies should follow calendar days and should not be adjusted for delays in cycle starts or extension. The same imaging technique should be used in a participant throughout the trial. After 
Week 45 tumor imaging should be performed every 12 weeks (84 ±7 days). CT scan of the head, neck, chest and abdomen (pelvis is optional) and any other locations with suspicion or evidence of disease 
involvement is required for the baseline assessment and during treatment period until PD. After the first documentation of response or the first documentation of progression (if the participant is clinically stable) per 
RECIST 1.1, confirmatory imaging should be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor 
assessment is not needed for participants who start another anti-cancer therapy.  
i 
Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is 
clinically contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of 
the brain as a site of disease as per protocol tumor assessment schedule. In all other cases, the lesions must be treated. Two additional scans obtained at least 4 weeks apart, should be obtained to document 
disease stability AFTER local treatment administration to the brain metastases has been completed. If participants receive systemic therapy during these 4 weeks stabilization at the treating physician's discretion, 
this systemic therapy will be considered as part of prior anti-cancer therapy. Participants with previously treated brain metastases may participate provided they are stable, which is defined as lack of progression 
on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to 
baseline or resolved, and the participant is not using steroids for at least 14 days prior to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment. 
j 
AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5.0, ICANS and cytokine release syndrome (CRS) will be graded using ASTCT criteria integrated with central laboratory cytokine results 
(1). 
k Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal) will be performed every 4 cycles during the Treatment period and as 
clinically indicated. 
l 
Cetuximab dosing only. 
Abbreviations: ADA: anti-drug antibodies; AE: adverse event; ASTCT: American Society for Transplantation and Cellular Therapy; C: Cycle; CT: computed tomography; D: Day; ECG: electrocardiogram; 
ECOG: Eastern Cooperative Oncology Group; EOT: end-of-treatment; FU: follow-up; HPV: Human Papilloma virus; ICANS: Immune effector cell-associated neurotoxicity syndrome; ICF: informed consent form; 
IMP: investigational medicinal product; IRT: Interactive Response Technology; LVEF: left ventricular ejection fraction; MRI: magnetic resonance imaging; NCI-CTCAE: National Cancer Institute-Common terminology 
criteria for adverse events; PD: progressive disease; PDy:  pharmacodynamic; PK: pharmacokinetic; RECIST: Response Evaluation Criteria in Solid Tumors; SAE: serious adverse event; SpO2: oxygen saturation. 
 
VV-CLIN-0616197 4.0
347
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 18 
1.4 
BIOMARKER FLOWCHART  
 
VV-CLIN-0616197 4.0
348
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 19 
1.5 
PHARMACOKINETIC FLOWCHART  
1.5.1 B2 Cohort  
 
Cycle 
Treatment Cycle 1 
Treatment 
Cycles 2, 3, 4, 6, 
8, 10 + every 4th 
cycle thereafter 
EOT visit 
30 (±7) days 
after last IMP 
admin 
Day 
D1 
D2 
D8 
D1 
 
Time after start of SAR444245 
dosing 
SOI 
EOI 
Any time 
Any time 
SOI 
EOI 
 
SAR444245 PK sample 
 
P00b 
P01 
 
 
P00b 
 
SAR444245 ADA sample 
AB00a 
 
 
AB01 
AB00a 
 
ABF00 
Time after start of dosing 
cetuximab 
SOI 
EOI 
D2 
D8 
SOI 
EOI 
 
Cetuximab PK sample  
SC00a 
SC01b 
 
 
SC00a 
SC01b 
 
a Samples collected strictly before start of infusion (SOI). 
b EOI samples must be taken at end of infusion (EOI) precisely ±5 minutes. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOI: end of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: start of infusion. 
 
VV-CLIN-0616197 4.0
349
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 20 
2 
INTRODUCTION  
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 in combination with various anticancer therapies by identifying early signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to Cohort B2 (participants with HNSCC previously treated with 
platinum-based regimen & cetuximab-naïve after failure of no more than 2 regimens for R/M 
disease), for the combination of SAR444245 with cetuximab. 
Please refer to the master protocol for an introduction for ACT16903 study. 
2.1 
STUDY RATIONALE  
2.1.1 Cohort B2: SAR444245 combined with cetuximab  
Clinical data from the on-going monotherapy dose escalation of SAR444245 (HAMMER study) 
has indicated a peripheral increase in the number of NK cells.  NK cells are important effector 
cells which mediate ADCC for IgG1 antibodies such as cetuximab. In vitro data where NK cells 
pretreated with SAR444245 and then co-cultured with the EGFR-expressing A431 cancer cells 
improved the ADCC function of cetuximab in a dose dependent fashion. These data support the 
evaluation of SAR444245 in combination with cetuximab. 
2.2 
BACKGROUND  
2.2.1 Cetuximab  
Cetuximab is an immunoglobulin G1 (IgG1) monoclonal antibody against the ligand binding 
domain of EGFR, which is abnormally activated in many epithelial cancers including HNSCC (2). 
The mechanism of action of cetuximab appears to include antibody dependent cell mediated 
cytotoxicity (3) in addition to EGFR blockade, which may contribute to its efficacy and may be 
further exploited. Erbitux (Cetuximab) is indicated for the treatment of locally or regionally 
advanced squamous cell carcinoma of the head and neck in combination with radiation therapy; 
recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in 
combination with platinum-based therapy with fluorouracil. It is also indicated for the treatment 
of recurrent or metastatic squamous cell carcinoma of the head and neck. 
2.2.2 Rationale for HNSCC and selected participant population  
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
350
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 21 
2.2.3 Current standard of care in HNSCC  
2.2.3.1 Cetuximab monotherapy as second line therapy  
Patients with platinum-refractory disease may also achieve a treatment benefit with cetuximab. In 
an open-label multicenter Phase II study, cetuximab demonstrated activity as monotherapy in 
patients with R/M HNSCC who had failed platinum-based chemotherapy with a 13% response 
rate, DCR of 46%, and median response duration of 126 days (4). This study provided the main 
support for the regulatory approval of single agent cetuximab for this population in the US. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 and other combinations may be found in the 
Investigator’s Brochure. 
2.3.1 Risk assessment  
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with cetuximab results from anticipated risks for 
SAR444245 and from the label information for Erbitux® (cetuximab), taking into account 
potential overlapping risks. The available safety data for cetuximab, along with proposed 
mitigation strategies are summarized below and also provided in Table 13. 
2.3.1.1 Cetuximab  
The important identified risks for cetuximab include but are not limited to: IRs (including 
anaphylaxis on the first dose); interstitial lung disease severe adverse skin reactions (with 
increased risk of secondary bacterial infection), electrolyte disturbances (hypomagnesemia, 
hypokalemia, hypocalcemia) cardiac AEs (including cardiopulmonary arrest/sudden death), and 
eye disorders (including ulcerative keratitis).  
The most common adverse reactions (incidence ≥25%) are cutaneous adverse reactions (including 
rash, pruritus, and nail changes), headache, diarrhea, and infection.  
The following precautions and warnings are to be acknowledged: 
Cetuximab can cause serious and fatal IRs. Infusion reactions of any grade occurred in 8.4% of 
patients who received cetuximab across clinical trials. Grades 3 and 4 IRs occurred in 2.2% of 
patients. Signs and symptoms included rapid onset of airway obstruction (bronchospasm, stridor, 
hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac 
arrest. The risk of anaphylactic reactions may be increased in patients with a history of tick bites, 
red meat allergy, or in the presence of IgE antibodies directed against galactose-α-1,3-galactose 
VV-CLIN-0616197 4.0
351
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 22 
(alpha-gal). Approximately 90% of severe IRs occurred with the first infusion despite 
premedication with antihistamines. Infusion reactions may occur during or several hours 
following completion of the infusion. Premedication with a histamine-1 (H1) receptor antagonist 
is recommended together with monitoring of patients for at least 1 hour following each infusion.  
Cardiopulmonary arrest or sudden death have occurred in 2%-3% patients with squamous cell 
carcinoma of the head and neck receiving cetuximab with radiation therapy or a cetuximab 
product with platinum-based therapy and fluorouracil cetuximab. A history of coronary artery 
disease, congestive heart failure, or arrhythmias and abnormal serum electrolytes may be 
predisposing factors.  
Interstitial lung disease (ILD), that may be fatal, has occurred in <0.5% of patients receiving 
cetuximab in clinical trials.  
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. Acneiform rash occurred in 82% of patients across clinical trials. 
Grades 3 or 4 acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed 
within the first two weeks of therapy; the rash lasted more than 28 days after stopping treatment in 
most patients. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, 
and skin sloughing, has been observed. It could not be determined whether these mucocutaneous 
adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related 
effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).  
Cetuximab can cause hypomagnesemia, which occurred in 55% of patients in various clinical trials, 
including Grades 3 and 4 in 6% to 17% of cases. Hypomagnesemia and accompanying electrolyte 
abnormalities can occur days to months after initiating treatment. It is recommended to monitor 
patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for at 
least 8 weeks following the completion of treatment, and to replete electrolytes as necessary. 
Based on animal data and its mechanism of action, cetuximab may potentially cause fetal harm 
when administered to a pregnant woman. There are no available data for cetuximab exposure in 
pregnant women. In an animal reproduction study, intravenous administration of cetuximab once 
weekly to pregnant cynomolgus monkeys resulted in an increased incidence of embryo-lethality 
and abortion. Disruption or depletion of EGFR in animal models results in impairment of embryo-
fetal development including effects on placental, lung, cardiac, skin, and neural development. 
Please refer to the country-approved cetuximab labeling (eg, United States product insert [USPI], 
Summary of Product Characteristics [SmPC]) for more detailed prescribing information. 
2.3.1.2 SAR444245 combined with cetuximab  
Combining SAR444245 with cetuximab may lead to an increased frequency and/or severity of 
AEs related to immune activation or may lead to additional AEs related to immune system 
activation for each substance individually or may cause occurrences of qualitatively different 
AEs. SAR444245 could also increase the incidence of cetuximab-induced cutaneous toxicities. 
VV-CLIN-0616197 4.0
352
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 23 
As these two substances are biologic agents, they may have the propensity to induce infusion-
related reactions (IRR) that may have higher rate of occurrence and severity when SAR444245 
with cetuximab are used in combination. 
The MTD of SAR444245 combined with the approved dosing of cetuximab is under assessment 
in the HAMMER study using a Q3W schedule. Safety data generated from the combination of 
SAR444245 and cetuximab have informed the selection of the combination dose in this study.  
2.3.2 Benefit assessment  
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and cetuximab are provided below. 
Head and neck squamous cell carcinoma (HNSCC) is a tumor type that benefits from cetuximab 
treatment.  Preclinical and preliminary clinical data indicates that SAR444245 expands NK cells 
which are important effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) for 
IgG1 antibodies such as cetuximab. In vitro experiments show that SAR444245 improved the 
ADCC function of cetuximab in a dose-dependent fashion. 
The combination regimen proposed to be evaluated in this study is anticipated to bring benefit to 
the cetuximab-naïve HNSCC cohort. 
2.3.3 Overall benefit: risk conclusion  
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. Overall, the potential risks identified in association with this new generation IL-2 
SAR444245 combined with cetuximab are justified by the anticipated benefits that may be 
afforded to participants with HNSCC.  
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity.  
There are no data regarding safety of cetuximab in metastatic HNSCC patients during the 
COVID-19 pandemic. Nevertheless, as cetuximab does not cause significant immune suppression, 
there is no direct evidence to support changing or withholding cetuximab. 
VV-CLIN-0616197 4.0
353
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 24 
3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of objectives and endpoints common to all 
study cohorts. Substudy-specific objectives and endpoints are summarized below. 
Table 2 - Objectives and endpoints 
Objectives 
Endpoints 
Secondary 
To assess the concentrations of cetuximab 
Concentrations of cetuximab 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
354
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 25 
4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This substudy will include participants with R/M HNSCC previously treated with platinum-based 
regimen & cetuximab-naïve after failure of no more than 2 regimens for R/M disease and will 
assess SAR444245 combined with cetuximab. 
Overall, approximately 40 participants will be enrolled and treated in the core phase of Cohort B2.
In the expansion phase, approximately 56 participants will be enrolled. 
Enrolled participants in this Cohort B2 will receive treatment with both SAR444245 and 
cetuximab until PD.  
Please refer to the master protocol for a full description of the study design and for therapy details 
applicable to all cohorts. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that non-alpha IL-2 SAR444245 
combined with cetuximab, will result in a significant increase in the percentage of participants 
with HNSCC previously treated with platinum-based regimen & cetuximab-naïve after failure of 
no more than 2 regimens for R/M disease experiencing an objective response.
Please refer to the master protocol for more information. 
4.2.1 Participant input into design  
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol.  
4.3.2 Cetuximab dose 
This study proposes to evaluate the clinical benefit of 24 µg/kg SAR444245 Q3W combined with 
the approved dose of 400 mg/m² cetuximab as an IV infusion on day 1 of the study followed by 
subsequent doses of 250 mg/m² cetuximab IV QW. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
355
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 26 
5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort B2-specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Provision of tumor tissue: 
-
Optional baseline biopsy for participants in Core Phase
-
Mandatory baseline biopsy for all participant in Expansion Phase (minimum
10 slides with 4-5 micron thickness). Archival tumor tissue samples should be
obtained from biopsies done within 6 months, and there should be no systemic anti-
cancer therapy between collection of biopsy and enrollment. Slides specifications are
detailed in Lab Manual.
-
The Sponsor may approve the written request to enroll, on a case-by-case basis,
participants with:
-
location of the tumor not amenable to biopsy due to significant risk, OR
-
less than required number of slides or archival tumor tissue sample collected
more than 6 months prior to enrollment.
I 02. Prior anticancer therapy 
-
Participants should have failed no more than 2 systemic anti-cancer regimens (at least
one should be a platinum-containing regimen, unless it's already given in locally
advanced disease) in R/M disease. Previous anti-programmed cell death-1 (PD1)/
programmed cell death ligand 1 (PDL-1) based regimen is allowed.
5.2 
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
E 01. Electrolytes (magnesium, calcium and potassium) outside the normal ranges. 
Prior/concomitant therapy 
E 02. Prior treatment with cetuximab (prior cetuximab allowed if used for the treatment of 
locally advanced disease, with no PD for at least 4 months from completion of prior 
cetuximab therapy). 
VV-CLIN-0616197 4.0
356
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 27 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES  
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
[ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION]  
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
357
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi Group - strictly confidential 
Page 28 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
Enrolled participants in this Cohort B2 will receive treatment with both SAR444245 and 
cetuximab until PD.  
Dosing sequence:
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245 and cetuximab administered as 
described in Section 4.1. Details of each IMP component to be administered are shown in Table 3. 
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol. 
Table 3 - Overview of IMP administered 
Intervention name 
SAR444245 
Cetuximab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
100 mg/ 50 mL (2 mg/mL) 
Dosage level(s)a 
24 μg/kg Q3W 
400 mg/m2 C1D1 and QW 250 mg/m2 at 
C1D8 and subsequent administrations 
Route of administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
IMP 
IMP 
Packaging and labeling 
See master protocol 
Supplied as 100 mg/50 mL (2 mg/mL) 
or 200 mg/100 mL in a single-dose vial 
or 100 mg/20 mL or 500 mg/100 mL or 
any other formulation approved locally. 
Current/Former name(s) or alias(es) 
NA
Erbitux 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the electronic 
case report form (e-CRF). For SAR44245, study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of 5 minutes and +10 minutes is permitted.
VV-CLIN-0616197 4.0
358
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 29 
6.1.2 Non-investigational medicinal product  
Please refer to the master protocol for SAR444245 premedication. 
Premedication for cetuximab 
All participants who will receive cetuximab should be pre-medicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab, or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior IRs. 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication. 
6.1.3 Hydration guidelines for SAR444245 administration 
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome 
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules 
Dose modifications for SAR444245 and cetuximab are permitted according to the guidelines 
described in this section. Modification of dose levels in case of dose reduction for cetuximab is 
described in Table 4. 
VV-CLIN-0616197 4.0
359
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 30 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, at Day 1 delay for all IMPs) or dose omission (ie, omission of any component of 
the IMP within a cycle) are permitted in case of treatment-emergent adverse event (TEAE). Dose 
modification will be made according to the worst grade of toxicity observed within a cycle. If a 
participant experiences several toxicities and there are conflicting recommendations, the most 
conservative recommended dose adjustment should be followed. Once a dose has been decreased, 
intra-patient re-escalation back to the previous dose level is not permitted. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case it is partial permanent discontinuation and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay and dose omission  
The treatment window is ±3 days for each of the Q3W IMP administrations. The treatment 
window is ±1 day for cetuximab administration on Day 8 and Day 15 of each cycle.  
A cycle is deemed to have been delayed if the treatment is administered ≥4 days beyond the 
theoretical day of Q3W IMP administration. The participant may receive the next dose after 
recovery from the toxicity as described in Section 6.5.3. After cycle delayed, such participants 
may be considered for treatment resumption once the toxicity resolves or improves to Grade 1 or 
baseline. 
Participants may have cycle delay, or dose omission if toxicity occurs and the participant does not 
recover according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on 
the day of planned administration; restart of study IMPs could occur only on the initiation 
of the subsequent cycle. 
• For cetuximab Day 8 and Day 15 administration in each cycle: if toxicity occurs and the 
patient does not recover on the day of planned infusion or within the following 3 days, 
infusion may be omitted. 
• In case of cycle delay or dose omissions for the recovery of toxicity, the following rules 
should be followed for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days or a dose omission, it is per Investigator’s 
decision to restart the study treatment. 
VV-CLIN-0616197 4.0
360
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 31 
-
After a cycle delay of >14 days and ≤84 days, or 2 to 4 consecutive dose omissions, it
is per Investigator’s decision to restart the study treatment or the IMP that is omitted, if
a clear benefit from treatment is observed and after consultation with the Sponsor.
-
The study treatment must be permanently discontinued if the cycle delay is longer than
84 days, or if the participant has more than 4 consecutive dose omissions.
-
For any delayed cetuximab treatment, do not repeat the initial dose of 400 mg/m². At
the restart of cetuximab treatment, all subsequent infusions will be at the appropriate
dose level according to Table 4.
•
Cycle delay or dose omission may be considered for situations other than TEAEs such as
medical/surgical events or logistical reasons not related to study therapy. Participants
should be placed back on study therapy within 21 days of the scheduled delay or dose
omission, unless otherwise discussed with the Sponsor (for example for national or
regional emergencies). The reason for this delay or dose omission should be documented
in the participant’s study record.
Modification of dose levels in case of dose reduction 
Dose reduction steps for cetuximab are shown in Table 4. One or several doses of cetuximab can 
be omitted. 
Table 4 - Dose levels for cetuximab dose reduction 
Starting dose 
Dose level 1 
Dose level 2 
400 mg/m2 then 
250 mg/m2 
200 mg/m2 
(20% decrease) 
150 mg/m2 
(20% decrease) 
6.5.3 General guidelines for the management of treatment-related adverse events 
Participants who experience Grade ≥3 treatment-related adverse events (TRAEs) at any time of 
the study (including clinically significant Grade 3 laboratory abnormalities as defined in 
Section 10.3.1 of the master protocol) will be required to delay or omit the IMP, unless specified 
otherwise in the protocol, and with the exception of the TRAEs resolving within 5 days. After 
cycle delay or dose omission, such participants may be considered for treatment resumption once 
the TRAE resolves or improves to Grade 1 or baseline. Treatment resumption is at the discretion 
of the Investigator and Sponsor, if thought to be in the best interest of the participant, except when 
specified otherwise in this protocol, or if the event has required the IMP temporary interruption 
for more than 84 days from the last scheduled dose.  
The delay or omission of treatment for Grade 2 events is left at the discretion of the Investigator 
unless otherwise specified in this protocol.  
No delay/omission or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
 µg/kg to 
 µg/kg or another lower dose may be decided 
when specified in the protocol or following discussions with the Sponsor. 
VV-CLIN-0616197 4.0
361
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 32 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific AEs including immune-related AEs 
(irAEs), cytokine release syndrome (CRS), vascular leak syndrome (VLS) and IRRs are presented 
in Section 6.5.4. 
6.5.4 Guidelines for the management of specific adverse events 
Specific AEs described in sections below may classify as adverse events of special interest 
(AESIs), depending on grading according to National Cancer Institute- Common Terminology 
Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master protocol). In case 
a specific adverse event meets the AESI definition, it must be documented in the e-CRF. 
6.5.4.1 Infusion-related reactions (IRR) 
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of IRRs. 
An IRR in this study is defined as any signs or symptoms which develop during the infusion or up 
to 24 hours after the completion of the infusion. The term IRR indicates only a specific temporal 
relationship with the infusion and does not specify a particular mechanism underlying the signs or 
symptoms.  
Guidelines for the management of SAR444245 IRR events are provided in Table 5. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
Table 5 - SAR444245 Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is 
per Investigator’s judgment following close direct monitoring of the 
participant’s clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary. 
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE 
definition. 
If IRR happens after completion of infusion, increase monitoring of vital 
signs as medically indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hrs. 
Interrupt SAR444245 infusion. 
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion 
may be restarted at 50% of the original infusion rate. Otherwise dosing will 
be held until symptoms resolve and the participant will be premedicated for 
the next scheduled dose according to Section 6.1.2.1 of the master 
protocol. 
VV-CLIN-0616197 4.0
362
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 33 
NCI CTCAE Grade 
Treatment 
Give the next infusion at half the infusion rate. 
During or after completion of infusion, additional appropriate medical 
therapy may include but not limited to IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics. 
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief interruption 
of infusion); recurrence of symptoms following 
initial improvement; hospitalization indicated for 
other clinical sequelae 
Permanently discontinue SAR444245. The participant can continue 
treatment with the other anti-cancer therapy in combination 
During or after completion of infusion, additional appropriate medical 
therapy may include but is not limited to epinephrineb, IV fluids, 
antihistamines, NSAIDs, acetaminophen, narcotics, oxygen, vasopressors, 
corticosteroids. 
Increase monitoring of vital signs as medically indicated until the 
participant recovers. 
Grade 4 
Life-threatening; urgent intervention  indicated 
Permanently discontinue SAR444245. The participant can continue 
treatment with the other anti-cancer therapy in combination 
During or after completion of infusion, additional appropriate medical 
therapy may include but is not limited to epinephrineb, IV fluids, 
antihistamines, NSAIDs, acetaminophen, narcotics, oxygen, vasopressors, 
corticosteroids. 
Increase monitoring of vital signs as medically indicated until the 
participant recovers. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
Participants who experience cetuximab-related IRs should have cetuximab reduced according to 
Table 6 and continue to receive antihistamine premedication prior to administration. Once the 
cetuximab infusion rate has been decreased due to an allergic/hypersensitivity reaction, it should 
remain decreased for all subsequent infusions. If the participant experiences a second infusion 
reaction at the decreased rate, cetuximab should be permanently discontinued. If any Grade 3-4 
infusion reaction occurs, cetuximab treatment should be discontinued immediately and 
permanently.  
Severe IRRs, including anaphylactic reactions, may commonly occur, in some cases with fatal 
outcome. Occurrence of a severe infusion-related reaction requires immediate and permanent 
discontinuation of cetuximab therapy and may necessitate emergency treatment. Some of these 
reactions may be anaphylactic or anaphylactoid in nature or represent a CRS. Symptoms may 
occur during the first infusion and for up to several hours afterwards or with subsequent infusions. 
VV-CLIN-0616197 4.0
363
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 34 
Table 6 - Cetuximab Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Dose modification 
Grade 1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated 
Decrease the cetuximab infusion rate by 50% and monitor closely for 
any worsening. 
Grade 2 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, IV fluids); 
prophylactic medications indicated for ≤24 hrs. 
Stop cetuximab infusion and administer bronchodilators, oxygen, etc. 
as medically indicated. 
Resume infusion at 50% of previous rate once allergic/hypersensitivity 
reaction has resolved or decreased to Grade 1 in severity, and monitor 
closely for any worsening 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); 
recurrence of symptoms following initial improvement; 
hospitalization indicated for other clinical sequelae 
(eg, renal impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; urgent intervention indicated 
Stop the cetuximab infusion immediately, administer epinephrine, 
bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc., as medically indicated. 
Permanently discontinue Cetuximab. The participant can continue 
treatment with SAR444245. 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion related reaction; NCI = National Cancer Institute. 
6.5.4.2 Anaphylaxis 
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of SAR444245 and cetuximab being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines in 
[5, 6, 7]). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards. 
Monitoring of vital signs is detailed in Safety Assessments (Section 8.2.2). 
Cetuximab may be associated with CRS. Cytokine-release syndrome typically occurs within one 
hour after infusion and is less commonly associated with bronchospasm and urticaria. Cytokine-
release syndrome is normally most severe in relation to the first infusion of cetuximab. Cetuximab 
related IRRs, including CRS, are discussed in Section 6.5.4.1 of the protocol. Please refer to 
Table 6 for Cetuximab IRR dose modifications and treatment guidelines. 
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 7. If any grade of CRS is suspected, sites should make every 
VV-CLIN-0616197 4.0
364
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 35 
effort to draw an additional blood sample for cytokines levels (by central laboratory) prior to the 
administration of tocilizumab or alternative therapies per site practice in CRS management, as 
well as CRP and ferritin (by local laboratory). 
Sites should have at least 2 full doses of tocilizumab or alternative therapies per site practice in 
CRS management available and access to an intensive care unit (ICU), in case participants 
develop CRS. 
Guidelines for management of CRS according to severity grading are provided in Table 7. 
ASTCT CRS consensus grading scale is provided in Section 10.13 of the master protocol. 
VV-CLIN-0616197 4.0
365
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 36 
Table 7 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT 
CRS Consensus 
Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
Grade 1 
•
Fever (Temperature
≥38°C)b
•
No hypotension
•
No hypoxia
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV fluids (care should be 
taken to not excessively hydrate if evidence of vascular leak), antihistamines, NSAIDs and 
acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and laboratory monitoring 
should initially be performed daily, then less frequently as the participant improves. 
Decrease the cetuximab infusion rate by 50% and 
monitor closely for any worsening. 
Grade 2 
•
Feverb (Temperature
≥38°C)
•
Hypotension not
requiring vasopressors
•
and/orc hypoxia
requiring low-flow nasal
cannulad or blow-by.
Temporarily interrupt SAR444245 event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to IV fluids (care should 
be taken to not excessively hydrate if evidence of vascular leak), antihistamines, NSAIDs and 
acetaminophen. 
Increase monitoring of vital signs, cardiac and other organ functions closely as medically 
indicated until the participant recovers. Transfer to ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, hypotension, or 
participants in whom symptoms (eg, high grade fever) that do not respond to antipyretics within 
72 hours treatment with corticosteroids and/or tocilizumab or alternative therapies per site 
practice in CRS management should be considered, as per guidance for Grade 3 events.  
IMP may be resumed when clinical symptoms have resolved or improved to Grade 1 and 
corticosteroid taper. No dose modification is required but decreasing to half the infusion rate 
can be considered. 
Stop cetuximab infusion and administer intravenous 
fluids, bronchodilators, oxygen, etc. as medically 
indicated. Resume infusion at 50% of previous rate once 
the event has resolved or decreased to Grade 1 in 
severity, and monitor closely for any worsening. 
VV-CLIN-0616197 4.0
366
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 37 
Event severity (ASTCT 
CRS Consensus 
Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
Grade 3 
• 
Feverb (Temperature 
≥38°C)  
• 
Hypotension requiring 
a vasopressor with or 
without vasopressin  
• 
And/orc hypoxia 
requiring high-flow 
nasal cannulad, face 
mask, nonrebreather 
mask, or Venturi mask 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
• 
Feverb (Temperature 
≥38°C) 
• 
Hypotension requiring 
multiple vasopressors 
(excluding 
vasopressin) 
• 
And/orc hypoxia 
requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
If CRS grade 3, temporarily cycle delay SAR444245, and resume subsequent treatment only when 
symptoms have resolved or improved to Grade 1. 
SAR444245 can be either restarted at 
 µg/kg or permanently discontinued, as clinically indicated.  
 
 
 
 
 
 
If CRS Grade 4, permanently discontinue SAR444245. 
If CRS Grade 3 or Grade 4, initiate IV corticosteroids (outside of the context of CAR-T cells, 
corticosteroids alone maybe initiated in first intention) and tocilizumab or alternative therapies 
per site practice in CRS management considered, and/or epinephrine and/or other 
vasopressors should be administered as needed. Participants with severe CRS may require 
management in intensive care setting, with monitoring of clinical status and laboratory tests 
performed at least daily. 
As the participant improves, the intensity of the monitoring and setting can be decreased, but 
the participant should not be discharged from the hospital until clinically stable. Corticosteroids 
can then be administered IV or orally every 8 hours for up to 3 days, then tapered over 4 days. 
In general, tapering of steroids can start when vasopressors and high-flow oxygen are no 
longer needed.  
CRS is considered resolved when there is sustained resolution of fever and there is no longer a 
need for oxygen supplementation to relieve hypoxia nor vasopressors to maintain blood 
pressure; however, normalization of temperature alone does not define resolution of CRS. 
Stop the cetuximab infusion immediately, administer 
epinephrine, bronchodilators, antihistamines, 
glucocorticoids, intravenous fluids, vasopressor agents, 
oxygen, etc., as medically indicated. Cetuximab should 
be permanently discontinued. The participant can 
continue treatment with SAR444245. 
VV-CLIN-0616197 4.0
367
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 38 
Event severity (ASTCT 
CRS Consensus 
Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Recommended Cetuximab dose 
modifications and supportive care 
guidelines 
 
If no clinical improvement in oxygenation, hypotension, fever, and other CRS manifestations is 
observed within 24 to 72 hours, initiate management for persistent or worsening CRS. Re-
evaluation for other contributing conditions will be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous Tocilizumab at 8 mg/kg (for participants 
weighing ≥30 kg) or alternative therapies per site practice in CRS management should be 
administered, and steroids should be administered concurrently. If still no improvement in 
oxygenation, hypotension fever and other manifestations is observed after the first dose of 
tocilizumab, it may be repeated after an interval of at least 8 hours and should not exceed 
4 doses in total. 
For participants with severe CRS who fail to improve after repetitive treatment with both 
tocilizumab or alternative therapies per site practice in CRS management and steroids, 
alternative options will be discussed with clinical site specialists 
 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine therapy such as tocilizumab or alternative therapies per site practice in 
CRS management or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with temperature of 39.5°C, hypotension requiring 1 vasopressor, and 
hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at 
>6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine 
release syndrome; ICU=intensive care unit; IL = Interleukin; IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
 
VV-CLIN-0616197 4.0
368
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 39 
6.5.4.4 Immune-related adverse events  
Of note, if the AE is considered immune-related, both drugs in the combination should be delayed 
according to recommended dose modifications. If a participant experiences several irAEs, the 
most conservative recommendation should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When SAR444245 can be restarted, they should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve, the combination of SAR444245 and cetuximab may be 
restarted at the discretion of the investigator.  
6.5.4.5 Immune Cell-Associated Neurotoxicity Syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which is 
frequently associated with CRS; however, it is specifically excluded from the definition of CRS and 
can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment of 
cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.13 of 
the master protocol). Recommendations for ICANS management mainly include the use of steroids, 
whereas tocilizumab or alternative therapies per site practice in CRS management should only be 
used in the context of CRS, as outlined in Table 8. The proposed management should be considered 
only as recommendations and in light of recommendations from site specialist. 
Table 8 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
Delay SAR444245a. 
Initiate treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement 
to Grade 1 after corticosteroid taper. Consideration for reduction of 
SAR444245 dose to
 µg/kg as per Investigator with Sponsor consultation. 
VV-CLIN-0616197 4.0
369
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 3 ICANS, delay SAR444245. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Table 7. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days. 
If Grade 4 ICANS, permanently discontinue SAR444245.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab or alternative therapies per site practice in CRS 
management and should be handled as described in Table 7. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) or alternative therapies per site practice in 
CRS management should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.5.4.6 Vascular Leak Syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic, shock 
with multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a 
balance between maintaining the intravascular volume to ensure organ perfusion to prevent organ 
failure, while avoiding volume overload. The management of VLS according to severity grading 
is described in Table 9. These guidelines are not comprehensive, and the Investigator should 
exercise clinical judgment based on the symptoms and condition of the individual participant and 
refer to current guidelines to the topic (8). 
VV-CLIN-0616197 4.0
370
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
Table 9 - Guidelines for the management of Vascular Leak Syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention 
indicated 
Delay SAR444245. Upon resolution of VLS or improvement to Grade 1, SAR444245a 
can be resumed at the reduced dose of 
 µg/kg  
The initial strategy is to administer boluses of crystalloids with a goal of providing the 
minimum effective volume that optimizes blood pressure together with a fluid-restrictive 
strategy is advocated to limit interstitial fluid volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention 
indicated 
Grade 4: 
Life-threatening consequences; 
urgent intervention indicated 
If Grade 3 or Grade 4 VLS, permanently discontinue SAR444245.   
In participants with severe shock, blood pressure may be only partially responsive or 
refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its efficacy is 
limited to those with a severe capillary leak. In those who remain with refractory shock in 
the setting of low filling pressures, high molecular weight starches such as hetastarch 
(MW 450 kDa) and pentastarch (MW 264 kDa) may be effective in expanding the 
intravascular volume. Supportive care with invasive and noninvasive ventilation as well 
as renal replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate recovery.  
During the recovery phase from severe capillary leak, the endothelial injury resolves and 
the capillary leak becomes less important, resulting in stabilization of blood pressure, at 
which time fluid overload symptoms and signs may predominate (eg, pulmonary edema, 
pleural effusions, acute respiratory distress syndrome, systemic edema, ascites). 
Volume removal with loop diuretics is the first-line therapy in these patients. In those 
with marginal blood pressure and fluid overload, the combination of loop diuretics and 
25% albumin IV may facilitate volume removal. Patients with AKI refractory to diuretics 
will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
6.5.4.7 Dermatologic Toxicity  
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. 
The dosing of cetuximab will be omitted 1 to 2 weeks in the case of severe (Grade 3 or 4) 
acneiform rash. If acneiform rash improves during this time, then the dose of cetuximab should be 
reduced as indicated in Table 10. The dose modification guidelines in Table 4 should be followed 
for dermatologic toxicities other than acneiform rash.  
If acneiform rash does not improve during this time, cetuximab will be permanently discontinued.  
VV-CLIN-0616197 4.0
371
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 42 
Participants who have omitted cetuximab therapy for more than 2 consecutive infusions due to 
acneiform rash, and upon resolution of the toxicity are still felt to be benefiting from cetuximab 
treatment may resume cetuximab with Sponsor approval. 
The management of dermatologic toxicities according to severity grading is described in Table 10. 
Table 10 - Cetuximab dose Modification for dermatologic toxicities  
Dermatologic toxicities and 
infectious sequelae 
(eg, acneiform rash, 
mucocutaneous disease) 
Recommended IMP  
dose modification 
1st occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves  
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, continue at the same 
dose of 250 mg/m2. If no improvement, discontinue cetuximab. 
2nd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently reduce at 
Dose level 1. If no improvement, discontinue cetuximab. 
3rd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently reduce at 
Dose level 2. If no improvement, discontinue cetuximab. 
4th occurrence; Grade 3 or 4 
Permanently discontinue cetuximab. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF STUDY  
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE  
Please refer to the master protocol for SAR444245. 
No specific information is available on the treatment of overdose of cetuximab. In the event of 
overdose, the participant should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated. 
6.8 
CONCOMITANT THERAPY  
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
372
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP  
Please refer to the master protocol.  
VV-CLIN-0616197 4.0
373
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 44 
8 
STUDY ASSESSMENTS AND PROCEDURES  
Please refer to the master protocol.  
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.2 
SAFETY ASSESSMENTS  
8.2.1 Physical examinations  
Please refer to the master protocol.  
8.2.2 Vital signs  
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be 
measured after 5 minutes rest.  
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;  
- 
Vital signs will be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5) 
hours after start of SAR444245 dose.  
- 
At Investigator’s discretion, participants (not in the safety run-in) may have intensive 
vital sign monitoring (to be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 
4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 20 (±1), 24 (±1) hours after start of SAR444245 
dose in an in-patient setting).  
• For the core phase participants: from Cycle 2 to Cycle 4 study therapy will be 
administered for all patients in out-patient clinic with vital signs taken at baseline, at least 
4 to 6 hours after the start of SAR444245 dosing, or for longer periods of time if clinically 
indicated.   
8.2.3 Electrocardiograms and left ventricular ejection fraction (LVEF) 
Please refer to the master protocol.  
8.2.4 Clinical safety laboratory assessments  
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
374
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 45 
8.2.5 Pregnancy testing  
Please refer to the master protocol. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information 
Please refer to the master protocol.  
8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For cetuximab, serious adverse events (SAEs) that are considered expected will be specified in the 
reference safety information (country-approved product labeling). 
8.3.5 Pregnancy  
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
375
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 46 
8.3.9 Guidelines for reporting product complaints  
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS  
Please refer to the master protocol for description of common pharmacokinetic (PK) evaluations, 
substudy specific evaluations are summarized below. 
Samples collected for analyses of cetuximab concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant.  
8.5 
GENETICS AND/OR PHARMACOGENOMICS  
Please refer to the master protocol. 
8.6 
BIOMARKERS  
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Please refer to the master protocol. 
VV-CLIN-0616197 4.0
376
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 47 
9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION 
Sample size: 
The plan is to treat a total of 40 participants in the core phase of Cohort B2. In the expansion 
phase, approximately 56 participants will be treated. 
Core Phase 
Please refer to the master protocol. 
Expansion Phase 
At the end of the core phase of Cohort B2, the overall antitumor activity and safety will be 
assessed. The sponsor may decide to open a 56-participant expansion part based on the totality of 
data if the posterior probability that the true ORR is greater than 9%, which is considered minimal 
efficacious signal of interest, is greater than 80% with durable response. Based on a conjugate 
non-informative prior of beta (0.5, 0.5) at the time of the design of the study, at least 6 responders 
out of 40 exposed participants at the confirmed dose (confirmed ORR=15%) need to be observed 
in the core phase. However, emerging data generated from outside of the study may warrant a 
different prior to be considered before the formal IA. Analyses based on the total 96 participants 
by combining core phase and expansion phase will be performed. Table 11 lists estimated ORR 
and the corresponding 95% exact CIs by number of responders from a sample size of 
96 participants evaluable for activity.  
Table 11 - Estimated objective response rate (ORR) and 95% CI for Cohort B2 (combining core and 
expansion phases) 
Number of responders 
(N=96) 
ORR 
95% CI for ORR 
(Clopper-Pearson) 
10 
10.4% 
(5.1%, 18.3%) 
12 
12.5% 
(6%, 20.8.5%) 
14 
14.6% 
(8.2%, 23.3%) 
15 
15.6% 
(9%, 24.3%) 
With a sample size of 40 study participants in the core phase, the probability of observing 1 or 
more instances of an AE with a true incidence rate of 1%, 2%, or 5% is 33.1%, 55.4%, or 87.1%, 
respectively. With a sample size of 96 study participants in total, the probability of observing 1 or 
more instances of an AE with a true incidence rate of 1%, 2%, or 5% is 61.9%, 85.6%, or >99%, 
respectively. This provides reasonable assurance that events occurring at ≥5% frequency can be 
identified in this substudy. 
VV-CLIN-0616197 4.0
377
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 48 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol.  
9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol for description of common objectives and endpoints. 
Substudy-specific objectives and endpoints are summarized below. 
9.4.3.1 Other secondary endpoints 
Plasma concentrations of cetuximab will be summarized with descriptive statistics.
9.4.4 Tertiary/exploratory endpoint(s) 
Please refer to the master protocol. 
9.5 
INTERIM ANALYSES  
Periodic Data Monitoring Committes are planned (details are in the master protocol). 
At the end of the core phase, Cohort B2 will have one formal interim analysis when all 
participants in the core phase have at least 2 post‑baseline tumor assessments or discontinued 
study treatment (whichever occurs first). The sponsor will decide if the expansion will be initiated 
based on totality of the data observed. 
Primary analysis cut-off will occur when the last participant response is maintained for 6 months 
in the expansion phase (approximately 9 months from the last participant’s first infusion in the 
expansion phase). 
VV-CLIN-0616197 4.0
378
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 49 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. Cohort 
B2-specific evaluations are presented in Table 12. 
Table 12 - Protocol-required laboratory assessments 
Laboratory assessments 
Parameters 
Clinical chemistrya 
See master protocol 
a For participants in Cohorts B2 electrolytes to be done weekly under treatment and then at the end of treatment, at FU visit 1 and as 
clinically indicated. Additional electrolytes monitoring for Cohort B2, outside the visits, maybe done according the local standard 
institutional care. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Not applicable. 
VV-CLIN-0616197 4.0
379
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 50 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS 
Please refer to the master protocol. 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Please refer to the master protocol. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol for detailed information about SAR444245. Available 
information about cetuximab is shown in Table 13. The information below is per currently 
available USPI and EU SmPC.  
Please always refer to the latest version of the SAR444245 IB and cetuximab local label for the 
most up-to-date safety data. 
Table 13 - Risk assessment 
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s)
Infusion reactions 
Cetuximab 
Cetuximab 
Premedicate with a histamine-1(H1) receptor 
antagonist as recommended. Monitor 
patients for at least 1 hour following each 
cetuximab infusion, in a setting with 
resuscitation equipment and other agents 
necessary to treat anaphylaxis. In patients 
requiring treatment for infusion reactions, 
monitor for more than 1 hour to confirm 
resolution of the reaction. Interrupt the 
infusion and upon recovery, resume the 
infusion at a slower rate or permanently 
discontinue cetuximab based on severity. 
Immediately interrupt cetuximab and 
permanently discontinue cetuximab for 
serious IRRs. 
VV-CLIN-0616197 4.0
380
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 51 
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Cetuximab can cause serious and fatal infusion 
reactions. Infusion reactions of any grade 
occurred in 8.4% of 1373 patients who received 
cetuximab across clinical trials. Severe (Grades 3 
and 4) infusion reactions occurred in 2.2% of 
patients. Signs and symptoms included rapid 
onset of airway obstruction (bronchospasm, 
stridor, hoarseness), hypotension, shock, loss of 
consciousness, myocardial infarction, and/or 
cardiac arrest. The risk of anaphylactic reactions 
may be increased in patients with a history of tick 
bites, red meat allergy, or in the presence of IgE 
antibodies directed against galactose-α-1,3-
galactose (alpha-gal). Consider testing patients 
for alpha-gal IgE antibodies using FDA-cleared 
methods prior to initiating cetuximab. Negative 
results for alpha-gal antibodies do not rule out the 
risk of severe infusion reactions. Approximately 
90% of severe infusion reactions occurred with 
the first infusion despite premedication with 
antihistamines. Infusion reactions may occur 
during or several hours following completion of 
the infusion. 
Advise patients that the risk of serious 
infusion reactions may be increased in 
patients who have had a tick bite or red meat 
allergy. Advise patients to contact their 
healthcare provider and to report signs and 
symptoms of infusion reactions, including 
late onset infusion reactions, such as fever, 
chills, or breathing problems. 
Cardiopulmonary arrest
Cetuximab 
Cetuximab can cause cardiopulmonary arrest. 
Cardiopulmonary arrest or sudden death 
occurred in 2% of 208 patients treated with 
radiation therapy and cetuximab in BONNER.  
BONNER (NCT00004227) was a randomized, 
multicenter, controlled trial of 424 patients with 
locally or regionally advanced HNSCC being 
treated with cetuximab in combination with 
radiation therapy. Three patients with prior history 
of coronary artery disease died at home, with 
myocardial infarction as the presumed cause of 
death. One of these patients had arrhythmia and 
one had congestive heart failure. Death occurred 
27, 32, and 43 days after the last dose of 
cetuximab. One patient with no prior history of 
coronary artery disease died one day after the 
last dose of cetuximab. In EXTREME, fatal 
cardiac disorders and/or sudden death occurred 
in 3% of 219 patients treated with a cetuximab 
product in combination with platinum-based 
therapy and fluorouracil. 
Carefully consider use of cetuximab with 
radiation therapy or platinum-based therapy 
with fluorouracil in patients with SCCHN with 
a history of coronary artery disease, 
congestive heart failure, or arrhythmias. 
Monitor serum electrolytes, including serum 
magnesium, potassium, and calcium, during 
and after cetuximab administration (see 
Hypomagnesemia and Accompanying 
Electrolyte Abnormalities). 
Advise patients of the risk of 
cardiopulmonary arrest or sudden death and 
to report any history of coronary artery 
disease, congestive heart failure, or 
arrhythmias. 
 
VV-CLIN-0616197 4.0
381
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Pulmonary effects 
Cetuximab can cause ILD. Interstitial lung 
disease (ILD), including 1 fatality, occurred in less 
than 0.5% of 1570 patients receiving cetuximab 
in clinical trials. 
Monitor patients for signs and symptoms of 
pulmonary toxicity. Interrupt or permanently 
discontinue cetuximab for acute onset or 
worsening of pulmonary symptoms. 
Permanently discontinue cetuximab for 
confirmed ILD. 
Advise patients to contact their healthcare 
provider immediately for new or worsening 
cough, chest pain, or shortness of breath. 
Electrolyte abnormalities 
(including 
Hypomagnesemia)  
Cetuximab can cause hypomagnesemia. 
Hypomagnesemia occurred in 55% of 365 
patients receiving cetuximab in Study CA225-025 
and two other clinical trials in patients with 
colorectal cancer (CRC) or head and neck 
cancer, including Grades 3 and 4 in 6% to 17%. 
In EXTREME, where a cetuximab product was 
administered in combination with platinum-based 
therapy, the addition of cetuximab to cisplatin and 
fluorouracil resulted in an increased incidence of 
hypomagnesemia of any grade (14%) and of 
Grade 3 or 4 hypomagnesemia (7%). 
Hypomagnesemia of any grade occurred in 4% of 
patients who received cetuximab, carboplatin, 
and fluorouracil. No Electrolyte abnormalities 
(including Hypomagnesemia) and accompanying 
electrolyte abnormalities can occur days to 
months after initiating cetuximab. 
Monitor patients weekly during treatment for 
hypomagnesemia, hypocalcemia, and 
hypokalemia, and for at least 8 weeks 
following the completion of cetuximab. 
Replete electrolytes as necessary. 
Dermatological effects 
Cetuximab: 
Cetuximab can cause dermatologic toxicities, 
including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for 
example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative 
keratitis with decreased visual acuity, cheilitis), and 
hypertrichosis. Acneiform rash occurred in 82% of 
the 1373 patients who received cetuximab across 
clinical trials. Severe (Grades 3 or 4) acneiform rash 
occurred in 9.7% of patients. Acneiform rash usually 
developed within the first two weeks of therapy; the 
rash lasted more than 28 days after stopping 
cetuximab in most patients. Life-threatening and 
fatal bullous mucocutaneous disease with blisters, 
erosions, and skin sloughing, has been observed in 
patients who received cetuximab. It could not be 
determined whether these mucocutaneous adverse 
reactions were directly related to EGFR inhibition or 
to idiosyncratic immune-related effects (eg, Stevens-
Johnson syndrome or toxic epidermal necrolysis). 
Cutaneous adverse reactions (including rash, 
pruritus and nail changes) are the most common 
adverse reaction (incidence greater than 25%).   
 Monitor patients receiving cetuximab for 
dermatologic toxicities and infectious 
sequelae. Instruct patients to limit sun 
exposure during cetuximab therapy. 
Withhold, reduce dose or permanently 
discontinue cetuximab based on severity of 
acneiform rash or mucocutaneous disease. 
Advise patients to limit sun exposure during 
cetuximab treatment and for 2 months after 
the last dose of cetuximab. Advise patients to 
notify their healthcare provider of any sign of 
acne-like rash, (which can include itchy, dry, 
scaly, or cracking skin and inflammation, 
infection or swelling at the base of the nails 
or loss of the nails), conjunctivitis, blepharitis, 
or decreased vision. 
VV-CLIN-0616197 4.0
382
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 53 
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Risks related to special 
populations 
 
 
Reproductive toxicity 
Cetuximab 
Based on animal data and its mechanism of action, 
cetuximab can cause fetal harm when administered 
to a pregnant woman. There are no available data 
for cetuximab exposure in pregnant women. In an 
animal reproduction study, intravenous 
administration of cetuximab once weekly to 
pregnant cynomolgus monkeys during the period of 
organogenesis resulted in an increased incidence of 
embryolethality and abortion. Disruption or depletion 
of EGFR in animal models results in impairment of 
embryo-fetal development including effects on 
placental, lung, cardiac, skin, and neural 
development.  Human IgG is known to cross the 
placental barrier; therefore, cetuximab may be 
transmitted from the mother to the developing fetus. 
Advise pregnant women of the potential risk to a 
fetus. In the U.S. general population, the estimated 
background risk of major birth defects and 
miscarriage in clinically recognized pregnancies is 
2 to 4% and 15-20% respectively.  
Pregnant cynomolgus monkeys were administered 
cetuximab intravenously once weekly during the 
period of organogenesis (gestation day [GD] 20-48) 
at dose levels 0.4 to 4 times the recommended dose 
of cetuximab based on body surface area (BSA). 
Cetuximab was detected in the amniotic fluid and in 
the serum of embryos from treated dams on GD 49. 
While no fetal malformations occurred in offspring, 
there was an increased incidence of embryolethality 
and abortions at doses approximately 1 to 4 times 
the recommended dose of cetuximab based on 
BSA. In mice, EGFR is critically important in 
reproductive and developmental processes 
including blastocyst implantation, placental 
development, and embryo-fetal/postnatal survival 
and development. Reduction or elimination of 
embryo-fetal or maternal EGFR signaling can 
prevent implantation, can cause embryo-fetal loss 
during various stages of gestation (through effects 
on placental development), and can cause 
developmental anomalies and early death in 
surviving fetuses. Adverse developmental outcomes 
were observed in multiple organs in 
embryos/neonates of mice with disrupted EGFR 
signaling. 
Advise pregnant women of the potential risk 
to a fetus. Advise females of reproductive 
potential to use effective contraception 
during treatment with cetuximab and for 
2 months after the last dose of cetuximab. 
Verify pregnancy status in females of 
reproductive potential prior to initiating 
cetuximab. 
VV-CLIN-0616197 4.0
383
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 54 
10.11 APPENDIX 11: ABBREVIATIONS  
 
ADCC: 
antibody-dependent cellular cytotoxicity 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CRS: 
cytokine release syndrome 
e-CRF: 
electronic case report form 
EGFR: 
epidermal growth factor receptor 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
HNSCC: 
head and neck squamous cell carcinoma 
ICANS: 
immune Cell-Associated Neurotoxicity Syndrome 
ICU: 
intensive care unit  
IgG1: 
immunoglobulin G1 
IMP: 
investigational medicinal product  
IR: 
infusion reaction 
irAEs: 
immune-related AEs 
IRR: 
infusion-related reactions 
IV: 
intravenous 
LVEF: 
left ventricular ejection fraction 
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
ORR: 
objective response rate 
PD: 
progressive disease 
PK: 
pharmacokinetic 
Q3W: 
every 3 weeks 
R/M: 
recurrent and/or metastatic 
SAEs: 
serious adverse events 
SmPC: 
Summary of Product Characteristics 
SoA: 
schedule of activities 
TEAE: 
treatment-emergent adverse event 
TRAEs: 
treatment-related adverse events 
USPI: 
United States product insert 
VLS: 
vascular leak syndrome 
 
VV-CLIN-0616197 4.0
384
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 55 
10.12 APPENDIX 12: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).  
Amended protocol 01 (26 July 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth 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 overall rationale for the amendment is to respond to the Health Authorities (Food and Drug 
Administration, [FDA]) requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.5.1 B2 Cohort 
The frequency of sampling for ADA has been increased to obtain 
data every cycle for the first 3 cycles, every other cycle for 4 
samples, then every 4th cycle. 
Regulatory Authority (FDA) 
request 
Section 6.5.4 Guidelines 
for the management of 
specific adverse events 
For clarity and brevity, command language has been used in the 
toxicity management sections. 
Regulatory Authority (FDA) 
request 
Section 6.5.4.1 Infusion-
related reactions (IRR)  
In Table 5 the following text has been revised: 
Under Grade 3 and Grade 4:  
- “prematurely” deleted from “prematurely permanently
discontinued”.
- “clearly attributable” deleted from “If IRR is clearly attributable to
SAR444245” as the table title already indicates treatment with
regards to SAR444245 IRRs.
Under Grade 2, Grade 3 and Grade 4: “if applicable” deleted in the 
sentence that reads “SAR444245 infusion should be interrupted if 
applicable”. 
Regulatory Authority (FDA) 
request 
In Table 5 and Table 6, the following text “requires therapy or 
infusion interruption” has changed to “Therapy or infusion 
interruption indicated', and “pressor or ventilator support indicated” 
has been changed to “urgent intervention indicated''.  
For consistency with 
Common terminology 
criteria for adverse events 
(CTCAE) guidelines 
(version 5) 
Section 6.5.4.1 Infusion-
related reactions (IRR) 
and Section 10.10 Risk 
assessment (Table 9) 
The text “SAR444245 infusion-associated reaction” was changed 
to “SAR444245 infusion-related reaction”.
For consistency 
VV-CLIN-0616197 4.0
385
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021
Version number: 1
Property of the Sanofi group - strictly confidential 
Page 56 
Section # and Name 
Description of Change 
Brief Rationale 
Section 6.5.4.3 Fever, flu-
like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 7 the following text “If subsequent administration is 
tolerated, increasing the SAR444245 dose to 
 µg/kg at 
subsequent administration can be considered based on the clinical 
judgement of the Investigator with the Sponsor” has been removed 
for Grade 3.  
For Grade 3, the following sentence has been changed from “If 
CRS grade 3, temporarily cycle delay SAR444245, and resume 
subsequent treatment only when symptoms have resolved or 
improved to Grade 1 at 
 µg/kg or permanently discontinued, as 
clinically indicated” to “If CRS grade 3, temporarily cycle delay 
SAR444245, and resume subsequent treatment only when 
symptoms have resolved or improved to Grade 1. SAR444245 can 
be either restarted at 
 µg/kg or permanently discontinued, as 
clinically indicated”. 
The following sentence has been added: “Monitoring of vital signs 
is detailed in Safety Assessments (Section 8.2.2)” for clarity. 
Regulatory Authority (FDA) 
request 
For consistency and clarity 
Section 6.5.4.5 Immune 
Cell-Associated 
Neurotoxicity Syndrome 
(ICANS) 
In Table 8 the following text has been added under Grade 3 
ICANS: “Treatment with IV corticosteroids should be initiated. 
Concomitant CRS may require tocilizumab and should be handled 
as described in Section 6.5.4.3. Corticosteroids can then be 
administered IV or orally every 8 hours for up to 3 days, then 
tapered over 4 days.” 
Regulatory Authority (FDA) 
request 
The following text “diffuse cerebral edema” has been revised to 
“signs of diffuse cerebral edema”. 
For consistency with the 
American Society for 
Transplantation and 
Cellular Therapy (ASTCT) 
Consensus 
Sections 8.2.1 Physical 
examinations, Section 
8.2.2 Vital signs, Section 
8.2.3 Electrocardiograms, 
Section 8.2.4 Clinical 
safety laboratory 
assessments, and 
Section 8.2.5 Pregnancy 
testing 
Sections newly inserted. 
For clarity 
Section 8.2.2 Vital signs 
Details regarding monitoring of vital signs provided in the Master 
protocol have been added. 
Regulatory Authority (FDA) 
request 
Section 10.10: 
Appendix 10: Risk 
assessment 
In Table 13, risk assessment for cetuximab was revised to be 
aligned with the most recent version of USPI for cetuximab. 
Regulatory Authority (FDA) 
request 
Reference to "pembrolizumab" has been deleted from 
Section 10.10. 
For correction 
Throughout the document 
Minor editorial corrections were made. 
Changes made for 
consistency  
VV-CLIN-0616197 4.0
386
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 57 
Amended protocol 02 (19 August 2021) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union (see Master protocol). 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to add a new study cohort (Cohort A2, substudy 
protocol 02) and clarify the priority of recruitment of participants between Cohorts A1 and A2 
(see Master protocol). Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis: 
Intervention groups and 
duration and Section 
6.1.1 Investigational 
medicinal product 
“Weekly” or “QW” has been added before “250 mg/m2” for 
administration of cetuximab dose regimen. 
Change made for clarification 
Section 1.3 Schedule of 
Activities (SoA) 
“IMP Administration” has been changed to “Cetuximab 
Administration”, and a row indicating “SAR444245 
Administration” has been added with a refence to the master 
protocol. 
Change made for clarification 
Section 5.1 Inclusion 
criteria 
In I06 “participants with less than required number of slides or 
archival tumor tissue sample collected more than 6 months 
prior to screening” has been revised to “participants with less 
than required number of slides or archival tumor tissue sample 
collected more than 6 months prior to enrollment”   
Harmonization per program 
level approach 
Section 6.5.2 Cycle delay 
and dose omission, and 
Section 6.5.3 General 
guidelines for the 
management of treatment-
related adverse events 
The following text regarding the treatment resumption after 
cycle delay (or dose omission) has been deleted: “or is stable 
and manageable through supportive/medical therapy”. 
Change made for correction 
Section 6.5.3 General 
guidelines for the 
management of 
treatment-related adverse 
events 
The name “Study Committee” has been changed to “Study 
Board”. 
Change made to ensure clarity 
and avoid confusion with any 
Independent Committee 
Section 6.5.4.1 Infusion-
related reactions (IRR) 
In Table 5, under Grade 3 and Grade 4, the following text 
“Interrupt SAR444245 infusion” has been removed. 
Change made for clarification 
Section 6.5.4.1 Infusion-
related reactions (IRR), 
and Section 6.5.4.7 
Dermatologic Toxicity 
The following text “and permanently” has been added after “If 
any Grade 3-4 infusion reaction occurs, cetuximab treatment 
should be discontinued immediately”. In Table 6 and Table 10, 
“prematurely” has been deleted from “prematurely, 
permanently discontinued”. 
Change made for clarification 
VV-CLIN-0616197 4.0
387
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 58 
Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.3 
Electrocardiograms and 
left ventricular ejection 
fraction (LVEF) 
The following text: “and left ventricular ejection fraction (LVEF)” 
has been added to the naming of the section. 
Change made for clarification 
Throughout the document 
Minor editorial corrections were made. 
Changes made for consistency  
 
VV-CLIN-0616197 4.0
388
VV-CLIN-0701966 1.0

Amended Clinical Trial Protocol 03 (Substudy 05) 
SAR444245-ACT16903-S05 
22-Dec-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
11 
REFERENCES  
1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
2. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology 
and treatment of cancer. J Clin Oncol. 2003;21(14):2787-99. 
3. Iannello A, Ahmad A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy 
of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 2005;24(4):487-99. 
4. Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, et al. Open-label, 
uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a 
single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head 
and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007;25(16):2171-7. 
5. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report- 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
6. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18. 
7. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
8. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, 
and management. Kidney Int. 2017;92(1):37-46. 
 
VV-CLIN-0616197 4.0
389
VV-CLIN-0701966 1.0

Signature Page for VV-CLIN-0616197 v4.0
act16903-16-1-1-amended-protocol03-substudy05
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0616197 4.0
390
VV-CLIN-0701966 1.0