A Phase 1/2 Non-randomized, Open-label, Multi-cohort, Multi-center Study Assessing the Clinical Benefit of SAR444245 (THOR- 707) Combined With Cemiplimab for the Treatment of Participants With Advanced Unresectable or Metastatic Skin Cancers
Phase: PHASE1
Conditions: Malignant Melanoma, Squamous Cell Carcinoma of Skin
Sponsor: Sanofi

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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 
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direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A Phase 1/2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR- 707) combined with cemiplimab for 
the treatment of participants with advanced unresectable 
or metastatic skin cancers 
Protocol number: 
ACT16845 
Amendment number: 04 
Compound number: 
(INN/Trademark): 
SAR444245  
(Not applicable) 
Brief title: 
A study of SAR444245 combined with cemiplimab for the 
treatment of participants with various advanced skin 
cancers  
Acronym: 
Pegathor Skin 201 
Study phase: 
Phase 1/2 
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: 
153865 
EudraCT: 
2020-005332-30 
WHO: 
U1111-1254-0189 
Date: 
20-Oct-2021
Total number of pages: 161 
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NCT Number: NCT04913220
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 04  
ALL 
20 October 2021, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 03  
ALL 
25 August 2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 02 
ALL 
04 May 2021, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 01 
ALL 
19 March 2021, version 1 (electronic 2.0) 
Original Protocol 
  
24 February 2021, version 1 (electronic 1.0) 
Amended protocol 04 (20 October 2021) 
This amended protocol (amendment 04) 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 purpose of this amendment is to meet German requirements to be consistent with the 
German GCP ordinance (§ 12 (4) GCP-V). Other changes have been made for clarification, 
accuracy, and correction.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page and 1.1 Synopsis 
The following study name: “Pegasus” has been 
removed from the protocol title and changed to 
“Pegathor” on the title page. 
Harmonization per 
program-level approach 
1.1 Synopsis, 6.1.2 Non-investigational 
medicinal product 
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 
1.2 Schema, 1.3 Schedule of activities 
(SoA), 1.4 Biomarker flowcharts, 
5.1 Inclusion criteria 
In Figure 2 and in the biomarker flowchart, tumor 
tissue collection has been removed from C1D15 
and C2D8 and added on C2D1.  
In the SoA, footnote “f” for blood draws and/or 
tumor biopsy for biomarker assessment has been 
removed and changed to: ”Study Board may decide 
to cancel safety assessment on C1D15, upon 
agreement with Sponsor, if safety data justifies it.” 
The reference to the footnote “f” has been deleted 
at C1D8 in the SoA. 
To make operational 
procedures easier 
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Section # and Name 
Description of Change 
Brief Rationale 
Inclusion criterion I06 has been revised to:” One 
biopsy on treatment is mandatory for participants in 
Cohort B, if clinically feasible”. 
5.2 Exclusion Criteria 
E 20 was changed from “Known hypersensitivity 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 hypersensitivity 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 
5.2 Exclusion criteria, 6.5.2 Prohibited 
concomitant medications,  
10.14 Appendix 14, and Risk assessment 
Table 12 
 
 
The following sentence in Section 6.5.2 has been 
deleted: “
In Table 12, the row for 
was 
deleted. 
Based on new de-risking 
in-vitro data 
5.4 Screen failures 
The following text was added “A participant may be 
rescreened only once”. 
For clarity 
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. 
Direct-to-patient shipment 
of IMP is not possible in 
this study. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6.4.5 Immune cell-associated 
neurotoxicity syndrome (ICANS) 
For clarity and brevity, command language has 
been used in Table 7. 
Harmonization per 
program-level approach  
 
In Table 7 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 
Table 5. Corticosteroids can then be administered 
IV or orally every 8 hours for up to 3 days, then 
tapered over 4 days.” 
Harmonization per 
program-level approach 
8.3.1 Time period and frequency for 
collecting AE and SAE information 
The instruction to stop collecting AE and SAE 
information should the participant initiate another 
anticancer therapy was 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 
8.3.1 Time period and frequency for 
collecting AE and SAE information,  
10.3.4 Reporting of SAEs  
10.7 Country-specific requirements 
(Germany) 
In Section 10.7, specific wording for the sites in 
Germany has been added indicating that “the 
Investigator must inform the Sponsor in case of a 
SAE/AESI immediately, after becoming aware 
without undue delay”. Reference to Appendix 7 for 
country-specific requirements for Germany has 
been added in Sections 8.3.1 and 10.3.4. 
 
Regulatory Authority 
(BfArM) request 
10.14 Appendix 14: Risk assessment and 
10.16 Appendix 16: Abbreviations 
The text “SAR444245 infusion-associated reaction” 
was changed to “SAR444245 infusion-related 
reaction”. 
For consistency 
Throughout the document 
Minor editorial updates. 
For clarity and 
consistency 
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 TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 21 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 26 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 28 
1.5.1 
All cohorts ...................................................................................................................................... 29 
2 
INTRODUCTION ............................................................................................................................ 30 
2.1 
STUDY RATIONALE...................................................................................................................... 30 
2.2 
BACKGROUND ............................................................................................................................. 31 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 32 
2.3.1 
Risk assessment ............................................................................................................................ 32 
2.3.1.1 
Aldesleukin experience .................................................................................................................. 32 
2.3.1.2 
SAR444245 .................................................................................................................................... 34 
2.3.1.3 
Cemiplimab .................................................................................................................................... 36 
2.3.1.4 
SAR444245 combined with cemiplimab ........................................................................................ 37 
2.3.2 
Benefit assessment ........................................................................................................................ 37 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 38 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 38 
2.3.4.1 
Risks in the context of COVID-19 .................................................................................................. 38 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 41 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 42 
4 
STUDY DESIGN ............................................................................................................................ 43 
4.1 
OVERALL DESIGN ........................................................................................................................ 43 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 46 
4.2.1 
Participant input into design ........................................................................................................... 47 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 47 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 49 
5 
STUDY POPULATION .................................................................................................................. 50 
5.1 
INCLUSION CRITERIA .................................................................................................................. 50 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 53 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 57 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 57 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 57 
5.3.3 
Activity ............................................................................................................................................ 57 
5.3.4 
Hydration ........................................................................................................................................ 58 
5.4 
SCREEN FAILURES...................................................................................................................... 58 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
SCREENING/ENROLLMENT/ADMINISTRATION OF STUDY INTERVENTION ......................... 58 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 59 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 59 
6.1.1 
Investigational medicinal product ................................................................................................... 59 
6.1.2 
Non-investigational medicinal product ........................................................................................... 60 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 60 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 60 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 61 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 61 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 62 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 62 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 62 
6.5.1 
Acceptable concomitant medications ............................................................................................. 63 
6.5.2 
Prohibited concomitant medications .............................................................................................. 63 
6.6 
DOSE MODIFICATION .................................................................................................................. 64 
6.6.1 
General rules .................................................................................................................................. 64 
6.6.2 
Cycle delay ..................................................................................................................................... 65 
6.6.3 
General guidelines for the management of treatment-related adverse events ............................. 65 
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6.6.4 
Guidelines for the management of specific adverse events .......................................................... 66 
6.6.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 66 
6.6.4.2 
Anaphylaxis .................................................................................................................................... 67 
6.6.4.3 
Fever, flu-like symptoms, and cytokine-release syndrome (CRS) ................................................. 68 
6.6.4.4 
Immune-related adverse events .................................................................................................... 70 
6.6.4.5 
Immune cell-associated neurotoxicity syndrome (ICANS) ............................................................. 79 
6.6.4.6 
Vascular leak syndrome (VLS) ...................................................................................................... 80 
6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 81 
6.8 
TREATMENT OF OVERDOSE ...................................................................................................... 81 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 83 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 83 
7.1.1 
Permanent discontinuation ............................................................................................................ 83 
7.1.1.1 
Unacceptable adverse events leading to permanent intervention discontinuation ........................ 84 
7.1.2 
Temporary discontinuation ............................................................................................................. 84 
7.1.3 
Rechallenge ................................................................................................................................... 85 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 85 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 86 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 87 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 87 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 88 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 90 
8.2.1 
Physical examinations ................................................................................................................... 90 
8.2.2 
Vital signs ....................................................................................................................................... 90 
8.2.3 
Electrocardiograms and LVEF ....................................................................................................... 91 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 91 
8.2.5 
Pregnancy testing .......................................................................................................................... 92 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 92 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 93 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 93 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 93 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 93 
8.3.5 
Pregnancy ...................................................................................................................................... 94 
8.3.6 
Cardiovascular and death events .................................................................................................. 94 
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8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 95 
8.3.8 
Adverse event of special interest ................................................................................................... 95 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 96 
8.4 
PHARMACOKINETICS .................................................................................................................. 96 
8.5 
PHARMACODYNAMICS ............................................................................................................... 97 
8.6 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 97 
8.7 
BIOMARKERS ............................................................................................................................... 97 
8.8 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 98 
8.9 
HEALTH ECONOMICS .................................................................................................................. 98 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 98 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 100 
9.1 
STATISTICAL HYPOTHESES ..................................................................................................... 100 
9.2 
SAMPLE SIZE DETERMINATION ............................................................................................... 100 
9.3 
POPULATIONS FOR ANALYSES ............................................................................................... 101 
9.4 
STATISTICAL ANALYSES .......................................................................................................... 101 
9.4.1 
General considerations ................................................................................................................ 101 
9.4.2 
Primary endpoint(s) ...................................................................................................................... 102 
9.4.2.1 
Objective response rate ............................................................................................................... 102 
9.4.3 
Secondary endpoint(s) ................................................................................................................. 102 
9.4.3.1 
Complete response rate ............................................................................................................... 102 
9.4.3.2 
Time to complete response .......................................................................................................... 102 
9.4.3.3 
Time to response ......................................................................................................................... 103 
9.4.3.4 
Duration of response .................................................................................................................... 103 
9.4.3.5 
Clinical benefit rate....................................................................................................................... 103 
9.4.3.6 
Progression-free survival ............................................................................................................. 103 
9.4.3.7 
Adverse events ............................................................................................................................ 104 
9.4.3.8 
Clinical laboratory evaluations ..................................................................................................... 105 
9.4.3.9 
Other secondary endpoints .......................................................................................................... 106 
9.4.4 
Tertiary/exploratory endpoint(s) ................................................................................................... 106 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................. 106 
9.4.4.2 
Biomarker endpoints .................................................................................................................... 106 
9.4.5 
Other safety analyse(s) ................................................................................................................ 107 
9.4.6 
Other analyse(s) ........................................................................................................................... 107 
9.5 
INTERIM ANALYSES .................................................................................................................. 107 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 108 
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10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 108 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 108 
10.1.2 
Financial disclosure...................................................................................................................... 109 
10.1.3 
Informed consent process ............................................................................................................ 109 
10.1.4 
Data protection ............................................................................................................................. 110 
10.1.5 
Committee structure ..................................................................................................................... 112 
10.1.6 
Dissemination of clinical study data ............................................................................................. 112 
10.1.7 
Data quality assurance ................................................................................................................ 113 
10.1.8 
Source documents ....................................................................................................................... 113 
10.1.9 
Study and site start and closure ................................................................................................... 114 
10.1.10 Publication policy ......................................................................................................................... 115 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 115 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 117 
10.3.1 
Definition of AE ............................................................................................................................ 117 
10.3.2 
Definition of SAE .......................................................................................................................... 118 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 119 
10.3.4 
Reporting of SAEs........................................................................................................................ 121 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 122 
10.4.1 
Definitions .................................................................................................................................... 122 
10.4.2 
Contraception guidance ............................................................................................................... 123 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 125 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 125 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 125 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 ........ 126 
10.9 
APPENDIX 9: 
 .................................................................................................................... 130 
10.9.1 
Response and stable disease duration (RECIST 1.1 and
) ........................................... 133 
10.9.2 
Methods of measurement ............................................................................................................ 133 
10.10 
APPENDIX 10: WHO CRITERIA FOR DIGITAL MEDICAL PHOTOGRAPHS AND 
COMPOSITE RESPONSE CRITERIA FOR PARTICIPANTS WITH LOCALLY ADVANCED 
CSCC ........................................................................................................................................... 134 
10.11 
APPENDIX 11: GUIDELINES FOR BIOPSIES OF LOCALLY ADVANCED CSCC FOR 
ASSESSMENT OF OBJECTIVE RESPONSE OR FOR INDETERMINATE-APPARENT 
LESIONS ...................................................................................................................................... 138 
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10.12 
APPENDIX 12: MEDICAL PHOTOGRAPHS PROCEDURES .................................................... 139 
10.13 
APPENDIX 13: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNAMENTAL AGENCY ............................... 139 
10.13.1 Informed consent ......................................................................................................................... 140 
10.13.2 Study procedures ......................................................................................................................... 140 
10.13.3 Statistical analysis ........................................................................................................................ 140 
10.13.4 Temporary discontinuation ........................................................................................................... 140 
10.14 
APPENDIX 14: RISK ASSESSMENT .......................................................................................... 141 
10.15 
APPENDIX 15: ASTCT ASSESSMENT FOR ICANS AND CRS ................................................ 146 
10.16 
APPENDIX 16: ABBREVIATIONS ............................................................................................... 147 
10.17 
APPENDIX 17: PROTOCOL AMENDMENT HISTORY .............................................................. 149 
11 
REFERENCES ............................................................................................................................. 157 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 41 
Table 2 - Dose escalation rule of the modified toxicity probability interval-2 method ................................... 44 
Table 3 - Overview of IMP administered ....................................................................................................... 59 
Table 4 - Guidelines for the management of infusion-related reactions ....................................................... 67 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 68 
Table 6 - Guidelines for the management of immune-related adverse reactions ......................................... 72 
Table 7 - Guidelines for the management of immune cell-associated neurotoxicity syndrome (ICANS) ..... 79 
Table 8 - Guidelines for the management of vascular leak syndrome (VLS) ................................................ 81 
Table 9 - Cohort A and B: Estimated objective response rate (ORR) depending on number of responders
 ..................................................................................................................................................................... 100 
Table 10 - Populations for analyses ............................................................................................................ 101 
Table 11 - Protocol-required laboratory assessments ................................................................................ 115 
Table 12 - Risk assessment ........................................................................................................................ 141 
Table 13 - Encephalopathy assessment ICE tool for ICANS grading ......................................................... 146 
Table 14 - ASTCT ICANS consensus grading for adults ............................................................................ 146 
Table 15 - ASTCT CRS consensus grading ............................................................................................... 147 
 
LIST OF FIGURES  
Figure 1 - Overall study schema ................................................................................................................... 15 
Figure 2 - Graphical study design ................................................................................................................. 20 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 1/2 non-randomized, open-label, multi-cohort, multi-center study 
assessing the clinical benefit of SAR444245 (THOR-707) combined with 
cemiplimab for the treatment of participants with advanced unresectable or 
metastatic skin cancers  
Brief title: 
A study of SAR444245 combined with cemiplimab for the treatment of 
participants with various advanced skin cancers 
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. 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 demonstrated as an increased number of complete responses 
(CR) and tumor-free surviving animals compared to each agent given 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 combining the anti-PD1 monoclonal 
antibody cemiplimab with the non-alpha IL-2 SAR444245 will result in a significant increase in 
the percentage of immune checkpoint inhibitors (ICI)-naïve patients with melanoma and 
cutaneous squamous cell carcinoma (CSCC) experiencing an objective response. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
 
• 
Cohort A (melanoma): Objective response rate 
(ORR) defined as the proportion of participants who 
have a confirmed CR or partial response (PR) 
determined by Investigator per response evaluation 
criteria in solid tumors (RECIST) 1.1 (1) 
• 
Cohort B (cutaneous squamous cell carcinoma): 
ORR defined as the proportion of participants who 
have a confirmed CR or PR determined by 
Investigator per RECIST 1.1, or modified World 
Health Organization (WHO) criteria for medical 
photographs of external skin lesions, or composite 
criteria. 
• 
To determine the antitumor activity of SAR444245 
in combination with cemiplimab. 
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Objectives 
Endpoints 
Secondary 
• 
To determine the recommended Phase 2 dose 
(RP2D) and to assess safety profile of 
SAR444245 when combined with cemiplimab 
• 
Incidence of treatment-emergent adverse event 
(TEAEs), dose limiting toxicities (DLTs), 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 gradings (2) 
• 
To assess other indicators of antitumor activity 
• 
Complete Response rate (CRR) defined as the 
proportion of participants who have a confirmed CR 
determined by Investigator per RECIST 1.1 for 
melanoma participants and when applicable for 
CSCC participants (CR in localized unresectable 
CSCC is exploratory). 
• 
Time to CR 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 CR that is 
subsequently confirmed and determined by 
Investigator per RECIST 1.1 for melanoma 
participants and when applicable for CSCC 
participants 
• 
Time to Response (TTR) 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 
and determined by Investigator per RECIST1.1 or 
modified WHO criteria or composite criteria, 
whichever relevant. 
• 
Duration of Response (DOR), defined as the time 
from first tumor assessment at which the overall 
response was recorded as CR or PR that is 
subsequently confirmed until documented progressive 
disease (PD) determined by Investigator per RECIST 
1.1 or modified WHO criteria for medical photographs 
or composite criteria when relevant, 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 
or modified WHO criteria for medical photographs or 
composite criteria whichever relevant)  
• 
Progression Free Survival (PFS), defined as the time 
from the date of first IMP administration to the date of 
the first documented disease progression determined 
by Investigator per RECIST 1.1, or modified WHO 
criteria for medical photographs when relevant or 
death due to any cause, whichever occurs first. 
• 
To assess the concentrations of SAR444245 
when given in combination with cemiplimab 
• 
Concentration of SAR444245  
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Objectives 
Endpoints 
• 
To assess the immunogenicity of SAR444245 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245 
• 
To assess active concentrations of cemiplimab 
when given in combination with SAR444245 
• 
Ctrough and Cend_of_Infusion of cemiplimab 
Exploratory 
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Overall design: 
This is a Phase 1/2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with the immune checkpoint 
inhibitor (ICI) cemiplimab in ICI-naïve participants with advanced, unresectable, or metastatic 
skin cancers.  
SAR444245 and cemiplimab will be administered every 3 weeks in 21-day cycles. 
The study includes 2 treatment cohorts: 
Cohort A will include approximately 40 participants with previously untreated locally advanced, 
unresectable or metastatic melanoma, and will assess the investigational combination regimen 
as first-line (1L) therapy. 
Cohort B will include approximately 40 participants with ICI-naïve metastatic CSCC or locally 
advanced CSCC who are not candidates for curative surgery or curative radiation and who have 
received no more than 2 prior lines of systemic therapy.  
The study will start with a dose escalation to determine the RP2D of SAR444245 when combined 
with cemiplimab. The starting dose will be 16 µg/kg Q3W (DL1) with a possibility to de-escalate 
to 8 µg/kg Q3W (DL -1) or escalate to 24 µg/kg Q3W (DL2) based on the occurrence of DLT and 
overall assessment of safety. The plan is to treat a minimum number of 3 DLT evaluable 
participants at each dose-cohort and a minimum of 6 DLT-evaluable participants treated at RP2D 
will be needed before starting the dose expansion. During the dose escalation, decision for next 
dose level (de-escalate, stay, escalate) will occur after the last patient has completed the DLT 
observation period (first 21 days) for the previous dose level. The Study Board (SB) will review 
DLT and overall safety data for these participants and will make the next dose recommendation. 
DLT-evaluable participants include all participants in the dose escalation 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. The determination of RP2D will be made by the SB after a minimum 
of 6 DLT-evaluable participants have been treated at this selected dose. Participants enrolled in 
the dose escalation and treated at the RP2D will be included in the total number of participants. 
A graphical presentation of the study schema is shown in Figure 1. 
 
Figure 1 - Overall study schema  
 
a Total number including participants in dose escalation at the RP2D. 
1L: first line;1-3L: first to third line CSCC: Cutaneous Squamous Cell Carcinoma; DLT: dose-limiting toxicity; ICI: immune checkpoint inhibitor; 
N: number of participants; SB: Study Board. 
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The DLT observation period is 21 days and will take into account the occurrence of DLT. The 
dose escalation will follow modified toxicity probability interval 2 (mTPI2) design. 
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 SAR444245. Please refer to the full list of events in Section 4.1.  
Special considerations pertaining to methodology  
Interactive Response Technology will be used to control recruitment, assignment per site and 
facilitate drug supply.  
Number of participants: 
Overall, approximately 80 participants will be enrolled and treated at the RP2D. 
Note: Enrolled participants are all participants from those 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 7, 
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 radiological or clinical PD or 
who complete 35 cycles of treatment without PD (per RECIST 1.1 or modified 
WHO Criteria for medical photographs), 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 radiological or clinical PD 
(per RECIST 1.1 or modified WHO Criteria for medical photographs) or 
 will be followed 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. However, 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.  
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The cohort cut-off for the primary ORR endpoint analysis is estimated to be approximately 
9 months from the date of the last participant’s first infusion (to document that last participant 
response is maintained for 6 months).  
After the cohort cut-off date for the primary ORR analysis, participants can continue to receive 
IMP, if clinical benefit is observed, until full permanent discontinuation criteria described in 
Section 7 are met, and will continue to undergo all assessments as per the study schedule of 
activities.  
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).  
Study interventions 
Dosing sequence for both Cohort A and Cohort B: 
 
Investigational medicinal products 
SAR444245 
SAR444245 will be given 
• 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: IV infusion over 30 minutes every 3 weeks on Day 1 of each cycle 
(21 days per cycle) for up to 35 cycles.:  
- 
dose escalation: 16 μg/kg (DL1), 8 μg/kg (DL-1), 24 μg/kg (DL2) 
- 
dose expansion: RP2D 
Study sites should make every effort to target infusion duration 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. 
Cemiplimab 
Cemiplimab infusion will start 
• Formulation: Libtayo® (cemiplimab) is a concentrate for solution for infusion supplied in 
a single-dose vial 350 mg/7 mL (50 mg/mL), clear to slightly opalescent, colorless to pale 
yellow solution that may contain trace amounts of translucent to white particles. 
• Route of administration: IV infusion. 
• Dose regimen: 350 mg administered as an IV infusion over 30 minutes every 3 weeks on 
Day 1 of each cycle (21 days per cycle) for up to 35 cycles. 
Beyond 35 cycles and outside of the frame of this clinical study, the Investigator may decide to 
pursue treatment with the anti-cancer treatment of his choice. 
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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: 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or oral route (or equivalent), and then 
optionally thereafter, as needed. 
• Diphenhydramine 25 to 50 mg IV or oral route (or equivalent eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter, as needed. 
• Ondansetron 8 mg or 0.15 mg/kg IV (or equivalent eg, granisetron, dolasetron, tropisetron, 
palonosetron), and then optionally thereafter, as needed. 
SAR444245 premedication may be optional after 4 cycles in the below scenarios: 
• For a participant who has no IRR during the first 4 cycles premedication for the subsequent 
infusions is optional at the Investigator’s discretion (based on participant medical history, 
disease characteristics and other TEAEs, for example but not limited to cytokine release 
syndrome (CRS), flu-like symptoms observed until Cycle 4, part or all premedication 
components may be omitted). However, if during the subsequent infusions without 
premedication the participant experiences an IR (any grade or other TEAEs that could be 
mitigated by any components of premedication), 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 (based on participant medical history, disease characteristics and 
other TEAEs, for example but not limited to CRS, flu-like symptoms observed until 
Cycle 4, part or all premedication components may be omitted). 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% CIs for ORR will be computed using the Clopper-Pearson method. 
• Analysis of secondary efficacy endpoints:  
- 
The complete response rate (CRR) will be assessed for melanoma participants and 
when applicable for CSCC participants. 
- 
The time to CR will be assessed on the subgroup of melanoma participants who 
achieved confirmed CR and when applicable for CSCC participants in the efficacy 
population.  
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- 
The TTR will be assessed on the subgroup of participants who have achieved 
confirmed objective response in the efficacy population. 
- 
The DOR will only be summarized on the subgroup of participants who have achieved 
confirmed objective response in the efficacy population. 
- 
The CBR will be estimated by dividing the number of participants with clinical benefit 
by the number of participants from the efficacy population. 
- 
The 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 PT will be summarized 
(all grades and Grade ≥3) for the exposed population. Similar summaries will be 
prepared for TEAEs related to SAR444245 and those related to cemiplimab, TEAEs 
leading to permanent partial intervention discontinuation (any of the IMP 
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 during study period (treatment, post-treatment) 
and reasons for death will be summarized. The NCI-CTCAE v 5.0 grading scale will 
be used for all events except cytokine release syndrome (CRS) and immune effector 
cell-associated neurotoxicity syndrome (ICANS), for which severity will be 
categorized using ASTCT consensus grading. 
- 
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 
on-treatment period will be provided for the exposed population. 
• Analysis of other secondary endpoints 
- 
Concentrations of each cohort by SAR444245 and cemiplimab will be summarized 
with descriptive statistics. 
Data Monitoring Committee: Yes. 
Study Board: Yes. Details are provided in Section 4.1.
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1.2 
SCHEMA  
Figure 2 - Graphical study design  
 
 
a SAEs & AESIs collected throughout study period, from the signing of the informed consent form (ICF) until 90 days following last administration of study treatment OR until the participant initiates another 
anticancer therapy, whichever is earlier; AEs collected throughout study period, from the signing of the ICF until 30 days following last administration of study treatment OR until the participant initiates another 
anticancer therapy, whichever is earlier. 
C: Study Cycle; D: Study Day; FU: Follow-Up; EOT: End-of treatment; PDy: Pharmacodynamic; IMP: Investigational medicinal product; SoA: Schedule of Activities. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Evaluationa Screening 
Treatment Periodb 
End of 
Treatment 
Observation Periodc 
Survival 
Phone 
Call FUd 
Notes 
Cycle 1 
Cycle 
2 
Cycles 
3-6 
Cycles 
7-35 
EOT Visit 
Follow-
up 
Visit 1 
Follow-
up  
Visit 2 
Follow-
up  
Visit 3 
and 
beyond 
Phone 
Call FU 
 
Cycle day 
(Visit 
window in 
Days) 
D-28 
to D-1 
D1 D2 D3e D8 
(±1)  
D15f 
(±1) 
D1 
(±3) 
D1 
(±3) 
D1 
(±3) 
30 (±7) days 
after last 
IMP or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin 
6 months 
(±7 days) 
from last 
IMP 
admin 
Every 
3 months 
±7 days  
Every 
3 months 
±14 days 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography & 
Medical/Surgical 
& Disease 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See  
Section 8 
PS (ECOG) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Body 
Weight/Heightg 
X 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Full physical 
examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
See 
Section 8.2.1 
Directed physical 
examination 
 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 8.2.1 
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Evaluationa Screening 
Treatment Periodb 
End of 
Treatment 
Observation Periodc 
Survival 
Phone 
Call FUd 
Notes 
Cycle 1 
Cycle 
2 
Cycles 
3-6 
Cycles 
7-35 
EOT Visit 
Follow-
up 
Visit 1 
Follow-
up  
Visit 2 
Follow-
up  
Visit 3 
and 
beyond 
Phone 
Call FU 
 
Cycle day 
(Visit 
window in 
Days) 
D-28 
to D-1 
D1 D2 D3e D8 
(±1)  
D15f 
(±1) 
D1 
(±3) 
D1 
(±3) 
D1 
(±3) 
30 (±7) days 
after last 
IMP or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin 
6 months 
(±7 days) 
from last 
IMP 
admin 
Every 
3 months 
±7 days  
Every 
3 months 
±14 days 
 
Vital Signs 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 8.2.2 
SpO2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and other investigations 
12-Lead ECG 
X 
As clinically indicated 
 
 
 
See 
Section 8.2.3 
LVEF 
X 
As clinically indicated 
 
 
 
See  
Section 8.2.3 
Troponin 
X 
As clinically indicated 
X (D1 
Cycle 4) 
As clinically indicated 
 
 
 
See 
Section 8.2.3 
and 
Section 10.2 
Pregnancy test 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
See 
Section 8.2.5 
& 
Section 10.2 
Hepatitis 
serology, CD4+ 
counts & HIV 
Viral Load 
X 
 
As clinically indicated 
 
 
 
See 
Section 10.2 
Hematology 
X 
X 
X 
Xe  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 
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Evaluationa Screening 
Treatment Periodb 
End of 
Treatment 
Observation Periodc 
Survival 
Phone 
Call FUd 
Notes 
Cycle 1 
Cycle 
2 
Cycles 
3-6 
Cycles 
7-35 
EOT Visit 
Follow-
up 
Visit 1 
Follow-
up  
Visit 2 
Follow-
up  
Visit 3 
and 
beyond 
Phone 
Call FU 
 
Cycle day 
(Visit 
window in 
Days) 
D-28 
to D-1 
D1 D2 D3e D8 
(±1)  
D15f 
(±1) 
D1 
(±3) 
D1 
(±3) 
D1 
(±3) 
30 (±7) days 
after last 
IMP or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin 
6 months 
(±7 days) 
from last 
IMP 
admin 
Every 
3 months 
±7 days  
Every 
3 months 
±14 days 
 
Coagulation 
X 
As clinically indicated 
 
 
 
See 
Section 10.2 
Blood Chemistry 
X 
X 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 
T3, FT4, TSH 
and cortisol 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 
Urinalysish 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
See 
Section 10.2 
IMP  
 
X 
 
 
 
 
X 
X 
X 
 
 
 
 
 
 
Prior Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE assessmentj 
X 
Continuous throughout treatment period 
X 
 
 
 
See 
Section 8.3 
Concomitant 
Meds 
X 
Continuous throughout treatment period 
 
 
 
 
See 
Section 6.5 
First 
subsequent 
anti-cancer 
therapy 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetic (PK)/Pharmacodynamic (PDy)/Immunogenicity assessments 
 
PK SAR444245 
and cemiplimab 
See Pharmacokinetic Flow-Chart in Section 1.5 
 
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Evaluationa Screening 
Treatment Periodb 
End of 
Treatment 
Observation Periodc 
Survival 
Phone 
Call FUd 
Notes 
Cycle 1 
Cycle 
2 
Cycles 
3-6 
Cycles 
7-35 
EOT Visit 
Follow-
up 
Visit 1 
Follow-
up  
Visit 2 
Follow-
up  
Visit 3 
and 
beyond 
Phone 
Call FU 
 
Cycle day 
(Visit 
window in 
Days) 
D-28 
to D-1 
D1 D2 D3e D8 
(±1)  
D15f 
(±1) 
D1 
(±3) 
D1 
(±3) 
D1 
(±3) 
30 (±7) days 
after last 
IMP or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin 
6 months 
(±7 days) 
from last 
IMP 
admin 
Every 
3 months 
±7 days  
Every 
3 months 
±14 days 
 
ADA 
SAR444245 
See Pharmacokinetic Flow-Chart in Section 1.5 
 
PDy – Blood 
and tumor 
tissue collection  
See Biomarkers Flow-Chart in Section 1.4 
 
Tumor assessment 
 
Brain imagingk 
X 
As clinically indicated 
 
See 
 Section 8.1.1  
CT/MRIl 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
See 
Section 8.1.1 
Digital medical 
photographsm 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
See 
Section 10.10 
Tumor biopsies 
for CR 
confirmation 
(optional)n 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. Baseline evaluations should be completed within 7 days prior to the first dose of IMP, except for 
tumor assessment that may be performed within 28 days prior to IMP administration, and unless specified otherwise. 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 C1D1. During the study treatment period, all assessments must be performed prior to IMP administration. Results should be reviewed by the Investigator prior to the 
administration of the next dose. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF can be signed more than 28 days prior 
to initiation of therapy and must be signed before any study-specific procedures. Screening time indicates the maximal time frame in which study procedures used to support eligibility are performed. 
b Cycle: a treatment cycle is 21 days. IMP can be administered for up to 35 cycles. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number.  
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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 imaging studies are obtained. 
d Survival Phone Call Follow-Up Period: Participants who moves into the Survival Follow-up Phase should be contacted by telephone approximately every 3 months ±14 days to assess for survival status. 
Updated survival status may be requested by the Sponsor at any time during the course of the study. 
e Visit and assessments on C1D3 are only for participants in the dose escalation part.  
f 
Study Board may decide to cancel safety assessment on C1D15, upon agreement with Sponsor, if safety data justifies it. 
g 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. 
h Urinalysis will be performed every 4 cycles during Treatment period and as clinically indicated, at EOT and at follow-up visit 1. 
i 
Only for dose escalation participants. 
j 
Severity will be graded according to NCI-CTCAE v 5.0. ICANS and CRS will be graded using ASTCT criteria integrated with central laboratory cytokine results (2). 
k 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. 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 therapy during these 4 weeks stabilization at the treating physician's discretion, it 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 four 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.  
l 
CT/MRI: The initial tumor imaging will be performed within 28 days prior to the date of enrollment. 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 first IMP administration or more frequently if 
clinically indicated. 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 chest, abdomen, pelvis and any other locations with suspicion or evidence of disease involvement is required for 
the baseline assessment. After the first documentation of response per RECIST 1.1 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 
anti-cancer therapy. Images (scans and/or photographs) and pathological reports when relevant for confirmation of CR or characterization of a new skin lesion in locally advanced CSCC will be prospectively 
collected for potential retrospective central analysis; the prospective collection of these materials can be cancelled at any time. 
m Digital medical photographs: Tumor assessment for participants with externally visible CSCC lesions should be done using digital medical photographs according the modified WHO Criteria using an adequate 
camera platform. 
n Tumor biopsies: For participants with externally visible CSCC lesions and objective response with visual or clinical CR, all effort should be made to collect a tumor biopsy in order to confirm CR, however, this 
biopsy remains optional. Tumor biopsies may also be done as deemed necessary to address special issues as per Appendix 10 (Section 10.11). 
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; C=Cycle; CR=complete response; CSCC=cutaneous squamous cell carcinoma; 
CT=computed tomography; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end-of-treatment; FT4=free thyroxine; FU=Follow-Up; ICANS=Immune effector cell-associated 
neurotoxicity syndrome; ICF=Informed consent form; IMP=investigational medicinal product; 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; PS=Performance Status; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious 
adverse event; SpO2= oxygen saturation; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; WHO=World Health Organization. 
 
 
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1.4 
BIOMARKER FLOWCHART  
The below flowchart applies to all participants in Cohort A and B. For participants in dose 
escalation, the plan is listed as below:  
 For participant enrolled in the dose escalation dose 16 μg/kg:  
  
For participant enrolled in the dose escalation dose 24 μg/kg:  
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Screening 
Treatment period 
End of treatment  
Evaluation 
 
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment 
Cycle 4 
EOT Visit 
Cycle day (sample collection 
window in Days) 
D-28 to -D1 
D1 
D2 
D3 
D8 (-1) 
D15 
D1 (-3) D8 
D1 
30 (±7) days after 
last IMP 
administration  
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1.5 
PHARMACOKINETIC FLOWCHART  
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.
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1.5.1 All cohorts  
 
Cycle 
Treatment Cycle 1 
Treatment Cycle 2, 4, 7, 10 + every 
5th cycle 
EOT visit 
Day 
D1 
D2 
D3c 
D15 
D1 
Time after start of 
SAR444245 dosing [h] 
SOI 
EOI 
At any time 
T24H 
At any time 
T48H 
At any time 
T360H 
SOI 
EOI 
30 (±7) days 
after last IMP 
administration  
SAR444245 PK sample ID 
 
P00b 
P01 
P02 
 
 
P00b 
 
SAR444245 ADA sample ID 
AB00a 
 
 
 
AB01 
AB00a 
 
ABF00 
Time after start of cemiplimab 
dosing [h] 
SOI 
EOI 
 
 
 
SOI 
EOI 
 
Cemiplimab PK sample ID 
PC00a 
PC01b 
 
 
PC00a 
PC01b 
PCF00 
a Samples collected strictly before start of infusion (SOI) 
b P00 or PC01 samples = end of infusion (EOI) sample. Must be taken at EOI after flush. 
c Only for participants in the dose escalation. 
In case of overdose, ad-hoc PK sample should be collected right after an overdose is identified (only if identified within 5 days from start of overdose infusion). 
Abbreviations: ADA: anti-drug antibodies, C: cycle; D: day; EOT: end of treatment; h: hour; PK: pharmacokinetic. 
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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 cytokine release syndrome (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 NK cells in vivo as observed in mice and 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  
Programmed cell death protein 1 inhibitors have emerged as one of the most important 
1L treatment arsenal for various advanced and metastatic skin cancers. Pembrolizumab and 
nivolumab are approved for the treatment of 1L melanoma and cemiplimab, and more recently 
pembrolizumab are approved for the treatment of CSCC in the US. Despite the remarkable 
advance that PD1 inhibitors have brought to the treatment of these skin cancers, 50 to 60% of 
patients do not respond, and others will later progress (4, 5, 6, 7, 8, 9, 10, 11, 12).  
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SAR444245 is anticipated to potentiate PD1 inhibitors activity, thus leading to better response 
rate and/or better quality of response in both melanoma and CSCC, which should result in an 
improvement of the overall survival (OS) of the treated population. In preclinical studies, 
treatment with SAR444245 induced polyclonal expansion of CD8+ T cells in murine and NHP 
models while anti-PD1 antibody prevented T cell suppression through the PD1/PD-L1 pathway. 
The combination of anti-PD1 treatment with SAR444245 was tested in the Ct-26 colon cancer 
murine syngeneic tumor model, which is relatively resistant to anti-PD1 treatment, and 
demonstrated enhanced anti-tumor activity as well as prolonged survival compared to each agent 
administered alone.  
These data support evaluation of SAR444245 in combination with a PD-1 inhibitor (SAR444245 
Investigator’s Brochure [IB]). 
2.2 
BACKGROUND  
Melanoma and CSCC have always been described as immunogenic tumors. Indeed, patients who 
have undergone solid-organ transplantation and are receiving immunosuppressive therapy have a 
very significant risk of CSCC (13), suggesting that immune surveillance is critical for preventing 
CSCC in immunocompetent subjects. 
Until recently, the standard of care (SoC) in metastatic melanoma was chemotherapy, which 
achieved a median survival time of about 6 months and 1-year OS of 25% (14). The only 
available immunological therapy was high-dose IL-2, which induced long-lasting responses only 
in a small subset of patients, and was associated with a high rate of severe toxicities (14).  
Immune checkpoint inhibitors were the first class of therapy to show improved OS in patients 
with advanced melanoma, and the anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab are now the 
SoC in everyday clinical practice (15). 
The introduction of ICIs, and in particular of anti-PD-1/PD-L1 therapeutic antibodies, has 
revolutionized the therapeutic paradigm not only in melanoma, leading to long-lasting responses 
in almost half of patients, but also in an increasing number of tumor types, including 
non-melanoma cancers (4, 5, 6, 7, 8, 9). Among these is advanced CSCC including locally 
advanced and metastatic CSCC not amenable to curative surgery or curative radiotherapy, or both. 
The prognosis is poor for patients with advanced CSCC treated with cytotoxic chemotherapy or 
epidermal growth factor receptor inhibitors, and is associated with substantial morbidity, impact 
on quality of life, and health care burden (16, 17, 18). The recent approval of cemiplimab in this 
indication has been a significant improvement in the care of these patients. 
In the CheckMate-066 study, nivolumab alone proved superior to dacarbazine chemotherapy 
(51.2% 3-year survival compared to 21.6%). In CheckMate-067 and KEYNOTE-006 trials, 
nivolumab and pembrolizumab respectively proved superior to the anti-CTLA-4 ipilimumab; 
nivolumab induced a 3-year OS rate of 52% vs 34%, and pembrolizumab induced a 3-year OS 
rate of 48.1% vs 37.8% (8, 9, 5). In CheckMate-067 study, nivolumab combined to ipilimumab 
appeared superior to nivolumab alone (ORR 58% vs 44%; PFS 11.5 vs 6.9 months; OS 58% vs 
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52% OS at 3 years), although the study was not designed to demonstrate superiority of the 
combination. This apparent improvement in efficacy was obtained at the cost of higher toxicity 
(9, 19). Overall, from these clinical trials, ORR induced by ICI alone in 1L melanoma lays 
between 36% and 44%, indicating that approximately 60% patients fail to respond. 
Advanced CSCC accounts for only 5% of all cases of CSCC but up to 60% of disease-related 
deaths (20). Until recently, there was no approved systemic therapy for patients with advanced 
CSCC. Substantial anti-tumor activity of cemiplimab with durable responses was demonstrated in 
both metastatic and locally advanced CSCC. Midgen et al. reported an ORR of 47% and 44% in 
the metastatic cohort and locally advanced cohort, respectively, leaving room for improvement 
(10, 11). 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SAR444245 may be found in the IB. 
2.3.1 Risk assessment  
Safety data from clinical studies conducted with SAR444245 in human is currently limited to 
available safety data from the Phase 1/2 first-in-human (HAMMER) study. Consequently, the 
assessment of the risks associated to SAR444245 is also based on existing preclinical data, and 
takes into consideration 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 and cemiplimab combination results therefore from anticipated 
risks for SAR444245 and from the label information for Libtayo® (cemiplimab), taking into 
account potential overlapping risks. 
Table 12 summarizes potential risks for SAR444245 identified from preclinical experience and 
from the Phase 1/2 first-in-human (HAMMER) study, as well as available safety data for Libtayo, 
along with proposed mitigation strategies. 
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. 
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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-2R and 
intermediate-affinity IL-2R 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 (21), 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 (22). 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 embryolethal effects in rats but there are no adequate 
well-controlled studies in pregnant women; this information can be extrapolated to SAR444245. 
Also, since is not known whether SAR444245 is excreted in human breast milk, nursing mothers 
cannot participate to this study. 
High doses of aldesleukin (IL-2) were associated with decreased expression of enzymes of hepatic 
metabolism (23). As SAR444245 also exercises IL-2 activity, the Investigator should monitor 
clinical effects of narrow therapeutic index drugs that are hepatically metabolized. 
Please refer to Proleukin Label and SmPC for more detailed information. 
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2.3.1.2 SAR444245  
2.3.1.2.1 Preclinical data  
Among the potential risks, preclinical data for SAR444245 are lacking for infusion-related 
reactions (IRRs), immunogenicity (anti-drug antibodies), hypersensitivity, and immune-mediated 
adverse events. 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 these risks 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 EU SmPC). 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 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 adverse events 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. Also, since is 
not known whether SAR444245 is excreted in human breast milk, nursing mothers cannot 
participate in this study. 
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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. This is an open-label, multicenter, dose escalation and 
expansion study of SAR444245 IV as a single agent and in combination with the checkpoint 
inhibitor pembrolizumab. 
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. 
2.3.1.2.3 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-2R receptor. 
In the first-in-human Phase I 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-2R-biased IL2 could be safely administered as outpatient basis, and there was no report of 
capillary leak syndrome (CLS) or VLS (24).  
In PIVOT-02, a single-arm, Phase I/II study, NKTR-214 plus nivolumab was administered to 
38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell 
carcinoma, and non-small cell lung cancer). Several treatment regimens were explored. The dose 
of 0.009 mg/kg had excessive toxicity (2 of 3 patients with DLT: Gr 3 hypotension [n=1] & 
Gr 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 Q3 weeks 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, 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 
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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, suggesting therapeutic potential for patients with poor 
prognostic risk factors for response to PD1/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 (25). 
2.3.1.3 Cemiplimab  
Cemiplimab is a monoclonal antibody that belongs to a class of drugs that binds to the PD-1 
receptor, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune 
response, with the potential for breaking of peripheral tolerance and inducing immune-mediated 
adverse reactions that can occur in any organ system or tissue. Immune-mediated adverse 
reactions reported from clinical trials with Libtayo® included: immune-mediated pneumonitis 
(2.4%, 62% resolution), immune-mediated colitis (0.9%, 80% resolution), immune-mediated 
hepatitis (2.1%, 64% resolution), immune-mediated nephritis and renal dysfunction 
(0.6%, 100% resolution). Immune-mediated endocrinopathies included adrenal insufficiency 
(0.4%), hypophysitis resulting in hypopituitarism (0.2%), hypothyroidism (6%, requiring hormone 
replacement), hyperthyroidism (1.5%, 38% resolution), Type 1 diabetes mellitus (0.7%). 
Immune-mediated dermatologic adverse reactions occurred in 1.7% (33% resolution) of patients, 
including erythema multiforme and pemphigoid. In addition, Stevens-Johnsons syndrome and 
toxic epidermal necrolysis (TEN) have also been observed as for other agent of this class. 
Approximately, 22% of patients had recurrence of dermatologic reactions after re-initiation of 
cemiplimab. Severe infusion-related reactions (Grade 3) occurred in 0.2% of patients.  
Other clinically significant immune-mediated adverse reactions occurred at an incidence of 
<1% or were reported with other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have 
been reported for some of these adverse reactions. Reported events by System Organ Class (SOC) 
included neurological (meningitis, encephalitis, myelitis and demyelination, myasthenic 
syndrome/myasthenia gravis, Guillain-Barre syndrome, nerve paresis, autoimmune neuropathy), 
cardiovascular (myocarditis, pericarditis, vasculitis), ocular (uveitis, iritis, and other ocular 
inflammatory toxicities that can be associated with retinal detachment and various grades of 
visual impairment to include blindness can occur), gastrointestinal (pancreatitis including 
increases in serum amylase and lipase levels, gastritis, duodenitis), musculoskeletal and 
connective tissue (myositis, rhabdomyolysis and associated sequelae including renal failure, 
arthritis, polymyalgia rheumatica), hematological and immunological (hemolytic anemia, aplastic 
anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, 
histiocytic necrotizing lymphadenitis, sarcoidosis, immune thrombocytopenic purpura, solid organ 
transplant rejection). Systemic corticosteroids were required in almost all patients presenting with 
these events. 
Furthermore, based on its mechanism of action, cemiplimab can cause fetal harm when 
administered to a pregnant woman. Conditions for eligibility of women of reproductive potential 
and male subjects with female partners of childbearing potential are detailed in Section 5.1. 
Please refer to Libtayo® Label, SmPC and most recent IB for more detailed information. 
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2.3.1.4 SAR444245 combined with cemiplimab  
Combining SAR444245 with cemiplimab may lead to an increased frequency and/or severity of 
AEs related to immune activation. Serious adverse drug reactions reported with agents known to 
increase immune activation include pneumonitis, hepatitis, nephritis, colitis, and hormonal 
dysfunction (see Section 2.3.1.3). 
As both substances are biologic agents, they may have the propensity to induce IRRs that may 
have higher rate of occurrence and severity when SAR444245 and cemiplimab are used in 
combination. 
The maximum tolerated dose of SAR444245 combined with the approved dosing of another 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 (See Section 4.3 for details). 
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 
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-2R the 
suppressor CD4+ Treg cells are preferentially enhanced at lower dose through the high-affinity 
IL-2R, 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. 
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.  
Both melanoma and CSCC are tumor types that are benefiting from ICI treatment. The companion 
anti-PD1 cemiplimab to be combined with SAR444245 in this study is approved as 1L treatment 
in CSCC, an indication behaving very similarly to melanoma in its response to an ICI, and shares 
the same mechanism of action with two other anti-PD-1 (nivolumab and pembrolizumab) that are 
approved for the treatment of melanoma (see cemiplimab, pembrolizumab, and nivolumab 
respective labels).  
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 complete responses 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 durable memory T-cell 
population in response to the initial treatment (see SAR444245 IB). Furthermore, preliminary 
clinical data from another new generation IL-2, NKTR-214, in 1L melanoma, induced increase 
ORR and better quality of response than historical data for anti-PD-1 treatment alone (12).  
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Based on cemiplimab and SAR444245 clinical and preclinical available data, the combination 
regimen proposed to be evaluated in this study is anticipated to bring benefit to CSCC and 
melanoma populations. 
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 vascular leak syndrome, 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 the 
anti-PD1 inhibitor cemiplimab are justified by the anticipated benefits that may be afforded to 
participants with melanoma or CSCC. In the 1L setting, in addition to investigational 
SAR444245, participants will be receiving either a standard-of-care anti-PD1 (CSCC) or an 
anti-PD1 with proven activity (melanoma). 
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  
Patients potentially eligible for this study have advanced or metastatic melanoma or CSCC. 
Gonzalez-Cao et al. (26) have completed a national registry of melanoma patients infected by 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from 01 April 2020 to 
08 June 2020. Patients with a previous diagnosis of melanoma presenting with SARS-CoV-2 
infection to their hospitals network, were eligible for enrollment. A prospective observational 
study with a case registry followed by a retrospective analysis of patient data has been performed. 
Sixty-four patients were included, 55% had stage IV melanoma, 33% were on active anticancer 
treatment with anti PD-1 antibodies. Asymptomatic/paucisymptomatic evolution of SARS-CoV-2 
infection was recorded in 30% patients and for 20% patients the infection was mild in severity, 
with no hospital admission required. Serious and life-threatening complications were recorded in 
28% and 22% patients, respectively, coronavirus disease 2019 (COVID-19) episode resolved in 
55 cases, including 34 (53%) patients cured, 12% patients died due to melanoma progression and 
20% patients due to COVID-19. The median age of patients who died from COVID-19 was 
74 years (ranging from 49 to 91 years), while for those cured it was 64 years (ranging from 6 to 
95 year). The majority of patients who died were males (85%), while this rate decreased to 
62% for those cured. The mortality rate from COVID-19 was 20% for both stage IV and localized 
melanoma, while according to melanoma treatment it was 21%, 16%, and 21% for 
immunotherapy, BRAF plus MEK inhibitors, and for those who were not undergoing active 
cancer treatment, respectively. The authors concluded that the risk of death from COVID-19 in 
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melanoma patients was higher in males and older patients, which is similar to what is observed in 
the general population, and that the risk was not associated with neither the stage of the disease 
nor its therapy.  
Another study (27) evaluated the impact of COVID-19 pandemic on the management of 
metastatic melanoma patients treated with immune checkpoint inhibitors. Of the 80 patients 
included in the trial (62 nivolumab and 18 pembrolizumab), a total of 57 patients maintained their 
treatment without interruptions, while 16 postponed it for one or two cycles. Therapy was then 
resumed in 10 of the 16 patients (62.5%) delayed. The remaining 7 patients suspended treatment 
due to progression, completion of schedule, or were lost to follow-up. None of the patients under 
immune checkpoint inhibitors developed SARS-CoV-2 infection. Findings from this study 
support the possibility of continuing ICI in metastatic melanoma patients, evaluating on a patient 
basis (elderly, comorbidities, ongoing response, adjuvant treatment) the possibility of delaying the 
subsequent course. 
There are no evidence-based guidelines for the management of melanoma in the era of 
COVID-19. However, several guidelines designed to help making clinical decisions have been 
published. These include the United Kingdom (UK)-based consensus (28), the ESMO Guidelines 
(29), and the National Comprehensive Cancer Network recommendation (30). In the UK-based 
consensus guidelines, the authors have recommended PD-1 inhibitors monotherapy for patients 
starting immunologic therapy, while combination immunotherapy has been considered still 
suitable for patients with higher-risk disease.  
There is no information on the risks associated with COVID-19 and advanced or metastatic 
CSCC, however, this cancer occurs in two important categories that are known to impact the 
prognosis of COVID-19 in the general population and also in melanoma: male and older 
populations. 
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). 
Patients known to have had SARS-CoV-2 infection prior to study entry must be fully clinically 
recovered in order to be eligible for participation in the study. 
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) (31), 
• European Society for Medical Oncology (ESMO) (32). 
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2.3.4.1.2 Risks related to study treatment  
The treatment regimen under evaluation in the study includes the anti-PD1 cemiplimab and the 
non-alpha IL-2 SAR444245.  
Data from a small registry cohort showed that immunotherapy was not associated with a poor 
outcome of COVID-19 in melanoma patients (26) and the UK-based consensus guidelines for the 
management of melanoma during the COVID-19 pandemic recommends PD-1 inhibitor 
monotherapy for patients starting immunologic therapy, combination immunotherapy being 
considered still suitable for patients with higher-risk disease (28).  
SAR444245 has the potential to induce CRS which could exacerbate the manifestations of 
COVID-19 infection. It is however worth noting that the 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 10.13, 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 pertaining to COVID-19  
Overall, benefit-risk is deemed acceptable in patients with advanced and metastatic melanoma and 
CSCC during COVID-19 pandemic. Sponsor will continue to evaluate benefit-risk during the 
study period. 
 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity 
of SAR444245 in combination with 
cemiplimab. 
• 
Cohort A (melanoma): Objective response rate (ORR) defined as the 
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). 
• 
Cohort B (CSCC): ORR defined as the proportion of participants who have a 
confirmed CR or PR determined by Investigator per RECIST 1.1, or modified 
WHO criteria for medical photographs of external skin lesions, or composite 
criteria. 
Secondary 
• 
To determine the RP2D and to 
assess the safety profile of 
SAR444245 when combined with 
cemiplimab 
• 
Incidence of TEAEs, DLTs, SAEs, laboratory abnormalities according to NCI 
CTCAE v 5.0 and ASTCT consensus gradings (2) 
• 
To assess active concentrations of 
cemiplimab when given in 
combination with SAR444245 
• 
C trough and C end_of_Infusion of cemiplimab 
• 
To assess other indicators of 
antitumor activity 
• 
Complete Response rate defined as the proportion of participants who have a 
confirmed CR determined by Investigator per RECIST 1.1 for melanoma 
participants and when applicable for CSCC participants (CR in localized 
unresectable CSCC is exploratory).  
• 
Time to CR defined as the time from the first administration of IMP to the first 
tumor assessment at which the overall response was recorded as CR that is 
subsequently confirmed and determined by Investigator per RECIST 1.1 for 
melanoma participants and when applicable for CSCC participants 
• 
Time to Response 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 and determined by Investigator per 
RECIST1.1 or modified WHO criteria or composite criteria, whichever relevant. 
• 
Duration of Response defined as the time from first tumor assessment at which 
the overall response was recorded as CR or PR that is subsequently confirmed 
until documented PD determined by Investigator per RECIST 1.1 or modified 
WHO Criteria for medical photographs or composite criteria when relevant, or 
death from any cause, whichever occurs first. 
• 
Clinical Benefit Rate including confirmed CR or PR at any time or SD of at least 
6 months (determined by Investigator per RECIST 1.1 or modified WHO criteria 
for medical photographs or composite criteria whichever relevant) 
• 
Progression Free Survival, defined as the time from the date of first IMP 
administration to the date of the first documented disease progression 
determined by Investigator per RECIST 1.1, or modified WHO Criteria for 
medical photographs when relevant or death due to any cause, whichever 
occurs first. 
• 
To assess the concentrations of 
SAR444245 when given in 
combination with cemiplimab. 
• 
Concentration of SAR444245  
• 
To assess the immunogenicity of 
SAR444245 
• 
Incidence of ADAs against SAR444245 
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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.  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 1/2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with the immune checkpoint 
inhibitor (ICI) cemiplimab in ICI-naïve participants with advanced, unresectable, or metastatic 
skin cancers.  
SAR444245 and cemiplimab will be administered every 3 weeks in 21-day cycles. 
The study includes 2 treatment cohorts: 
Cohort A will include approximately 40 participants with previously untreated locally advanced, 
unresectable or metastatic melanoma, and will assess the investigational combination regimen 
as 1L therapy.  
Cohort B will include approximately 40 participants with ICI-naïve metastatic CSCC or locally 
advanced CSCC who are not candidates for curative surgery or curative radiation and who have 
received no more than 2 prior lines of systemic therapy. 
The study will start with a dose escalation to determine the RP2D of SAR444245 when combined 
with cemiplimab. The starting dose will be 16 µg/kg Q3W (DL1) with a possibility to de-escalate 
to 8 µg/kg Q3W (DL -1) or escalate to 24 µg/kg Q3W (DL2) based on the occurrence of DLT and 
overall assessment of safety. The plan is to treat a minimum number of 3 DLT evaluable 
participants at each dose-cohort and a minimum of 6 DLT-evaluable participants treated at RP2D 
will be needed before starting the dose expansion. During the dose escalation, decision for next 
dose level (de-escalate, stay, escalate) will occur after the last patient has completed the DLT 
observation period (first 21 days) for the previous dose level. The Study Board (SB) will review 
DLT and overall safety data for these participants and will make the next dose recommendation. 
DLT-evaluable participants include all participants in the dose escalation 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. The determination of RP2D will be made by the SB after a minimum 
of 6 DLT-evaluable participants have been treated at this selected dose. Participants enrolled in 
the dose escalation and treated at the RP2D will be included in the total number of participants. 
The DLT observation period is 21 days and will take into account the occurrence of DLT. The 
Modified Toxicity Probability Interval 2 (mTPI2) design will be used in the dose escalation 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 current dose, increase the 
dose or reduce the dose) will be made by the SB 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 
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escalation, equivalence interval (0.25,0.35) indicates staying at the current dose level, and 
intervals that are higher than 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 dose escalation part of the study, mTPI2 rules (see Table 2) will be applied, unless decided 
otherwise by the SB. 
Table 2 - 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 SAR444245.  
Hematologic abnormalities:  
• Any Grade 4 neutropenia irrespective of duration 
• Any febrile neutropenia  
• Grade 3 thrombocytopenia associated with transfusion in addition to bleeding and any 
Grade 4 thrombocytopenia  
Non-hematologic abnormalities:  
• Grade 3 or above ALT and AST increase 
• Grade 3 or above Vascular Leak Syndrome (VLS)  
• Grade 3 or above hypotension 
• Grade 3 or above cytokine release syndrome 
• Grade 3 or above AE that does not resolve to grade ≤2 within 7 days of starting accepted 
standard of care medical management 
• Grade 4 laboratory abnormalities 
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Study Board 
The study Investigators (or designee) participating in the dose escalation part of the trial and the 
Sponsor clinical team members will constitute the Study Board (SB). The SB will meet first when 
the first patient is treated in the dose escalation part and will review clinical data of each 
individual patient treated in the dose escalation part on a regular basis, in order to adjust the 
number of patients to be enrolled and to decide dose confirmation, dose reduction, dose escalation 
as appropriate 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 dose escalation. Decisions 
regarding final dose selection will be made during one of the study board meeting and 
documented in the meeting minutes.  
After dose escalation, occurrence of any treatment related G3 or higher AE (excluding 
lymphocyte count decrease) not resolving within 72 hours in >25% of participants per regimen 
will trigger SB to rapidly convene to assess safety or need to pause enrollment to allow for a 
safety review. Study Board (during dose escalation), Data Monitoring Committee (DMC) (during 
dose expansion) and Sponsor can decide to stop any cohort in case excessive toxicity (for example 
but not limited to excessive ir-AE or excessive number of G4/5 events) is observed. 
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 7, 
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 radiological or clinical PD or 
who complete 35 cycles of treatment without PD (per RECIST 1.1 or modified 
WHO Criteria for medical photographs), 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 radiological or clinical PD 
(per RECIST 1.1 or modified WHO Criteria for medical photographs or
will be followed 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.  
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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. However, 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.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The proposed study aims to establish proof-of-concept that combining the immune-checkpoint 
inhibitor cemiplimab with the non-alpha IL-2 SAR444245 will result in a significant increase in 
the percentage of ICI-naïve patients with melanoma and CSCC experiencing an objective 
response. 
Several new generation IL-2 are currently under clinical development. The most advanced 
compound is NKTR-214 (bempegaldesleukin), an IL-2-biased cytokine that has shown 
therapeutic benefit when combined with nivolumab in early phase clinical trials, which brought it 
to earn FDA breakthrough therapy designation for advanced melanoma. The FDA’s decision was 
based on 12-month follow-up results of the ongoing PIVOT-02 Phase 1/2 clinical trial 
(NCT02983045). In this subset, 63.6% of the patients showed response to treatment, including 
participants whose tumor were PD-L1 negative with minimal T-cell infiltration, with a complete 
response rate of 34% (25). It is currently in Phase 3 development in various indications including 
in 1L melanoma (NCT03635983). The ORR of ~64% is increased by 20% from the ORR of 44% 
reported for nivolumab alone in CheckMate-067 (9), as per Investigator’s assessment, although 
translation of this effect on OS has not yet been demonstrated.  
As single agent, cemiplimab has demonstrated an ORR of 47% and 44% for in ICI-naïve 
metastatic CSCC and locally advanced CSCC, respectively, as per independent central review, 
rates that are similar to that observed with other ICIs in the ICI-naïve melanoma (10, 11). We may 
anticipate a similar effect of the SAR444245 + cemiplimab combination in that indication. 
The proposed study is a non-randomized study where the experimental combination will be 
assessed in a single cohort for each indication, using historical data for single agent 
immune-checkpoint as a benchmark to show outstanding objective response rate. The ORR will 
be assessed using either RECIST 1.1, and/or the modified WHO criteria for medical photographs 
of skin lesions, whichever the most relevant, for participants with locally advanced diseases or 
with metastatic disease with or without skin target lesions. The objective response will be 
assessed per Investigator in first intention; a central review will only be done for confirmation of 
compelling results. In patients with localized CSCC, the documentation of complete response will 
be exploratory from an optional tumor biopsy specimen.  
Although cemiplimab is approved for the treatment of ICI-naïve metastatic or locally advanced 
CSCC, it is not approved for the treatment of patients with melanoma. However, as an anti-PD1, 
cemiplimab shares the same mechanism of action as nivolumab and pembrolizumab, both 
approved for the treatment of melanoma, and has exhibited an antitumor activity comparable to 
pembrolizumab in NSCLC patients with PDL-1 TPS ≥50% (33), thus justifying its investigation 
for both tumor types in this clinical study. 
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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. 
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), and 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-related reaction 
(occurred at 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. 
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%). 
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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 PDy change of CD8+ T, NK 
and Treg cells in HAMMER study as supportive information for R2PD selection. 
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. 
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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 that: SAR444245 monotherapy up to 32 µg/kg Q3W and pembrolizumab 
combination up to 32 µg/kg Q3W are cleared in HAMMER study; sustained relevant PDy effect 
in blood was documented in all patients tested to date; the Sponsor does not anticipate early 
overlapping toxicities when combined with an approved dose of an anti-PD1, as suggested by the 
tolerability reported in the patient cohort receiving SAR444245 at the 16 µg/kg Q3W dose in 
combination with the pembrolizumab 200 mg dose.  
As the safety profile of anti-PD-1 is generally overlapping a dose escalation will be conducted 
starting at 16 µg/kg Q3W with a potential option to de-escalation to 8 µg/kg Q3W or escalate to 
24 µg/kg Q3W based on the occurrence of DLT and overall assessment of safety. The minimum 
number of DLT evaluable participants will be 3 at each dose decision and a minimum of 6 DLT-
evaluable participants treated at RP2D are needed before starting the dose expansion. 
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 Schedule of Activities for the last participant in the trial 
globally. 
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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  
Participants are eligible to be included in the study only if 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 
Cancer diagnosis 
I 02. For participants in Cohort A: Participants with histologically-confirmed unresectable 
locally advanced or metastatic melanoma that are not amenable to local therapy, based on 
the Investigator’s judgement at the time of potential enrollment. The eligibility of 
participants to take part in the study will be validated at a multidisciplinary collegial 
meeting in countries where it is required.  
- 
In Ireland Cohort A will not be open to enrollment (See Appendix 7, Section 10.7) 
- 
In France participants with BRAF-mutant melanoma will not be included in Cohort A 
(See Appendix 7, Section 10.7) 
I 03. For participants in Cohort B: Participants with histologically-confirmed metastatic CSCC 
or locally advanced CSCC, with special considerations for the following categories: 
- 
Participants with tumors arising on the cutaneous hairbearing (non-glabrous) lip with 
extension onto dry red lip (vermillion) may be eligible after communication with and 
approval from the Sponsor.  
- 
Participants for whom the primary site is nose are only eligible if the Investigator is 
able to establish unambiguously that the primary site was skin, not nasal mucosa with 
outward extension to skin.  
- 
Participants with mixed histology in which the predominant histology is invasive 
CSCC (with only a minimal component of mixed histology) may be eligible after 
communication with and approval from the Sponsor. 
I 04. For participants in Cohort B: Participants with locally advanced CSCC who are not 
candidates for curative surgery. 
- 
Surgery must be deemed contraindicated in the opinion of a Mohs dermatologic 
surgeon, a head and neck surgeon, or plastic surgeon. A copy of the surgeon’s 
consultation note from a clinical visit within 60 days of enrollment must be submitted. 
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I 05. For participants in Cohort B: Participants with locally advanced CSCC who are not 
candidates for curative radiation. 
- 
Participants must be deemed as not appropriate for radiation therapy, EITHER in the 
opinion of a radiation oncologist, with copy of the consultation note from a clinical 
visit within 60 days of enrollment that must be submitted, OR in the opinion of the 
Investigator indicating that the benefit/risk assessment was performed by a 
multidisciplinary team (consisting of, at minimum, a radiation oncologist AND 
EITHER a medical oncologist with expertise in cutaneous malignancies, OR a 
dermato-oncologist, OR a head and neck surgeon. A clinic note from the Investigator 
stating that this benefit/risk assessment was performed should be submitted. 
I 06. Provision of tumor tissue: 
- 
Mandatory baseline biopsy for participants in Cohort A with skin metastasis and 
participants in Cohort B. Archival tumor tissue sample is acceptable if obtained 
within 6 months, and there should be no systemic anti-cancer therapy between 
collection of biopsy and enrollment (minimum 10 slides with 4-5 microns 
thickness). Mandatory on-treatment biopsy for participants in Cohort A with skin 
metastasis and participants in Cohort B. One biopsy on treatment is mandatory for 
participants to Cohort A with skin metastasis, if clinically feasible. One biopsy on 
treatment is mandatory for participants in Cohort B, if clinically feasible. 
- 
For participant enrolled in the dose escalation dose 16 μg/kg: Screening (baseline) 
tumor tissue collection is optional, but highly recommended. On-treatment tumor 
collection is not required  
- 
For participant enrolled in the dose escalation dose 24 μg/kg: Screening (baseline) 
tumor tissue collection is mandatory. On-treatment tumor collection is optional but 
highly recommended. 
- 
 Depending on the number of acquisitions of on-treatment tumor biopsies, a participant 
who does not agree to on-treatment biopsy or agrees to only one on-treatment biopsy 
may still be eligible after discussion with the Sponsor. On-treatment biopsies should be 
preferably sampled from same site as baseline/archival tumor. Slide 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 
- 
Optional for participants in Cohort A without skin metastasis. 
- 
Tumor site used for biopsy must not have been irradiated previously and must not be 
the only measurable lesion. 
I 07. Measurable disease: 
- 
For participants in Cohort A: At least one measurable lesion per RECIST 1.1 criteria. 
- 
For participants in Cohort B: At least one measurable lesion per RECIST 1.1 or at 
least a lesion that can be followed by serial digital medical photographs using modified 
WHO criteria. 
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Sex 
I 08. 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 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: 
- 
Refrain from donating or cryopreserving sperm 
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 when having sexual intercourse with a woman of childbearing 
potential 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 180 days [corresponding to the time 
needed to eliminate any study intervention(s) plus 30 days (a menstrual cycle)] 
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 09. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.  
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Cancer diagnosis 
E 01. For participants in Cohort A: Participants with uveal or ocular or desmoplastic melanoma.  
E 02. For participants in Cohort B: Participants for whom the primary site of CSCC was the dry 
red lip (vermillion) or the anogenital area (vulva, penis, scrotum, and perianal region). 
E 03. For participants in Cohort B: Participants with mixed CSCC histologies (eg, sarcomatoid, 
adenosquamous). 
Medical conditions 
E 04. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. 
E 05. Predicted life expectancy ≤3 months. 
E 06. 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 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 07. History of allogenic tissue/solid organ transplant (participants with prior corneal transplant 
may be allowed to enroll after discussion with and approval from Sponsor). 
E 08. 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 09. 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.  
E 10. History of pneumonitis within the last 5 years, active pneumonitis, interstitial lung disease 
requiring the use of steroids, idiopathic pulmonary fibrosis, confirmed pleural effusion, 
severe dyspnea at rest or requiring supplementary oxygen therapy.  
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E 11. 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 12. 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 17), or other infection that is not controlled or requires IV or oral antibiotics. 
E 13. 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 (eg, ≥160 mmHg 
systolic or ≥100 mmHg diastolic), uncontrolled cardiac arrhythmia requiring medication 
(≥Grade 2, according to NCI-CTCAE v 5.0), or myocardial infarction.  
E 14. Ongoing AEs caused by any prior anti-cancer therapy ≥Grade 2 (NCI-CTCAE v 5.0). 
Participants with ≤Grade 1 peripheral neuropathy, or Grade 2 alopecia, are permitted. 
E 15. 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 16. Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted. 
E 17. HIV infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease or known uncontrolled infection with human immunodeficiency virus (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. 
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E 18. 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 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. 
E 19. Known second malignancy either progressing or requiring active treatment within the last 
3 years, except for tumors with negligible risk of metastasis or death, such as adequately 
treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, or ductal 
carcinoma in situ of the breast, or history of prostate adenocarcinoma treated with curative 
intent at least 3 years ago, and with undetectable prostate-specific antigen for at least 
3 years prior to enrollment.  
E 20. Known hypersensitivity 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 21. Participants with baseline SpO2 ≤92% (without oxygen therapy). 
Prior/concomitant therapy 
E 22. Has received prior IL-2 based anti-cancer treatment. 
E 23. Is unable or unwilling to take premedication. 
E 24. Deleted in Amended protocol 04  
E 25. For participants in Cohort A: Participants who have received any systemic treatment for 
their advanced/metastatic disease.  
E 26. For participants in Cohort B: Participants who have received more than 2 prior lines of 
any systemic treatment for their advanced/metastatic disease.  
E 27. For participants in Cohort A and Cohort B: Participants who have received approved or 
investigational anti-PD1, anti-PD-L1, or anti-PD-L2 or anti-CTLA4 (or any other antibody 
or drug specifically targeting T-cell co-stimulation) except in the context of adjuvant or 
neoadjuvant. Participants who joined a study with an investigational anti-PD-1/PD-L1 but 
have written confirmation they were on control arm are allowed. 
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E 28. For participants in Cohort A and Cohort B: Participants who have received adjuvant or 
neoadjuvant therapy during the 6 months prior to development of metastatic disease.  
E 29. For participants in Cohort B: Any anticancer treatment (chemotherapy, targeted systemic 
therapy, radiation therapy, photodynamic therapy), investigational or standard of care, 
within 30 days of the initial administration of IMP or planned to occur during the study 
period (participants receiving bisphosphonates or denosumab are not excluded). Notes: For 
participants with multiple CSCCs at baseline that are not designated by the Investigator as 
target lesions, treatment of these non-target CSCCs with surgery may be permitted but 
must be discussed with the Sponsor prior to any surgical procedure. 
E 30. Participants treated 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 31. Participation in a concurrent clinical study in the treatment period. 
Organ and bone marrow function 
E 32. Absolute neutrophil count <1500/µL (1.5 × 109/L) (after at least one week off G-CSF). 
E 33. Platelets <100 × 10³/µL (after at least 3 days without platelet transfusion). 
E 34. 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 35. 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 36. Aspartate aminotransferase and alanine aminotransferase >2.5 × ULN (or >5 × ULN for 
participants with liver metastases). 
E 37. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² (Modification of Diet in 
Renal Disease [MDRD] Formula). 
E 38. 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. 
Diagnostic assessments 
E 39. Inability to undergo any contrast-enhanced radiologic response assessment with the 
following precision and exception: 
- 
A participant who is unable to undergo computed tomography (CT) with iodinated 
contrast (eg, due to contrast allergy) would not be excluded if his/her disease can be 
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measured by magnetic resonance imaging (MRI) with gadolinium. A participant who 
is unable to undergo MRI with gadolinium would not be excluded if his/her disease 
can be measured by CT scan with contrast. 
- 
A participant with CSCC who is unable to undergo any contrast enhanced radiographic 
imaging (neither CT with iodinated contrast nor MRI with gadolinium) may be eligible 
if the participant’s disease can be comprehensively assessed with digital medical 
photography, after communication and approval from the Sponsor. 
Other exclusions 
E 40. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 41. Any country-related specific regulation that would prevent the participant from entering 
the study (see Section 10.7). 
E 42. 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 43. 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 44. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 45. History or current evidence of any condition, therapy 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. 
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. 
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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. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
SCREENING/ENROLLMENT/ADMINISTRATION OF STUDY INTERVENTION  
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 10.13. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
In both Cohort A and Cohort B, study interventions will be administered according to the 
following sequence: 
.  
Participants will receive study treatment until confirmed PD, unacceptable toxicity, other full 
permanent discontinuation criteria as described in Section 7, or completion of Cycle 35. Beyond 
35 cycles and outside of the frame of this clinical study, the Investigator may decide to pursue 
treatment with the anti-cancer treatment of his choice. 
6.1.1 Investigational medicinal product  
Investigational medicinal product is defined as SAR444245 + cemiplimab combination. 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 before and after SAR444245 infusion. Details are provided in Section 6.1.3. 
Table 3 - Overview of IMP administered  
Intervention name 
SAR444245 
cemiplimab 
Type  
Biologic 
Biologic 
Dose formulation 
Concentrate for solution for infusion 
Concentrate for solution for infusion 
Unit dose strength(s) 
2 mg/mL 
350 mg/7 mL 
Dosage level(s)a 
Dose escalation: 16 μg/kg (DL1), 8 μg/kg 
(DL-1), 24 μg/kg (DL2) every 3 weeks. Dose 
expansion: RP2D (recommended by SB)  
350 mg every 3 weeks 
Route of administration 
IV infusion over 30 minutes 
 
IV infusion over 30 minutes through an 
IV line containing a sterile 0.2 micron to 
5 micron in-line or add-on filter 
Use 
experimental 
experimental 
Packaging and labeling 
Supplied in a single-dose vial in a treatment 
box. Each vial contains 2 mg/mL and has an 
extractable volume of 1 mL. Each vial and 
treatment box will be labeled as required per 
country requirement. 
Supplied in a single-dose vial in a treatment 
box. Each vial contains 350 mg/7 mL 
(50 mg/mL). Each vial and treatment box 
will be labeled as required per country 
requirement. 
Current names or aliases Not applicable 
Libtayo® 
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 eCRF. 
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6.1.2 Non-investigational medicinal product  
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 (IRRs) or flu-like symptoms, approximately 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 oral route (or equivalent), and then 
optionally thereafter as needed. 
• Diphenhydramine 25 to 50 mg IV or oral route (or equivalent eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability) and then optionally 
thereafter, as needed. 
• Ondansetron 8 mg or 0.15 mg/kg IV (or equivalent eg, granisetron, dolasetron, tropisetron, 
palonosetron), and then optionally thereafter, as needed. 
SAR444245 premedication may be optional after 4 cycles in the below scenarios: 
• For a participant who has no IRR for the first 4 cycles premedication for the subsequent 
infusions is optional at the Investigator’s discretion (based on participant medical history, 
disease characteristics and other TEAEs, for example but not limited to CRS, flu-like 
symptoms observed until Cycle 4, part or all premedication components may be omitted). 
However, if during the subsequent infusions without premedication the participant 
experiences an IRR (any grade or other TEAEs that could be mitigated by any components 
of premedication), 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 for the next cycle without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion (based on participant medical history, disease characteristics and other TEAEs, 
for example but not limited to CRS, flu-like symptoms observed until Cycle 4, part or all 
premedication components may be omitted). 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  
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6.1.4 Readiness for treatment of severe cytokine release syndrome  
Doses of tocilizumab should be available at site at all time in the event that a participant requires 
rapid intervention for the treatment of severe CRS. Please refer to Section 6.6.4.3 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. 
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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). 
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 8.3.8). 
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 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements, or other specific categories of interest) 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 
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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 trial therapy may be required. The Investigator 
should discuss any questions regarding this 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. 
6.5.1 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 electronic case report form 
(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. 
All concomitant medications received within 30 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 (34). 
6.5.2 Prohibited concomitant medications  
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment period of this trial: 
• Antineoplastic systemic chemotherapy (including chemotherapies and targeted therapies) 
or biological therapy not specified in this protocol. 
• Immunotherapy not specified in this protocol. 
• Investigational agents other than specified in this protocol. 
• Radiation therapy for tumor control (please refer to Section 6.5.1 for allowed 
radiotherapy). 
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• Live vaccines within 28 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live 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 Table 4, Table 5, Table 6, and Table 7), 
- 
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 Period. 
For withholding antihypertensive medications as part of hydration guidelines, please refer to 
Section 6.1.3. 
6.6 
DOSE MODIFICATION  
6.6.1 General rules  
Dose modifications for SAR444245 (reduction) are permitted according to the guidelines 
described in this section. No dose modification is recommended for cemiplimab. 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, delay of both IMP components) is permitted in case of 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. 
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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 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 both IMP 
components are permanently discontinued it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the e-CRF. 
6.6.2 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 all IMP components once the toxicity resolves or 
improves to Grade 1 or baseline, as described in Section 6.6.3. 
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 interruption, 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. 
6.6.3 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) will be required to temporarily withhold the IMP, unless specified otherwise in the 
protocol, and with the exception of the TRAEs resolving within 5 days. After treatment withhold, 
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 
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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 withholding of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No withholding of treatment or dose modification is required for Grade 1 events. 
No dose reduction is recommended for cemiplimab. Dose reduction for SAR444245 during the 
dose escalation 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. 
Study intervention should be held in case of significant cardiac event (if possible, confirmed by a 
cardiologist) or suspicion of an immune-mediated myocarditis until it has been assessed for a 
relationship to SAR444245 or cemiplimab. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
VLS and IRR are presented in Section 6.6.4. 
6.6.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as AESIs, depending on grading 
according to NCI-CTCAE v 5.0 (see Section 8.3.8). In case a specific adverse event meets the 
AESI definition it must be documented in the e-CRF. 
6.6.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1, prior to 
SAR444245 administration, to prevent or reduce the incidence or severity of IRRs. 
An infusion-related reaction 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 IRR events are provided in Table 4. 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 instructions, please see Section 6.1.2.1. 
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Table 4 - Guidelines for the management of infusion-related reactions  
Event severity (NCI-CTCAE v 5.0) 
Recommended IMP  
dose modification and Supportive care guidelines 
Grade 1: Infusion interruption or intervention not 
indicated 
If IRR happens during infusion, continuation of SAR444245a or cemiplimaba 
infusion is per Investigator’s judgment following close direct monitoring of 
the participant’s clinical status. 
SAR444245 or cemiplimab infusion may be interrupted at any time if 
deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE v.5.0 
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 hours) 
Interrupt SAR444245 or cemiplimab infusion.  
If symptoms resolve within 1 hour of stopping 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 
according to Section 6.1.2.1 for the next scheduled dose. 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 (eg, not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae 
 
Grade 4: Life-threatening; urgent intervention 
indicated 
For both Grade 3 and Grade 4 IRRs: 
If IRR is clearly attributable to SAR444245 infusion, permanently 
discontinue SAR444245. The participant can continue treatment with 
cemiplimab. 
 
If IRR occurs during cemiplimab infusion, permanently discontinue both 
SAR444245 and cemiplimab.  
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 and cemiplimab 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; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.6.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and cemiplimab.  
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 
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monitoring of vital signs as medically indicated, until the participant recovers (see guidelines in 
35, 36, 37). 
6.6.4.3 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 v 5.0 and managed according 
to institutional standards.  
Cytokine release syndrome should be graded as per ASTCT criteria integrated with central 
laboratory cytokine results and managed per guidelines in Table 5. 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, as well as CRP and ferritin 
(by local laboratory). 
Sites should have at least 2 full doses of tocilizumab available and access to an intensive care unit 
(ICU), in case participants develop CRS. 
Guidelines for management of CRS events according to severity grading are provided in Table 5. 
ASTCT CRS consensus grading scale is provided in Section 10.15. 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS)  
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended IMP  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)a 
• 
No hypotension  
• 
No hypoxiab. 
No dose modification of SAR444245d/cemiplimabd. 
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 patient’s clinical status. Clinical and laboratory 
monitoring should initially be performed daily, then less frequently as the 
participant improves 
Grade 2  
• 
Fever (Temperature ≥38°C)a 
• 
Hypotension not requiring 
vasopressors 
• 
And/orb hypoxia requiring low-
flow nasal cannulac or blow-by 
 
Temporarily interrupt both SAR444245 and cemiplimab, if events occur during the 
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 patients with comorbidities, older age, or with oxygen requirement, 
hypotension, or patients in whom symptoms (eg, high grade fever) that do not 
respond to antipyretics within 72 hours treatment with corticosteroids and/or 
tocilizumab 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. 
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Event severity (ASTCT CRS 
Consensus Grading) 
Recommended IMP  
dose modification and supportive care guidelines 
Grade 3 
• 
Fever (Temperature ≥38°C)a 
• 
Hypotension requiring 
vasopressors 
• 
And/orb hypoxia requiring high-
flow nasal cannulac, facemask, 
nonrebreather mask, or Venturi 
mask 
If CRS Grade 3, temporarily withheld both SAR444245 and cemiplimab, and 
resume subsequent treatment only when symptoms have resolved or improved to 
Grade 1. SAR444245 can be either restarted at the dose below the current dose 
level or permanently discontinued, as clinically indicated. The participant can 
continue treatment with cemiplimab without dose modification. If subsequent 
administration is tolerated, resuming SAR444245 at the previous dose for 
subsequent administrations can be considered based on the clinical judgement of 
the Investigator with the Sponsor. 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Fever (Temperature ≥38°C)a 
• 
Hypotension requiring multiple 
vasopressors 
• 
And/orb hypoxia requiring 
positive pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
If CRS Grade 4, permanently discontinue SAR444245 and temporarily withhold or 
permanently discontinue cemiplimab. If temporarily interrupted, cemiplimab can be 
resumed without dose modification only when symptoms have resolved or 
improved to Grade 1.  
If 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 
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. 
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 patients weighing ≥30 kg) 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 and steroids, alternative options will be discussed with clinical 
site specialists. 
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 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. 
d Information for preparation and storage of SAR444245 and cemiplimab are provided in the pharmacy manual. 
 
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; IMP=investigational medicinal product; 
IV=intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs.  
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6.6.4.4 Immune-related adverse events  
Cemiplimab may be associated with a unique set of toxicities termed immune-related adverse 
events (irAEs), and SAR444245 may increase the incidence and severity of these events.  
IrAEs are thought to be caused by unstrained cellular immune responses directed at the normal 
host tissues and can occur shortly after the first dose or several months after the last dose of 
treatment. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. 
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 emerging safety profile of cemiplimab and other antibodies targeting the PD1/PDL1 
axis (38, 39), the following working case definitions are provided to help Investigators distinguish 
irAEs from non-immune AEs. These case definitions pertain to the more commonly reported 
irAEs associated with PD-1 inhibition (38, 39), and is not exhaustive of all possible irAEs. 
Clinical presentations of less common irAEs, including neurologic, musculoskeletal, cardiac, 
renal, and ocular events (40, 41) should be reviewed in participants with concerning presentations. 
The case definitions below have not been validated and are intended only as guidance for 
investigators to help distinguish irAEs from non-immune AEs. Investigators’ clinical judgment 
may include other factors when determining immune-relatedness. The case definitions for irAEs 
may evolve as clinical experience increases with cemiplimab and other antibodies targeting the 
PD-1/PD-L1 axis. 
a. Immune-related diarrhea/colitis: These events are on a continuum, where diarrhea is 
defined as increased stool frequency and colitis involves abdominal pain and either clinical 
or radiologic evidence of colonic inflammation (38). Onset at 4 to 6 weeks is common 
(39). A CT scan usually demonstrates diffuse colitis (42). Exclude clostridium difficile or 
other infectious etiologies and laxative misuse. 
b. Immune-related encephalitis: Patients may present with a variety of symptoms ranging 
from headache and word finding difficulties to seizures, altered mental status, and 
somnolence. Untreated, this syndrome can be fatal. Neurological consult is strongly 
encouraged, and therapy usually includes systemic corticosteroids. 
c. Immune-related hepatitis: Laboratory studies are notable for elevated ALT and/or AST 
that is usually asymptomatic. Viral or other drug-induced hepatitis is excluded. Exclude 
alcohol-related liver toxicity. If clinically appropriate, consider radiologic imaging to 
exclude malignant causes. If clinically appropriate, exclude worsening of underlying 
cirrhosis. 
d. Immune-related hypophysitis: Laboratory studies are notable for panhypopituitarism 
including low am cortisol with normal or low adrenocorticotropic hormone, low 
thyroid-stimulating hormone (TSH) with a low free T4, low luteinizing 
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hormone/follicle-stimulating hormone or testosterone (sex specific), and low prolactin. 
The most common side effect is headache, but side effects may also include fatigue, 
weakness, confusion, hallucinations, memory loss, labile mood, insomnia, anorexia, 
temperature intolerance, chills, decreased libido, and visual impairment. Untreated, this 
syndrome can be fatal. Treatment includes hormone replacement. 
e. Immune-related hypothyroidism: Laboratory studies are notable for elevated TSH 
associated with low serum free thyroxine (free T4). If elevated TSH is detected, it is 
recommended that free T4 level also be tested. Elevated TSH with low free T4 establishes 
the diagnosis of hypothyroidism. Hypothyroidism may be asymptomatic or associated 
with symptoms such as fatigue, constipation, cold intolerance, dry skin, weight gain, 
and/or bradycardia. Exclude other causes of hypothyroidism, such as prior radiation 
therapy to the neck. In patients with prior history of hypothyroidism, exclude 
noncompliance with thyroid replacement medication. 
f. Immune-related hyperthyroidism: Hyperthyroidism should be managed with standard 
antithyroid pharmacotherapy, and consultation with an endocrinologist is recommended. 
g. Immune-related mucositis: Mucositis should be treated according to standard of care. 
h. Immune-related nephritis: Nephritis can present with generalized edema and weight 
gain, and should be managed with diuretics. Consultation with a nephrologist is 
recommended. 
i. Immune-related pneumonitis: Pneumonitis, defined as inflammation of the lung 
parenchyma, may present as shortness of breath, cough, fever, and/or chest pain. Median 
time from start of anti-PD-1 therapy to onset of pneumonitis is 2.6 months but delayed 
onset of pneumonitis has been reported. The most common radiologic pattern on CT chest 
has been described as cryptogenic organizing pneumonia (COP), but other radiographic 
patterns may occur. If performed, biopsy may demonstrate lymphocyte-predominant 
interstitial pneumonitis with areas of organizing pneumonia. Exclude infectious causes of 
pneumonitis. 
j. Immune-related rash: Skin examination demonstrates a rash that is usually 
maculopapular, but other presentations may occur, including papulopustular, follicular, or 
urticarial dermatitis. Consider dermatologic consultation and biopsy for atypical 
presentations. Exclude other causes such as virally-induced rash or contact dermatitis. 
k. Immune-related uveitis: Uveitis can present with redness of the eye, ocular pain, 
photosensitivity, and vision changes. Patients with uveitis should be urgently referred to 
ophthalmology for consultation and treatment. 
Dose modification and toxicity management guidelines for irAEs are provided in Table 6. 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. Where the toxicity is attributed to the 
combination or to SAR444245 alone, re-initiation of cemiplimab as a monotherapy may be 
considered after communication with the Sponsor. 
The CTCAE v 5.0 must be used to grade the severity of AEs.  
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Table 6 - Guidelines for the management of immune-related adverse reactions  
 
Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
Pneumonitis 
Grade 1 
Consider withholdingb. 
May be continued with 
close monitoring 
Consider withholdingb.  
May be continued with 
close monitoring 
• Radiologic findings should be followed on serial imaging studies at least every 3 weeks 
• Monitor for symptoms every 2-3 days. 
• Consider pulmonary consultation and/or bronchoscopy if clinically indicated 
• If SAR444245 and cemiplimab have been withheld, they can be restarted upon 
resolution and after corticosteroid taper, without dose modification. 
 
Grade 2 
Withholdb 
Withholdb 
To rule out other causes such as infection: 
• Consider pulmonary consultation with bronchoscopy and biopsy/bronchoalveolar lavage 
(BAL). 
• Consider pulmonary function tests. 
• Follow radiologic findings on serial imaging studies every 1-3 days 
If the patient is determined to have study drug associated pneumonitis: 
• Monitor symptoms daily; consider hospitalization. 
• Treat with systemic corticosteroids at a dose of 1-2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Treatment with SAR444245 and cemiplimab may be resumed if the event improves to 
≤Grade 1 within 12 weeks and corticosteroids have been reduced to the equivalent of 
methylprednisolone 10 mg by mouth daily or less. Repeat chest imaging monthly as 
clinically indicated. 
• For recurring Grade 2 event, SAR444245 may be either permanently discontinued or 
resumed at the dose below the current dose level after discussion with Sponsor, as 
clinically relevant, and cemiplimab withheld and resumed without dose modification, 
upon event resolution and after corticosteroid taper. Any additional recurrence should 
lead to permanent treatment discontinuation. 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
 
Grade 3 and 4 
 
Permanently 
discontinue 
 
Permanently discontinue 
 
• Consider pulmonary function tests with pulmonary consult. 
• Bronchoscopy with biopsy and/or BAL is recommended. 
• Treat with IV steroids (2 to 4 mg/kg per day prednisone or equivalent). When symptoms 
improve to Grade 1 or less, a high-dose oral steroid (1 to 2 mg/kg prednisone once per 
day or 4 mg dexamethasone every 4 hours) taper should be started and continued over 
no less than 4 weeks. 
• Add prophylactic antibiotics for opportunistic infections. 
• If IV steroids followed by high-dose oral steroids does not reduce initial symptoms within 
48-72 hours, treat with infliximab at 5 mg/kg once every 2 weeks. Discontinue infliximab 
upon symptom relief and initiate a prolonged steroid taper over 45–60 days. If symptoms 
worsen during steroid reduction, initiate a re-tapering of steroids starting at a higher 
dose of 80 or 100 mg followed by a more prolonged taper and administer infliximab 
Colitisc 
Grade 1 
No change in dose 
No change in dose 
• Ensure adequate hydration 
• For diarrhea, treat symptomatically (loperamide, oral hydration, electrolyte substitution 
and American Dietetic Association colitis diet). Endoscopy is recommended if symptoms 
persist. 
• Grade 1 diarrhea that persist for >1 week should be treated with the addition of oral 
diphenoxylate hydrochloride and atropine sulfate four times daily and budesonide 9 mg 
daily. 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
 
Grade 2 
Withholdb 
Withholdb 
• Ensure adequate hydration 
• GI consultation and endoscopy is recommended to confirm or rule out colitis for Grade 2 
diarrhea that persists >1 week or Grade 1-2 diarrhea with rectal bleeding (additional 
guidelines for the treatment of persistent colitis are provided below). 
• Grade 2 diarrhea should be treated with the addition of oral diphenoxylate hydrochloride 
and atropine sulfate four times daily and budesonide 9 mg daily. 
• Grade 2 diarrhea with diffuse ulceration and bleeding seen on endoscopy may require 
oral steroids with prolonged taper and represent an increased risk for the development 
of bowel perforation. Consider prophylactic antibiotics for opportunistic infections. 
• When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• In patients with Grade 2 enterocolitis, SAR444245 and cemiplimab should be withheld 
and antidiarrheal treatment should be started. If symptoms are persistent for more than 
one week, systemic corticosteroids should be initiated (eg, 0.5 mg/kg/day of prednisone 
or equivalent). When symptoms improve to Grade 1 or resolve, corticosteroid taper 
should be started and continued over at least 1 month. 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
 
 
Grade 3 
Withholdb OR 
Permanently 
discontinue if clinically 
necessary 
Withholdb 
• Ensure adequate hydration 
For Grade 3 to 4 diarrhea (or Grade 2 diarrhea that persists after initial steroid treatment), 
• Rule out bowel perforation. Imaging with plain films or CT can be useful. 
• Consider consultation with gastroenterologist and confirmation biopsy with endoscopy. 
• Treat with intravenous (IV) steroids (methylprednisolone 125 mg) followed by high-dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 
4 hours). When symptoms improve to Grade 1 or resolve, steroid taper should be 
started and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients 
with diffuse and severe ulceration and/or bleeding. 
• If IV steroids followed by high-dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, consider treatment with infliximab at 5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom relief and initiate a prolonged steroid taper over 
45–60 days. If symptoms worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper 
and administer infliximab. CAUTION: infliximab is contraindicated in patients with bowel 
perforation or sepsisf 
• If symptoms persist despite the above treatment a surgical consult should be obtained. 
• Treatment can only be resumed for Grade 3 event and if event has improved to Grade 
≤1 within 12 weeks and after corticosteroid taper. SAR444245 can then be resumed at 
the dose below the current dose level after discussion between Investigator and 
Sponsor or be permanently discontinued if clinically necessary and cemiplimab can be 
resumed without dose modification.  
• For recurring Grade 3 event or for Grade 4 events, both IMP components should be 
permanently discontinued. 
 
Grade 4 
Permanently 
discontinue 
Permanently discontinue 
 
Hepatitis 
Grade 2 (AST or ALT>3 to 
≤5×ULN 
or total bilirubin >1.5 to 
≤3×ULNe) 
Withholdd 
Withholdd 
• Initial dose of 1-2 mg/kg/day prednisone or equivalent followed by a taper 
• Resume cemiplimab and SAR444245 if hepatitis improves and remain at Grade 0 - 1 
after corticosteroid taper to ≤10 mg/day prednisone or equivalent or return to baseline 
AST or ALT after completion of corticosteroid taper 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
 
Grade ≥3 (AST or ALT 
>5×ULN 
or total bilirubin >3×ULNe) 
Permanently 
discontinue 
Permanently discontinue  • Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, 
if necessary. 
• Treat with high-dose IV glucocorticosteroids for 24 to 48 hours. When symptoms 
improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks. 
• If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is 
not recommended due to its potential for hepatotoxicityf 
• Several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. 
Endocrinopathies 
Grades 2, 3,  
or 4 
Withholdb if clinically 
necessary (no need to 
withhold for Grade 2 
diabetes, Grade 2 
hyperthyroidism, and 
all grades 
hypothyroidism) 
Withholdb if clinically 
necessary (no need to 
withhold for Grade 2 
diabetes or 
hyperthyroidism, and all 
grades hypothyroidism) 
• Consider endocrine consultation. 
• Rule out infection and sepsis with appropriate cultures and imaging as appropriate for 
the management of the event, according the dysfunction observed 
• Replacement of appropriate hormones as required. 
Grade 3-4 hypophysitis with clinically significant adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis; hospitalization and IV methylprednisolone should be initiate 
• In situation when IMP is withheld, restarting of treatment should involve discussion with 
Investigator and Sponsor, and may require the input of specialty clinician. Restarting 
SAR444245 at dose below the current dose level may be considered. Cemiplimab 
should be restarted without dose modification. 
Nephritis 
Grade 1 
Consider 
Withholdingb. May be 
continued with close 
monitoring 
Consider Withholdingb. 
May be continued with 
close monitoring 
• Provide symptomatic treatment. 
• Monitor creatinine weekly; when it returns to baseline, resume routine creatinine 
monitoring per protocol. 
Grade 2 
Withholdb 
Consider Withholdingb. 
May be continued with 
close monitoring 
• Systemic corticosteroids at a dose of 1 to 2 mg/kg/day of prednisone or equivalent may 
be indicated. When symptoms improve to Grade 1 or resolve, corticosteroid taper should 
be started and continued over at least 1 month. 
• Consider prophylactic antibiotics for opportunistic infections. 
• Consider renal biopsy. 
If elevations persist >7 days or worsen, treat as Grade 4. 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
Grade 3 and 4 
Permanently 
discontinue 
Permanently discontinued • Renal consultation with consideration of ultrasound and/or biopsy as appropriate. 
• Monitor creatinine daily. 
• Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent 
once per day. 
• When symptoms improve to Grade 1 or resolve, steroid taper should be started and 
continued over no 
less than 4 weeks. 
Uveitis 
Grade 1 
Withholdb OR 
Permanently 
discontinue if clinically 
necessary 
Withholdb OR 
Permanently discontinue 
if clinically necessary 
• Evaluation by an ophthalmologist is strongly recommended. 
• Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
• Discontinue both SAR444245 and cemiplimab if symptoms persist despite treatment 
with topical immunosuppressive therapy. 
Grade 2 
Permanently 
discontinue 
Withholdb OR 
Permanently discontinue 
if clinically necessary 
• Evaluation by an ophthalmologist is strongly recommended. 
• Treat with topical steroids such as 1% prednisolone acetate suspension and 
iridocyclitics. 
• Discontinue both SAR444245 and cemiplimab if symptoms persist despite treatment 
with topical immunosuppressive therapy and do not improve to Grade 1 within the 
retreatment period OR requires systemic treatment. 
Grade 3 and 4 
Permanently 
discontinue 
Permanently discontinue 
• Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per 
day. When symptoms improve to ≤Grade 1, steroid taper should be started and 
continued over no less than 4 weeks. 
Other immune-
mediated adverse 
reactions involving a 
major organ 
Grade 3 
Withholdb OR 
Permanently 
discontinue if clinically 
necessary 
Withholdb OR 
Permanently discontinue 
if clinically necessary 
• Consider specialty consultation whenever relevant 
• Corticosteroids administration as previously mentioned 
• Please refer to most recent guidelines (43, 44). 
• Grade 3 events that require full permanent discontinuation include, but are not limited to 
Guillain-Barré syndrome, encephalititis, Stevens-Johnson syndrome and toxic epidermal 
necrosis. 
Grade 4 
Permanently 
discontinue 
Permanently discontinue 
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Event 
Severity  
(NCI-CTCAE v 5.0) 
Action with IMP 
IMP dose modification details & Supportive care guidelines 
SAR444245a 
Cemiplimaba 
Recurrent or 
persistent immune-
mediated adverse 
reactions 
Grade 2 or 3 persistent for  
≥12 weeks after last IMP 
dose, recurrent Grade 3 or 
4 events, and events 
requiring 10 mg per day or 
greater prednisone or 
equivalent lasting 
≥12 weeks after last IMP 
dose 
Permanently 
discontinue 
Permanently discontinue Please refer to above mentioned recommendations for the management of the recurring 
event. 
a Information for preparation and storage of SAR444245 and cemiplimab are provided in the pharmacy manual 
b Can be resumed if improvement to Grade ≤1 within 12 weeks and after corticosteroid taper. 
c All patients who experience diarrhea 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. 
d Can be resumed if improvement to Grade ≤1 or baseline within 12 weeks and after corticosteroid taper.  
e Or above baseline. If baseline was abnormal as per NCI-CTCAE v 5.0. 
f 
REMICADE (infliximab) prescribing information. 
Abbreviations: CTCAE=common terminology criteria for adverse events; NCI=National Cancer Institute.
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6.6.4.5 Immune cell-associated neurotoxicity syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome 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 10.15). 
Recommendations for ICANS management mainly include the use steroids, whereas tocilizumab 
should only be used in the context of CRS, as outlined in Table 7. The proposed management 
should be considered only as recommendations and in light of recommendations from site 
specialist. 
Table 7 - Guidelines for the management of immune cell-associated neurotoxicity syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading 
criteria) 
Recommended IMP  
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. 
Withhold SAR444245a and cemiplimaba. 
Initiate treatment with IV corticosteroids as needed.  
SAR444245 and/or cemiplimab may be resumed only after patient recovery 
or improvement to Grade 1 after corticosteroid taper. No modification in 
cemiplimab dose is recommended, and consideration for reduction of 
SAR444245 to the dose below the current dose level 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. 
If Grade 3 ICANS, withhold SAR444245 and cemiplimab. When symptoms 
have resolved or improved to Grade 1 after corticosteroid taper, SAR444245 
can be either restarted at the dose below the current dose level or 
permanently discontinued, as clinically indicated, and upon discussions 
between the Investigator and Sponsor. Treatment with cemiplimab can be 
restarted without dose modification. 
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab and should be handled as described in Table 5. 
Corticosteroids can then be administered IV or orally every 8 hours for up to 
3 days, then tapered over 4 days.  
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Event severity 
(ASTCT Consensus Grading 
criteria) 
Recommended IMP  
dose modification and supportive care guidelines 
Grade 4:  
ICE score: 0 (patient is unarousable and 
unable to perform ICE). 
Patients is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or 
coma. 
Life-threatening prolonged (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as 
hemiparesis or paraparesis. 
Signs of diffuse cerebral edema on 
neuroimaging; decerebrate or decorticate 
posturing; or cranial nerve VI palsy; or 
papilledema; or Cushing’s triad. 
If Grade 4 ICANS, permanently discontinue SAR444245 and cemiplimab.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab and should be handled as described in Table 5. 
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, re-evaluation for 
other contributing conditions should be done. Administration of 
IV tocilizumab at 8 mg/kg (for patients weighing ≥30 kg, total dose should 
not exceed 800 mg) should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant specialties should be involved whenever 
indicated. 
a Information for preparation and storage of SAR444245 and cemiplimab are provided in the pharmacy manual 
Abbreviations: AE=adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS=cytokine release syndrome; 
EEG= electroencephalography; ICE=immune effector cell-associated encephalopathy; IV=intravenous. 
6.6.4.6 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 8. 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 (45). 
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Table 8 - Guidelines for the management of vascular leak syndrome (VLS)  
Event severity 
(NCI-CTCAE v 5.0a) 
Recommended IMP  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention 
indicated 
IMP should be withheld. Upon resolution of VLS or improvement to Grade 1, 
SAR444245b can be resumed at the dose below the current dose level, and 
cemiplimabb can be resumed without dose reduction. 
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, SAR444245 should be permanently discontinued. 
The participant can continue treatment with cemiplimab upon resolution of the 
event or improvement to Grade 1. 
In patients 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 In NCI-CTCAE v 5.0 Vascular leak syndrome referred to as Capillary leak syndrome.  
b Information for preparation and storage of SAR444245 and cemiplimab are provided in the pharmacy manual. 
Abbreviations: AE=adverse event; CTCAE=common terminology criteria for adverse events; IV=intravenous; NCI=National Cancer Institute. 
6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There will be no intervention beyond the end of the study.  
6.8 
TREATMENT OF OVERDOSE  
There is no specific antidote for overdose with SAR444245 or cemiplimab.  
If overdose occurs (see Section 8.3.8 for definition), symptomatic management is indicated.  
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Treatment of overdose should consist of general supportive care with aggressive fluid 
management, if clinically indicated. 
Procedures for treating symptoms and complications of immune-related adverse events are 
provided in Section 6.6.4.4. 
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. 
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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 (including both radiological PD and clinical PD).  
-
Clinical Stability is defined 
as:1) Absence of symptoms and signs indicating clinically significant progression 
of disease (including worsening of laboratory values) indicating disease 
progression. 2) No decline in ECOG performance status. 3) Absence of rapid 
progression of disease or progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention. 
- 
Poor compliance to the study protocol. 
- 
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. 
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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 Table 6, or if the 
Investigator believes that it is in best interest of the participant.  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
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 6.6.4 (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 (Appendix 13 Section 10.13: Contingency Measures for a regional or 
national emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
e-CRF.  
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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 Appendix 13: Contingency Measures for a regional or national emergency 
(Section 10.13) that is declared by a governmental agency.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the treatment, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. 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 
e-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 been withdrawn from the study treatment cannot be re-included in the 
study. Their inclusion and intervention numbers must not be reused.  
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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions 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). 
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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 10.13. 
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 using 
 may be done at the discretion of the Investigator when clinically indicated. 
Please refer to Section 7.1.1 for details on documented disease progression. 
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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. Images (scans and/or 
medical photographs) and pathological reports when relevant for confirmation of CR or 
characterization of a new skin lesion in locally advanced CSCC will be prospectively collected for 
potential retrospective central analysis; the prospective collection of these materials can be 
cancelled at any time. 
Assessment of tumor response will be conducted using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 criteria, modified WHO criteria, or composite response criteria 
(see Section 10.8 and 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 can be measured radiologically according to RECIST 1.1 criteria 
(Section 10.8), a CT or MRI for tumor assessment will be performed as detailed in Section 1.3. 
The choice of whether the imaging is by CT or MRI is an investigator decision, but preferred 
imaging choices are provided in below. Once the choice of CT scan or MRI has been made, 
subsequent assessments should be made using the same modality. For participants whose CSCC 
lesions are evaluable on the skin, composite response criteria (Section 10.9) should be used on the 
same schedule, in combination with radiologic imaging if appropriate. Brain MRI is required at 
screening if not performed in the prior 60 days. For participants with CSCC, baseline brain 
imaging is only indicated in the presence of clinical suspicion of brain metastases. Brain scans 
during the treatment and follow-up periods are required if there is a prior history of lesions present 
at screening or as clinically indicated. A brain CT may be performed if an MRI is contraindicated. 
• For Cohort A and Cohort B Participants with metastatic disease: Baseline imaging 
should include all known target lesions. Baseline scans must evaluate extent of disease, 
including imaging of chest, abdomen, and pelvis. This may be accomplished with CT 
chest, abdomen, and pelvis with contrast, or CT chest with contrast and MRI 
abdomen/pelvis with gadolinium. The imaging modality for metastatic lesions may be 
either CT with iodinated contrast or MRI with gadolinium, per investigator discretion. 
Magnetic resonance imaging with gadolinium is generally preferred for bone lesions, 
perineural lesions, abdomen, pelvis, extremity, and head and neck. Computed tomography 
with contrast is generally preferred for chest. For participants who also have externally 
visible lesions, digital medical photography will be used, and these lesions generally will 
be followed as non-target lesions. Whole-body imaging, as performed at the baseline 
assessment, is strongly recommended at each response assessment. 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. Additionally, radiologic imaging of anatomic area of externally visible target 
lesions should be performed at baseline and at each response assessment (MRI with 
gadolinium is preferred for all anatomic sites except lung). Externally visible CSCC 
lesions noted at baseline should be photographed at each response assessment  
(Section 10.12) and will generally be deemed non-target. New externally visible lesions 
that are clinically suspicious for malignancy should be photographed (Section 10.12) and 
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biopsied. Note: In participants with metastatic disease that is not measurable by RECIST 
criteria (eg, bone only lesions, perineural disease) and with externally visible CSCC target 
lesions, digital medical photography may be used to follow the externally visible lesions as 
target lesions. Brain scans during the treatment and follow-up periods are required if there 
is a prior history of lesions present at screening or as clinically indicated. A brain CT may 
be performed if an MRI is contraindicated. 
• For CSCC participants with locally advanced skin lesions and skin metastases: 
Externally visible lesions will be followed by digital medical photography. Baseline 
assessments will include radiologic imaging of all target lesions (preferably MRI with 
gadolinium for all anatomic sites except lung, but CT with iodinated contrast allowed at 
any anatomic site, per investigator discretion) to assess for deep invasion. All externally 
visible CSCC lesions should be photographed in a consistent manner at each response 
assessment as described in Section 10.12. Radiologic imaging (MRI with gadolinium 
preferred) of anatomic area of externally visible target lesions should be performed at each 
response assessment. In cases in which it is the opinion of the Investigator that no 
significant added information was provided by anyone of the radiologic imaging or digital 
medical photography modality, it is allowed to use either one of these at subsequent 
response assessments of that lesion, at the discretion of the Investigator. 
For participants with non-skin metastatic disease, participants will generally be followed by 
RECIST 1.1 criteria (Section 10.8). It is possible that some of these participants may also have 
externally visible lesions that are measurable by digital medical photography. Generally, it will be 
clinically appropriate to follow these externally visible lesions as non-targets. However, for these 
participants with externally visible lesions that are deemed clinically significant by the 
investigator, the clinical and composite response criteria in Section 10.9 may be used in selected 
cases. However, it is anticipated that most participants with metastatic disease will be followed by 
RECIST 1.1 only. 
For participants with locally advanced skin lesions and skin metastasis, response assessment is 
according to the clinical and composite response criteria in Section 10.9. For externally visible 
lesions that are indeterminate appearing regarding presence of CSCC, see Section 10.11 for 
guidelines on tumor biopsies. 
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All radiology, photography and biopsy reports will be collected centrally for potential 
independent central review to determine overall response for each participant based on the 
integration of these modalities. 
8.2 
SAFETY ASSESSMENTS  
The main anticipated adverse effect for the combination of SAR444245 with cemiplimab 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 cemiplimab may increase the frequency and severity of immune-related adverse 
events related to cemiplimab. 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 and LVEF 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. 
• 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 cytokine release syndrome 
should also prompt a thorough clinical assessment to identify the involvement of a specific 
organ system, including neurological system. 
8.2.2 Vital signs  
• Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be 
measured after 5 minutes rest. 
• 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). 
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• Vital signs should be taken pre-dose as per SoA and repeated as clinically indicated at 
Investigator’s discretion during and after study medication administration. 
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;  
- 
For the participants of dose escalation 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 in an inpatient setting.  
- 
For other participants, 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 dose escalation) may have intensive vital sign 
monitoring.  
• From Cycle 2 and beyond study therapy will be administered for all patients in out-patient 
clinic with vital signs taken at baseline, 4 to 6 hours post-dose, or as clinically indicated. 
8.2.3 Electrocardiograms and LVEF  
• Includes single 12-lead ECG and LVEF that will be performed at screening and then, as 
clinically indicated. 
• Triplicate 12-lead ECG will be obtained when indicated, for instance to further document 
a QTc prolongation, using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  
• Each time a triplicate ECG is required, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
• 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. 
• During treatment, or post treatment follow-up: 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 
to 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 significant changes occurring during the study. The laboratory reports must be 
filed with the source documents. Abnormal laboratory findings associated with the 
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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 assessments, 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 assessments 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 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 
7 days prior to first IMP administration of each cycle, at EOT and every 30 (±7) days until 
180 days 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. 
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). 
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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 last administration of study treatment.  
All SAEs and AESIs will be collected throughout 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) 
(See instructions specific for participants in Germany in Appendix 7, Section 10.7). The 
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 
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 a 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 
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relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB for SAR444245 and SmPC for Libtayo [cemiplimab]). 
- 
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 a 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 180 days 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. 
• 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. 
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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  
- 
Infusion of IMP: 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.  
• An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, 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 
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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  
No PK parameters will be assessed, as only sparse sampling for pharmacokinetic concentrations 
of SAR444245 and cemiplimab is implemented in the study. 
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. 
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 or cemiplimab 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. 
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8.5 
PHARMACODYNAMICS  
Refer to Section 8.7 for details of pharmacodynamics biomarker.  
8.6 
GENETICS AND/OR PHARMACOGENOMICS  
8.7 
BIOMARKERS  
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8.8 
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 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. 
8.9 
HEALTH ECONOMICS  
No health economics data will be collected. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The two independent cohorts of the study are designed to obtain antitumor activity, safety 
pharmacokinetic (PK) and pharmacodynamic (PDy) data on SAR444245 administered in 
combination with cemiplimab to participants with advanced unresectable or metastatic skin 
cancers. 
The study is designed to assess clinical benefit of SAR444245 when combined with cemiplimab 
in the two indications of interest. 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 going to be considered. 
9.2 
SAMPLE SIZE DETERMINATION  
The study will start with a dose escalation to determine the RP2D of SAR444245 when combined 
with cemiplimab. 
The plan is to treat approximately 40 participants in Cohort A and 40 participants in Cohort B at 
the RP2D. 
Table 9 lists estimated ORR and the corresponding 90% exact CIs by number of responders from 
a sample size of 40 participants exposed in Cohort A and in Cohort B. 
Table 9 - Cohort A and B: Estimated objective response rate (ORR) depending on number of 
responders  
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
18 
45.0% (31.5% - 59.1%) 
20 
50.0% (36.1% - 63.9%) 
22 
55.0% (40.9% - 68.5%) 
24 
60.0% (45.8% - 73.1%) 
26 
65.0% (50.8% - 77.5%) 
CI: confidence interval 
For each Cohort A and Cohort B individually, with a sample size of 40 study participants, 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. 
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9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 10): 
Table 10 - 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 cemiplimab). 
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. 
DLT-evaluable 
DLT-evaluable population will include all participants in the dose escalation who have been 
treated and observed for at least 21 days. Any participants who have experienced a DLT during 
DLT observation period will also be DLT-evaluable. 
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 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% confidence interval (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 and by 
dose (as applicable). Objective response rate, as well as PFS, DOR, and CBR will be derived 
using the local radiologist’s/Investigator’s assessment for both cohorts. 
All safety analyses will be performed on the exposed population by cohort, by dose (if applicable) 
and overall (if applicable). The 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. 
• The post-treatment period is defined as the time from the 31 days after the last 
administration of IMP. 
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9.4.2 Primary endpoint(s)  
9.4.2.1 Objective response rate  
The primary endpoint is the ORR. Central imaging may be done retrospectively if significant 
activity is observed. 
For Cohort A (melanoma), the ORR is defined as the proportion of participants who have a 
confirmed CR or PR determined by Investigator per RECIST 1.1. 
For Cohort B (CSCC), the ORR is defined as the proportion of participants who have a 
confirmed CR or PR determined by Investigator per RECIST 1.1, or modified WHO criteria for 
medical photographs of external skin lesions, or composite criteria.  
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 ORR and the BOR will be summarized with descriptive statistics. In addition, two-sided 
90% CIs will be computed using the Clopper-Pearson method. 
9.4.3 Secondary endpoint(s)  
The secondary endpoints include safety, efficacy (CRR, DOR, CBR, PFS per RECIST 1.1 or 
modified WHO criteria, or composite criteria when relevant), immunogenicity, and PK. 
9.4.3.1 Complete response rate  
For Cohort A (melanoma), CRR is defined as the proportion of participants from the analysis 
population who have a confirmed CR determined by Investigator per RECIST 1.1. 
For Cohort B (CSCC), CRR is defined as the proportion of participants from the analysis 
population who have a confirmed CR determined by Investigator per RECIST 1.1, or modified 
WHO criteria for photographs of external skin lesions, or composite criteria.  
9.4.3.2 Time to complete response  
Time to CR will be assessed on the subgroup of participants who achieved confirmed CR for 
melanoma participants and when applicable for CSCC participants. 
Time to CR 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 CR that is subsequently confirmed and 
determined by Investigator per RECIST 1.1 or modified WHO criteria for medical photographs, 
or composite criteria, whichever relevant. 
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9.4.3.3 Time to response  
Time to Response will be assessed on the subgroup of participants who have achieved confirmed 
objective 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 and determined by Investigator per RECIST1.1 or modified WHO criteria 
for medical photographs, or composite criteria, whichever relevant. 
9.4.3.4 Duration of response  
The DOR will only be summarized on the subgroup of participants who have achieved confirmed 
objective response.  
The DOR will be defined as the time from the first tumor assessment at which the overall 
response was recorded as CR or PR that is subsequently confirmed to the date of first 
documentation of objective PD determined by Investigator per RECIST 1.1 or modified WHO 
Criteria for medical photographs or composite criteria when relevant before the initiation of any 
post-treatment anti-cancer therapy or death due to any cause, whichever occurs first. 
In the absence of disease progression or death before the cut-off date, DOR will be censored at the 
date of the last valid tumor assessment performed before the cut-off date or date of initiation of 
new anti-cancer therapy, whichever is earlier. Duration of response will be summarized by cohort 
with descriptive statistics using Kaplan-Meier methods. The median DOR and associated 90% CI 
will be provided. 
9.4.3.5 Clinical benefit rate   
The CBR is defined as the proportion of participants with clinical benefit (confirmed CR or PR as 
BOR, or SD lasting at least 6 months, determined by Investigator per RECIST 1.1 or modified 
WHO Criteria for medical photographs or composite criteria, whichever relevant). For 
participants with measurable disease at baseline, they will be considered as clinical benefit 
responders if they achieve a CR or PR as BOR, or SD with an overall 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). 
9.4.3.6 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 determined by Investigator per RECIST 1.1 
or modified WHO Criteria for medical photographs when relevant, or death due to any cause, 
whichever occurs first.  
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The analysis of PFS will be based on the following censoring rules: 
• If progression or death is not observed before the cut-off date and prior to the initiation of 
a further anti-cancer therapy, then PFS will be censored at the date of the last valid tumor 
assessment performed before the cut-off date or date of initiation of a further anti-cancer 
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 using Kaplan-Meier methods. The median PFS times 
and associated 90% CI will be provided. 
9.4.3.7 Adverse events  
All AEs will be classified by SOC and Preferred Term (PT) according to the latest available 
version of the medical dictionary for regulatory activities (MedDRA) and will all be categorized 
according to NCI-CTCAE v 5.0, except for CRS and ICANs events, for which severity will be 
categorized using ASTCT Consensus Grading. 
• 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 
experiencing 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). 
• Serious TEAEs. 
• Serious treatment-related TEAEs (for each individual drug). 
• TEAE leading to permanent partial intervention discontinuation (for each individual drug). 
• TEAE leading to full intervention discontinuation. 
• Treatment-related TEAEs (for each individual drug). 
• Treatment-related TEAEs of Grade ≥3 (for each individual drug). 
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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) for the exposed population. 
Missing grades, if any, will be included in the “all grades” category. Similar summaries will be 
prepared for TEAEs related to SAR444245 and those related to cemiplimab, TEAEs leading to 
permanent 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, 
post-treatment) 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. 
9.4.3.8 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. These analyses will be performed 
using local measurements for laboratory variables.  
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 for the exposed 
population.  
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.   
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9.4.3.9 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).  
Concentrations of each cohort by SAR444245 and cemiplimab will be summarized with 
descriptive statistics. 
9.4.4 Tertiary/exploratory endpoint(s)  
9.4.4.1 Exploratory antitumor indicators  
9.4.4.2 Biomarker endpoints  
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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 
variables (raw data and changes from baseline) will be calculated for baseline, last on treatment 
value and/or worst value.  
9.4.6 Other analyse(s)  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.13. 
9.5 
INTERIM ANALYSES  
No formal interim analyses are planned. However, at the end of the dose escalation, the 
occurrence of DLT and other safety data will be reviewed by SB to determine the RP2D.  
After the dose is confirmed by the SB, the cumulative safety data for each study intervention 
across cohorts will be reviewed periodically by the DMC. The enrollment will not be paused or 
stopped during the safety monitoring unless severe safety concern arises. DMC will review safety 
data periodically. Ad hoc DMC meetings may also be held if a significant safety issue or an issue 
deemed important for discussion arises on this or other SAR444245 studies. The DMC procedures 
will be detailed in the DMC charter and approved by the DMC members. 
In addition, for each cohort, in order to support project strategic planning and design of future 
studies, informal interim analysis(es) may be conducted during the study, eg, after 20 participants 
have undergone at least two post-baseline tumor assessment or have discontinued study treatment, 
whichever is earlier.  
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).  
After the cohort cut-off date for the primary ORR analysis, participants can continue to receive 
IMP, if clinical benefit is observed, until full permanent discontinuation criteria described in 
Section 7 are met and will continue to undergo all assessments as per the study schedule of 
activities. 
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). 
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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.  
• 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 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.  
- 
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. 
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- 
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. 
• 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. 
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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 13: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
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 they 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. 
• 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.  
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• 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, 
- 
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. 
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• 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 phamaceutical 
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 Committee structure  
Data Monitoring Committee 
Independent from the Sponsor and Investigators, the DMC role will 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, 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. 
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.  
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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. 
• 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. 
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• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the e-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 for 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 
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). If there is a decision of the 
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Sponsor to pause recruitment in a cohort to allow decision making, then the Investigator should 
pause all screening activities until further notice. 
If the cohort/study is early terminated the patients who are receiving and benefitting from study 
treatment as per Investigator judgment may continue study treatment 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 11 will be performed by local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 11 - 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 chemistryb 
Urea or blood urea nitrogen (BUN) 
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Laboratory 
assessments 
Parameters 
 
Creatinine and eGFR (MDRD formulac) 
 
Glucose  
 
Potassium 
 
Sodium 
 
Calcium 
 
Phosphate 
 
Chloride 
 
Magnesium 
 
Bicarbonated 
 
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 
Endocrine function testse 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
Coagulation  
International normalized ratio (INR) or Prothrombin Time (PT) (or Activated Partial 
Thromboplastin Time [aPTT]) 
Routine urinalysis 
Specific gravity, pH, glucose, protein, blood, ketones, and leukocytes by dipstick 
Microscopic examination (if blood or protein is abnormal) 
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)f  
• 
Serology (hepatitis B surface antigen [HBsAg], hepatitis C virus antibody), Hepatitis B 
viral load, HCV RNA level, CD4 counts & HIV viral Loadg 
• 
Troponin 
• 
The results of each test must be entered into the e-CRF. 
NOTES: 
a Hematology will be performed every cycle up to Cycle 12, then every other cycle during Treatment Period, except for WBC with differential 
that is to be done on D1 pre-dose, D2, D3, D8 and D15 during Cycle 1. If Grade 4 neutropenia, assess ANC every 2-3 days until  
ANC ≥0.5 x 109/L. During the Observation Period, hematology will be performed at Follow-Up Visit 1. 
b Blood Chemistry should be done with an overnight fasting if possible, (should not interfere with hydration requirements). It will be performed 
weekly on D1 pre-dose, D2, D8 and D15 during Cycle 1, then every cycle up to Cycle 12, then every other cycle during Treatment Phase. For 
participants in the dose escalation part, it will be also performed at D3. 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. 
c 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). 
d 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) 
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e Endocrine function tests will be performed every 2 cycles until Cycle 12 (ie, Cycles 2, 4, 6, 8, 10 and 12). During the Observation Period, they 
will be performed at Follow-Up Visit 1. They can also be performed as clinically indicated. 
f 
Pregnancy Test: Women of childbearing potential must have a negative urine pregnancy test result within 7 days prior to IMP administration 
of each cycle, at EOT and every 30 (±7) days until 180 days 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. 
g Participants with known HIV infection under antiretroviral treatment should have HIV viral load & CD4+ count done at baseline 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 serology at screening will only be tested in any countries 
where mandatory as per local requirements. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: 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. 
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. 
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• "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. 
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. 
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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. 
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. 
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• 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. 
• 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 v 5.0 definitions: 
• 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 should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to study treatment SAR444245, cemiplimab or 
the combination.    
• 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. 
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• 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. 
• 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 completed e-CRF. 
• 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’s representative 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 (refer to Section 10.7 for 
country-specific requirements for Germany). 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
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• 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. 
SAE reporting to the Sponsor’s representative via paper CRF 
• Facsimile transmission of the SAE paper CRF 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 CRF pages 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: 
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• 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. 
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 up to 
180 days and sperm up to 210 days (see inclusion criteria). 
 
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. 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
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. 
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. 
• 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.  
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• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
10.5 
APPENDIX 5: GENETICS  
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
France  
In France, the eligibility of patients to take part in the study is to be validated at the 
Multidisciplinary Collegial Meeting. 
In France participants with BRAF-mutant melanoma will not be included in Cohort A (See 
Inclusion criterion I02, Section 5.1). 
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Ireland 
In Ireland Cohort A will not be open to enrollment (See Inclusion criterion I02, Section 5.1). 
Germany  
For the sites in Germany, the Investigator must inform the Sponsor in case of a SAE/AESI 
immediately, after becoming aware without undue delay (see Section 8.3.1). 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1  
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.  
Confirmatory scans should also be obtained at least 4 weeks following initial documentation of 
objective response. 
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 
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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 
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. 
• 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 closely 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. 
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• 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. 
• 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. 
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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). 
• 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) 
 
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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 
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; NE = inevaluable; PD = Progressive disease; PR = Partial response; SD = Stable disease. 
a In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
10.9 
APPENDIX 9: 
 
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10.9.1 Response and stable disease duration (RECIST 1.1 and
)  
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). 
10.9.2 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." 
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. 
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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. 
10.10 APPENDIX 10: WHO CRITERIA FOR DIGITAL MEDICAL PHOTOGRAPHS AND 
COMPOSITE RESPONSE CRITERIA FOR PARTICIPANTS WITH LOCALLY 
ADVANCED CSCC  
This appendix describes clinical response criteria for externally visible lesions that can be 
measured bi-dimensionally using digital medical photography. This appendix also provides 
composite response criteria for disease that is measurable by both clinical response criteria and 
RECIST 1.1.  
Participants will be followed by digital medical photography and will also undergo radiologic 
imaging (typically, MRI with gadolinium) at baseline, and this will also be performed serially at 
each response assessment unless the investigator deems that baseline radiologic imaging was 
uninformative. Radiologic imaging (preferably, MRI with gadolinium) will be essential in the 
evaluation of tumors that have subdermal components that cannot be adequately assessed by 
digital medical photography. See protocol Section 8 for further information on imaging 
requirements. 
Response assessments occur every 9 weeks up to Week 45, and every 12 weeks thereafter. 
Standardized digital photographs of the externally visible component of all target lesions must be 
obtained at baseline and at the time of each subsequent tumor assessment. Guidelines for digital 
medical photography are provided in Appendix 12 (Section 10.12). Investigators will also provide 
a clinical description of the externally visible target lesion(s) at baseline and at each tumor 
assessment, as well as comments on any changes in the lesion(s) since the previous assessment. 
SPECIAL ISSUES FOR EXTERNALLY VISIBLE TUMORS: 
1) Anatomic Defects 
Regarding tumor around a surgical cavity/anatomic defect (eg, rhinectomey), such lesions should 
be considered non-measurable unless there is a nodular lesion measuring ≥10 mm in maximal 
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bi-dimensional perpendicular diameters. The surgical cavity or anatomic defect should not be 
considered in measuring the lesion. 
2) Indeterminate-Appearing Tissue 
If there is uncertainty about whether a given lesion or area of a lesion represents malignancy 
versus benign process (eg, scarring, fibrosis), biopsies should be obtained. Indeterminate-
appearing areas (eg, scarring, fibrosis) are included in the tumor measurements unless biopsies are 
obtained to establish benign status. 
To reduce risk of sample error, biopsy of only a single area on the tumor is not allowed. Biopsy of 
at least two separate areas of the lesion are required when biopsy is indicated. Each biopsy will be 
performed in a pairwise manner (approximately adjacent) so that there will be one sample for 
local review and one for central review for each biopsy, as per Appendix 11 (Section 10.11). 
As such, when the decision is made to perform biopsy, at least 4 biopsy samples are obtained 
(biopsy of two separate areas, with two biopsies in each area: one for central review, one for local 
review from each area). Biopsy samples will not be bisected or split in half for local and central 
review; rather, separate adjacent samples will be obtained. See Appendix 11 for biopsy details. 
Note on timeline for finalization of measurement/response assessment: Generally, baseline 
disease measurements and response assessments should be completed on the day of the visit at 
which digital medical photography was performed. However, for visits in which tumor biopsies 
are performed, it is understood that the local pathology report may not be available for up to 
5 business days after the biopsy. 
When biopsies are performed to distinguish between benign versus malignant tissue, the 
annotated photograph for that visit should clearly indicate the region of the tumor that was 
biopsied to distinguish benign versus malignant tissue. Within one week of the date of biopsies, 
the investigator should finalize the tumor measurements for that visit with the benefit of the local 
pathology report. 
For circumstances in which the intent of the biopsy is to distinguish between disease stability and 
response, it is not necessary to hold study treatment while the local pathology report is pending. 
For circumstances in which the biopsy, if positive, would result in discontinuation of study 
treatment due to progression, treatment should be held until biopsy results are finalized and 
progression has been ruled out. 
3) Local Versus Central Review 
De-identified digital medical photography results, biopsy results (Cohort B) as well as scans when 
relevant (Cohort A & B) will be collected prospectively for potential central review to provide 
response assessments as required by the Sponsor to address study objectives (Section 3). The 
prospective collection of these materials may be cancelled by the Sponsor at any time during the 
study. Clinical management decisions will be as per Investigator response assessments and local 
pathology review.  
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4) Confirmation of Responses 
After any objective response, confirmatory digital photography (and radiologic imaging, if 
performed as part of the initial response assessment) will be obtained at least 4 weeks following 
initial documentation of objective response. Confirmatory biopsies are not required for partial 
response. 
5) Participants with Externally Visible Tumors 
Participants with metastatic CSCC will generally be followed by RECIST 1.1 criteria 
(Appendix 8). It is possible that some patients may also have externally visible lesions that are 
measurable by digital medical photography. In such circumstances, the externally visible lesions 
generally will be followed as non-target lesions. The exception to this rule would be a patient with 
externally visible lesions in whom the only M1 lesions are not measurable by RECIST 
(eg, a patient with bone-only metastases), in which case the externally visible lesions (lesion 
size ≥10 mm in baseline dimensional perpendicular axes) would be target lesions and followed as 
per clinical response criteria in this appendix, and the non-measurable metastatic lesions (eg, bone 
metastases) would be followed as non-target lesions. 
Clinical Response Criteria for Externally Visible Tumors (for all patients with locally 
advanced CSCC) 
Externally Visible Tumor Dimension 
The externally visible component of target lesion(s) will be measured using bi-dimensional WHO 
criteria as the sum of the products (of individual target lesions) in the longest dimension and 
perpendicular second longest dimension - at each tumor assessment and will be documented using 
standardized digital photography (Appendix 12). In the absence of substantial change in lesion 
geometry, subsequent visit measurements should be performed in the same axes and the 
investigator should refer to the previous visit’s annotated photographs as a starting point to 
identify axis for measurement when making subsequent assessments. 
Clinical response criteria for externally visible tumor(s) require bidimensional measurements 
according to WHO criteria and are as follows: 
• Complete response of externally visible disease (vCR): all target lesion(s) no longer 
visible, maintained for at least 4 weeks. Documentation of vCR requires confirmation by 
biopsy of site(s) of externally visible target lesion(s) with histologic confirmation of no 
residual malignancy. In the absence of such histologic confirmation, a patient cannot be 
deemed to have experienced vCR and the best response would be partial response. Note 
that in the study, a biopsy for confirmation of CR is not mandatory but highly 
recommended.  
• Partial response of externally visible disease (vPR): decrease of 50% (WHO criteria) or 
greater in the sum the products of perpendicular longest dimensions of target lesion(s), 
maintained for at least 4 weeks 
• Stable externally visible disease (vSD): not meeting criteria for vCR, vPR, or progressive 
disease 
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• Progression of visible disease (vPD): increase of ≥25% (WHO criteria) in the sum of the 
products of perpendicular longest dimensions of target lesion(s) 
New Lesions 
A new cutaneous lesion consistent with CSCC will be considered as cPD if the lesion is ≥10 mm 
in both maximal perpendicular diameters and can be clearly documented as not being previously 
present, unless it is confirmed on biopsy not to be consistent with CSCC. If a new cutaneous 
lesion is not biopsied or if the histology is inconclusive, it should be considered CSCC and 
deemed cPD. 
Overall Clinical Responses For All Possible Combinations of Clinical Tumor Responses For Locally 
Advanced CSCC 
Externally Visible Tumor Dimensiona 
New Lesionsa 
Clinical Response 
vCR 
No 
cCRb 
vPR 
No 
cPRc 
vSD 
No 
cSDd 
vPD 
Yes or No 
cPDe 
Any 
Yes 
cPD 
a See above for definitions 
b Clinical Complete Response 
c Clinical Partial Response 
d Clinical Stable Disease 
e Clinical Progression of Disease 
Composite Response Criteria: For patients who have disease that is measurable by BOTH 
clinical response criteria by digital medical photography and RECIST 1.1 using radiologic 
imaging. 
 
Clinical Response  
(Digital Medical Photography) 
RECIST 1.1 Response 
(Radiology) 
Composite (Overall): 
Clinical + RECIST Response 
cCR 
CR 
cCR 
cCR 
PR or SD 
PR 
cPR 
CR, PR, or SD 
PR 
cSD 
CR or PR 
PR 
SD 
SD 
SD 
PD 
Any 
PD 
Any 
PD 
PD 
In addition, if all previously inoperable target lesions are rendered operable with clear margins 
obtained at the time of surgery, this will be considered a PR. If the investigator deems a 
previously unresectable lesion to be potentially resectable due to response to SAR444245 and/or 
cemiplimab, the Sponsor should be consulted prior to any surgical procedure being performed. A 
decision will be rendered by the Sponsor as to whether the planned surgical intervention is 
compatible with study requirements. (This statement does not apply to patients in emergency 
life-threatening situations that require immediate surgery). 
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10.11 APPENDIX 11: GUIDELINES FOR BIOPSIES OF LOCALLY ADVANCED CSCC FOR 
ASSESSMENT OF OBJECTIVE RESPONSE OR FOR INDETERMINATE-APPARENT 
LESIONS  
This appendix provides guidance for biopsies in patients with locally advanced CSCC. Because of 
the potential for sampling error with any single biopsy, two separate sites (preferably on the same 
target lesion) should be biopsied for any biopsy assessment. 
Note that biopsies for biomarkers and pharmacodynamic exploratory purposes are addressed in 
the Laboratory Manual. 
Timepoints: 
• Baseline or at any scheduled response assessment (not mandatory, will be performed if 
needed to differentiate benign versus malignant area of skin): 
Areas of indeterminate-appearing tissue should be biopsied to distinguish malignant tissue 
versus benign process (eg, scarring, fibrosis). In circumstances in which biopsies are planned, 
it is preferred that these be performed on the day of a regularly-scheduled response 
assessment. 
• At clinical complete response (not mandatory): Complete response status for externally 
visible lesions requires biopsies of 2 sites on the same lesion which are histologically 
negative for malignancy. 
Research procedures for ALL biopsies: 
1. Where and How: 
The technique and sites of biopsies will be selected by the investigator based on the sizes 
and locations of lesions. Generally, biopsies will be 3 to 5 mm punches. Biopsies should 
not be taken at the perimeter of a lesion because this could interfere with measurement of 
bi-dimensional perpendicular diameters for response assessments. Whenever possible, 
biopsy sites should be ≥5 mm from the edge of baseline lesional area. 
For indeterminate-appearing tissue: Biopsies should be taken at baseline and at any 
response assessment if there is tissue that is indeterminate-appearing regarding presence of 
benign versus malignant tissue. When the decision is made to biopsy a lesion (or an area 
of a lesion) to clarify benign versus malignant status, it is recommended to obtain 
2 biopsies from 2 sites (1 from each site), to be sent for local pathology review). Pathology 
reports will be sent for central review.  
2. Annotation and Photography 
The punch biopsies should be labeled (annotated) on the patient and photographed, such 
that on review of the photograph the following information is clear for each biopsy site: 
the study week and day of the biopsy (eg, Baseline, when relevant for distinguishing 
benign from malignant or Cycle X, Day Y), the identifying number of the biopsy (because 
at least 2 sites would be biopsied), and which samples are for central review and which 
samples are for local review. The tumor will also be annotated with a skin pen to indicate 
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the tumor perimeter and delimiters of the longest bi-dimensional perpendicular axes. All 
biopsies will be photographed and annotated. 
Annotated photographs must be uploaded into the secured system indicated by the Sponsor 
(see Appendix 12 [Section 10.12]). 
For each site that is biopsied to clarify indeterminate tissue, the entire block for one biopsy 
sample (designated for central) must be submitted to the vendor as per the Central 
Laboratory Manual. Because each biopsy site is sampled twice (closely adjacent samples) 
when there is indeterminate-appearing tissue, the second sample may be used for local 
pathology review. If only 1 adequate (eg, interpretable by pathologist) sample is obtained 
at a biopsy site, it will be provided to the Sponsor for potential central review to address 
the study objectives. 
3. Classification of Pathology Samples  
For response assessments in which biopsies were performed, pathology results guide the 
determination of the area of invasive CSCC versus benign tissue. Residual squamous 
carcinoma in situ will not be deemed to be invasive cancer. A minute focus of residual 
CSCC in an otherwise benign responding biopsy sample will not automatically supersede 
a determination of partial response. However, the best response that can be recorded if the 
pathology report demonstrates any residual CSCC is partial response (not complete 
response). 
10.12 APPENDIX 12: MEDICAL PHOTOGRAPHS PROCEDURES  
Image Capture 
• Close-up view with millimeter scale of the target area of the CSCC 
• Global view of the target CSCC area 
The supplied equipment is to be used exclusively for this study. Details are included in the 
photography manual. All supplied photographic equipment remains the property of the Sponsor. 
10.13 APPENDIX 13: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNAMENTAL 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. 
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. 
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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). 
10.13.1 
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). 
10.13.2 
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, digital medical 
photographs, 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 
10.13.3 
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.  
10.13.4 
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 
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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. 
10.14 APPENDIX 14: RISK ASSESSMENT  
The information shown in Table 12 reflects the clinical safety data currently available in 
SAR444245 IB. For cemiplimab, the information below is per currently available USPI and EU 
SmPC. Please always refer to the latest version of the SAR444245 IB and cemiplimab local label 
for the most up-to-date safety data. 
Table 12 - Risk assessment  
Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Infusion-related 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 
SAR444245 IB. 
Cemiplimab 
Common. The most common symptoms of infusion-
related reaction were nausea, pyrexia, vomiting, 
abdominal pain, chills, and flushing. 
SAR444245 
Standard pre-medication 
Dose modification and treatment 
guidelines for SAR444245 infusion-
related reactions are provided in 
Table 4. 
Cemiplimab 
Treatment guidelines for cemiplimab 
infusion-related reactions are provided 
in Table 4. 
Hypersensitivity, 
including anaphylaxis 
SAR444245 
Not observed in non-clinical toxicology studies. 
No reports of anaphylaxis in the HAMMER study to 
date. 
Cemiplimab 
Not reported. 
Exclusion of participants with known 
hypersensitivity or contraindication for 
the use of any component of 
SAR444245, PEG, pegylated drugs or 
cemiplimab 
 
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. 
Cemiplimab 
The most common Grade 3-4 infections (≥2%) were 
cellulitis, sepsis, pneumonia, skin infection, urinary tract 
infection. 
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. 
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 high grade CRS as detailed in the SAR444245 
IB. 
 
Study to be conducted at sites 
experienced with CRS management, 
with bed available in ICU. 
Premedication with paracetamol, 
diphenhydramine, ondansetron 
(or equivalent medications). 
Hydration guidelines, including 
management of anti-hypertensive 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Cemiplimab 
Not specifically reported. 
treatment around the time of infusion, 
are provided. 
Extensive post-dosing monitoring will 
be performed.  
Dose modification and treatment 
guidelines for CRS are provided in 
Table 5. 
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 for VLS are provided in 
Table 8. 
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. 
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 Section 6.6.3). 
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. 
Cemiplimab 
Increase in liver enzymes is common. Grade 3-4 
increased AST, INR and hypoalbuminemia were 
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 provided under immune-related 
reactions in Table 6. 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
reported in 3%, 2%, and 1% of participants in clinical 
trials, respectively.  
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. 
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. 
Cemiplimab 
Nephritis is uncommon (under immune-related 
reactions). 
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 
provided under immune-related 
reactions in Table 6. 
 
Neurological AEs, 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 μg/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 mins after treatment with 
tocilizumab and steroid. This patient later discontinued 
the study. 
Cemiplimab 
Described under immune-mediated adverse events. 
US label: meningitis, encephalitis, myelitis and 
demyelination, myasthenic syndrome/myasthenia 
gravis, Guillain-Barre syndrome, nerve paresis, 
autoimmune neuropathy.  
Uncommon in the EU SmPC: meningitis (Grade 4), 
paraneoplastic encephalomyelitis (Grade 5), Guillain-
Barre syndrome, central nervous system inflammation, 
chronic inflammatory demyelinating 
polyradiculoneuropathy, encephalitis, myasthenia 
gravis, neuropathy peripheral. 
Exclusion of participants with: 
active brain metastases or 
leptomeningeal metastases. See E 06 
for details. 
 
Guidelines for the management of 
ICANS are provided in Table 7. 
 
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 
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. See E 13 for details. 
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Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
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 IB. 
Cemiplimab 
Uncommon: myocarditis (including autoimmune 
myocarditis), pericarditis. Vasculitides also reported. 
ECG, LVEF, and vital sign monitoring 
and coagulation tests performed at 
screening and thereafter as clinically 
indicated.  
Blood pressure and vital signs 
monitored closely during the 24-hour 
hospitalization for C1 and C2. For 
subsequent cycles, 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. 
  
Cemiplimab 
Immune-mediated pneumonitis, colitis, hepatitis, 
endocrinopathies, immune-mediated dermatologic 
events including erythema multiforme and pemphigoid, 
SJS and TEN. Other reactions: 
- Ocular: Uveitis, iritis, and other ocular inflammatory 
toxicities. Some cases can be associated with retinal 
detachment. Various grades of visual impairment to 
include blindness can occur. If uveitis occurs in 
combination with other immune-mediated adverse 
reactions, consider a VogtKoyanagi-Harada like 
syndrome, as this may require treatment with 
systemic corticosteroids to reduce the risk of 
permanent vision loss. 
- Gastrointestinal: Pancreatitis to include increases in 
serum amylase and lipase levels, gastritis, duodenitis. 
- Musculoskeletal and Connective Tissue: Myositis, 
rhabdomyolysis and associated sequelae including 
renal failure, arthritis, polymyalgia rheumatica. 
- Hematological and Immunological: Hemolytic anemia, 
aplastic anemia, hemophagocytic lymphohistiocytosis, 
systemic inflammatory response syndrome, histiocytic 
necrotizing lymphadenitis (Kikuchi lymphadenitis), 
sarcoidosis, immune thrombocytopenic purpura, solid 
organ transplant rejection. 
Cardiovascular, renal, and neurological reported in the 
respective sections. 
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 immune-related reactions 
are provided in Table 6. 
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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. 
Cemiplimab 
Cemiplimab is not recommended during pregnancy and 
in women of childbearing potential not using effective 
contraception unless the clinical benefit outweighs the 
potential risk. If a woman chooses to be treated with 
cemiplimab, she should be instructed not to breast-feed 
while being treated with cemiplimab and for at least 
4 months after the last dose. 
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 I 08. 
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. 
Exclusion of participants under 18 
years of age. 
Participants over 75 
years of age 
SAR444245 
At this stage of development, no safety data are 
available for this population. 
Cemiplimab 
Of the 163 patients with metastatic and locally 
advanced CSCC who received LIBTAYO in clinical 
studies, 72% were 65 years or older and 37% were 75 
years or older. No overall differences in safety or 
effectiveness were observed between these subjects 
and younger subjects. 
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%) (48, 49, 50). 
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. 
No specific information is available on the treatment of 
overdose of cemiplimab. 
Strict adherence to the protocol. 
Adequate and verified training of staff 
at investigational sites.  
See Section 6.8. 
Study procedures 
Biopsies of (potentially) 
tumor tissue are 
expected during the trial. 
 
Strict adherence to the guidance in the 
protocol 
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10.15 APPENDIX 15: ASTCT ASSESSMENT FOR ICANS AND CRS  
Table 13 - 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 
Following commands: 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 14 - 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 (patient is unrousable and unable to 
perform ICE) 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens 
to voice 
Awakens only to tactile 
stimulus 
Patient 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 v 5.0, 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 v 5.0.  
Abbreviations: ASCT=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). 
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Table 15 - 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 v 5.0 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 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: ASCT=American Society for Transplantation and Cellular Therapy; BiPAP=Bi-level positive airway pressure CPAP= Continuous 
Positive Airway Pressure; CRS=Cytokine release syndrome. 
Source: (2). 
10.16 APPENDIX 16: ABBREVIATIONS  
 
1L: 
first-line 
ADA: 
anti-drug antibody 
AESI: 
adverse event of special interest 
ANSM: 
National Agency for the Safety of Medicines and Health Products 
ART: 
anti-retroviral therapy 
ASTCT: 
American Society for Transplantation and Cellular Therapy  
BfArM: 
German Federal Institute for Drugs and Medical Devices 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CI: 
confidence interval 
CLS: 
capillary leak syndrome 
COVID-19: 
coronavirus disease 2019 
CR: 
complete response 
CRF: 
case report form 
CRR: 
complete response rate 
CRS: 
cytokine release syndrome 
CSCC: 
cutaneous squamous cell carcinoma 
CSF: 
colony-stimulating factor 
CT: 
computed tomography 
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CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
CyTOF: 
mass cytometry time of flight 
 
DLT: 
dose-limiting toxicity 
DMC: 
Data Monitoring Committee 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
EOT: 
end of treatment 
FU: 
follow-up 
HPRA: 
Health Products Regulatory Authority  
IB: 
Investigator's Brochure 
ICANS: 
immune effector cell-associated neurotoxicity syndrome 
ICF: 
Informed Consent Form 
ICI: 
immune checkpoint inhibitor 
IHC: 
immunohistochemistry 
IL: 
interleukin 
ILC-2: 
innate lymphoid cell 
IMP: 
investigational medicinal product 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
IV: 
intravenous 
MRI: 
magnetic resonance imaging 
MTD: 
maximum tolerated dose 
mTPI2: 
modified toxicity probability interval 2  
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP: 
non-human primate  
ORR: 
objective response rate 
OTC: 
over-the-counter 
PCSA: 
potentially clinically significant abnormalities 
PD: 
progressive disease 
PD1: 
programmed cell death protein 1 
PD-L1: 
programmed cell death-ligand 1 
PDy: 
pharmacodynamic 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
RECIST: 
response evaluation criteria in solid tumor 
RP2D: 
recommended Phase 2 dose 
SARS-CoV-2: 
Severe acute respiratory sundrome coronavirus 2  
SB: 
Study Board 
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SD: 
stable disease 
SOC: 
system organ class, standard of care 
SpO2: 
oxygen saturation 
TEAE: 
treatment-emergent adverse event 
TEN: 
toxic epidermal necrolysis 
TLS: 
tumor lysis syndrome 
TRAE: 
treatment-related adverse event 
TTR: 
time to response 
UK: 
United Kingdom 
VLS: 
vascular leak syndrome 
WHO: 
World Health Organization 
 
10.17 APPENDIX 17: 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 (19 March 2021) 
This amended protocol 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 rationale for the amendment is to clarify criteria for cytokine release syndrome reporting. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SoA)  
Footnote J has been updated to add that CRS will be graded 
using ASTCT criteria integrated with central laboratory 
cytokine results. 
To clarify CRS grading criteria 
for reporting 
1.4 Biomarker flowchart 
Clarified that every effort should be made to obtain a cytokine 
sample for an event of CRS of any grade. 
To facilitate comprehensive CRS 
reporting 
6.6.4.3 Fever, flu-like 
symptoms, and cytokine-
release syndrome (CRS) 
Clarified that central laboratory cytokine results will be 
integrated into the grading of CRS events and the guidelines 
provided are for any suspected CRS event. 
To facilitate comprehensive CRS 
reporting 
Amended protocol 02 (04 May 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. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The rationale for the amendment is to respond to the Health Authority (Food and Drug 
Administration, [FDA]) requests, including revision of study design to include a dose escalation. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis and relevant 
sections of the protocol 
(Sections 4, 6 and 9) 
Initial safety run-in part replaced by dose escalation with SAR444245 
starting dose of 16 μg/kg (DL1) to determine the recommended Phase 2 
dose (RP2D) in combination with cemiplimab. Due to these modifications 
the study design has changed from Phase 2 to Phase 1/2. 
Regulatory Authority 
(FDA) request  
1.1 Synopsis and 6.1.2.1 
Premedication for 
SAR444245 
Details on decision criteria to stop SAR444245 premedication after cycle 
4 have been added. 
Regulatory Authority 
(FDA) request 
1.3 Schedule of activities 
(SoA) 
Footnote K has been updated. 
To clarify and be in 
alignment with 
exclusion criterion 
E06 
1.4 Biomarker flowchart  
The following text has been added: 
i
To have the sample 
drawn from patients 
enrolled in RP2D  
1.5 Pharmacokinetic 
flowchart 
Footnote A related to ADA sampling has been removed. 
Regulatory Authority 
(FDA) request 
4.1 Overall design 
The following DLT criteria have been updated as follows:  
“Grade 4 neutropenia for ≥7 consecutive days” updated to “Any Grade 4 
neutropenia irrespective of duration” 
 “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” replaced by “Any febrile neutropenia” 
“Grade 3 or 4 thrombocytopenia associated with clinically significant 
bleeding requiring clinical intervention” updated to “Grade 3 
thrombocytopenia associated with transfusion in addition to bleeding and 
any Grade 4 thrombocytopenia” 
“Grade 3 or above ALT or AST in combination with a bilirubin >2 times 
ULN with no evidence of cholestasis or another cause such as viral 
infection or other drugs” updated to “Grade 3 or above ALT and AST 
increase” 
The following DLT criterion has been added: 
“Grade 4 laboratory abnormalities” 
The following DLT criterion has been removed: 
“The following non-hematologic AEs are exceptions: Grade 3 or 4 
laboratory abnormalities that are not clinically significant per recruiting 
Investigator and Sponsor” 
Regulatory Authority 
(FDA) request 
 
Specified that in the event of an excessive toxicity any cohort can be 
stopped as per Study Committee and Sponsor decision 
Regulatory Authority 
(FDA) request 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion criteria 
E14 updated to allow individuals with ≤Grade 1 peripheral neuropathy 
instead of Grade 2. 
E36 “Aspartate aminotransferase and/or alanine aminotransferase  
>2.5 × ULN (or >5 × ULN for participants with liver metastases)” updated 
to “Aspartate aminotransferase and alanine aminotransferase  
>2.5 × ULN (or >5 × ULN for participants with liver metastases)” 
Regulatory Authority 
(FDA) request 
8.2.2 Vital signs 
Collection of vital signs including timing and in/out-patient settings has 
been clarified for participants in dose escalation and other participants at 
Cycle 1 and beyond. 
The following text has been added: 
“From Cycle 2 and beyond study therapy will be administered for all 
patients in out-patient clinic with vital signs taken at baseline, 4 to 
6 hours post-dose, or as clinically indicated”. 
Regulatory Authority 
(FDA) request 
8.7 Biomarkers 
The following text has been added: 
"
To have the sample 
drawn from patients 
enrolled in RP2D 
10.3.3 Recording and 
follow-up of AE and/or 
SAE 
The following text has been added to further clarify assessment of 
causality: 
The Investigator should use their knowledge of the patient, the 
circumstances surrounding the event, and an evaluation of any potential 
alternative causes to determine whether an adverse event is considered 
to be related to study treatment SAR444245, cemiplimab or the 
combination.    
Regulatory Authority 
(FDA) request 
All Sections 
Minor editorial and document formatting revisions 
Minor corrections for 
consistency 
Amended protocol 03 (25 August 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 
In response to requests from the French (National Agency for the Safety of Medicines and Health 
Products [ANSM]), Irish (Health Products Regulatory Authority [HPRA]), and German (Federal 
Institute for Drugs and Medical Devices [BfArM]) Health Authorities after initial review, the 
protocol is being amended to correspond with the responses previously provided. Other changes 
have been made for clarification, accuracy, and correction. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol title 
“(Pegasus Skin 201)” has been added to protocol title 
Harmonization per 
program level approach 
1.1 Synopsis,  
3 Objectives and Endpoints,  
9.4.3 Secondary endpoint(s) 
Definitions of Time to complete response, Time to response, and 
Duration of response have been revised as follows: 
• 
Time to CR defined as the time from the first administration 
of IMP to the first tumor assessment at which the overall 
response was recorded as CR that is subsequently 
confirmed and determined by Investigator per RECIST 1.1 
for melanoma participants and when applicable for CSCC 
participants 
• 
Time to Response 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 and determined by Investigator 
per RECIST1.1 or modified WHO criteria or composite 
criteria, whichever relevant. 
• 
Duration of Response defined as the time from first tumor 
assessment at which the overall response was recorded as 
CR or PR that is subsequently confirmed until documented 
PD determined by Investigator per RECIST 1.1 or modified 
WHO Criteria for medical photographs or composite criteria 
when relevant, or death from any cause, whichever occurs 
first. 
For clarification 
1.1 Synopsis 
Figure 1 
1.3 Schedule of Activities (SoA)  
4.1 Overall Design 
6.1.1 Investigational medicinal 
product 
9.5 Interim analysis 
“Study Committee” has been replaced by “Study Board” and its 
description in Section 4.1 updated as follows: 
“The study Investigators (or designee) participating in the dose 
escalation part of the trial and the Sponsor clinical team 
members will constitute the Study Board (SB). The SB will meet 
first when the first patient is treated in the dose escalation part 
and will review clinical data of each individual patient treated in 
the dose escalation part on a regular basis, in order to adjust the 
number of patients to be enrolled and to decide dose 
confirmation, dose reduction, dose escalation as appropriate 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 dose escalation. Decisions regarding final 
dose selection will be made during one of the study board 
meeting and documented in the meeting minutes.”. 
Harmonization per 
Sanofi standard 
terminology 
1.1 Synopsis 
4.1 Overall Design 
Observation and Follow-up period have been revised as follows:  
• 
Under the definition of End of Treatment and Follow-up 
for participants who discontinue study treatment 
without radiological or clinical PD or who complete 
35 cycles of treatment without PD, “final” has been 
added to cohort cut-off 
• 
Under the definition of End of Treatment and Follow-up 
for participants who discontinue study treatment with 
radiological or clinical PD (per RECIST 1.1 or modified 
WHO Criteria for medical photographs) or i
 the 
following text “or until start of another anticancer 
For clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
therapy or cohort cut-off, whichever comes first” has 
been removed 
• 
Under the definition of Survival Phone Call Follow-Up 
Period the following text “or until the last participant to 
enter Survival Follow-Up has been followed for no 
more than 3 years” has been replaced by “final cohort 
cut-off” 
9.5 Interim Analyses 
The study cut-off date has been replaced by cohort cut off for 
final analysis.  
 
1.1 Synopsis 
4.1 Overall Design 
9.3 Populations for Analyses 
The definition of DLT-evaluable participants has been updated to 
“all participants in the dose escalation who have been treated 
and observed for at least 21 days”. 
Harmonization per 
program level approach 
1.1 Synopsis 
“Independent” has been removed before “Data Monitoring 
Committee” and “No” has been replaced with “Yes”. 
DMC remains 
independent.  
Harmonization per 
Sanofi standard 
terminology 
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. 
Regulatory Authorities 
(ANSM and HPRA) 
request 
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”. 
 
8.2.3 Electrocardiograms and 
LVEF 
Troponin has been added as an example of cardiac enzymes 
within additional evaluation to carry out when clinically indicated.  
Regulatory Authorities 
(ANSM, BfArM and 
HPRA) request 
 
The following text has also been added for evaluations during 
treatment and post treatment follow-up: 
“In case of a suspicion of a drug related cardiac event (eg, 
including signs/symptoms of cardiac disease, ECG and/or echo 
changes, cardiac troponin elevation, etc.) Investigators are 
encouraged to do ECG, echocardiography and/or cardiac 
biomarker tests, as medically indicated, including cardiology 
consultation". 
Regulatory Authorities 
(ANSM and HPRA) 
request  
10.2 Clinical laboratory tests 
Troponin has been added to other screening tests. 
Regulatory Authorities 
(ANSM and HPRA) 
request 
1.4 Biomarker Flowchart 
Sample collections for participants enrolled in the dose 
escalation dose 16 μg/kg and dose 24 μg/kg have been 
specified. 
For clarification 
5.1 Inclusion Criteria 
In I06, provision of tumor tissue, collection at screening and on-
treatment for participants in dose 16 μg/kg and dose 24 μg/kg 
have been specified. 
8.7 Biomarkers 
The following text has been removed: 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design  
Following decision to set up a DMC the text following text “Study 
Committee and Sponsor can decide to stop any cohort in case 
excessive toxicity (for example but not limited to excessive ir-AE 
or excessive number of G4/5 events) is observed” has been 
revised as: “Study Board (during dose escalation), Data 
Monitoring Committee (DMC) (during dose expansion) and 
Sponsor can decide to stop any cohort in case excessive toxicity 
(for example but not limited to excessive ir-AE or excessive 
number of G4/5 events) is observed”. 
Regulatory Authorities 
(ANSM, HPRA and 
BfArM) request 
9.5 Interim analyses 
The following text has been added: 
“After the dose is confirmed by the SB the cumulative safety data 
for each study intervention across cohorts will be reviewed 
periodically by the DMC. The enrollment will not be paused or 
stopped during the safety monitoring unless severe safety 
concern arises. DMC will review safety data periodically. Ad hoc 
DMC meetings may also be held if a significant safety issue or 
an issue deemed important for discussion arises on this or other 
SAR444245 studies. The DMC procedures will be detailed in the 
DMC charter and approved by the DMC members”. 
10.1.5 Committee structure 
The description of the DMC has been added. 
4.1 Overall Design 
The following text has been added: “After dose escalation, 
occurrence of any treatment related G3 or higher AE (excluding 
lymphocyte count decrease) not resolving within 72 hours in 
>25% of participants per regimen will trigger SB to rapidly 
convene to assess safety or need to pause enrollment to allow 
for a safety review”. 
Regulatory Authority 
(ANSM) request 
4.3 Justification for Dose 
Updated based on most recent data. 
To include the most 
recent dose justification 
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 
5.1 Inclusion Criteria 
10.7 Appendix 7: Country-
Specific Requirements 
I02 has been updated with the following country specific 
requirements: 
- Cohort A will not be open in Ireland 
- In France participants with BRAF-mutant melanoma will not be 
included in Cohort A 
Regulatory Authorities 
requests (HPRA and 
ANSM, respectively) 
5.2 Exclusion Criteria  
E07 “History of allogenic or solid organ transplant” has been 
revised to “History of allogenic tissue/solid organ transplant”. 
Harmonization per 
program level approach 
 
E20 “Known hypersensitivity to or contraindication for the use of 
SAR444245, PEG, pegylated drugs, cemiplimab, and 
SAR444245 premedication (acetaminophen, diphenhydramine 
[or cetirizine, promethazine, dexchlorpheniramine], ondansetron 
[or granisetron, dolasetron, tropisetron, palonosetron])” has been 
revised to “Known hypersensitivity 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”. 
Regulatory Authority 
(BfArM) request 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6 Dose modification 
In subsections 6.6.1 and 6.6.2, dose omission has been 
removed and replaced by cycle delay when relevant. In 
subsections 6.6.2 and 6.6.3 the following text regarding the 
treatment resumption after cycle delay and treatment withhold 
has been deleted: “or is stable and manageable through 
supportive/medical therapy”. 
As per protocol if one 
drug is held then other 
drug will also be held, 
so this will constitute 
cycle delay 
 
In subsection 6.6.3 (General guidelines for the management of 
treatment-related adverse events) the following text has been 
added:   
“Study intervention should be held in case of significant cardiac 
event (if possible, confirmed by a cardiologist) or suspicion of an 
immune-mediated myocarditis until this has been assessed for a 
relationship to SAR444245 or cemiplimab”. 
Regulatory Authorities 
(ANSM and HPRA) 
request 
In Table 6 the guidelines for the management of immune-related 
hepatitis have been revised to separate management of Grade 2 
and Grade ≥3 hepatitis. 
Regulatory Authority 
(ANSM) request 
8.2.2 Vital signs 
The requirement to measure vital signs in a semi-supine position 
has been removed. 
Harmonization per 
program level approach 
7.1.1 Permanent 
discontinuation 
8.3 Adverse events (AEs), 
Serious adverse events (SAEs) 
and other safety reporting 
10.1.3 Informed consent 
process 
10.13.1 Informed consent 
“If allowed by local regulations” has been added after “legally 
authorized representative” to cover for country-specific 
regulations. 
Regulatory Authority 
(BfArM) request 
8.10 Use of biological samples 
and data for future research  
The following text: “Study participant coded data will be stored 
for future research for up to 25 years after the end of the study. If 
data are still considered of important scientific value after this 
period, coded data already available will be anonymized unless 
otherwise required by applicable laws (the same will apply to the 
data of a study participant who has requested the destruction of 
his/her samples)” has been deleted. 
Duration of biological sample storage has been updated to “up to 
25 years”. 
Harmonization per 
Sanofi standard 
terminology 
9.3 Populations for Analyses 
The definition of efficacy population has been revised to “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”. 
To characterize efficacy 
excluding participants 
newly enrolled 
9.4.1 General considerations 
“By dose (as applicable)” has been added to efficacy analyses. 
For clarification 
9.4.3 Secondary endpoint(s)  
9.4.5 Other safety analyse(s) 
“When relevant” has been added before “for laboratory variables” 
in Section 9.4.3.8 and before “the summary statistics (including 
mean, median, standard error, minimum and maximum) of all 
vital signs” in Section 9.4.5, respectively. 
These analyses will be 
done as needed 
following analyses of 
abnormalities according 
to NCI-CTCAE grade 
9.4.5 Other safety analyse(s) 
“ECG” has been removed from quantitative analyses 
Harmonization per 
program level approach 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.9 Study and site start and 
closure 
The following paragraph has been added: “If the cohort/study is 
early terminated the patients who are receiving and benefitting 
from study treatment as per Investigator judgment may continue 
study treatment 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.” 
For clarification 
10.8 Appendix 8: 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”. 
Typographical error 
10.14 Appendix 14: Risk 
assessment 
The following text has been added to clarify the source of 
information for Table 12: 
”For cemiplimab, the information below is per currently available 
USPI and EU SmPC” 
Reference to cemiplimab local label for up-to-date safety data 
has also been added. 
For clarification 
Throughout the document 
Minor editorial updates. 
 
 
For consistency and 
clarification 
 
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11 
REFERENCES  
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