Conditions: Oesophageal Squamous Cell Carcinoma Gastric Cancer Hepatocellular Carcinoma Colorectal Cancer Oesophageal Adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 138
Healthy volunteers: no

Brief summary:
The study is a phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical benefit of SAR444245 (THOR-707) combined with other anticancer therapies for the treatment of participants aged 18 years and older with advanced and metastatic gastrointestinal cancer. This study is structured as a master protocol for the investigation of SAR444245 with other anticancer therapies.

Sub study 01 - Cohort A aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC).

Sub study 02 - Cohort B1, B2 and B3 would focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior PD1/PD-L1-based regimens.

Sub study 03 - Cohort C aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the percentage of patients experiencing an objective response in participants with advanced unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens.

Sub study 04 - Cohort D1 and D2 aims to establish proof-of-concept that combining the non-alpha-IL2 SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 antibody cetuximab will result in a significant increase in the percentage of patients experiencing an objective response in the setting of advanced unresectable or metastatic colorectal cancer (mCRC).

Detailed description:
The duration of the study for an individual patient will start from the signature of the main informed consent and include a screening period of up to 28 days, a treatment period \[max 35 cycles {cohort A; B1,B2, B3, C and D1} = 735 days or until PD {cohort D2}\], an end-of-treatment visit at least 30 days following the last administration of study drug (or until the patient receives another anticancer therapy, whichever is earlier), and a follow-up visit 3 months after treatment discontinuation and every 3 months following, until disease progression, or initiation of another antitumor treatment, or death, whichever is earlier.

Arms:
arm 1: Participants with advanced unresectable or metastatic esophageal squamous cell carcinoma (ESCC), regardless of programmed cell death-ligand 1 (PD-L1) expression (any combined positive score \[CPS\]), who had received at least 1 but no more than 2 prior lines of treatment and had progressed after primary or secondary resistance to an anti-programmed cell death-1 (PD-1)/PD-L1 based regimen were included in this cohort. Participants received SAR444245 24 microgram per kilogram (mcg/kg) along with pembrolizumab 200 milligram (mg) via intravenous (IV) infusion every 3 weeks (q3w) on Day 1 of each cycle (each cycle is 21 days) (as second-line or third-line \[2/3L\] therapy), until disease progression (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 2: Cohort B1: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS \>=1; SAR444245 24mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic gastric cancer (GC) or Siewert Type 2 \& 3 gastro-esophageal junction adenocarcinoma (GEJ) and for whom standard of care (SOC) was not in best interest or where no SOC was established, non-high-level microsatellite instability (MSI-H) disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS \>=1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as first to \[1-\]3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 3: Cohort B2: GC/GEJ PD-1/PD-L1 naïve non-MSI-H CPS \<1; SAR444245 24 mcg/kg+Pembrolizumab as 1-3L Therapy. Participants with advanced unresectable or metastatic GC or Siewert Type 2 \& 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had not received more than 2 prior lines of treatment that did not include an anti-PD-1/PD-L1-based regimen with the level of PD-L1 expression at baseline as CPS \<1 GC/GEJ were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 1-3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 4: Participants with advanced unresectable or metastatic GC or Siewert Type 2 \& 3 GEJ and for whom SOC was not in best interest or where no SOC was established, non-MSI-H disease and had received atleast 1 and no more than 3 prior lines of treatment and had progressed after primary or secondary resistance to an anti-PD-1/PD-L1-based regimen (regardless of the disease CPS status) were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2-fourth \[4\]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 5: Participants with advanced unresectable or metastatic hepatocellular carcinoma (HCC), regardless of any CPS, who relapsed on prior PD-1/PD-L1-based regimens, with at least stable disease (SD) as best response and with no more than 2 prior lines of treatment were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 2/3L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 6: Participants with advanced unresectable or metastatic colorectal cancer (CRC), regardless of any CPS, non-MSI-H disease, any RAS type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg along with pembrolizumab 200 mg via IV infusion q3w on Day 1 of each cycle (each cycle is 21 days) (as 3-sixth \[6\]L therapy), until PD, unacceptable AE or other full permanent discontinuation criteria was met or completion of Cycle 35. arm 7: Participants with advanced unresectable or metastatic CRC, regardless of any CPS, non-MSI-H disease, RAS wild type, who had progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of treatments were included in this cohort. Participants received SAR444245 24 mcg/kg q3w on Day 1 of each cycle along with cetuximab as an initial loading dose of 400 mg/square meter (m\^2) on Cycle 1 Day 1 followed by 250 mg/m\^2 starting via IV infusion once weekly from Cycle 1 Day 8 (each cycle is 21 days) (as 3-6L therapy) until PD.

Interventions: intervention 1: THOR-707 intervention 2: Pembrolizumab intervention 3: Cetuximab
Intervention descriptions: intervention 1: Solution for infusion: intravenous infusion intervention 2: Solution for infusion: intravenous infusion intervention 3: Solution for infusion: intravenous infusion

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 02 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with other 
anticancer therapies for the treatment of participants 
with advanced and metastatic gastrointestinal cancer 
Protocol number: 
ACT16902 Master 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with other anticancer 
therapies for the treatment of participants with 
gastrointestinal cancer (Master protocol) 
Acronym 
Pegathor Gastrointestinal 203 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
156424 
2021-002181-41
NCT05104567 
U1111-1251-4981 
Date: 
21-Jan-2022 
Total number of pages: 118 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Master Protocol 02 
All 
21 January 2022, version 1 
(electronic 4.0) 
Amended Clinical Trial Master Protocol 01  All 
30 August 2021, version 1 
(electronic 2.0) 
Clinical Trial Master Protocol 
 
20 July 2021, version 1 
(electronic 1.0) 
Amended protocol 02 (21 January 2022) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Belgian, Italian, German (Federal 
Institute for Drugs and Medical Devices [BfArM]), and South Korean Health Authorities after 
initial review. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover page and 
1.1 Synopsis 
The following study name: “Pegasus 
Gastrointestinal 203” has been removed from the 
protocol title and the new study acronym 
“Pegathor Gastrointestinal 203” has been added 
on the cover page. 
For consistency across the program. 
1.1 Synopsis, 
3 Objectives and 
Endpoints, and 
9.4.3 Secondary 
endpoint(s)  
Definitions of Time to response and Duration of 
response have been revised as follows: 
• Time to response (TTR) defined as the time from 
the first administration of investigational medicinal 
product (IMP) to the first tumor assessment at 
which the overall response was recorded as PR or 
For clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
CR that is subsequently confirmed and 
determined by Investigator per RECIST 1.1. 
• Duration of response (DoR), defined as the time 
from first tumor assessment at which the overall 
response was recorded as CR or PR that is 
subsequently confirmed until documented 
progressive disease (PD) determined by 
Investigator per RECIST 1.1 or death from any 
cause, whichever occurs first. 
1.1 Synopsis and 
6.1.2 Non-
investigational 
medicinal products 
Oral administration of diphenhydramine is now 
permitted, in addition to IV administration. 
Intravenous administration of acetaminophen is 
now permitted, in addition to oral administration. 
To allow local approved dosing regimens to be 
followed. 
1.1 Synopsis, 
6.1.2 Non-
investigational 
medicinal products, and 
10.10 Appendix 12: 
Table 8 Risk 
assessment 
Antiemetic SAR444245 premedication with 
ondansetron or equivalent has been removed. 
Antiemetic is removed from premedication list 
based on new tolerability data from the first-in-
human study. 
1.1 Synopsis and 
9.4.3.5 Adverse events 
Treatment-related TEAEs will be analyzed overall, 
regardless of the drug 
To assess treatment-related AE of the regimen 
as whole (SAR444245 with other anticancer 
therapies). 
1.3 Schedule of 
Activities (SoA),  
Troponin test has been added at screening, at 
C4D1, and as clinically indicated during treatment 
period until Follow-up visit 1. 
To allow assessment of any potential 
cardiotoxity. 
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, echocardiography and troponin level”. 
8.2.3 
Electrocardiograms and 
left ventricular ejection 
fraction (LVEF) 
 
 
 
 
 
 
 
 
 
Troponin has been added as an example of 
cardiac enzymes within additional evaluation to 
carry out when clinically indicated. 
The following text has also been added for 
evaluations during treatment and post treatment 
follow-up: 
“During treatment, or post treatment follow-up:  
Troponin will be performed at Cycle 4 Day 1. In 
case of a suspicion of a drug related cardiac event 
(eg, including signs/symptoms of cardiac disease, 
ECG and/or echo changes, troponin elevation, 
etc.), Investigators are encouraged to do ECG, 
echocardiography and/or cardiac biomarker tests, 
as medically indicated, including cardiology 
consultation”.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
10.2 Clinical laboratory 
tests 
Troponin has been added to “other screening 
tests”. 
1.3 Schedule of 
Activities (SoA) 
Footnote h “For participants with known HIV, 
hepatitis B and hepatitis C infection under antiviral 
treatment to confirm controlled infection, and for 
all participants in Germany and Italy (see details 
and specific instructions in Section 10.2 and 
Section 10.7).” has been added. The numbering of 
the remaining footnotes has been updated. 
“and microscopic examination (if blood or protein 
is abnormal)” has been added for footnote i for 
urinalysis. 
“Tumor biopsy during treatment period should be 
limited to non-target lesions or new lesions if their 
pathologic etiology is ambiguous” has been 
removed from footnote l. 
For consistency and clarity.  
1.4 Biomarker flowchart, 
6.1.4 Readiness for 
treatment of severe 
cytokine release 
syndrome 
The following statement “alternative therapies per 
site practice in CRS management” has been 
added to “tocilizumab”. 
For flexibility following an issue with 
tocilizumab availability. 
1.4 Biomarker flowchart 
The following sentence has been added for 
footnote f “If there is not a baseline biopsy, an on-
treatment biopsy is not needed or recommended”. 
For clarity. 
1.5 Pharmacokinetic 
flowcharts 
In Section 1.5.1, 'D2','D3','D4' are removed and 
replaced by D1 within the line 'Day' at Cycles 1 
and 4. 
In Section 1.5.2, footnote c “PK sample can be 
collected at any time during the second day of the 
cycle” is added to PK sample collection at 24h. 
For consistency and clarity. 
5.1 Inclusion Criteria, 
8.2.5 Pregnancy 
testing, 
8.3.5 Pregnancy, and 
10.2 Clinical laboratory 
tests 
In I03, the requirement for contraception for male 
participants has been changed from “at least 
210 days [corresponding to time needed to 
eliminate study intervention(s) plus an additional 
90 days (a spermatogenesis cycle)] after the last 
dose of study intervention” to “at least 3 days 
[corresponding to time needed to eliminate 
SAR444245] after the last dose of SAR444245”.  
 
 
The recommended duration for continuing 
contraception after last dose of study intervention 
has been changed for female participants in 
Cohorts A, B1, B2, B3, C, and D1 (SAR444245 
plus pembrolizumab) from 180 days to 120 days, 
and 60 days for participants in Cohort D2, and the 
requirement of extension extra 30 days (1 month) 
has been removed. 
To change measures for male participants as 
per Clinical Trials Facilitation and Coordination 
Group (CTFG) guideline on recommendations 
related to contraception and pregnancy testing 
in clinical trials version 1.1 of 21 Sept 2020. As 
SAR444245 is not genotoxic, there is no need 
to extend the requirement for contraception to 
90 days (3 months) for male participants, but 
to take into account the 5 half-lives of the 
study intervention before its elimination. 
None of the products in combination is 
genotoxic in this study, there is no need to 
extend the requirement for contraception to 
30 days (1 month) corresponding to 
a menstrual cycle for female participants. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
E 18 has been changed from “Known 
hypersensitivity (≥ Grade 3) to or contraindication 
for the use of any study intervention, including 
premedication to be administered in this study, as 
well as PEG or any pegylated drug” to “Known 
hypersensitivity (≥ Grade 3) to or contraindication 
for the use of any study intervention or 
components thereof, including premedication to 
be administered in this study, as well as PEG or 
any pegylated drug and E. coli-derived protein”. 
To clarify that that patients with known 
hypersensitivity to any excipient of the study 
interventions and hypersensitivity to any E. 
Coli-derived protein must be excluded. 
E 23 has been changed from: “Participation in a 
concurrent clinical study in the treatment period” 
To  
“Current enrollment or past participation in a study 
of an investigational treatment or an 
investigational device within 28 days prior to the 
first dose of study treatment.  
Note:  Participants who have entered the follow-up 
phase of an investigational study may participate 
as long as it has been 28 days after the last dose 
of the previous investigational treatment”. 
For clarification. 
5.4 Screen Failures 
The following text: “A participant may be 
rescreened only once” has been added. 
For clarity. 
6.2 
Preparation/handling/st
orage/accountability 
The text was revised as shown below 
Under no circumstances will the Investigator 
supply IMP to a third party (except for DTP 
shipment, for which a courier company has been 
approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial 
protocol, or dispose of IMP in any other manner. 
For correction. Direct-to-patient shipment of 
IMP is not possible in this study. 
7.1.1 Permanent 
discontinuation, 8.3 
Adverse events (AEs), 
Serious adverse events 
(SAEs) and other safety 
reporting, 
10.1.3 Informed 
consent process, and 
10.9.1 Informed 
consent process 
“If allowed by local regulations” has been added 
after “legally authorized representative” to cover 
for country-specific regulations. 
Regulatory Authority (BfArM) request. 
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 has been removed. All AEs 
and SAEs are to be collected until 30 days and 
90 days, respectively, following cessation of study 
treatment. 
For consistency with Sanofi standards. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8.6 Biomarkers 
s been added for 
“This method will only 
apply to samples from clinical sites not exhibiting 
feasibility constrains on handling/shipment”. 
To improve flexibility in case local constrains 
exist. 
8.6 Biomarkers 
Concerning collection of samples, the following 
text “will be stored for a period of up to 15 years 
after the last participant’s last visit for potential re-
analyses” has been changed to “may be used for 
further research if consent is provided 
(see Section 8.9)”. 
Harmonization per Sanofi standard 
terminology. 
8.9 Use of biological 
samples and data for 
future research and 
10.5 Appendix 5: 
Genetics 
The text was revised to state that the duration of 
storage for biological samples and relating data is 
up to 25 years. The duration of biological sample 
storage was previously given as a maximum of 
15 years. 
For consistency with the latest Sanofi 
standards. 
9.3 Population of 
analyses 
Update of Efficacy population definition 
To characterize efficacy excluding participants 
newly enrolled. 
9.4.3.2 Duration of 
response 
Update the definition for DoR analysis. 
For clarity. 
9.5 Interim analysis 
The following sentence has been added 
“Occurrence of any treatment related G3 or higher 
AE (excluding lymphocyte count decrease) not 
resolving within 72 hours in >25% of participants 
will trigger ad hoc DMC.” 
For clarity. 
10.2 Appendix 2: 
Clinical laboratory tests 
The following footnote d: “Urinalysis using dipstick 
for glucose, blood, pH, protein, ketones, 
leukocytes and microscopic examination (if blood 
or protein is abnormal), will be performed every 
4 cycles during the Treatment period and as 
clinically indicated” has been added. The 
numbering of the remaining footnotes has been 
updated. 
For clarification. 
For footnote f virus serology testing, hepatitis B 
and C tests at screening have been added. 
Regulatory Authority request. 
10.7 Appendix 7:  
Country-specific 
requirements 
Country-specific requirements for Italy has been 
added. 
Regulatory Authority request. 
10.10 Appendix 10: 
Risk assessment 
In Table 5, the row for drug-drug interactions has 
been deleted. 
For consistency. 
Throughout 
Minor editorial updates 
For consistency and clarification. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 02 .............................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 12 
LIST OF FIGURES ........................................................................................................................................ 12 
1 
PROTOCOL SUMMARY ............................................................................................................... 13 
1.1 
SYNOPSIS ..................................................................................................................................... 13 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 25 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 26 
1.5.1 
Participants with more intensive PK sampling ............................................................................... 26 
1.5.2 
All other participants....................................................................................................................... 27 
2 
INTRODUCTION ............................................................................................................................ 28 
2.1 
STUDY RATIONALE...................................................................................................................... 28 
2.2 
BACKGROUND ............................................................................................................................. 29 
2.2.1 
Overall rationale for GI studies ...................................................................................................... 29 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Risk assessment ............................................................................................................................ 29 
2.3.1.1 
Aldesleukin experience .................................................................................................................. 30 
2.3.1.2 
SAR444245 .................................................................................................................................... 31 
2.3.1.3 
NKTR-214 (bempegaldesleukin) clinical data ................................................................................ 32 
2.3.2 
Benefit assessment ........................................................................................................................ 33 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 33 
2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 34 
2.3.4.1 
Risks in the context of COVID-19 .................................................................................................. 34 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 36 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 37 
4 
STUDY DESIGN ............................................................................................................................ 38 
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4.1 
OVERALL DESIGN ........................................................................................................................ 38 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 39 
4.2.1 
Participant input into design ........................................................................................................... 39 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 39 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 42 
5 
STUDY POPULATION .................................................................................................................. 43 
5.1 
INCLUSION CRITERIA .................................................................................................................. 43 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 44 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 49 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 49 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 49 
5.3.3 
Activity ............................................................................................................................................ 49 
5.3.4 
Hydration ........................................................................................................................................ 49 
5.4 
SCREEN FAILURES...................................................................................................................... 49 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 50 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 51 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 51 
6.1.1 
Investigational medicinal product (IMP) ......................................................................................... 51 
6.1.2 
Non-investigational medicinal products ......................................................................................... 52 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 52 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 52 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 53 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 53 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 54 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 54 
6.5 
DOSE MODIFICATION .................................................................................................................. 54 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 54 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 54 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 55 
6.8.1 
Acceptable concomitant medications ............................................................................................. 55 
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6.8.2 
Prohibited concomitant medications .............................................................................................. 56 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 58 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 58 
7.1.1 
Permanent discontinuation ............................................................................................................ 58 
7.1.1.1 
Unacceptable adverse events leading to permanent intervention discontinuation ........................ 58 
7.1.2 
Temporary discontinuation ............................................................................................................. 59 
7.1.3 
Rechallenge ................................................................................................................................... 59 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 60 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 60 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 62 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 62 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 63 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 64 
8.2.1 
Physical examinations ................................................................................................................... 64 
8.2.2 
Vital signs ....................................................................................................................................... 64 
8.2.3 
Electrocardiograms and LVEF ....................................................................................................... 65 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 65 
8.2.5 
Pregnancy testing .......................................................................................................................... 66 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 66 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 67 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 67 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 67 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 67 
8.3.5 
Pregnancy ...................................................................................................................................... 68 
8.3.6 
Cardiovascular and death events .................................................................................................. 69 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 69 
8.3.8 
Adverse event of special interest ................................................................................................... 69 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 70 
8.4 
PHARMACOKINETICS .................................................................................................................. 70 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 71 
8.6 
BIOMARKERS ............................................................................................................................... 71 
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8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 72 
8.8 
HEALTH ECONOMICS .................................................................................................................. 73 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 73 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 74 
9.1 
 STATISTICAL HYPOTHESES ...................................................................................................... 74 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 74 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 74 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 74 
9.4.1 
General considerations .................................................................................................................. 75 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 75 
9.4.2.1 
Objective response rate ................................................................................................................. 75 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 75 
9.4.3.1 
Time to response ........................................................................................................................... 76 
9.4.3.2 
Duration of response ...................................................................................................................... 76 
9.4.3.3 
Clinical benefit rate......................................................................................................................... 76 
9.4.3.4 
Progression-free survival (RECIST 1.1)......................................................................................... 76 
9.4.3.5 
Adverse events .............................................................................................................................. 77 
9.4.3.6 
Clinical Laboratory evaluations ...................................................................................................... 78 
9.4.3.7 
Other secondary endpoints ............................................................................................................ 78 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 78 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 78 
9.4.4.2 
Biomarker endpoints ...................................................................................................................... 79 
9.4.5 
Other safety analysis...................................................................................................................... 79 
9.4.6 
Other analysis ................................................................................................................................ 79 
9.5 
INTERIM ANALYSES  ................................................................................................................... 79 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 81 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 81 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 81 
10.1.2 
Financial disclosure........................................................................................................................ 82 
10.1.3 
Informed consent process .............................................................................................................. 82 
10.1.4 
Data protection ............................................................................................................................... 83 
10.1.5 
Committees structure ..................................................................................................................... 85 
10.1.6 
Dissemination of clinical study data ............................................................................................... 85 
10.1.7 
Data quality assurance .................................................................................................................. 86 
10.1.8 
Source documents ......................................................................................................................... 87 
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10.1.9 
Study and site start and closure ..................................................................................................... 87 
10.1.10 Publication policy ........................................................................................................................... 88 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 88 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 90 
10.3.1 
Definition of AE .............................................................................................................................. 90 
10.3.2 
Definition of SAE ............................................................................................................................ 92 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 93 
10.3.4 
Reporting of SAEs.......................................................................................................................... 95 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 96 
10.4.1 
Definitions ...................................................................................................................................... 96 
10.4.2 
Contraception guidance ................................................................................................................. 96 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 98 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 99 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 99 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 ........ 100 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 105 
10.9.1 
Informed consent ......................................................................................................................... 105 
10.9.2 
Study procedures ......................................................................................................................... 105 
10.9.3 
Statistical analysis ........................................................................................................................ 105 
10.9.4 
Temporary discontinuation ........................................................................................................... 106 
10.10 
APPENDIX 10: RISK ASSESSMENT .......................................................................................... 106 
10.11 
APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS ................................................ 111 
10.12 
APPENDIX 12: ABBREVIATIONS  .............................................................................................. 112 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 113 
10.13.1 Amended protocol 01 (30 August 2021) ...................................................................................... 113 
11 
REFERENCES ............................................................................................................................. 116 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 36 
Table 2 - Overview of IMP administered ....................................................................................................... 51 
Table 3 - Populations for analyses ................................................................................................................ 74 
Table 4 - Protocol-required laboratory assessments .................................................................................... 89 
Table 5 - Risk assessment .......................................................................................................................... 106 
Table 6 - Encephalopathy assessment ICE tool for ICANS Grading .......................................................... 111 
Table 7 - ASTCT ICANS consensus grading for adults .............................................................................. 111 
Table 8 - ASTCT CRS consensus grading.................................................................................................. 112 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with other anticancer therapies for the treatment of 
participants with advanced and metastatic gastrointestinal cancer  
Brief title: 
A study of SAR444245 combined with other anticancer therapies for the treatment 
of participants with gastrointestinal cancer (Master protocol) 
Rationale: 
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the interleukin (IL)-2 α receptor, while retaining stimulatory activity for cells expressing the 
moderate affinity IL-2 βγ receptor. 
The proposed study aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with other anticancer therapies will result in a significant increase in the percentage 
of patients experiencing an objective response in the setting of various advanced gastrointestinal 
cancers. 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. This design is 
with the flexibility to open new treatment cohorts as new treatment combinations become 
available and close existing treatment cohorts that demonstrate minimal clinical activity or 
unacceptable toxicity.  
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
Objectives and endpoints  
  
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245 
in combination with other anticancer therapies  
• 
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) 
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Secondary 
 
 
 
 
For China, please see Section 10.7 for details.  
Overall design: 
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with advanced or metastatic gastrointestinal cancer. 
Brief summary:  
A graphical presentation of the study schema is shown Figure 1.  
• 
To assess the safety of SAR444245 in combination 
with other anticancer therapies 
• 
Incidence of treatment emergent adverse events 
(TEAEs), serious adverse events (SAEs), 
laboratory abnormalities according to National 
Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) V5.0 and American 
Society for Transplantation and Cellular Therapy 
(ASTCT) consensus grading (2) 
• 
To assess other indicators of antitumor activity 
• 
Time to response (TTR), defined as the time from 
the first administration of investigational medicinal 
product (IMP) to the first tumor assessment at 
which the overall response was recorded as PR or 
CR that is subsequently confirmed and determined 
by Investigator per RECIST 1.1 
• 
Duration of response (DoR), defined as the time 
from first tumor assessment at which the overall 
response was recorded as CR or PR that is 
subsequently confirmed until documented 
progressive disease (PD) determined by 
Investigator per RECIST 1.1 or death from any 
cause, whichever occurs first 
• 
Clinical benefit rate (CBR) including confirmed CR 
or PR at any time or stable disease (SD) of at least 
6 months determined by Investigator per 
RECIST 1.1. 
• 
Progression-free survival (PFS), defined as the 
time from the date of first IMP administration to the 
date of the first documented disease progression 
determined by Investigator as per RECIST 1.1 or 
death due to any cause, whichever occurs first 
• 
To assess the pharmacokinetics (PK) of 
SAR444245 in combination with other anticancer 
therapies 
• 
Plasma concentrations and where applicable PK 
parameters of SAR444245 
• 
To assess the immunogenicity of SAR444245 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245 
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Special considerations pertaining to methodology  
Interactive Response Technology (IRT) will be used to control recruitment, assignment per site 
and to facilitate the handling, management, and accountability of drug supply.  
Number of participants: 
Please refer to the individual substudy for the numbers of participants to be enrolled and treated at 
the recommended safe dose. 
Note: Enrolled participants are all participants from screened participants who have been 
allocated to an intervention regardless of whether the intervention was received or not.  
Intervention groups and duration: 
The duration of the study for a participant will include: 
Screening Period: up to 28 days 
Treatment Period: enrolled participants will receive continuous treatment until PD, unacceptable 
adverse event (AE) or other full permanent discontinuation criteria as described in Section 7; or 
completion of Cycle 35 (if applicable). 
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, whichever comes first. 
Participants will then enter the Observation Period and will be followed differently depending 
on the reason leading to End of Treatment (EOT).  
1. Participants who discontinue study treatment without PD or who complete 35 cycles of 
treatment without PD will be followed every 3 months ±7 days from last IMP 
administration, for safety (as per Schedule of Activities [SoA]) and tumor imaging 
assessments until PD, start of another anticancer therapy, final cohort cut-off, whichever 
comes first, before moving to the Survival Phone Call Follow-Up Period. 
2. Participants who discontinue study treatment with PD will be followed for safety in the 
Follow-Up Visit 1 occurring 3 months ±7 days from last IMP administration, before 
moving to the Survival Phone Call Follow-Up Period.  
Participants who move into the Survival Phone Call Follow-Up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Updated survival status may be 
requested by the Sponsor at any time during the study. Survival Phone Call Follow-up will 
continue until death, participant request to discontinue from follow-up, or cut-off date for the 
given cohort final analysis has been reached, or upon cancellation of Survival follow-up in the 
given cohort at the discretion of the Sponsor at any prior timepoint, whichever occurs first. 
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The cohort cut-off for the primary ORR endpoint analysis in each individual cohort is estimated to 
be approximately 9 months from the date of the last participant first infusion. This would allow 
the possibility to observe the response of the last participant for 6 months, assuming there is 
a response at first treatment assessment. 
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 18 months from the corresponding cohort LPI. After this cut-
off date for the final analysis, the participants of the given cohort still receiving study treatment in 
that specific cohort will be followed up as the cohorts after early termination described in 
Section 10.1.9. 
Study intervention(s) 
Investigational medicinal products 
SAR444245 
• Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion 
in a single-dose vial with an extractable volume of 1 mL. 
• Route of administration: IV infusion  
• Dose regimen: 24 μg/kg administered as an IV infusion over 30 minutes every 3 weeks on 
Day 1 of each cycle (21 days per cycle) for the treatment duration defined in the individual 
substudy. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted. 
See substudy protocols for other IMPs. 
Noninvestigational medicinal products 
Premedication for SAR444245 
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, 30 to 60 minutes prior to SAR444245 
infusion (no longer than 60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or oral route (PO) (or equivalent), and 
then optionally thereafter as needed. 
Diphenhydramine 25 to 50 mg IV or PO (or equivalent, eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter as needed. 
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SAR444245 premedication may be optional after 4 cycles 
• For a participant who has no IRR during the first 4 cycles: Premedication for the 
subsequent infusions is optional at the Investigator’s discretion. However, if during the 
subsequent infusions without premedication the participant experiences an IRR (any 
grade), premedication must be restarted for all subsequent infusions.  
• If a participant develops an IRR Grade <2 during their first cycle only and then 
experiences no further IRRs during their next 3 cycles: The Investigator may consider 
omitting premedication for Cycle 5. If no IRR is observed during Cycle 5 without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during Cycle 5 without premedication the participant experiences 
an IRR (any grade), premedication must be restarted for all subsequent cycles. 
Statistical considerations: 
• Analysis of primary endpoint:  
- 
Objective response rate (ORR) and best overall response (BOR) will be summarized 
for the efficacy population with descriptive statistics. In addition, two-sided 90% 
confidence intervals (CIs) for ORR will be computed using the Clopper-Pearson 
method. 
• Analysis of secondary efficacy endpoints:  
- 
The time to response (TTR) will be summarized on the subgroup of participants who 
have achieved confirmed objective response in the efficacy population.  
- 
The duration of response (DoR) will only be summarized on the subgroup of 
participants who have achieved confirmed objective response in the efficacy 
population. 
- 
The clinical benefit rate (CBR) will be estimated by dividing the number of participants 
with clinical benefit by the number of participants in the efficacy population. 
- 
The progression free survival (PFS) will be summarized on the efficacy population 
using Kaplan-Meier methods. The median PFS times and associated 90% CI will be 
provided. 
• Analysis of secondary safety endpoints: 
- 
Number and percentage of participants experiencing treatment-emergent adverse 
events (TEAEs) by primary System Organ Class (SOC) and Preferred Term (PT) will 
be summarized by National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) V 5.0 or American Society for Transplantation and 
Cellular Therapy (ASTCT) grade (all grades and Grade ≥3) for the exposed 
population. Similar summaries will be prepared for treatment-related TEAEs, TEAEs 
leading to permanent partial intervention discontinuation (any of the IMP 
components), TEAEs leading to permanent 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), participants who died by study period (treatment-emergent period, 
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post-treatment period) and reasons for death will be summarized. Immune Cell-
Associated Neurotoxicity Syndrome (ICANS) and cytokine release syndrome (CRS) 
events will be graded using ASTCT Consensus Grading and will be summarized 
separately. 
- 
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: 
- 
Plasma concentrations of each cohort by SAR444245 will be summarized with 
descriptive statistics. Where applicable, in addition PK parameters for SAR444245 
will be summarized with descriptive statistics  
Data Monitoring/Other Committee: Yes (see Section 10.1.5 for details) 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
AE: adverse event; ORR: objective response rate; RECIST: Response Evaluation Criteria in Solid Tumors 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
 
Evaluationa  
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to D-1 D1 
D8f 
(±1) 
D15f 
(±1) 
D1 
(±3) 
 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months after 
last IMP 
admin ±7 
days 
6 months 
after last 
IMP admin 
±7 days 
Every 3 
months after 
FU visit 2 ± 7 
days 
Every 3 
months+/- 
14 days 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
 
Inclusion and exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical and 
disease history  
X 
  
  
  
  
  
  
  
  
  
See Section 8 
Body Weight / Heightg 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Full physical 
examination 
X 
 
 
 
 
X 
 
 
 
 
See 
Section 8.2.1 
Directed Physical 
examination 
 
X 
X 
X 
X 
 
X 
  
  
  
See 
Section 8.2.1 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
  
  
  
See 
Section 8.2.2 
Performance status 
(ECOG) 
X 
X  
X 
X 
X 
X 
X 
  
  
  
 
SpO2 
X 
As clinically indicated 
  
  
  
  
  
 
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Evaluationa  
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to D-1 D1 
D8f 
(±1) 
D15f 
(±1) 
D1 
(±3) 
 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months after 
last IMP 
admin ±7 
days 
6 months 
after last 
IMP admin 
±7 days 
Every 3 
months after 
FU visit 2 ± 7 
days 
Every 3 
months+/- 
14 days 
 
Laboratory and other investigations 
 
12-Lead ECG  
X 
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 (Cycle 4 
Day 1) 
As clinically indicated 
 
 
 
See 
Section 8.2.3 
and 
Section 10.2 
Pregnancy test  
X 
X 
  
  
X 
X 
X 
X 
  
  
See 
Section 8.2.5 
and 
Section 10.2 
Hepatitis serology, CD4 
counts and viral load  
Xh 
As clinically indicated 
  
  
  
See 
Section 10.2 
and 
Section 10.7 
Hematology  
X 
X 
X 
X 
X 
X 
X 
  
  
  
See 
Section 10.2 
Coagulation 
X 
As clinically indicated 
  
  
  
See 
Section 10.2 
Blood Chemistry  
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 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to D-1 D1 
D8f 
(±1) 
D15f 
(±1) 
D1 
(±3) 
 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months after 
last IMP 
admin ±7 
days 
6 months 
after last 
IMP admin 
±7 days 
Every 3 
months after 
FU visit 2 ± 7 
days 
Every 3 
months+/- 
14 days 
 
Urinalysisi 
X 
X 
  
  
X 
X 
X 
  
  
  
See 
Section 10.2 
IMP 
 
SAR444245  
  
X 
  
  
X 
  
  
  
  
  
 
Hospitalizationj  
  
X 
  
  
  
  
  
  
  
  
 
AE/SAE assessmentk 
X 
Continuously throughout treatment period 
 X 
  
  
  
See Section 8.3 
Prior/Concomitant Meds 
X 
Continuously throughout treatment period 
  
  
  
  
See Section 6.8 
First subsequent anti-
cancer therapy 
  
  
  
  
  
X 
X 
X 
X 
X 
 
Survival status 
  
  
  
  
  
  
  
  
  
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy) / Immunogenicity assessments 
 
PK SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
 
ADA SAR444245  
See PK flowcharts in  Section 1.5.1 and Section 1.5.2 
 
PDy - Blood and tumor 
tissue collectionl,m  
See Biomarker Flowchart in Section 1.4 
 
Tumor assessment 
 
Brain imagingn 
X 
  
  
  
  
 
 
 
 
  
See Section 8.1 
CT/MRIo 
X 
  
  
  
X 
X 
X 
X 
X 
  
See Section 8.1 
 
 
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a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as 
part of screening within 3 days prior to first IMP administration. During the study treatment period, all assessments must be performed, and results should be reviewed by the investigator prior to IMP administration 
at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are 
performed and can be signed more than 28 days prior to first IMP administration. Screening time indicates the maximum time frame relative to the first IMP administration in which study procedures used to support 
eligibility are done. 
b Cycle: a treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1. For participant's convenience, all 
Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and 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 study. 
e For Cycle 4 visits, please refer to PK flowchart in Section 1.5. 
f 
C1D8 and/or C1D15 visits must be performed on site for the following participants only: 1) Participants scheduled to have blood draws for biomarker assessment and/or ADA on Day 8; 2) Participants who will 
receive IMP on Day 8 and Day 15. For all other participants, these 2 on-site visits may be done remotely as appropriate based on investigator’s discretion per institutional standard and local regulations. If this is 
the case, this must be documented in the source document. Sponsor may decide to cancel safety assessment on C1D8 and C1D15 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 For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.7). 
i 
Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal), will be performed every 4 cycles during Treatment Period and as 
clinically indicated. 
j 
Only for participants who will participate in the intensive PK sample collection. 
k AE/SAE assessment: 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).   
l 
 If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
m Will not be done for participants enrolled in China. 
n Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is clinically 
contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease as per protocol tumor assessment (TA) schedule. In all other cases, the lesions must be treated. Two additional scans, obtained at least 4 weeks apart, should be obtained to document disease 
stability after local treatment administration to the brain metastases has been completed. If participants receive 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 
4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or have 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. 
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o CT/MRI: The initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ± 7 days) after the date of first IMP and if clinically indicated. Imaging studies should 
follow calendar days and should not be adjusted for delays in cycle starts or extension. 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, during 
treatment period until PD. Per the primary tumor assessment criteria, after the first documentation of response or the first documentation of progression (if the participant is clinically stable), confirmatory imaging 
may be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor assessment is not needed for 
participants who start another anti-cancer therapy.  
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AST=aspartate transaminase; ALT=alanine transaminase; C=Cycle; ANC=Absolute neutrophil count; AP=Alkaline phosphatase; BUN=Blood urea 
nitrogen; CRF=case report form; CRS=Cytokine release syndrome; CT=computed tomography; 
; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; e-CRF=electronic case report form; EOT=end-of-treatment; FT4=free thyroxine; FU=follow-up; HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; ICF=Informed consent form; 
IMP=investigational med
ed ratio; LDH=Lactate hydrogenase; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA= multigated acquisition; 
PD=progressive disease
 PDy=pharmacodynamic; PK=pharmacokinetic; PR=partial response; PS=Performance Status; SpO2= oxygen saturation; Q3W=every 3 weeks; 
RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; WBC=White blood cells.  
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1.4 
BIOMARKER FLOWCHART  
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1.5 
PHARMACOKINETIC FLOWCHARTS  
For participants who will undergo more intensive pharmacokinetic (PK) sampling, the schedule is shown in the flowchart in Section 1.5.1.  
For all other participants, the PK sampling schedule is shown in the flowchart in Section 1.5.2. 
The sampling time-points for PK and anti-drug antibody (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. 
1.5.1 Participants with more intensive PK sampling  
 
Cycle 
 
Cycle 1 
Cycle 2, 3 
Cycle 4 
Cycles 6, 8, 10 + 
every 4th cycle 
thereafter 
EOT 
visit 
  30 
(±7) 
days 
after 
last 
IMP 
admi
n 
Day 
D1 
D8 
D1 
D1 
D1 
Time after 
SAR4442
45 dosing 
(EOI, 
except 
SOI) [h] 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
168 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
SOI 
EOI 
SAR444245 
PK sample 
ID 
P00a P01b P02 P03 P04 P05 
P06 
P07 
P08 
 
P00a 
P01b 
P00a 
P01b P02 P03 P04 P05 
P06 
P07 
P08 
P00a 
P01b 
  
Sample time 
window 
 
 
±15 
min 
±30 
min 
±30 
min 
±30
 min 
±4 h 
±6 h 
±8 h 
 
 
 
 
 
±15
 min 
±30
 min 
±30
 min 
±30
 min 
±4 h 
±6 h 
±8 h 
 
  
SAR444245 
ADA sample 
IDc 
AB00
a 
  
  
  
  
  
  
  
 
 AB01 
AB00
a 
  
AB00
a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI), 
b PK sample must be taken at EOI after flush. 
c ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
In the event the infusion is interrupted, a PK sample should be drawn immediately after interruption. If infusion is not likely to be resumed by clinical assessment, subsequent samples should be drawn at EOI + 1 h, 
+2 h, +4 h, +8 h, +24 h, +48 h and +72 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent samples should be drawn at 1 h, 2 h, 4 h, 8 h, 24 
h, 48 h and 72 h after end of resumed infusion (as per protocol). 
ADA: anti-drug antibodies; EOI: End of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: Start of infusion.   
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1.5.2 All other participants  
 
Cycle 
Cycle 1 
Cycles 2, 3. 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
Day 
D1 
D8 
D1 
Time after SAR444245 dosing (EOI, 
except SOI) [h] 
SOI 
EOI 
24 
168 
SOI 
EOI 
30 (±7) days after 
last IMP admin 
SAR444245 PK sample 
 
P01b 
P06c 
 
 
P01b 
 
SAR444245 ADA sample 
AB00a 
 
AB01 
AB00a 
 
ABF00 
a Samples collected strictly before start of infusion (SOI) 
b EOI samples = end of infusion samples. Must be taken at end of infusion precisely 
c PK sample can be collected at any time during the second day of the cycle. 
ADA: anti-drug antibodies, PK: pharmacokinetic: SOI: start of infusion; EOI: end of infusion   
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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 complete response (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  
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models.  
The proposed study aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with other anticancer therapies will result in a significant increase in the percentage 
of participants experiencing an objective response in the setting of various advanced 
gastrointestinal cancers. 
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2.2 
BACKGROUND  
2.2.1 Overall rationale for GI studies  
Immune checkpoint inhibitors are approved in most of the indications’ proposed cohorts. In 
esophageal squamous cell carcinoma (ESCC) and gastric or gastroesophageal junction cancer 
(GC/GEJ), pembrolizumab monotherapy has received approvals as the 2L or 3L+ treatment. 
However, the benefit is limited to patients whose tumor expresses programmed death-ligand 1 
(PD-L1) (CPS ≥1 or ≥10) and the objective response was 16% (CPS ≥1) and 22% (CPS ≥10) 
(3, 4). Combining SAR444245 (THOR-707) with pembrolizumab is anticipated to expand to 
population responding to the anti-PD1 and to increase the quality of the response. Such effects 
have been demonstrated in the PIVOT-02 study for bempegaldesleukin combined with nivolumab 
in locally advanced or metastatic solid tumors. In this study, 53% ORR including 34% CR was 
obtained for melanoma (5), 54% ORR for RCC (6), 50% ORR for non-small cell lung cancer (6), 
48% ORR for urothelial carcinoma (7) and 13% ORR for triple-negative breast cancer (8), 
respectively. The ORR was high regardless of PD-L1 status, eg, 50% (PD-L1+) and 45%  
(PD-L1-) for metastatic urothelial carcinoma (7), 64% (PD-L1+) and 39% (PD-L1-) 
for melanoma (5), and 57% (PD-L1+) and 54% (PD-L1-) for renal cell carcinoma (6). Based on 
such evidence, we consider also, that combining THOR-707 with pembrolizumab is anticipated to 
bring benefit to patients with ESCC and GC/GEJ even in the context of low PD-L1 and could 
rescue patients who have progressed or relapsed following an anti-PD1/PD-L1 treatment. 
In advanced hepatocellular carcinoma, the ICI-based combination regimen (atezolizumab + 
bevacizumab) has become the new SoC in 1L based on improved durable response and survival. 
Combining SAR444245 (THOR-707) with ICI will be evaluated to rescue patients who have 
failed the ICI-based 1L regimen.  
Non-MSI-H metastatic colorectal cancer (CRC) is known to not respond to ICI, being qualified as 
immune excluded or restricted tumors. Combining ICI with SAR444245 (THOR-707) may 
initiate inflammatory response in the tumor microenvironment and sensitize CRC to anti-PD1. 
More details will be provided on the rationale of each cohort and tumor type in appropriate 
substudies. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 may be found in the Investigator’s Brochure. 
2.3.1 Risk assessment  
Safety data from clinical studies conducted with SAR444245 in humans is currently limited to 
available from the Phase 1/2 first-in-human study (Study TCD16843 [HAMMER], hereafter 
referred to as HAMMER). Consequently, the assessment of the risks associated with SAR444245 
is based on existing preclinical data and takes into consideration the known safety profile of the 
structurally similar product aldesleukin (Proleukin®) and current knowledge of the new 
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
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Table 5 summarizes potential risks for SAR444245 identified from preclinical experience and from 
the Phase 1/2 first-in-human (HAMMER) study. 
2.3.1.1 Aldesleukin experience  
There is currently one marketed IL-2 product, Proleukin (aldesleukin). It is an IL-2 therapeutic 
that is currently licensed in the US for the treatment of metastatic RCC and metastatic melanoma, 
and in several European countries for the treatment of metastatic RCC. 
Aldesleukin is a human recombinant interleukin-2 which has been shown to possess the biological 
activities of human native IL-2 mediated through its binding with the high-affinity IL-2Rαβγ and 
intermediate-affinity IL-2Rβγ receptors. The widespread use of aldesleukin has been limited by its 
low response rate, a short t1/2 that requires dosing three times per day, and toxicities (9), 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 (10). Aldesleukin 
mediates activation of ILC-2s via interaction with the high affinity IL-2R⍺ chain that exists at low 
levels on ILC-2s. 
Treatment with aldesleukin is associated with impaired neutrophil function (reduced chemotaxis) 
and the resulting increase in the risk of disseminated infection, including sepsis and bacterial 
endocarditis. Consequently, preexisting bacterial infections should be adequately treated prior to 
initiation of Proleukin therapy. 
Proleukin toxicity threat mandates that it should be administered in a hospital setting under the 
supervision of a qualified physician experienced in the use of anticancer agents. An intensive care 
facility and cardiopulmonary or intensive care specialists must be available. 
Proleukin has been shown to have embryo lethal effects in rats but there are no adequate 
well-controlled studies in pregnant women; this information can be extrapolated to SAR444245. 
Also, since it is not known whether SAR444245 is excreted in human breast milk, nursing 
mothers cannot participate in this study. 
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High doses of aldesleukin (IL-2) were associated with decreased expression of enzymes of hepatic 
metabolism (11). As SAR444245 also exercises IL-2 activity, the Investigator should monitor 
clinical effects of narrow therapeutic index drugs that are hepatically metabolized.  
2.3.1.2 SAR444245  
2.3.1.2.1 Preclinical data  
Among the potential risks, preclinical data for SAR444245 are lacking for 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 nephrotoxicity and neurotoxicity are also proposed in the protocol. 
Preclinical data for SAR444245 do not indicate higher risk for infections. However, infections are 
typically associated with the use of aldesleukin and are to be expected. 
There are no preclinical data for tumor lysis syndrome (TLS) associated with the use of 
SAR444245, but it is known to occur when aldesleukin is combined with cisplatinum, vinblastine 
and dacarbazine (refer to Proleukin US label) (12). The participants at greatest risk of TLS are 
those with high tumor burden prior to treatment, elevated uric acid level, poor hydration or tumor 
infiltration of the kidney, or receiving intensive cytoreductive therapy. 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been described 
in the setting of immunotherapy with T cell engagement. It is characterized by a variety of 
symptoms including high fevers, hypotension, rigors and malaise, and may progress to cytokine 
storm (uncontrolled immune hyperactivation involving myriad cytokines) with more severe and 
potentially life-threatening manifestations. As SAR444245 mediates immune activation, it may 
induce 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 NHP, 
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 it 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. 
2.3.1.3 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 1 study, NKTR-214 was administered as an outpatient regimen and 
was well tolerated. Twenty-eight patients with advanced or locally advanced solid tumor 
malignancies were enrolled in the study. Grade 3 treatment-related adverse events (TRAEs) were 
reported by 21.4% of patients; there were no Grade 4 TRAEs or any treatment related deaths. The 
most common TRAEs included fatigue (71%), flu-like symptoms (68%), pruritus (64%), 
hypotension (57%), rash (50%), decreased appetite (46%), arthralgia and cough (each 32%). The 
majority of these events coincided with the peak plasma concentrations of the active cytokine and 
resolved spontaneously or were mitigated by nonprescription oral or topical treatments. There was 
one reported immune-related adverse event (irAE) of hypothyroidism associated with NKTR-214, 
which was treated with replacement therapy. All Grade 3 hypotension events (18%) were rapidly 
reversed with IV fluid administration and did not require treatment discontinuation. 
NKTR-214-related hypotension was predictable, manageable, and reversible and the incidence of 
Grade 3 hypotension was reduced once hypotension risk mitigation strategies were implemented. 
The maximum tolerated dose (MTD) was determined to be 0.009 mg/kg Q3W. This new 
generation, IL-2R-biased IL2 could be safely administered as outpatient basis, and there was 
no report of capillary leak syndrome (CLS) or VLS (13).  
In PIVOT-02, a single-arm, Phase 1/2 study, NKTR-214 plus nivolumab was administered to 
38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, RCC, and 
non-small cell lung cancer [NSCLC]). Several treatment regimens were explored. The dose of 
0.009 mg/kg had excessive toxicity (2 of 3 patients with DLT: Grade 3 hypotension [n=1] & 
Grade 4 hyperglycemia + metabolic acidosis [n=1]) when combined with 360 mg of nivolumab. 
All 38 patients had TEAEs that were considered related to the study combination. The MTD of 
the combination was defined as NKTR-214 0.006 mg/kg + nivolumab 360 mg Q3W and this dose 
was selected as the recommended Phase 2 dose (RP2D). The most common TRAEs (≥30%) at the 
RP2D were flu-like symptoms (80%), rash (80%), fatigue (76%), pruritis (48%), arthralgia (44%), 
headache and diarrhea (40%), nausea (40%), decreased appetite (36%) and peripheral edema 
(36%), myalgia (32%), and nasal congestion (32%). Grade ≥3 TRAEs occurred in 16% of patients 
at the RP2D (hyperglycemia, lipase increase, rash, cerebrovascular accident, hyponatremia, 
infectious pleural effusion, syncope). Immune-mediated AEs were observed in 31.6% overall: 
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hypothyroidism (11), hyperthyroidism (2), hyperglycemia (2). Cytokine-related symptoms were 
observed primarily in Cycles 1 & 2 and became 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 PD-1/PD-L1 blockade. These data demonstrated that 
NKTR-214 can be safely combined with a checkpoint inhibitor as dual immunotherapy for the 
treatment of a range of advanced solid tumors (14).  
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-2Rβγ, the 
suppressor CD4+ Treg cells are preferentially enhanced at lower dose through the high-affinity 
IL-2Rαβγ which is probably responsible for the limited proportion of responding patients (ORR 
16% in metastatic melanoma patients - US Label), and at the price of significant toxicities. 
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. 
2.3.3 Overall benefit: risk conclusion  
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the IL-2 α receptor, while retaining stimulatory activity for cells expressing the moderate 
affinity IL-2 βγ receptor. These design features are anticipated to minimize safety liability 
associated with Proleukin® by avoiding expansion of immunosuppressive immune cell 
populations (regulatory T cells) and off-target complications such as VLS, while still promoting 
the expansion of immune populations that can support anti-tumor immune responses. 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with this new generation IL-2 SAR444245 combined with other 
anticancer therapies are justified by the anticipated benefits that may be afforded to participants 
with gastrointestinal cancer.  
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2.3.4 Benefit and risk 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  
Cancer patients with weakened immune systems are vulnerable to COVID-19 due to the cancer 
itself and treatments. A large case-control study reported patients with cancer had a higher risk for 
COVID-19 infection with an odds ratio (OR) of 1.5 compared to those without cancer and those 
with recent (in the past year) diagnosis of cancer were at a significant increased risk with an OR 
of 7.1 (15). Among patients with recent diagnosis of cancer, the adjusted OR for COVID-19 
infection was 6.5 for liver cancer and 6.4 for colorectal cancer, respectively. COVID-19 increases 
the severity and complications in patients with cancer. Patients with cancer and COVID-19 had 
significantly worse outcomes (hospitalization, 47.46%; death, 14.93%) than patients with 
COVID-19 without cancer (hospitalization, 24.26%; death, 5.26%) and patients with cancer 
without COVID-19 (hospitalization, 12.39%; death, 4.03%) (15). This was agreed by other 
studies where the OR for death in COVID-19 patients with cancer was reported from 2.54 to 
3.16 compared to those without cancer (16, 17, 18).  
The impact of COVID-19 on cancer outcomes differs by cancer type. A meta-analysis of cancer 
patients with COVID-19 demonstrated gastrointestinal cancer is one of the most common cancer 
types reported with an estimated rate of 15.2% and its all-cause in-hospital mortality rate 
(approximately 20%) ranked the third following hematological malignancies and lung cancer (16). 
In one of these studies, esophageal cancer had a high risk of death (17%), high ICU administration 
rate (33%) and high risks of severe/critical symptoms (50%), whereas approximately 8%, 23% 
and 31% were reported respectively for gastrointestinal cancer (19). COVID-19 has caused delays 
in cancer diagnosis and treatment especially for gastrointestinal cancers, which potentially result 
in poor clinical outcomes (20, 21, 22). Furthermore, patients with advanced and metastatic 
gastrointestinal cancer often suffer from gastrointestinal symptoms and chronic bleeding, thus 
experiencing malnutrition, poor immune status and anemia (22). In addition, patients may suffer 
from poor mental status such as anxiety or depression during the pandemic. All of these can lead 
to further deterioration of patients’ condition and expose them to high risk of getting COVID-19 
and developing more severe clinical outcomes. To that end, trial participation will proceed during 
the COVID-19 pandemic, however, measures will be taken to mitigate the potential risks of 
SARS-CoV-2 infection to trial participants. 
Testing for SARS-CoV-2 infection during the screening phase should be at Investigator’s 
discretion and should also follow local/international guidelines (eg, patients who are 
asymptomatic but with high risk of infection, 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. 
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During the study, if a participant is diagnosed with SARS-CoV-2 infection, dose modification of 
study intervention should be based on the recommendations provided in Section 6.5. 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) (23) 
• European Society for Medical Oncology (ESMO) (24) 
2.3.4.1.2 Risks related to study treatment  
SAR444245 has the potential to induce CRS which could exacerbate the manifestations of 
COVID-19 infection. It is, however, worth noting that pegylated IL-2 bempegaldesleukin is 
currently being evaluated for the treatment of patients with mild COVID-19 in a Phase 1b study 
(NCT04646044). 
2.3.4.1.3 Risks related to study-related activity  
It is important to minimize the risk of exposure of patients to COVID-19. In addition to the 
contingency measures described in Section 10.9, 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.  
• 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 
gastrointestinal cancer during the COVID-19 pandemic. The 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 
 
Secondary 
 
Exploratory 
 
• 
To determine the antitumor activity of SAR444245 
in combination with other anticancer therapies   
• 
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) 
• 
To assess the safety of SAR444245 in combination 
with other anticancer therapies 
• 
Incidence of treatment emergent adverse events 
(TEAEs), serious adverse events (SAEs), laboratory 
abnormalities according to National Cancer Institute 
Common Terminology Criteria for Adverse Events 
(NCI CTCAE) V5.0 and American Society for 
Transplantation and Cellular Therapy (ASTCT) 
consensus grading (2) 
• 
To assess other indicators of antitumor activity 
• 
Time to response (TTR), defined as the time from 
the first administration of investigational medicinal 
product (IMP) to the first tumor assessment at which 
the overall response was recorded as PR or CR that 
is subsequently confirmed and determined by 
Investigator per RECIST 1.1 
• 
Duration of response (DoR), defined as the time 
from first tumor assessment at which the overall 
response was recorded as CR or PR that is 
subsequently confirmed until documented 
progressive disease (PD) determined by 
Investigator per RECIST 1.1 or death from any 
cause, whichever occurs first 
• 
Clinical benefit rate (CBR)  including confirmed CR 
or PR at any time or stable disease (SD) of at least 
6 months determined by Investigator per 
RECIST 1.1. 
• 
Progression-free survival (PFS), defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by Investigator as per RECIST 1.1 or 
death due to any cause, whichever occurs first 
• 
To assess the pharmacokinetics of SAR444245 in 
combination with other anticancer therapies 
• 
Plasma concentrations and where applicable PK 
parameters of SAR444245 
• 
To assess the immunogenicity of SAR444245 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245 
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For China, please see Section 10.7 for details. 
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 gastrointestinal 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 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with advanced or metastatic gastrointestinal cancer.  
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. This design is 
with the flexibility to open new treatment cohorts as new treatment combinations become 
available and close existing treatment arms that demonstrate minimal clinical activity or 
unacceptable toxicity. 
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
This study is designed with the flexibility to open new treatment arms or add new indications as 
permitted by scientific rationale.  
A graphical presentation of the study schema is shown in the individual substudy. 
Interactive Response Technology (IRT) will be used to control recruitment, assignment per site 
and to facilitate the handling, management, and accountability of 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 
progressive disease (PD), unacceptable adverse event (AE) or other full permanent 
discontinuation criteria as described in Section 7; or completion of Cycle 35 (if 
applicable). 
• 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, whichever comes 
first. Participants will then enter the Observation Period and will be followed differently 
depending on the reason leading to End of Treatment (EOT).  
1. Participants who discontinue study treatment without PD or who complete 35 cycles of 
treatment without PD will be followed every 3 months ±7 days from last IMP 
administration, for safety (as per Schedule of Activities [SoA]) and tumor imaging 
assessments until PD, start of another anticancer therapy, final cohort cut-off, whichever 
comes first, before moving to the Survival Phone Call Follow-Up Period. 
2. Participants who discontinue study treatment with PD will be followed for safety in the 
Follow-Up Visit 1 occurring 3 months ±7 days from last IMP administration, before 
moving to the Survival Phone Call Follow-Up Period.  
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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. Updated survival status may be 
requested by the Sponsor at any time during the study. Survival Phone Call Follow-up will 
continue until death, participant request to discontinue from follow-up, or cut-off date for the 
given cohort final analysis has been reached, or upon cancellation of Survival follow-up in the 
given cohort at the discretion of the Sponsor at any prior timepoint whichever occurs first.  
The cohort cut-off for the primary ORR endpoint analysis for each individual cohort is estimated 
to be approximately 9 months from the date of the last participant first infusion. This would allow 
the possibility to observe the response of the last participant for 6 months, assuming there is 
a response at first treatment assessment. 
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 18 months from the corresponding cohort LPI. After this cut-
off date for the final analysis, the participants of the given cohort still receiving study treatment in 
that specific cohort will be followed up as the cohorts after early termination described in 
Section 10.1.9. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The proposed study aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with other anticancer therapies will result in a significant increase in the percentage 
of participants experiencing an objective response. 
The design of the 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 as 
a benchmark to show outstanding ORR. The ORR will be assessed using RECIST 1.1 for 
participants with advanced and metastatic gastrointestinal cancer. The objective response will be 
assessed per Investigator as primary endpoint. Central imaging reading may be done 
retrospectively if significant activity is observed.  
4.2.1 Participant input into design  
There was no participant involvement in the design of the trial. 
4.3 
JUSTIFICATION FOR DOSE  
Dose escalation for SAR444245 monotherapy and in combination with pembrolizumab or 
cetuximab is ongoing in the first-in-human HAMMER study. Data from a total of 68 patients who 
have received SAR444245 Q2W or Q3W in monotherapy, in a Q3W regimen in combination with 
pembrolizumab 200 mg Q3W, or with cetuximab 400/250 mg/m² QW is available as of 18 June 
2021. SAR444245 24 µg/kg Q3W pembrolizumab combination and cetuximab combination dose 
level have been cleared by HAMMER Safety Review Committee based on this data cut-off. 
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The dose levels tested to date for SAR444245 monotherapy administered using a Q3W schedule 
are 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=11), 32 µg/kg (n=6) and 40 µg/kg (n=2). 
In combination with pembrolizumab, SAR444245 has been administered Q3W at the doses of 
8µg/kg (n=4), 16µg/kg (n=9), 24 µg/kg (n=6), 32 µg/kg (n=1). In combination with cetuximab, 
SAR444245 has been administered Q3W at 16 µg/kg (n=5) or 24 µg/kg (n=5). 
For monotherapy cohort, the only DLT observed to date is a Grade 3 infusion reaction (occurred 
in C2D1 which resolved on the same day with supportive care) reported in a patient on 32 µg/kg 
Q3W monotherapy.  
For SAR444245 in combination with pembrolizumab 200 mg Q3W, 1 DLT (Grade 3 liver 
enzyme elevation with Grade 2 bilirubin elevation meeting drug-induced liver injury [DILI] 
criteria occurred in C1D1 which resolved after 7 days with steroids) was observed in a participant 
with SAR444245 24 µg/kg Q3W with pembrolizumab. 
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%). 
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. 
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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, 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 post-dose peak of 
expansion. The day 8 sample timepoint was added after the first 3 participants in the 8 µg/kg 
cohort were dosed. 
In addition, the average increase in peripheral blood NK cells was 4.22-fold at 72 hours for 
8 µg/kg. The 16 µg/kg and 24 µg/kg dose levels resulted in 5.9 and 7.67-fold NK expansion, 
compared to baseline at the day 8 peak expansion. Among the dose levels tested to date for 
SAR444245 in combination with pembrolizumab administered using Q3W schedule, we have 
collected available PDy data for the 8 µg/kg (n=4) and 16 µg/kg cohort (n=6), in which the 
average increase in CD8+ T cells, compared to baseline, is 2.06-fold and 3.71-fold, respectively; 
and the average increase in NK cells, compared to baseline, is 6.73-fold and 13.43-fold, 
respectively at the peak expansion day 8. In addition, the comparison of T and NK cell expansion 
between 
 µg/kg and 
 µg/kg cohorts indicated that the anticipated maximum CD8+ T and NK 
cells expansion PDy effect may have been achieved at 
 µg/kg cohort. Based on these data, 
additional quantitative systems pharmacology (QSP) and population PK/PDy models were 
developed and indicated that the increase of CD8+ T and NK cells was less than proportional with 
increasing dose, suggesting a flattening of the dose-response curve. 
In addition, preclinical studies using human whole blood to assess the induction of cytokines 
showed no change in cytokine profiles when administering SAR444245 with and without 
pembrolizumab. This study used SAR444245 concentration ranges that went significantly higher 
than current clinical dosages (0.2-4.5 µg/mL) and showed that SAR444245-induced cytokine 
release in human whole blood was not affected in the presence of pembrolizumab at Q3W 
schedule. 
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Considering below, Sponsor proposes to evaluate the clinical benefit of SAR444245 24 µg/kg in 
this Phase 2 study. 
1. SAR444245 monotherapy up to 32 µg/kg Q3W, pembrolizumab combination up to 
32 µg/kg Q3W and cetuximab combination 24 µg/kg Q3W are all cleared in HAMMER 
study. 
2. Sustained relevant PDy effect in blood, higher at higher dose, was documented in 
participants;  
3. And overlapping toxicities not suggested by comparing safety data from SAR444245 
monotherapy cohort, SAR444245 in combination with pembrolizumab cohort, or 
SAR444245 in combination with cetuximab cohort. Though theoretically, combining 
SAR444245 with either pembrolizumab or cetuximab may lead to increase and/or severity 
of certain AEs (detailed in Section 2.3.1 of the substudies).  
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  
The inclusion criteria listed in the master protocol are only those applicable to all the participants 
common to all substudies. For additional substudy specific criteria, refer to the particular 
substudy. 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age (or country’s legal age of majority if >18 years), at 
the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Measurable disease: 
At least 1 measurable lesion per RECIST 1.1 criteria. Target lesions may be located in 
a previously irradiated field if there is documented radiographic disease progression in that 
site. 
Weight (not applicable) 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 03. All (male and female)   
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
A) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 3 days [corresponding to time needed to eliminate 
SAR444245] after the last dose of SAR444245: 
- 
Refrain from donating or cryopreserving sperm 
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 
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- 
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 Section 10.4 Appendix 4 
when having sexual intercourse with a woman of childbearing potential (WOCBP)  
who is not currently pregnant, or during homosexual intercourse. 
B) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
- 
Is not a 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 
Section 10.4 Appendix 4 during the intervention period (to be effective before starting 
the intervention) and for at least 120 days (for Cohort A, B1, B2, B3, C, and D1) or 
60 days (for Cohort D2) [corresponding to the time needed to eliminate any study 
intervention(s) ] after the last dose of study intervention and agrees not to donate or 
cryopreserve eggs (ova, oocytes) for the purpose of reproduction during this period. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (as required by local 
regulations) within 72 hours before the first dose of study intervention. 
- 
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 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 04. Capable of giving signed informed consent as described in Section 10.1 Appendix 1 which 
includes compliance with the requirements and restrictions listed in the informed consent 
form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply. For additional 
individual substudy specific criteria, refer to the particular substudy: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. 
E 02. Predicted life expectancy ≤3 months. 
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E 03. Active brain metastases or leptomeningeal metastases.  
- 
Patients with previously treated brain metastases are eligible provided they are 
clinically stable for at least 4 weeks with no evidence of new or enlarging brain 
metastases and have not received corticosteroids at least 2 weeks prior to first IMP 
administration.  
- 
 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 as per protocol tumor assessment (TA) 
schedule. 
E 04. History of allogenic tissue/solid organ transplant.  
E 05. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents and anti-cytotoxic T 
lymphocyte associated protein 4 monoclonal antibodies) that caused permanent 
discontinuation of the agent, or that were Grade 4 in severity. 
E 06. Last administration of prior antitumor therapy (chemotherapy, targeted agents, and 
immunotherapy) or any investigational treatment within 28 days or less than 5 times the 
half-life, whichever is shorter; major surgery within 28 days prior to first IMP 
administration.  
E 07. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 2 weeks of IMP initiation. Inhaled or topical steroids are permitted, provided that 
they are not for treatment of an autoimmune disorder. Participants who require a brief 
course of steroids (eg, as prophylaxis for imaging studies due to hypersensitivity to 
contrast agents) are not excluded. 
E 08. Antibiotic use (excluding topical antibiotics) ≤14 days prior to first dose of IMP, or any 
serious systemic fungal, bacterial, viral (excluding viral infection settings as described in  
E 15), or other infection that is not controlled. 
E 09. Severe or unstable cardiac condition within 6 months prior to starting study treatment, such 
as congestive heart failure (New York Heart Association Class III or IV), cardiac bypass 
surgery or coronary artery stent placement, angioplasty, left ventricular ejection fraction 
(LVEF) below 50%, unstable angina, medically uncontrolled hypertension 
(eg, ≥160 mmHg systolic or ≥100 mmHg diastolic), uncontrolled cardiac arrhythmia 
requiring medication (≥ Grade 2, according to NCI-CTCAE v5.0), or myocardial 
infarction. 
E 10. Ongoing AEs (caused by any prior anti-cancer therapy ≥Grade 2 (NCI-CTCAE Version 
5.0). Participants with Grade 2 peripheral neuropathy, or Grade 2 alopecia, are permitted. 
Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone 
replacement may be eligible. 
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E 11. Active, known, or suspected autoimmune disease that has required systemic treatment in 
the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs), except controlled by replacement therapy (eg, thyroxine, 
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc). The following are not exclusionary: vitiligo, childhood asthma that has 
resolved, psoriasis that does not require systemic treatment. 
E 12. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or 
has current pneumonitis / interstitial lung disease.  
E 13. Participant who has received prior radiotherapy within 2 weeks of start of study 
intervention. Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. 
E 14. Receipt of a live or live attenuated-virus vaccine within 28 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted. 
E 15. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease or known uncontrolled infection with HIV. HIV-infected participants must be on 
anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:   
- 
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of 
screening.  
- 
Participants on ART must have achieved and maintained virologic suppression defined 
as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification 
(below the limit of detection) using the locally available assay at the time of screening 
and for at least 12 weeks prior to screening.  
- 
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1).  
- 
Combination ART regimen must not contain any antiretroviral medications other than: 
abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenoforvir. 
See instructions specific to Germany and Italy at screening in Appendix 2 (Section 10.2) 
and Appendix 7 (see Section 10.7). 
E 16. Known uncontrolled hepatitis B infection, known untreated current hepatitis C infection, 
active tuberculosis, or severe infection requiring parenteral antibiotic treatment. 
- 
To control HBV infection, participants with positive HBsAg should have started 
anti-HBV therapy before initiation of IMP. Antiviral therapy for HBV must be given 
for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose 
of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL 
should stay on the same therapy throughout study treatment. 
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- 
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. 
See instructions specific to Germany and Italy at screening in Appendix 2 (Section 10.2) 
and Appendix 7 (see Section 10.7). 
E 17. Known second malignancy either progressing or requiring active treatment within the 
last 3 years. Participants with non-melanomatous skin cancer or cervical cancer that has 
been curatively surgically resected are eligible. 
E 18. Known severe hypersensitivity (≥ Grade 3) to or contraindication for the use of any study 
intervention or components thereof, including premedication to be administered in this 
study, as well as PEG or any pegylated drug and E. coli-derived protein. 
E 19. Participants with baseline SpO2 ≤92% (without oxygen therapy). 
Prior/concomitant therapy 
E 20. Has received prior IL2-based anticancer treatment. 
E 21. Is unable or unwilling to take premedication. 
E 22. Participants treated under anti-hypertensive treatment who cannot temporarily (at least 
36 hours) withhold antihypertensive medications prior to each IMP dosing. 
Prior/concurrent clinical study experience 
E 23. Current enrollment or past participation in a study of an investigational treatment or 
an investigational device within 28 days prior to the first dose of study treatment. 
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 28 days after the last dose of the previous investigational 
treatment.  
Organ and bone marrow function 
E 24. Absolute neutrophil count <1500 /uL (1.5 × 109/L) (after at least one week off G-CSF). 
E 25. Platelets <75 × 10³ u/L for participants in Cohort C and platelets <100 × 10³ u/L for 
participants in all other cohorts (after at least 3 days without platelet transfusion). 
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E 26. Hemoglobin <9 g/dL (without packed red blood cell [pRBC] transfusion within prior 
2 weeks). Participants can be on stable dose of erythropoietin (≥ approximately 3 months). 
E 27. Total bilirubin >1.5 x upper limit of normal (ULN) unless direct bilirubin ≤ ULN 
(Participants with known Gilbert disease who have serum bilirubin level ≤3 × ULN may 
be enrolled). 
E 28. Aspartate aminotransferase and/or alanine aminotransferase >2.5 × ULN (or >5 × ULN for 
participants with liver metastases or participants in Cohort C). 
E 29. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² (Modification of Diet in 
Renal Disease [MDRD] Formula). 
E 30. International Normalized Ratio (INR) or Prothrombin Time (PT) (or Activated Partial 
Thromboplastin Time [aPTT]) >1.5 × ULN unless the participant is receiving 
anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of 
anticoagulants. 
Other exclusions 
E 31. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 32. Any country-related specific regulation that would prevent the participant from entering 
the study - see Section 10.7 Appendix 7 (country-specific requirements). 
E 33. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 34. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with section 1.61 of the ICH-GCP Ordinance E6). 
E 35. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 36. History or current evidence of any condition, therapy 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.  
 
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5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No food or drink restrictions are required. Guidelines on fluid intake are presented in 
Section 6.1.3. 
5.3.2 Caffeine, alcohol, and tobacco  
No restrictions are required. 
5.3.3 Activity  
Participants are advised to abstain from strenuous exercise and avoid long hot showers and saunas 
on Days 1 to 4 of every treatment cycle. 
5.3.4 Hydration  
Since SAR444245 may induce episodes of hypotension, participants should be informed of the 
importance of being well hydrated and be provided with 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.  
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once only. A participant who screen failed may be rescreened; in this situation, the 
rescreened participant should sign a new ICF. A participant may be rescreened only once. 
Rescreened participants should be assigned a different participant number as for the initial 
screening. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/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 10.9. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), intended 
to be administered to a study participant according to the study protocol. 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Participants will receive study treatment until PD, unacceptable toxicity, other permanent 
discontinuation criteria as described in Section 7, or completion of Cycle 35 (if applicable). 
6.1.1 Investigational medicinal product (IMP)  
Details of each SAR444245 are shown in Table 2.  
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Section 10.9. 
Preparation and administration of SAR444245 are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3.  
Table 2 - Overview of IMP administered  
Intervention name 
SAR444245 
Type 
Biological  
Dose formulation 
Concentrate for solution for infusion 
Unit dose strength(s) 
2.0 mg/mL 
Dosage level(s)a 
24 μg/kg Q3W  
Route of administration 
IV infusion 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and labeling 
Supplied in a single-dose vial in a treatment box. Each vial contains 2 mg/mL with 
an extractable volume of 1 mL. Each vial and treatment box will be labeled as required 
per country requirement. 
Current/Former name(s) 
or alias(es) 
NA 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in 
a reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the e-CRF. Study 
sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted. 
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6.1.2 Non-investigational medicinal products  
Non-investigational medicinal products include the premedication administered for SAR444245. 
6.1.2.1 Premedication for SAR444245  
All participants will receive the following premedication to prevent or reduce the acute effect of 
IRR or flu-like symptoms, 30 to 60 minutes prior to SAR444245 infusion (no longer than 
60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg (IV or PO) (or equivalent), and then 
optionally thereafter as needed. 
• Diphenhydramine 25 to 50 mg IV or PO (or equivalent, eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter as needed. 
SAR444245 premedication may be optional after 4 cycles: 
• For a participant who has no IRR for the first 4 cycles, premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the participant experiences an IRR (any grade), 
premedication must be restarted for all subsequent infusions.  
• If a participant develops an IRR Grade <2 during their first cycle only and then 
experiences no further IRRs during their next 3 cycles the Investigator may consider 
omitting premedication for Cycle 5. If no IRR is observed during Cycle 5 without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during Cycle 5 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 or alternative therapies per site practice in CRS management should be 
available at the site at all times in the event that a participant requires rapid intervention for the 
treatment of severe CRS. Please refer to Section 6.5 of individual substudies for detailed 
guidelines for the management of CRS. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
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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 e-CRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by 
a member of the study site staff other than the person administering the study intervention. 
6.5 
DOSE MODIFICATION  
Please see respective substudy protocols. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There will be no intervention beyond the end of the study. 
6.7 
TREATMENT OF OVERDOSE  
There is no specific antidote for overdose with SAR444245.  
If overdose occurs (see Section 8.3.8 for definitions), symptomatic management is indicated.  
Treatment of overdose should consist of general supportive care with aggressive fluid 
management, if clinically indicated. 
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Procedures for treating symptoms and complications of irAEs are provided in the individual 
substudies. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 90 days). 
3. Obtain a plasma sample for PK analysis right after the overdose event is identified (only if 
an overdose is identified within 5 days from start of overdose infusion). 
4. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant. 
6.8 
CONCOMITANT THERAPY  
Any medication 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. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from study intervention may be required. The 
Investigator is to discuss prohibited medication/vaccination with the Sponsor. The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the participant's 
primary physician. However, the decision to continue the participant on trial therapy schedule 
requires the mutual agreement of the Investigator, the Sponsor and the participant. 
6.8.1 Acceptable concomitant medications  
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the 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. 
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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 28 days before the first dose of trial treatment 
through the Follow-up Visit should be recorded. 
Colony-Stimulating Factors 
Routine use of colony-stimulating factors (CSFs) is not permitted. American Society of Clinical 
Oncology guidelines for use of CSFs should be followed (25). 
6.8.2 Prohibited concomitant medications  
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol. 
• Immunotherapy not specified in this protocol. 
• Investigational agents other than specified in this protocol. 
• Radiotherapy for tumor control (please refer to Section 6.8.1 for allowed radiotherapy). 
• Live or live attenuated virus vaccines within 28 days prior to the first dose of trial 
treatment and while participating in the trial. Examples of live-virus vaccines include, but 
are not limited to, the following: measles, mumps, rubella, chickenpox, yellow fever, 
seasonal flu (seasonal flu vaccines that do not contain live virus are permitted), nasal 
H1N1 flu, rabies, Bacillus Calmette-Guérin (BCG), and typhoid. 
• Systemic glucocorticoids and other immunosuppressive therapies such as anti-TNF, 
anti-IL6, etc, except for: 
- 
Treatment of AEs when indicated (irAE, CRS, ICANS, IRR, see Section 6.5 of 
individual substudies),  
- 
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. 
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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. 
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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.
-
Poor compliance to the study protocol.
-
Completion of 35 cycles when applicable.
-
Other, such as concurrent illness, that prevents further administration of study
intervention, or that in the Investigator’s opinion, in the best interest of the participant.
•
In case of pregnancy occurrence.
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for serial tumor assessment if permanent discontinuation is not due to PD, for safety 
assessment as per SoA (Section 1.3) and until resolution or stabilization of AE, and any other 
assessment as per SoA. Data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed are reported in the SoA. 
7.1.1.1 Unacceptable adverse events leading to permanent intervention discontinuation 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the dose modification and 
toxicity management guidelines (see individual substudy protocols), 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. 
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Any potentially clinically significant abnormal laboratory value or ECG parameter will be 
immediately rechecked for confirmation and repeated after 24 hours to document evolution before 
making a decision of permanent intervention discontinuation for the concerned participant. 
Decision criteria for discontinuation following immune-mediated AEs are described in Section 6.5 
of individual substudies (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. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed.  
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 10.9). For all temporary intervention discontinuations, 
duration should be recorded by the Investigator in the appropriate pages of the e-CRF.  
7.1.3 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator has 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 9 Contingency Measures for a regional or national emergency 
(Section 10.9) that is declared by a governmental agency.  
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, see SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
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 withdrawn from the study cannot be re-included in the study. Their 
inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
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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  
(see Section 10.1.9). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures are summarized in this section and their timing is presented in the SoA 
(Section 1.3). 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 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, echocardiography 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 10.9. 
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. 
A partial or complete response must be confirmed on a second examination done at least 4 weeks 
apart, in order to be documented as a confirmed response to therapy. Confirmation of PD may be 
done at the discretion of the Investigator when clinically indicated. 
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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. Study sites must retain 
tumor assessment images, as Sponsor may decide to collect these images for possible Independent 
Central Review in the future. 
Assessment of tumor response will be conducted using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 (see Section 10.8) according to the nature of the measurable lesions, as 
described below. 
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s)  
For participants with disease that is measured radiologically according to RECIST 1.1 criteria 
(see 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 (preferred) or MRI is an Investigator 
decision. Once the choice of CT scan or MRI has been made, the same imaging technique should 
be used in a participant throughout the trial. 
Baseline imaging should include all known target lesions. Baseline scans must evaluate extent of 
disease, including imaging of chest, abdomen, and pelvis and any other locations with suspicion 
or evidence of disease involvement. This may be accomplished with CT chest, abdomen, and 
pelvis with contrast, or CT chest with contrast and MRI abdomen/pelvis with gadolinium.  
The initial CT/MRI tumor imaging will be performed within 28 days prior to C1D1. Scans 
performed as part of routine clinical management are acceptable for use as the screening scan if 
they are of diagnostic quality and performed within 28 days prior to the date of enrollment. On 
study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP and if 
clinically indicated. Imaging studies should follow calendar days and should not be adjusted for 
delays in cycle starts or extension. After Week 45 tumor imaging should be performed every 
12 weeks (84 ±7 days). Per the primary tumor assessment criteria, after the first documentation of 
response or the first documentation of progression (if the participant is clinically stable), 
confirmatory imaging may be performed no fewer than 28 days later. Alternately, the scan 
performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. 
Tumor assessment is not needed for participants who start another anticancer therapy. 
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. If lesions are identified, the lesions must be treated, regardless of 
symptoms. 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 prior anticancer therapy. Participants with 
previously treated brain metastases may participate provided they are stable, which is defined as 
lack of progression on two sets of imaging obtained at least 4 weeks apart. Stability as defined 
above should be documented prior to the first dose of trial treatment. In addition, any neurologic 
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. 
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RECIST 1.1  
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of 
disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention).  
8.2 
SAFETY ASSESSMENTS   
The main anticipated adverse effect for the combination of SAR444245 with other anticancer 
therapies includes manifestations of cytokine release that can range from fever to hypoxia to 
hypotension, with or without manifestations that may include any of the organ systems. These 
mild events occur between around 12 to 18 hours after the first administration and a more 
intensive monitoring of vital signs is planned during that period. Targeted physical exams and 
standard laboratory tests will be conducted to monitor potential changes in the main body 
functions. Measurement of cytokines in plasma are planned at relevant timepoints. White blood 
cell differential count will be measured to monitor for transient lymphopenia which is commonly 
observed in the first few days following SAR444245 infusion. Eosinophilia that is surrogate to 
VLS will also be monitored. IL-5, which is also a marker of VLS, will be included in the PDy 
cytokine panel. When clinically indicated, on-treatment ECG, LVEF, and troponin will be 
assessed and compared to baseline. More details on the safety assessment are provided below. 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A full physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, neurological, and skin systems. Height and weight will also 
be measured and recorded. 
• 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  
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• 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 including temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed after 5 minutes rest  
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively; 
vital signs will be measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5) hours 
after start of SAR444245 dose in an in-patient setting.  
• At Investigator’s discretion, participants may have intensive vital sign monitoring: to be 
measured at Pre-dose, 0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 
20 (±1), 24 (±1) hours after start of SAR444245 dose in an in-patient setting. 
• From Cycle 2 to Cycle 4 study therapy will be administered for all participants in out-
patient clinic with vital signs taken at baseline, at least 4 to 6 hours after the start of 
SAR444245 dosing, or for longer periods of time if clinically indicated. 
• From Cycle 5, vital signs will be measured at Pre-dose. 
8.2.3 Electrocardiograms and LVEF  
• Includes single 12-lead ECG, LVEF, and troponin that will be performed at screening and 
troponin at Cycle 4 Day 1, then, as clinically indicated.  
• At Cycle 1 Day 1, ECG will be obtained, at pre-dose and at end of SAR444245 infusion. 
• 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:  Troponin will be performed at Cycle 4 
Day 1. In case of a suspicion of a drug related cardiac event (eg, including signs/symptoms 
of cardiac disease, ECG and/or echo changes, troponin elevation, etc.), Investigators are 
encouraged to do ECG, echocardiography and/or cardiac biomarker tests, as medically 
indicated, including cardiology consultation. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
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 relevant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within Follow-Up Visit 1 should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Sponsor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded.  
8.2.5 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria I 03 for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• Women of childbearing potential must have a negative urine pregnancy test result within 
72 hours prior to first IMP administration of each cycle, at EOT and every 30 (±7) days 
until 120 days (for Cohort A, B1, B2, B3, C, and D1) or 60 days (for Cohort D2) 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. 
AE 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 cessation of study treatment.  
All SAEs and AESIs will be collected throughout the study period, from the signing of the 
informed consent form (ICF) until 90 days following last administration of study treatment.  
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
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 10.3), will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3).  
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 an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
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• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB for SAR444245).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, should be expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 120 days (for Cohort A, B1, 
B2, B3, C, and D1) or 60 days (for Cohort D2) 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. 
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8.3.6 Cardiovascular and death events  
Cardiovascular events that meet AESI criteria should be reported as such (see Section 8.3.8 for 
details). 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI 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 Appendix 3 [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 Appendix 4 
[Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP  
- 
An overdose of IMP is defined as: increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half 
the recommended duration of administration.  
- 
An overdose (accidental or intentional) with the NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug. 
• An elevated AST or ALT lab value that is greater than or equal to 3 × ULN and 
an elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at the 
same time, an alkaline phosphatase lab value that is less than 2 × ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing*. 
For Participants with HCC, please refer to substudy 03 Corhort C. 
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*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be made available. It may also be appropriate to 
conduct additional evaluation for an underlying etiology in the setting of abnormalities of 
liver blood tests including AST, ALT, bilirubin, and alkaline phosphatase that do not meet 
the criteria noted above. In these cases, the decision to proceed with additional evaluation 
will be made through consultation between the study investigators and the Sponsor.  
• Other project-specific AESIs 
- 
IRR Grade ≥2  
- 
CRS Grade ≥2 
- 
ICANS of any grade 
- 
VLS of any grade 
- 
SARS-CoV-2 infection/COVID-19 disease 
- 
Any immune-related AE Grade ≥3 
- 
Arrhythmia Grade ≥3 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS  
The sampling time-points for PK and ADA for/against SAR444245 and/or other IMPs may be 
updated during the course of the study based on the updated knowledge of drug behavior upon 
notification from the Sponsor. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in the laboratory manual. The actual date and time (24-hour clock time) of each sample will be 
recorded while for samples to be collected at time of biomarker sampling, no specific time on the 
given day is necessary. 
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. 
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Samples collected for analyses of SAR444245 concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant. 
For China, please see Section 10.7 for details.  
8.5 
GENETICS AND/OR PHARMACOGENOMICS  
8.6 
BIOMARKERS  
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8.7 
IMMUNOGENICITY ASSESSMENTS  
The sampling time points for ADAs may be reduced or increased during the course of the study 
based on the updated knowledge of drug behavior and its immunogenicity, upon notification from 
the Sponsor. 
Samples for the immunogenicity assessment of SAR444245 will be collected according to the PK 
flowcharts. Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. Sample analysis will be performed at a laboratory designated by the Sponsor. 
Samples will be screened and then confirmed for anti-drug antibodies and the titer of confirmed 
positive samples will be reported. Additional analyses may be performed to further characterize 
the immunogenicity of SAR444245. 
Anti-drug antibody (ADA) samples remaining after determination of immunogenicity may be 
kept for possible exploratory analysis of biomarkers. The exploratory data will not be included in 
the study report but will be kept on file. 
For China, please see Section 10.7 for details. 
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8.8 
HEALTH ECONOMICS  
No health economics data will be collected. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
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9 
STATISTICAL CONSIDERATIONS  
Please refer to substudies protocols for additional statistical considerations. 
9.1 
 STATISTICAL HYPOTHESES  
This study is designed to assess antitumor activity, safety, pharmacokinetic (PK), 
pharmacodynamic (PDy) and immunogenicity data on SAR444245 when combined with other 
anticancer therapies in participants with gastro-intestinal cancer. As the study is not intended to 
explicitly test a hypothesis, calculations of power and Type I error were not considered in the 
study design. 
9.2 
SAMPLE SIZE DETERMINATION  
Number of participants to be enrolled in each cohort is described in the individual substudy. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined (Table 3):  
Table 3 - Populations for analyses  
Population 
Description 
Exposed 
Exposed population will include all participants who have given their informed 
consent and received at least one dose (even incomplete) of IMP (SAR444245 or 
other anticancer therapies).  
Efficacy 
Efficacy population will include all participants from the exposed population with at 
least one evaluable post-baseline tumor assessment or who permanently 
discontinued study treatment. 
PK 
The PK population will include all participants from the exposed population with at 
least 1 PK concentration available after the first dose of study intervention. 
PDy 
The PDy population will include all participants from the exposed population with 
at least 1 PDy parameter assessed after the first dose of study intervention.  
 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary, key secondary endpoints, and 
exploratory endpoints. 
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9.4.1 General considerations  
This study is not intended to explicitly test a hypothesis, 90% CIs will be provided for primary 
and secondary efficacy endpoints for descriptive purposes only.  
All efficacy analyses will be performed on the efficacy population and analyzed by cohort and 
pooled cohorts (if applicable). Objective response rate, as well as all other efficacy variables will 
be derived using the local radiologist’s/Investigator’s assessment for all cohorts. Unless otherwise 
specified, the assessments are based on RECIST 1.1. 
All safety analyses will be performed on the exposed population by cohort and overall (if 
applicable). A 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. 
9.4.2 Primary endpoint(s)  
9.4.2.1 Objective response rate  
For all cohorts, the ORR is defined as the proportion of participants who have a confirmed CR or 
PR as per Investigator’s assessment. 
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. 
ORR and BOR will be summarized with descriptive statistics. In addition, two-sided 90% CIs will 
be computed using the Clopper-Pearson method. All objective responses need to be confirmed by 
a subsequent assessment performed at least 4 weeks apart from the initial response observation. 
9.4.3 Secondary endpoint(s)  
The secondary endpoints include safety, efficacy (TTR, DoR, CBR, PFS per RECIST 1.1), 
immunogenicity, and PK. 
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9.4.3.1 Time to response  
Time to response will be assessed on the subgroup of participants who have achieved confirmed 
objective response in the efficacy population. 
Time to response will be defined as the time from the date of first IMP administration to the 
first tumor assessment at which the overall response was recorded as PR or CR that is 
subsequently confirmed. 
9.4.3.2 Duration of response  
The DoR will only be summarized on the subgroup of participants who have achieved confirmed 
objective response in the efficacy population.  
The duration of response will be defined as the time from the date of 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 progressive disease 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 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 with descriptive statistics using Kaplan-Meier methods. 
The median DoR and associated 90% CI will be provided. 
9.4.3.3 Clinical benefit rate  
The CBR will be defined as the proportion of participants with clinical benefit (confirmed CR or 
PR as BOR, or SD lasting at least 6 months). Specifically, participants will be considered as 
clinical benefit responders if they achieve a CR or PR as BOR, or have an overall response 
recorded as SD at 6 months (ie, 26 weeks) or later from first IMP intake, allowing for the ±7 days 
visit window for tumor assessment scheduled at 27 weeks. 
9.4.3.4 Progression-free survival (RECIST 1.1)  
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 or death due to any cause, whichever occurs 
first. 
The analysis of PFS will be based on the following censoring rules: 
• If progression or death is not observed before the cut-off date and prior to the initiation of 
a further anticancer therapy, then PFS will be censored at the date of the last valid tumor 
assessment performed before the cut-off date or date of initiation of a further anticancer 
therapy, whichever is earlier. 
• A participant without event (death or disease progression) and without any valid 
post‑baseline tumor assessment will be censored at the day of first IMP (Day 1). 
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Progression-free survival will be summarized using Kaplan-Meier methods. The median PFS 
times and associated 90% CI will be provided. 
9.4.3.5 Adverse events  
All AEs will be categorized according to NCI-CTCAE v5.0 (except for CRS and ICANS that will 
be graded using ASTCT criteria) and classified by system organ class (SOC) and Preferred Term 
(PT) according to the latest available version of the Medical Dictionary for Regulatory Activities 
(MedDRA). 
• 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 treatment-emergent 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 
• Grade ≥3 TEAEs 
• Grade 5 TEAEs (any TEAE with a fatal outcome during the treatment-emergent period) 
• Serious TEAEs 
• Serious treatment-related TEAEs 
• TEAEs leading to permanent partial intervention discontinuation (any of the IMP 
components) 
• TEAEs leading to permanent full intervention discontinuation 
• Treatment-related TEAEs 
• Treatment- related TEAEs Grade ≥3  
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v 5.0 or ASTCT grade (all grades and Grade ≥3). Missing grades, if 
any, will be included in the “all grades” category. Similar summaries will be prepared for 
treatment-related TEAEs, TEAEs leading to permanent discontinuation of SAR444245, or 
permanent discontinuation of other anticancer therapies in combination, 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.  
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The following deaths summaries will be generated: 
• Number and percentage of participants who died by study period (treatment-emergent 
period, post-treatment period) and reasons for death (disease progression, AE, or other 
reason). 
• All TEAEs leading to death by primary SOC and PT showing number and percentage (%) 
of participants. 
9.4.3.6 Clinical Laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
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. 
9.4.3.7 Other secondary endpoints  
Immunogenicity analyses will be described in the SAP finalized before database lock. The PK 
analysis and pharmacodynamic analyses will be presented separately from the main clinical study 
report (CSR). 
Plasma concentrations (or where applicable PK parameters) of SAR444245 will be summarized with 
descriptive statistics by each cohort.  
9.4.4 Tertiary/exploratory endpoint(s)  
9.4.4.1 Exploratory antitumor indicators  
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9.4.5 Other safety analysis  
All vital signs will be summarized according to potentially clinically significant abnormalities 
(PCSA). 
9.4.6 Other analysis  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9.  
9.5 
INTERIM ANALYSES   
No formal interim analyses are planned. However, for each cohort, in order to support project 
strategic planning and design of future studies, informal interim analyses will be conducted during 
the study without enrollment hold (eg, after half of the planned number of participants have 
undergone two post-baseline tumor assessment or have discontinued study treatment, whichever is 
earlier). 
In addition, the cumulative safety data for each study intervention across cohorts will be reviewed 
periodically by the Data Monitoring Committee (DMC). The enrollment will not be paused or 
stopped during the safety monitoring unless severe safety concern arises. 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. Occurrence of any 
treatment related G3 or higher AE (excluding lymphocyte count decrease) not resolving within 
72 hours in >25% of participants will trigger ad hoc DMC. The DMC procedures will be detailed 
in the DMC charter and approved by the DMC members. 
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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 first infusion. This would allow the possibility to 
observe the response of the last participant for 6 months, assuming there is a response at 
first treatment assessment. 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of primary objective) will be 18 months from cohort LPI.  After this cut-off date for the 
final analysis, the participants still receiving study treatment in that specific cohort will be 
followed up as the cohorts after early termination described in Section 10.1.9. 
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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, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of 
an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
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- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial  that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants or their legally authorized representative (if allowed by local regulations), and 
answer all questions regarding the study, including what happens to the participant when 
his/her participation ends (post-trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative (if allowed by local regulations) 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. 
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• 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 (if allowed by local regulations), where applicable.  
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.9).  
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. 
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Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
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• 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. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
Data Monitoring Committee 
Independent from the Sponsor and Investigators, the DMC role will be to monitor the safety of the 
participants enrolled in the study (ie, exposed to study treatment and/or to study procedures) and 
to provide the Sponsor with appropriate recommendations in due time to ensure the safety of the 
participants.  
10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, 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. 
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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. 
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. 
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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. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study or one or 
more cohorts at any time for any reason at the sole discretion of the Sponsor. Study sites will be 
closed upon study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study or cohort termination by the Sponsor, as well as reasons for the early closure of 
a study site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For cohort termination 
- 
Early evidence of lack of benefit 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
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- 
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).  Should the Sponsor decide to 
pause recruitment in a cohort to allow decision making, the Investigator should pause all 
screening activities until further notice. 
If the study or a given cohort is early terminated the patients who are receiving and benefitting 
from study treatment as per Investigator judgment may continue study treatment provided by the 
Sponsor until protocol defined treatment discontinuation criteria are met.  The patients who 
continue study treatment after early study termination should be followed for safety (ie, study 
treatment administrations, ongoing SAE/related AE, new related AE, AESI or SAE and their 
associated concomitant medications and lab if any) and end of treatment reason during this time 
period. This recommendation also apply for patients still on study treatment at the final cut-off 
date for a given cohort. 
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 4 will be performed by local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations 
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Table 4 - Protocol-required laboratory assessments  
Laboratory tests 
Parameters 
Hematologya 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
Urea or urea nitrogen  
 
Creatinine and eGFR (MDRD formulab) 
 
Glucose  
 
Potassium 
 
Sodium 
 
Corrected Calcium 
Phosphate 
Chloride 
 
Magnesium 
 
Bicarbonatec 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Total protein 
 
Lactate dehydrogenase (LDH) 
 
Albumin 
 
Amylase  
 
Lipase 
Coagulation 
International normalized ratio (INR) or Prothrombin Time (PT) (or Activated Partial 
Thromboplastin Time [aPTT]) 
Routine urinalysisd 
Specific gravity, pH, glucose, protein, blood, ketones, and leukocytes by dipstick 
Microscopic examination (if blood or protein is abnormal) 
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Laboratory tests 
Parameters 
Other screening tests 
Follicle-stimulating hormone and estradiol may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy (HRT) 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for women of childbearing potential)e 
Serology (hepatitis B surface antigen [HBsAg], hepatitis C virus antibody), Hepatitis B viral 
load, HCV RNA level, CD4 counts & HIV viral Loadf 
Troponin 
The results of each test must be entered into the e-CRF 
NOTES : 
a Blood Chemistry/hematology should be done with an overnight fasting if possible (should not interfere with hydration requirements). It will 
be performed weekly on D1 pre-dose, D8 and D15 during Cycle 1, then on Day 1 of every cycle up to Cycle 12, then every other cycle 
during Treatment Phase. During the Observation Period, it will be performed at Follow-Up Visit 1. It can also be performed as clinically 
indicated. In case of Grade ≥3 liver function abnormal tests, additional tests will be repeated every 2-3 days until recovery to baseline 
value. 
b Modification of Diet in Renal Disease (MDRD) equation: Glomerular filtration rate (mL/min/1.73 m2) = 175 × (Serum Creatinine [mg/dl])-1.154 × 
(Age)-0.203 × (0.742 if Female) × (1.212 if African American) 
c Bicarbonate or carbon dioxide (venous) (if bicarbonate or carbon dioxide are assessed only on arterial blood at site level, to be done only 
if clinically indicated) 
d Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is 
abnormal), will be performed every 4 cycles during the Treatment period and as clinically indicated. 
e Pregnancy Test: Women of childbearing potential must have a negative urine pregnancy test result within 72 hours prior to first IMP 
administration of each cycle, at EOT and every 30 (±7) days until 120 days (for Cohort A, B1, B2, B3, C, and D1) or 60 days (for Cohort 
D2) after the last dose of study treatment. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
f 
Participants with known HIV infection under antiretroviral treatment should have HIV viral load & CD4+ count done at screening to confirm 
controlled infection. Participants with known HBV hepatitis under treatment must have viral load determined at baseline to document 
controlled infection. Participants with positive serology against HCV must have determination of HCV RNA levels. The need for additional 
testing due to positive test results will be at the discretion of the Investigator. HIV, hepatitis B and C serology at screening will be tested in 
any countries where mandatory as per local requirements (see Section 10.7). 
 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
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. 
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10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
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) 
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- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- Development of drug dependence or drug abuse  
- Suicide attempt or any event suggestive of suicidality  
- Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)  
- Bullous cutaneous eruptions   
The purpose of the seriousness criteria listed above is to guide regulatory reporting obligations by 
the Sponsor. The Sponsor is required to expedite serious unexpected adverse reactions to 
regulatory health authorities and Investigators. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the e-CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE e-CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories, as per NCI CTCAE V5.0 definitions (except 
for ICANS and CRS that will be graded using ASTCT criteria integrated with central laboratory 
cytokine results): 
• 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**. 
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• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (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 an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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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, if available the Investigator will provide the Sponsor’s representative with a copy 
of any post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator study file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator study file.  
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). A postmenopausal state is 
defined as the period of time after a woman has experienced no menses for 12 consecutive months 
without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 Contraception guidance  
Participants should be given advice about donation and cryopreservation of germ cells prior to the 
start of the study intervention, in line with the fact that study intervention may affect ova and 
sperm for up to the number of days specified respectively for each cohort in the inclusion criteria. 
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 
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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.  
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the study and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to 
those which inhibit ovulation as the primary mode of action. 
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). 
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Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. 
10.5 
APPENDIX 5: GENETICS  
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS  
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
China  
• Global exploratory endpoints and relevant collection procedures, as described in Section 3 
and Section 1.3, are optional for Chinese participants. 
• Exploratory genetic and biomarker sample will not be collected for participants in China. 
Therefore, exploratory genetic and biomarker sample collection as described in 
Section 1.3, Section 8.5 and Section 8.6 are not applicable to participants in China. 
• In accordance with local requirements, use of biological samples as described in 
Section 8.9 is not applicable for participants in China. All residual mandatory samples 
collected from participants in China have to be destroyed upon clinical study report (CSR) 
completion at the latest. 
• Protein expression sample as described in Section 10.2 will not be collected for 
participants in China. 
Germany 
Section 5.2 Exclusion Criteria (see Section 5.2)  
E 15. HIV-infected participants with a history of Kaposi sarcoma and/or Multicentric Castleman 
Disease or known uncontrolled infection with HIV. HIV-infected participants must be on anti-
retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: 
- 
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of 
screening.  
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- 
Participants on ART must have achieved and maintained virologic suppression defined 
as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification 
(below the limit of detection) using the locally available assay at the time of screening 
and for at least 12 weeks prior to screening.  
- 
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1).  
- 
Combination ART regimen must not contain any antiretroviral medications other than: 
abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenoforvir.  
HIV serology at screening will be tested for German participants. 
E 16. Known uncontrolled hepatitis B infection, known untreated current hepatitis C infection, 
active tuberculosis, or severe infection requiring parenteral antibiotic treatment. 
- 
To control HBV infection, participants with positive HBsAg should have started 
anti-HBV therapy before initiation of IMP. Antiviral therapy for HBV must be given 
for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose 
of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL 
should stay on the same therapy throughout study treatment.   
- 
Participants who are positive for anti-hepatitis B core antibody HBc, negative for 
hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B 
surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not 
require HBV anti-viral prophylaxis. 
- 
Participants with past or ongoing 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.  
Serology for hepatitis B and C at screening will be tested for German participants. 
Italy 
Serology for HIV, hepatitis B and C at screening will be tested for Italian participants. 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1  
Confirmatory scans should be obtained at least 4 weeks following initial documentation of 
objective response. 
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline Version 1.1. 
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. 
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Selection of Lesions 
 
Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest X-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, 
a lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and 
in follow-up, only the short axis will be measured and followed. 
 
Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm 
[≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
 
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. 
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Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as close as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (eg, skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter as 
assessed using calipers (eg, skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Chest X-ray. Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT scans 
have slice thickness greater than 5 mm (0.5 cm), the minimum size for a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situation. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of 
a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which may 
bias an investigator if it is not routinely or serially performed. 
 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
 
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. 
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Cytology, Histology. These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (eg, residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain).The 
cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease 
is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
FDG-PET. While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this is 
not PD. 
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A “positive” FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
Response Criteria 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm (<1 cm). 
 
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). 
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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 are summarized in the table: 
Response According to Revised Response Evaluation Criteria in Solid Tumors (Version 1.1) 
 
Target lesions 
 Non-target 
lesions 
New lesions Overall response 
 Best overall response 
when confirmation is 
requireda  
CR 
CR 
No 
CR 
>4 weeks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
>4 weeks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not 
evaluated 
No 
SD 
Documented at least once 
>4 weeks from baseline 
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = Complete response; PD = Progressive disease; PR = Partial response; SD = Stable disease. 
a In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as PD. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening and enrollment of participants and administration of study intervention may 
be temporarily delayed (see also Section 7.1.2). 
10.9.1 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). 
10.9.2 Study procedures  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  If onsite visits are possible and there is a need to reduce the time spent on site 
to a minimum, the focus should be on IMP infusion/administration, collection of safety 
information (vital signs, adverse events) and safety blood collection (mainly biochemistry, 
hematology and ADA, if planned for the visit). However, all efforts should be made to perform 
the measurements of key parameters for efficacy endpoints, namely CT/MRI scan and tumor 
tissue collection for this study. 
If onsite visits are not possible due to a temporary disruption caused by an emergency, focus 
should be given to assessments necessary to ensure the safety of participants and those important 
to preserving the main scientific value of the study.   
• Remote visits (eg, with home nurses, home health vendor, etc.) may be planned for the 
collection of possible safety and/or efficacy data. 
• Visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely.   
• Use of local clinic or laboratory locations may be allowed. 
10.9.3 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. 
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10.9.4 Temporary discontinuation  
Study intervention must be administered intravenously and at study site under the responsibility of 
the Investigator. Consequently, for participants who have started treatment but are unable to come 
to the site, administration of study intervention must be paused until regular study visits can be 
safely resumed at the study site.   
In the event of  disruption of the clinical trial due to an epidemic/pandemic (eg, COVID-19), 
reinitiation of IMP can only occur once the Investigator has determined, according to his/her best 
judgement, that the contribution of the IMP(s) to the occurrence of the epidemic event 
(eg, COVID-19) was unlikely. 
Contingencies implemented due to emergency will be documented. 
 
10.10 APPENDIX 10: RISK ASSESSMENT  
The information shown in Table 5 reflects the clinical safety data available at the time of 
Edition 4 of the SAR444245 IB. Please always refer to the latest version of the IB for the most 
up-to-date safety data. 
Table 5 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
A minority of patients in the THOR-
707-101/HAMMER study has reported 
such AE as detailed in the 
SAR444245 IB. 
SAR444245 
Standard pre-medication 
Dose modification and treatment guidelines 
for SAR444245 infusion related reactions 
are provided in individual substudies. 
Hypersensitivity, including anaphylaxis 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
No reports of anaphylaxis in the 
HAMMER study to date. 
Exclusion of participants with known 
hypersensitivity to or contraindication for 
any components of SAR444245, PEG, or 
pegylated drugs.  
 
Infections 
SAR444245 
Nonclinical data do not indicate higher 
risk for infections. 
Adverse events of infections have 
been reported in the HAMMER study 
and are presented in the SAR444245 
IB. 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function to 
be included. 
During treatment, regular hematology and 
biochemistry is examined. 
Signs and symptoms of infection are 
monitored as part of TEAE. 
Cytokine release syndrome 
SAR444245 
No major increases in cytokines have 
been reported in non-clinical 
toxicology studies. 
Study to be conducted at sites experienced 
with CRS management, with bed available 
in ICU. 
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Potential risk of clinical 
significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
A minority of patients in the HAMMER 
study have reported such AE as 
detailed in the SAR444245 IB. 
 
Premedication with paracetamol, 
diphenhydramine (or equivalent 
medications)  
Hydration guidelines, including 
management of anti-hypertensive treatment 
around the time of infusion, are provided. 
Extensive post-dosing monitoring will be 
performed.  
Dose modification and treatment guidelines 
are provided in individual substudies. 
Capillary leak syndrome (CLS) / 
Vascular leak syndrome (VLS) 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
None reported in the HAMMER study. 
Intensive monitoring in C1D1 and beyond in 
the first cycle.  
Participants are monitored for signs and 
symptoms of VLS. 
Dose modification and treatment guidelines 
are provided in individual substudies. 
Hematological/bone marrow toxicity 
SAR444245 
In 28-day repeat-dose study of IV 
SAR444245 in non-human primates, 
SAR444245-related changes in 
clinical pathology parameters were 
observed at all doses and were 
generally most prominent 3 days 
following each dose. Changes in 
hematology parameters included 
decreased or attenuated reticulocytes 
followed by decreases in red blood 
cell (RBC) mass at
 mg/kg/dose, 
and increased WBCs (lymphocytes 
and monocytes) and transiently mildly 
decreased platelets at 
mg/kg/dose. The increases in 
lymphocytes were attributed to the 
expected pharmacology of 
SAR444245 and correlated with the 
gross and microscopic findings of 
splenic and lymph node enlargement 
and increased lymphoid cellularity; 
there were no microscopic or clinical 
correlates for the decreases in 
platelets. 
Adverse events of bone marrow 
toxicity have been reported in the 
HAMMER study are presented in the 
SAR444245 IB. 
Transient lymphopenia has also been 
observed. 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function to 
be included. 
During treatment, regular hematology and 
biochemistry is examined. 
Dose modification/discontinuation of IMP 
for Grade 3/4 anemia, thrombocytopenia 
and/or neutropenia as per general 
guidelines for the management of TRAEs 
(see individual substudies).  
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Potential risk of clinical 
significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
Hepatotoxicity 
SAR444245  
In 28-day repeat-dose study of IV 
SAR444245 in mice, males at 
 mg/kg/dose and females at  and 
mg/kg/dose also had mild increases 
in AST and ALT activity that 
corresponded to a spectrum of 
microscopic findings in the liver 
including mononuclear cell infiltration, 
apoptosis, necrosis, mixed leukocyte 
inflammation, oval cell hyperplasia, 
and Kupffer cell hypertrophy. 
No such data are reported in 28-day 
Repeat-Dose Study of IV SAR444245 
in non-human primates 
A minority of patients in the HAMMER 
study have reported such AE as 
detailed in the SAR444245 IB.  
Patients with significant impaired liver 
functions are excluded. 
Monitor clinical signs and symptoms of 
hepatic impairment as part of TEAE. 
Monitor liver function parameters (AST, 
ALT, bilirubin & ALP) regularly from 
screening and throughout the study. 
Dose modification and treatment guidelines 
for liver enzyme increase are provided 
under immune-related reactions in 
individual substudies.   
 
Nephrotoxicity 
SAR444245 
There are no non-clinical data 
indicating a potential for 
nephrotoxicity. 
One relevant serious adverse event 
(SAE) considered related to 
SAR444245 (Acute Kidney Injury) has 
been reported in the HAMMER study 
within a monotherapy cohort. 
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. 
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 individual 
substudies.  
Neurological AEs, including ICANS 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
A minority of patients in the HAMMER 
study have reported such AE as 
detailed in the IB. 
One SAE of CRS (Grade 4 with 
24 ug/kg monotherapy) associated 
with neurological manifestations 
[hypertension, chills/rigors, flushing, 
fever (maximum temperature: 
102.8°F), as well as neurological 
symptomatology (loss of ability to 
follow commands, confusion, aphasia, 
and involuntary fist clinching)] was 
reported in the HAMMER study. The 
event resolved completely within 30 to 
60 mins after treatment with 
Exclusion of participants with active brain 
metastases or leptomeningeal metastases. 
See E 03 for details. 
Guidelines for the management of ICANS 
are provided in individual substudies. 
 
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Potential risk of clinical 
significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
tocilizumab and steroid. This patient 
later discontinued. 
Cardiovascular effects, including QT 
interval prolongation 
SAR444245 
In 28-day repeat-dose study of IV 
SAR444245 in non-human primates, 
there were no SAR444245-related 
changes to the PR or QRS intervals or 
the heart rate (HR) corrected QTca 
interval. There was a SAR444245-
related, dose dependent, non adverse 
higher HR at doses of 
 mg/kg/dose beginning on Day 1 
compared to the control dose group 
and persisting through each 
respective dose following applicable 
telemetry recording sessions, with 
recovery. There was also an expected 
physiologic inverse relationship in the 
respiration rate (RR) intervals as well 
as the raw QT intervals, which 
correlated to the changes in HR, and 
were also considered to be non-
adverse. There were increases in 
individual females of troponin I 
minimal post first dose. There were 
marked decreases in females and 
males.  
These changes correlated with 
findings of mononuclear cell infiltrates 
and/or myocardial degeneration. All 
changes however, recovered by the 
end of a 28 day or 42/44 day 
treatment free period. 
A minority of patients in the HAMMER 
study have reported such AE as 
detailed in SAR444245 IB.  
Routine mitigation:  
Selection of qualified investigative centers 
with availability of intensive critical 
care/equipment. 
Exclusion of patients with severe or 
unstable cardiac condition within 6 months 
prior to starting study treatment, see E 09 
for details. 
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. 
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 individual substudies. 
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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. 
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 03. 
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. 
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%)(26, 27, 28). 
Strict adherence to the protocol.  
Adequate and verified training of staff at 
investigational sites 
Overdose and its treatment 
There is no specific antidote for 
overdose with SAR444245. 
Strict adherence to the protocol; Adequate 
and verified training of staff at 
investigational sites. 
See Section 6.8. 
Study procedures 
Biopsies of tumor tissue are expected 
during the trial. 
 
Strict adherence to the guidance in the 
protocol 
 
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10.11 APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS  
Table 6 - 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 7 - ASTCT ICANS consensus grading for adults  
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7-9 
3-6 
0-2 
0 (participant is unrousable and unable 
to perform ICE). 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to tactile 
stimulus 
Participant is unarousable or requires 
vigorous or repetitive tactile stimuli to 
arouse. Stupor or coma. 
Seizure 
N/A  
N/A  
Any clinical seizure 
focal or generalized 
that resolves rapidly or 
nonconvulsive seizures 
on EEG that resolve 
with intervention. 
Life-threatening prolonged seizure 
(>5 min); or Repetitive clinical or 
electrical seizures without return to 
baseline in between. 
Motor findingsc 
N/A  
N/A  
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis. 
Elevated ICP cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimagingd 
Diffuse cerebral edema on 
neuroimaging; decerebrate or 
decorticate posturing; or Cranial nerve VI 
palsy; or Papilledema; or Cushing’s triad. 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) 
not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may 
be classified as Grade 4 ICANS if unrousable. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medications). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE V5.0, but they do not influence 
ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It 
may be graded according to CTCAE V5.0.  
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CTCAE = Common Terminology Criteria for Adverse Events; 
EEG = Electroencephalogram; ICANS = Immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy; ICP = Intracranial pressure;  
N/A = Not applicable. 
Source:(2). 
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Table 8 - ASTCT CRS consensus grading  
CRS parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fevera 
Temperature ≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
Temperature ≥38°C 
 
With 
Hypotensionb 
None 
Not requiring 
vasopressors 
Requiring a vasopressor 
with or without 
vasopressin 
Requiring multiple 
vasopressors (excluding 
vasopressin) 
 
And/orb 
Hypoxia 
None 
Requiring low-flow 
nasal cannulac or 
blow-by 
Requiring high-flow nasal 
cannulac, facemask, 
nonrebreather mask, or 
Venturi mask 
Requiring positive pressure 
(eg, CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading.  
a Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5° C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as grade 3 CRS.  
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP=Bi-level positive airway pressure CPAP= Continuous 
Positive Airway Pressure; CRS=Cytokine release syndrome. 
Source: (2). 
10.12 APPENDIX 12: ABBREVIATIONS   
 
ADL: 
activities of daily living 
AESI: 
adverse event of special interest 
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CR: 
complete response 
ICANS: 
immune cell-associated neurotoxicity syndrome 
IHC: 
immunohistochemistry 
IR: 
infusion reaction 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
MedDRA: 
medical dictionary for regulatory activities 
MTD: 
maximum tolerated dose 
ORR: 
objective response rate 
PD: 
progressive disease 
 
PFS: 
progression-free survival 
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PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred term 
RCC: 
renal cell carcinoma 
SAE: 
serious adverse event 
TEAE: 
treatment emergent adverse event 
TLS: 
tumor lysis syndrome 
 
TRAE: 
treatment-related adverse event 
TTR: 
time to response 
VLS: 
vascular leak syndrome 
WOCBP: 
woman of childbearing potential 
 
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.13.1 
Amended protocol 01 (30 August 2021)  
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is to include stopping rules for futility for each cohort, 
update the rules for dose modification in case of treatment-related adverse events (TRAEs), and 
clarify the population for Cohorts B1, B2 and B3 in substudy 02. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 4.1 Overall 
design 
The follow sentence has been deleted “or until 
start of another anticancer therapy or final cohort 
cut-off, whichever comes first” for the reason 
leading to EOT for the participants who 
discontinue study treatment with PD, 
For consistency and clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SOA) 
Footnote i “Only for participants who will 
participate in the intensive PK sample collection” 
has been added for Hospitalization. 
Correction for consistency and clarity. 
Section 1.5 
Pharmacokinetic 
flowcharts 
The frequency of sampling for PK and ADA has 
been increased to obtain data every cycle for the 
first 3 cycles, every other cycle for 4 samples, 
then every 4th cycle. 
Regulatory Authorities (FDA) request to 
generate more comprehensive evidence. 
Section 4.3 Justification 
for dose 
The following text “Overlapping toxicities not 
expected for SAR444245 in combination with 
pembrolizumab or cetuximab, as suggested by 
safety data observed” has been changed to “And 
overlapping toxicities not suggested by comparing 
safety data from SAR444245 monotherapy cohort, 
SAR444245 in combination with pembrolizumab 
cohort, or SAR444245 in combination with 
cetuximab cohort. Though theoretically, combining 
SAR444245 with either pembrolizumab or 
cetuximab may lead to increase and/or severity of 
certainly AEs (detailed in Section 2.3.1 of the 
substudies).”  
For consistency  
6.8.2 Prohibited 
concomitant 
medications 
The following sentence has been removed: 
“Participants requiring medication(s) that are 
metabolized by the liver and have narrow 
therapeutic index require close monitoring (drug 
blood levels or other surrogate of drug exposure) 
when on study treatment. If a participant cannot 
be closely monitored, he/she should be removed 
from the trial.” 
Based on new de-risking in-vitro data 
Section 8.2.2 Vital signs 
“in an in-patient setting” has been added for vital 
sign measured at Cycle 1 Day 1. 
The following sentence has been added:” From 
Cycle 5, vital signs will be measured at Pre-dose”. 
For clarity. 
Section 8.2.3 
Electrocardiograms and 
LVEF 
The following sentence has been added: “At Cycle 
1 Day 1, at pre-dose and at end of SAR444245 
infusion, ECG will be obtained”. 
Regulatory Authorities (FDA) request to 
generate more comprehensive evidence. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 9.5 Interim 
analyses 
The following sentence “However, for each cohort, 
in order to support project strategic planning and 
design of future studies, informal interim analyses 
may be conducted during the study (eg…) ” has 
been changed to “However, for each cohort, in 
order to support project strategic planning and 
design of future studies, informal interim analyses 
will be conducted during the study without 
enrollment hold (eg..,)”. 
For clarity. 
Throughout 
Minor editorial updates 
For consistency and clarification. 
 
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11 
REFERENCES  
1. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 
2. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
3. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Safety and Efficacy of 
Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and 
Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 
2018;4(5):e180013. 
4. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. Randomized phase III 
KEYNOTE-181 study of pembrolizumab versus chemotherapy in advanced esophageal 
cancer. Journal of Clinical Oncology: official journal of the American Society of Clinical 
Oncology. 2020;38(35):4138-48. 
5. Diab A, Tykodi S, Daniels G, Maio M, Hurwitz M. 420 Progression-free survival and 
biomarker correlates of response with BEMPEG plus NIVO in previously untreated patients 
with metastatic melanoma: results from the PIVOT-02 study. Journal for ImmunoTherapy of 
Cancer 2020;8(Suppl 3): A256. 
6. Diab A, Hurwitz ME, Cho DC, Papadimitrakopoulou V, Curti BD, Tykodi SS, et al. NKTR-
214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: 
Preliminary phase 1/2 results of PIVOT. Journal of Clinical Oncology. 
2018;36(15_suppl):3006. 
7. Siefker-Radtke AO, Fishman MN, Balar AV, Grignani G, Diab A, Gao J, et al. NKTR-214 + 
nivolumab in first-line advanced/metastatic urothelial carcinoma (mUC): Updated results from 
PIVOT-02. Journal of Clinical Oncology. 2019;37(7_suppl):388. 
8. Tolaney SB, Spira AC, Cho D, et al. Clinical activity of BEMPEG plus NIVO observed in 
metastatic TNBC: preliminary results from the TNBC cohort of the Ph1/2 PIVOT-02 study 
[abstract]. Presented at CICON, September 23-26, 2019, Paris, France. [Online]. Available 
from: URL:https://www.nektar.com/application/files/9215/6949/4543/PIVOT-
02_TNBC_CICON_2019_Poster.pdf. 2019. 
9. Proleukin® (aldesleukin) [prescribing Information]. San Diego, CA: Prometheus Laboratories 
Inc.2011. [revised 2012 Jul; cited 2020 Oct 07]. [Online]. Available from: 
URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf 
10. Van Gool F, Molofsky AB, Morar MM, Rosenzwajg M, Liang HE, Klatzmann D, et al. 
Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by 
interleukin-2 therapy. Blood. 2014;124(24):3572-6. 
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11. Elkahwaji J, Robin MA, Berson A, Tinel M, Lettéron P, Labbe G, et al. Decrease in hepatic 
cytochrome P450 after interleukin-2 immunotherapy. Biochem Pharmacol. 1999;57(8):951-4. 
12. Prescribing Information. Proleukin® (Aldesleukin). Revised July 2012. [Online]. Accessed 
2020 Jul 03. Available from: 
URL:https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/103293s5130lbl.pdf 
13. Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A 
First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rßγ-Biased 
Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discov. 
2019;9(6):711-21. 
14. Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. 
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: 
Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). 
Cancer Discov. 2020;10(8):1158-73. 
15. Wang Q, Berger NA, Xu R. Analyses of risk, racial disparity, and outcomes among US 
patients with cancer and COVID-19 infection. JAMA Oncology. 2021;7(2):220-7. 
16. Venkatesulu BP, Chandrasekar VT, Girdhar P, Advani P, Sharma A, Elumalai T, et al. A 
systematic review and meta-analysis of cancer patients affected by a novel coronavirus. 
medRxiv: the preprint server for health sciences. 2020. 
17. Tian Y, Qiu X, Wang C, Zhao J, Jiang X, Niu W, et al. Cancer associates with risk and severe 
events of COVID-19: A systematic review and meta-analysis. International journal of cancer. 
2021;148(2):363-74. 
18. Zhou Y, Yang Q, Chi J, Dong B, Lv W, Shen L, et al. Comorbidities and the risk of severe or 
fatal outcomes associated with coronavirus disease 2019: A systematic review and meta-
analysis. International journal of infectious diseases : IJID : official publication of the 
International Society for Infectious Diseases. 2020;99:47-56. 
19. Dai M, Liu D, Liu M, Zhou F, Li G, Chen Z, et al. Patients with Cancer Appear More 
Vulnerable to SARS-CoV-2: A Multicenter Study during the COVID-19 Outbreak. Cancer 
discovery. 2020;10(6):783-91. 
20. Khan A, Bilal M, Morrow V, Cooper G, Thakkar S, Singh S. Impact of the coronavirus 
disease 2019 pandemic on gastrointestinal procedures and cancers in the United States: A 
multicenter research network study. Gastroenterology. 2021;160(7):2602-4. 
21. Morris EJA, Goldacre R, Spata E, Mafham M, Finan PJ, Shelton J, et al. Impact of the 
COVID-19 pandemic on the detection and management of colorectal cancer in England: a 
population-based study. The lancet Gastroenterology & hepatology. 2021;6(3):199-208. 
22. Kang WZ, Zhong YX, Ma FH, Liu H, Ma S, Li Y, et al. Treatment strategies for gastric 
cancer during the COVID-19 pandemic. World J Clin Cases. 2020;8(21):5099-103. 
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23. ASCO. COVID-19 Patient Care Information. [Online]. [cited 2020 Dec 11]. Available from: 
URL:https://www.asco.org/asco-coronavirus-information/care-individuals-cancer-during-
covid-19. 
24. ESMO. COVID-19 AND CANCER. [Online]. [cited 2020 Dec 11]. Available from: 
URL:https://www.esmo.org/covid-19-and-cancer 
25. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations 
for the use of WBC growth factors: American society of clinical oncology clinical practice 
guideline update. J Clin Oncol. 2015;33(28):3199-212. 
26. Moon JY, Lee Y, Han JM, Lee MH, Yee J, Song MK, et al. Effects of pharmacist 
interventions on reducing prescribing errors of investigational drugs in oncology clinical trials. 
J Oncol Pharm Pract. 2020;26(1):29-35. 
27. Weingart SN, Zhang L, Sweeney M, Hassett M. Chemotherapy medication errors. Lancet 
Oncol. 2018;19(4):e191-9. 
28. Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. American society 
of clinical oncology 2007 clinical practice guideline update on the role of bisphosphonates in 
multiple myeloma. J Clin Oncol. 2007;25(17):2464-72. 
 
 
 
 
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Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
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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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According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 01) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab 
for the treatment of participants with advanced and 
metastatic esophageal squamous cell carcinoma  
Protocol number: 
ACT16902-S01 
Amendment number: 
02  
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab 
for the treatment of participants with esophageal 
squamous cell carcinoma  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
156424 
2021-002181-41 
NCT05104567
U1111-1251-4981 
Date: 
12-Jan-2022 
Total number of pages: 70 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 02 
(Substudy 01) 
All 
12 January 2022, version 1 
(electronic 3.0) 
Amended Clinical Trial Protocol 01 
(Substudy 01) 
All 
30 August 2021, version 1 
(electronic 2.0) 
Clinical Trial Protocol (Substudy 01) 
 
20 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 02 (12 January 2022) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Belgian, Italian, German (Federal 
Institute for Drugs and Medical Devices [BfArM]), and South Korean Health Authorities after 
initial review. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities (SoA) 
A complete Table of SoA is provided for this substudy with 
procedures taken from the master protocol. And the 
previous footnote a for endocrine function tests has been 
renumbered as footnote j in the current document 
Regulatory Authorities (BfArM) request. 
 
Troponin test has been added at screening, at C4D1, and 
as clinically indicated during treatment period until Follow-
up visit 1. 
To allow assessment of any potential 
cardiotoxity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.4 Biomarker flowchart 
A complete Table of biomarker flowchart is provided for 
this substudy with biomarker sample collections taken 
from the master protocol. 
Regulatory Authorities (BfArM) request. 
1.5 Pharmacokinetic 
flowcharts 
A complete Table of pharmacokinetic (PK) flowcharts are 
provided for this substudy with PK sample collections 
taken from the master protocol. 
Regulatory Authorities (BfArM) request. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 01) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 14 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 20 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 21 
1.5.1 
Participants with more intensive PK sampling ............................................................................... 21 
1.5.2 
All other participants....................................................................................................................... 22 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.2.1 
Pembrolizumab .............................................................................................................................. 23 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 23 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 24 
2.2.2 
Rationale for ESCC and selected population (Cohort A) ............................................................... 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 26 
2.3.1 
Risk assessment ............................................................................................................................ 26 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 26 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 27 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 28 
2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
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3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 30 
4.2.1 
Participant input into design ........................................................................................................... 30 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 30 
4.3.1 
SAR444245 dose ........................................................................................................................... 30 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 31 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 34 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 34 
5.4 
SCREEN FAILURES...................................................................................................................... 34 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 34 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 35 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 35 
6.1.1 
Investigational medicinal product (IMP) ......................................................................................... 35 
6.1.2 
Non-investigational medicinal products ......................................................................................... 36 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 36 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 36 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 36 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 36 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 36 
6.5 
DOSE MODIFICATION .................................................................................................................. 36 
6.5.1 
General rules .................................................................................................................................. 36 
6.5.2 
Cycle delay ..................................................................................................................................... 37 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 38 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 39 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 39 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 42 
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6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 42 
6.5.4.4 
Immune-related adverse events .................................................................................................... 44 
6.5.4.5 
Immune cell-associated neurotoxicity syndrome (ICANS) ............................................................. 47 
6.5.4.6 
Vascular leak syndrome (VLS) ...................................................................................................... 48 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 49 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 50 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 50 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 51 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 51 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 51 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 52 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 52 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 52 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 52 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 52 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 52 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 53 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 53 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 53 
8.3.5 
Pregnancy ...................................................................................................................................... 53 
8.3.6 
Cardiovascular and death events .................................................................................................. 53 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 53 
8.3.8 
Adverse event of special interest ................................................................................................... 53 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 53 
8.4 
PHARMACOKINETICS .................................................................................................................. 53 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 54 
8.6 
BIOMARKERS ............................................................................................................................... 54 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 54 
8.8 
HEALTH ECONOMICS .................................................................................................................. 54 
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8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 54 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 55 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 55 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 55 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 55 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 55 
9.4.1 
General considerations .................................................................................................................. 56 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 56 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 56 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 56 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 56 
9.4.5 
Other safety analysis...................................................................................................................... 56 
9.4.6 
Other analysis ................................................................................................................................ 56 
9.5 
INTERIM ANALYSES .................................................................................................................... 56 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 57 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 57 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 57 
10.1.2 
Financial disclosure........................................................................................................................ 57 
10.1.3 
Informed consent process .............................................................................................................. 57 
10.1.4 
Data protection ............................................................................................................................... 57 
10.1.5 
Committees structure ..................................................................................................................... 57 
10.1.6 
Dissemination of clinical study data ............................................................................................... 57 
10.1.7 
Data quality assurance .................................................................................................................. 57 
10.1.8 
Source documents ......................................................................................................................... 57 
10.1.9 
Study and site start and closure ..................................................................................................... 57 
10.1.10 Publication policy ........................................................................................................................... 58 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 58 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 58 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 58 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 58 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 58 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 58 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 .......... 59 
10.9 
 ...................................................................................................................... 59 
10.9.1 
Response and stable disease duration (RECIST 1.1
) ............................................. 61 
10.9.2 
Methods of measurement .............................................................................................................. 61 
10.10 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 62 
10.11 
APPENDIX 11: RISK ASSESSMENT ............................................................................................ 62 
10.12 
APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 64 
10.13 
APPENDIX 13: ABBREVIATIONS ................................................................................................. 64 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY ................................................................ 64 
10.14.1 Amended protocol 01 (30 August 2021) ........................................................................................ 65 
11 
REFERENCES ............................................................................................................................... 67 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 29 
Table 2 - Overview of IMP administered ....................................................................................................... 35 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 39 
Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 41 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 42 
Table 6 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 45 
Table 7 - Guidelines for the management of immune cell-associated neurotoxicity syndrome (ICANS) ..... 47 
Table 8 - Guidelines for the management of vascular leak syndrome (VLS) ................................................ 49 
Table 9 - Estimated objective response rate (ORR) depending on number of responders .......................... 55 
Table 10 - Protocol-required laboratory tests ................................................................................................ 58 
Table 11 - Risk assessment .......................................................................................................................... 63 
 
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LIST OF FIGURES 
Figure 1 - Overall study schema - Substudy 01 ............................................................................................ 11 
Figure 2 - Graphical study design - Cohort A ................................................................................................ 13 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Cohort-specific 
protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of 
participants with advanced and metastatic esophageal squamous cell carcinoma 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of 
participants with esophageal squamous cell carcinoma 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti programmed cell 
death-1 (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 CT-26 colon cancer model and 
induced enhanced anti-tumor activity as demonstrated by an increased number of complete 
responses (CR) and tumor-free surviving animals compared to each agent in monotherapy. These 
data support evaluation of SAR444245 in combination with an anti-PD1 antibody. 
The proposed study aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the 
percentage of patients experiencing an objective response in the setting of advanced unresectable 
or metastatic esophageal squamous cell carcinoma (ESCC).  
Objectives and endpoints  
Please refer to the master protocol. 
Overall design: 
Please refer to the master protocol. 
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Brief summary:  
Cohort A will assess SAR444245 adding on to pembrolizumab in participants with advanced 
unresectable or metastatic ESCC, regardless of PD-L1 expression (any combined positive score 
[CPS]), who have received at least one but no more than two prior lines of treatment and have 
progressed after primary or secondary resistance to an anti-PD-1/PD-L1 based regimen (detailed 
in Section 5.1). Patients with known high microsatellite instability (MSI-H) will not be eligible, 
but the determination of the MSI status will not be required for enrollment. 
A graphical presentation of the substudy schema is shown in Figure 1. 
Figure 1 - Overall study schema - Substudy 01 
 
Abbreviations: 2-3L: second-line or third-line; CPS: combined positive score; ESCC: esophageal squamous cell carcinoma; N: number; PD-1: 
programmed cell death 1; PD-L1: programmed cell death ligand 1 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in Cohort A. 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration for a participant 
in Cohort A. For treatment period, the completion of Cycle 35 is applicable for Cohort A.  
Study intervention(s) 
Dosing sequence:
Investigational medicinal products 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in 
single-dose vials 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered as a dose of 200 mg using 
a 30-minute IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles. 
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Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min). 
SAR444245 
SAR444245 formulation, route of administration, and dose regimen as described in the master 
protocol. Treatment duration for Cohort A is up to 35 cycles. 
Noninvestigational medicinal products 
Please refer to the master protocol. 
After 4 cycles, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, premedication no longer needs to be 
administered.  
Statistical considerations: 
Please refer to the master protocol. 
Data Monitoring/Other committee: Yes 
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1.2 
SCHEMA 
Figure 2 - Graphical study design - Cohort A 
 
C=Study cycle; D=Study day; EOT=end of treatment; IMP=Investigational medicinal product; Q9W=every 9 weeks; Q12W=every 12 weeks. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
 
Inclusion and 
exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical and 
disease history  
X 
  
  
  
  
  
  
  
  
  
See Section 8 of 
the master 
protocol 
Body Weight / 
Heightg 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Full physical 
examination 
X 
 
 
 
 
X 
 
 
 
 
See 
Section 8.2.1 of 
the master 
protocol  
Directed Physical 
examination 
 
X 
X 
X 
X 
 
X 
  
  
  
See 
Section 8.2.1 of 
the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
  
  
  
See 
Section 8.2.2 of 
the master 
protocol  
Performance status 
(ECOG) 
X 
X  
X 
X 
X 
X 
X 
  
  
  
 
SpO2 
X 
As clinically indicated 
  
  
  
  
  
 
Laboratory and other investigations 
 
12-Lead ECG  
X 
X 
As clinically indicated 
  
  
  
See 
Section 8.2.3 of 
the master 
protocol  
LVEF 
X 
As clinically indicated 
  
  
  
See 
Section 8.2.3 of 
the master 
protocol  
Troponin 
X 
As clinically 
indicated 
X (Cycle 4 
Day 1) 
As clinically indicated 
 
 
 
See 
Section 8.2.3 of 
the master 
protocol and 
Section 10.2 of 
the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Pregnancy test  
X 
X 
  
  
X 
X 
X 
X 
  
  
See 
Section 8.2.5 of 
the master 
protocol and 
Section 10.2 of 
the master 
protocol 
Hepatitis serology, 
CD4 counts and viral 
load  
Xh 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol and 
Section 10.7 of 
the master 
protocol  
Hematology  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Coagulation 
X 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol  
Blood Chemistry  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Urinalysisi 
X 
X 
  
  
X 
X 
X 
  
 
  
See Section 10.2 
of the master 
protocol 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
T3, FT4, TSH & 
cortisolj 
X 
   
  
  
X 
X 
X 
  
  
  
See Section 10.2 
IMP 
 
SAR444245 
 
X 
 
 
X 
 
 
 
 
 
 
Pembrolizumab 
  
X 
  
  
X 
  
  
  
  
  
  
Hospitalizationk 
  
X 
  
  
  
  
  
  
  
  
 
AE/SAE assessmentl 
X 
Continuously throughout treatment period 
 X 
  
  
  
See Section 8.3 
of the master 
protocol  
Prior/Concomitant 
Meds 
X 
Continuously throughout treatment period 
  
  
  
  
See Section 6.8 
of the master 
protocol 
First subsequent anti-
cancer therapy 
  
  
  
  
  
X 
X 
X 
X 
X 
 
Survival status 
  
  
  
  
  
  
  
  
  
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy) / Immunogenicity assessments 
 
PK SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
ADA SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
PDy - Blood and 
tumor tissue 
collectionm,n 
See Biomarker flowchart in Section 1.4 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Tumor assessment 
 
Brain imagingo 
X 
  
  
  
  
 
 
 
 
  
See Section 8.1 
of the master 
protocol  
CT/MRIp 
X 
  
  
  
X 
X 
X 
X 
X 
  
See Section 8.1 
of the master 
protocol  
 
 
 
a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as 
part of screening within 3 days prior to first IMP administration. During the study treatment period, all assessments must be performed, and results should be reviewed by the investigator prior to IMP administration 
at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are 
performed and can be signed more than 28 days prior to first IMP administration. Screening time indicates the maximum time frame relative to the first IMP administration in which study procedures used to support 
eligibility are done. 
b Cycle: a treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1. For participant's convenience, all 
Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and 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 study. 
e For Cycle 4 visits, please refer to PK flowchart in Section 1.5. 
f 
C1D8 and/or C1D15 visits must be performed on site for the following participants only: 1) Participants scheduled to have blood draws for biomarker assessment and/or ADA on Day 8; 2) Participants who will 
receive IMP on Day 8 and Day 15. For all other participants, these 2 on-site visits may be done remotely as appropriate based on investigator’s discretion per institutional standard and local regulations. If this is 
the case, this must be documented in the source document. Sponsor may decide to cancel safety assessment on C1D8 and C1D15 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. 
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h For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.7 of the master protocol). 
i 
Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal), will be performed every 4 cycles during Treatment Period and as 
clinically indicated. 
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated.  
k Only for participants who will participate in the intensive PK sample collection. 
l 
AE/SAE assessment: 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 (1).   
m If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
n Will not be done for participants enrolled in China. 
o Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is clinically 
contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease as per protocol tumor assessment (TA) schedule. In all other cases, the lesions must be treated. Two additional scans, obtained at least 4 weeks apart, should be obtained to document disease 
stability after local treatment administration to the brain metastases has been completed. If participants receive 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 
4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or have 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. 
p CT/MRI: The initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ± 7 days) after the date of first IMP and if clinically indicated. Imaging studies should 
follow calendar days and should not be adjusted for delays in cycle starts or extension. 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, during 
treatment period until PD. Per the primary tumor assessment criteria, after the first documentation of response or the first documentation of progression (if the participant is clinically stable), confirmatory imaging 
may be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor assessment is not needed for 
participants who start another anti-cancer therapy.  
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AST=aspartate transaminase; ALT=alanine transaminase; C=Cycle; ANC=Absolute neutrophil count; AP=Alkaline phosphatase; BUN=Blood urea 
nitrogen; CRF=case report form; CRS=Cytokine release syndrome; CT=computed tomography;
 D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; e-CRF=electronic case report form; EOT=end-of-treatment; FT4=free thyroxine; FU=follow-up; HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; ICF=Informed consent form; 
IMP=investigational medicinal product; INR=international normalized ratio; LDH=Lactate hydrogenase; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA= multigated acquisition; 
PD=progressive disease; 
; PDy=pharmacodynamic; PK=pharmacokinetic; PR=partial response; PS=Performance Status; SpO2= oxygen saturation; Q3W=every 3 weeks; 
RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; WBC=White blood cells.  
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1.4 
BIOMARKER FLOWCHART 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
For participants who will undergo more intensive pharmacokinetic (PK) sampling, the schedule is shown in the flowchart in Section 1.5.1. Up to 
30 participants enrolled across cohorts treated with SAR444245 + pembrolizumab (including Cohort A) will undergo more intensive PK sampling, 
up to 10 participants from China will undergo intensive PK sampling.  
For all other participants, the PK sampling schedule is shown in the flowchart in Section 1.5.2. 
1.5.1 Participants with more intensive PK sampling  
 
Cycle 
 
Cycle 1 
Cycle 2, 3 
Cycle 4 
Cycles 6, 8, 
10 + every 
4th cycle 
thereafter 
EOT 
visit 
  30 (±7) 
days 
after 
last 
IMP 
admin 
Day 
D1 
D8 
D1 
D1 
D1 
Time after 
SAR444245 
dosing 
(EOI, 
except SOI) 
[h] 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
168 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
SOI 
EOI 
SAR444245 
PK sample ID 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08  
P00a 
P01b 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P00a 
P01b 
  
Sample time 
window 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
 
 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
  
SAR444245 
ADA sample 
IDc 
AB00a 
  
  
  
  
  
  
  
 
 AB01 
AB00a 
  
AB00a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI), 
b PK sample must be taken at EOI after flush. 
c ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
In the event the infusion is interrupted, a PK sample should be drawn immediately after interruption. If infusion is not likely to be resumed by clinical assessment, subsequent samples should be drawn at EOI + 1 h, +2 
h, +4 h, +8 h, +24 h, +48 h and +72 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent samples should be drawn at 1 h, 2 h, 4 h, 8 h, 24 h, 
48 h and 72 h after end of resumed infusion (as per protocol). 
ADA: anti-drug antibodies; EOI: End of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: Start of infusion.   
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1.5.2 All other participants  
 
Cycle 
Cycle 1 
Cycles 2, 3. 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
Day 
D1 
D8 
D1 
Time after SAR444245 dosing (EOI, 
except SOI) [h] 
SOI 
EOI 
24  
168 
SOI 
EOI 
30 (±7) days after 
last IMP admin 
SAR444245 PK sample 
 
P01b 
P06c 
 
 
P01b 
 
SAR444245 ADA sample 
AB00a 
 
AB01 
AB00a 
 
ABF00 
a Samples collected strictly before start of infusion (SOI) 
b EOI samples = end of infusion samples. Must be taken at end of infusion precisely 
c PK sample can be collected at any time during the second day of the cycle. 
ADA: anti-drug antibodies, PK: pharmacokinetic: SOI: start of infusion; EOI: end of infusion   
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2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to cohort with ESCC for the combination therapy with pembrolizumab. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models while anti-PD1 antibody prevents T cell suppression 
through the PD1/PD-L1 pathway. The combination of anti-PD1 treatment with SAR444245 was 
tested in a syngeneic mouse CT-26 colon cancer model and induced enhanced anti-tumor activity 
as demonstrated by an increased number of CR and tumor-free surviving animals compared to 
each agent in monotherapy. These data support evaluation of SAR444245 in combination with 
pembrolizumab. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across 
a number of indications. 
Refer to the country approved labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background  
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (3, 4). 
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The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (6, 8, 9, 10). The mechanism by which PD1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins (11, 12).  
2.2.1.2 Pre-clinical trials  
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(13, 14, 15, 16, 17, 18, 19). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (7, 16, 18, 19, 20). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo (18). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see pembrolizumab IB). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
2.2.2 Rationale for ESCC and selected population (Cohort A)  
Esophageal cancer is ranked as the sixth leading cause of cancer-related deaths. Although the 
incidence of adenocarcinoma is increasing in Western countries, esophageal squamous cell 
carcinoma (ESCC) is the major histology in Asian countries including Japan. Although driver 
gene mutations have not been detected in ESCC, the somatic mutation rate in ESCC is relatively 
high compared with other solid tumors (21). Up to the event of ICI, there was no agents that had 
shown clear efficacy in ESCC (22).  
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In the multi-cohort Phase 1b KEYNOTE-028 study, pembrolizumab monotherapy demonstrated 
promising antitumor activity in patients having heavily pre-treated esophageal carcinoma with 
PD-L1 ≥ 1%. Thirty-seven (45%) of patients had PD-L1 positive tumor, and ORR was 30% (28% 
in ESCC) with a median duration of response of 15 months (23). The subsequent phase II, 
single-arm KEYNOTE-180 study evaluated the activity of pembrolizumab monotherapy in 
patients with advanced, metastatic esophageal carcinoma who have failed two or more lines of 
therapy (24). PD-L1 expression, defined as a CPS of 10 or higher assessed by 
immunohistochemistry (IHC), was reported in 47.9%, and 52.1% of the 121 enrolled patients had 
ESCC. The ORR of the entire cohort was 9.9%, and numerically higher response rate was 
observed in those tumors with PD-L1 expression (ORR 13.8%) and ESCC (ORR 14.3%). The 
results were echoed in the phase II, single-arm Attraction-01/ONO-4538-07 study in which 
nivolumab monotherapy was given in Japanese patients with ESCC refractory or intolerant to 
standard treatments (25). PD-L1 expression was not required for study entry; the ORR was 17.2% 
and the responses were durable (26).  
In the KEYNOTE-181 randomized Phase 3 study, pembrolizumab monotherapy was compared to 
the investigator's choice of chemotherapy in patients with advanced esophageal cancers, all 
histologies, who had received only one prior line of treatment. The primary objectives were 
overall survival (OS) in patients with PD-L1 CPS ≥10, ESCC and in the total population. 
Compared with investigator’s choice of chemotherapy, pembrolizumab monotherapy significantly 
improved OS in PD-L1 CPS ≥10 (9.3 versus 6.7 months, HR 0.69) and ESCC (8.2 versus 
7.1 months, hazard ratio [HR] 0.78) but not in the total population (7.1 versus 7.1 months, HR 
0.89). In addition, the ORRs were significantly higher with pembrolizumab than chemotherapy. It 
reached 21.5% in PD-L1 CPS ≥10 (versus 6.1% with chemotherapy; p = 0.0006), 16.7% in ESCC 
(versus 7.4% with chemotherapy; p = 0.0022), and 13.1% in total population (versus 6.7% with 
chemotherapy; p = 0.0037). In patients with ESCC and PD-L1 CPS ≥10, the ORR (22% versus 
6%) and OS (10.3 months versus 6.7 months, HR=0.64) were significantly higher with 
pembrolizumab than chemotherapy.  For the specific setting of patients with ESCC and PD-L1 
CPS ≥10, the ORR of 22% (versus 6%) and OS of 10.3 months (versus 6.7 months, HR=0.64) 
were significantly higher with pembrolizumab than chemotherapy. Based on these data of 
Keynote-181 study, pembrolizumab received FDA approval for use in patients with recurrent or 
metastatic ESCC with a CPS ≥10 in the 2L setting (27). Nivolumab single agent is approved 
regardless of PDL1 expression in Japan and other Asian countries, and was also recently approved 
in the US and EU based on Attraction-3 data (28). Results from the randomized, international, 
double-blind KEYNOTE-590 study of 1L pembrolizumab + chemotherapy vs chemo alone in 
patients with locally advanced/unresectable or metastatic esophageal adenocarcinoma or ESCC or 
Siewert type 1 gastroesophageal junction cancer (GEJ) were reported at ESMO 2020 (29). At data 
cutoff, 749 patients (73% ESCC) were randomized. Median follow-up was 10.8 months. Pembro 
+ chemo versus chemo was superior for OS in patients with ESCC CPS ≥10 (13.9 versus 
8.8 months; HR 0.57), ESCC (12.6 versus 9.8 months; HR 0.72), CPS ≥10 (13.5 versus 
9.4 months; HR 0.62), and all patients (median 12.4 versus 9.8 months; HR, 0.73). Confirmed 
ORR was 45.0% versus 29.3% (P <0.0001) in all patients, with median DoR of 8.3 versus 6.0 
months. Safety profile was manageable but discontinuation rates from drug-related AEs was 
slightly higher in the combination arm (19% versus 12%). Pembrolizumab + chemotherapy may 
be the new SoC for this population in 1L, regardless of histology and PD-L1 expression. 
Nevertheless, >50% of patients do not respond, and some will relapse. In the proposed study, the 
antitumor activity of pembrolizumab when combined with SAR444245 will be evaluated in the 
population patients in 2-3L that will have failed or relapsed on an anti-PD-1/PD-L1.  
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2.3 
BENEFIT/RISK ASSESSMENT 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin).  
Risk assessment of SAR444245 when combined with pembrolizumab results from anticipated 
risks for SAR444245 and from the label information for Keytruda® (pembrolizumab), taking into 
account potential overlapping risks. The available safety data for pembrolizumab, along with 
proposed mitigation strategies are summarized below and also provided in Table 11. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment (TME). 
The use of pembrolizumab may cause IRRs (drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, and hypersensitivity). Pembrolizumab use may be associated with 
infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, leukopenia), 
increase in the level of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well as adverse effects 
on the functioning of nervous system (dizziness, headache, peripheral neuropathy, dysgeusia (very 
common) and lethargy). In combination therapy with other chemotherapeutic drugs, 
pembrolizumab administration is commonly associated with hypertension and cardiac arrhythmia 
(including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risks for pembrolizumab 
(30). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in 
post-marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis.  
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Please refer to the country-approved product labeling (eg, United States Package Insert [USPI], 
Summary of Product Characteristics [SmPC]) for pembrolizumab for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab 
Combining SAR444245 with pembrolizumab may lead to an increased frequency and/or severity 
of adverse events (AEs) related to immune activation or may lead to additional AEs related to 
immune system activation for each substance individually or may cause occurrences of 
qualitatively different AEs. Serious adverse drug reactions reported with agents known to increase 
immune activation include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction 
(see Section 2.3.1.1).  
As both substances are biologic agents, they may have the propensity to induce infusion-related 
reactions that may have higher rate of occurrence and severity when SAR444245 with 
pembrolizumab are used in combination. 
The maximum tolerated dose (MTD) of SAR444245 combined with the approved dosing of the 
anti PD-1 pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. 
Safety data generated from the combination of SAR444245 and pembrolizumab have informed 
the selection of the combination dose in this study.  
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of 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). 
Immune checkpoint inhibitors are approved in most of the indications proposed to be tested in this 
study (please refer to Section 2.1 - Study Rationale): ESCC, gastric and gastroesophageal, HCC. 
In gastric cancer and ESCC, the main benefit of pembrolizumab is brought to patients with 
diseases that have a relatively high expression of PD-L1 (CPS ≥10). Combining SAR444245 to 
pembrolizumab is anticipated to expand to population responding to the anti-PD1 and to increase 
the quality of the response. Such effects have been demonstrated in the PIVOT-02 study for 
bempegaldesleukin combined with nivolumab in metastatic melanoma, achieving deep and 
durable responses with rates of CR of 34% and PFS (30.9 months) exceeding that reported in 
clinical trials for approved treatments (31). Objective responses were also documented in PDL1 
negative cases (n=13), with an ORR of 39% and 3 patients achieving 100% reduction of target 
lesions, and 2 patients achieving CR. Echoing these results are those of the same combination in 
1L metastatic urothelial carcinoma, an indication where response to immune checkpoint is linked 
to the level of expression of PD-L1. In this study, bempegaldesleulin when combined with 
nivolumab induced significant ORR with 17% CR, with ORR similar and PD-L1 negative (50%) 
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and PD-L1 positive (56%)(15), which contrast with data from Keynote-052 for pembrolizumab 
(32, 33). Combining SAR444245 with pembrolizumab is anticipated to bring benefit to patients 
with ESCC and GC/GEJ even in the context of low PD-L1 and could rescue patients who have 
progressed or relapsed following an anti-PD1/PD-L1. 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. 
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 pembrolizumab are justified by the anticipated benefits that may be afforded to 
participants with ESCC.  
2.3.4 Benefit and risk assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity. 
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was also explored by 2 groups and did not find a clinically meaningful signal (34, 35). 
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Exploratory 
 
•
(36). 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Cohort A will assess SAR444245 adding on to pembrolizumab in participants with advanced 
unresectable or metastatic esophageal squamous cell carcinoma (ESCC), regardless of 
programmed cell death-ligand 1 (PD-L1) expression (any combined positive score [CPS]), who 
have received no more than two prior lines of treatment and have progressed after primary or 
secondary resistance to an anti-PD-1/PD-L1 based regimen (detailed in Section 5.1). Patients with 
known high MSI-H will not be eligible, but the determination of the MSI status will not be 
required for enrollment. 
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts.   
A graphical presentation of the substudy schema is shown in Figure 1. For treatment period, the 
completion of Cycle 35 is applicable for Cohort A. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the 
population experiencing an objective response. 
The design of the 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 RECIST 1.1 for participants with advanced unresectable and metastatic ESCC.  
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol. 
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4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is justified 
by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold exposure range 
(refer to the pembrolizumab IB). 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W. 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications. And 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, 
a PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
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Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort A specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Histologically or cytologically confirmed diagnosis of esophageal cancer of the squamous 
cell carcinoma subtype. 
I 02. Confirmed diagnosis at study entry of advanced unresectable or metastatic disease.   
Note: For participants in Cohort A: Disease with any CPS scoring. No need for CPS 
determination at local laboratory. 
I 03. MSI status: Participants must have either unknown MSI status or if MSI status is known, 
participants must have non-MSI-H disease to be eligible. 
I 04. Prior anticancer therapy: Participants should have received at least one but no more than 
2 prior lines of treatment, including an anti-PD-1/PDL-1 containing regimen and have 
progressed after a primary or secondary resistance to an anti-PD-1/PDL-1. 
Note: For Cohorts A:  
Primary resistance is defined as a patient who has experienced progressive disease (PD) or SD 
lasting <6 months of initiation of PD-1/PD-L1 inhibitor-based treatment and who received at least 
6 weeks of the PD1/PD-L1. Radiographic confirmation of the PD must be documented after 
a minimum of 4 weeks after the initial identification of progression, unless: i) investigator 
confirms clinical progression/ deterioration attributed to PD, or ii) the first radiographic 
assessment indicated critical tumor growth by imaging (size or location).   
Or 
Secondary resistance: patients must have experienced PD, either during or within 3 months of 
discontinuing treatment with anti-PD1-based therapy, occurring after previous clear benefit (any 
complete [CR] or partial response [PR]), or after previous stable disease (SD) >6 months. 
No requirement for radiographic confirmation of progression. 
An anti-PD1/PD-L1 containing regimen is defined as either an anti-PD1/PD-L1 monotherapy, or 
an anti-PD1/PD-L1 agent administered in the same cycle as another systemic anticancer therapy. 
If PD1/PD-L1 was used beyond initial radiological progression while continuing to use the same 
PD1/PD-L1 agent used before PD, it’s still considered as the same regimen. The site’s study team 
must have reviewed previous tumor assessments (including screening tumor imaging) to 
determine that radiographic progression has occurred per RECIST 1.1 following initiation of the 
anti-PD1/PD-L1 containing regimen. 
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I 05. Provision of tumor tissue: 
- 
Mandatory baseline biopsy for participants in Cohort A: minimum 5 slides with 
4-5 micron thickness for the first 20 participants who have signed ICF (excluding 
screen failure participants), minimum 10 slides with 4-5 micron thickness for 
subsequent participants. Archival tumor tissue samples should be obtained from 
biopsies done within 6 months, and there should be no systemic anti-cancer therapy 
between collection of biopsy and enrollment. Slides specifications are detailed in Lab 
Manual.  
- 
Optional on-treatment biopsy for Cohort A per Investigator’s discretion and 
evaluation. 
- 
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. 
5.2 
EXCLUSION CRITERIA  
Please refer to the master protocol. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
Please refer to the master protocol. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
For study treatment duration, completion of Cycle 35 is applicable for Cohort A. 
Dosing sequence:
In addition, if a participant has immune unconfirmed progression of disease (iUPD) and is 
clinically stable, it is at the discretion of the Investigator to continue treating the participant with 
the assigned treatment per protocol until progression of disease is confirmed (iCPD) at least 
4 weeks, but no longer than 8 weeks from the date of the scan suggesting progression of disease 
(Section 10.9). 
6.1.1 Investigational medicinal product (IMP)  
Investigation medicinal product is defined as SAR444245 and pembrolizumab administered in 
combination as described in Section 4. Details of each IMP component to be administered are 
shown in Table 2.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.  
Table 2 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
100 mg/vial 
Dosage level(s)a 
24 μg/kg Q3W 
200 mg Q3W 
Route of administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
See master protocol 
IMP 
Packaging and labeling 
See master protocol 
Supplied in single dose vials containing 100 mg/4 mL 
pembrolizumab labelled with a multilingual booklet. 1 vial 
per treatment box. 
Current/Former name(s) or 
alias(es) 
See master protocol 
Keytruda 
a See master protocol. 
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6.1.2 Non-investigational medicinal products 
Please refer to the master protocol. 
In case of permanent SAR444245 discontinuation and continuation of pembrolizumab treatment 
as part of AE management, SAR444245 premedication no longer needs to be administered. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modifications for SAR444245 are permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed.  
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In participants who have SAR444245 dose reduction due to SAR444245 related 
Grade ≥3 treatment-related adverse events (TRAEs), SAR444245 dose may be re-escalated to 
 μg/kg if:  
• no SAR444245 related Grade ≥3 TRAE or clinically significant laboratory abnormality 
within at least 2 subsequent cycles, AND  
• both Investigator and Sponsor agree that the participant has clinical benefit. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case, it is partial permanent discontinuation, and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued, it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF).  
6.5.2 Cycle delay  
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administered ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3 and Section 6.5.4. After cycle is delayed, such participants may be 
considered for treatment resumption once the toxicity resolves or improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on the 
day of planned administration, the cycle will be delayed; restart of study IMPs could occur 
only on the initiation of the subsequent cycle. 
• In case of cycle delay for the recovery of toxicity, the following rules should be followed 
for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to restart 
the study treatment, if a clear benefit from treatment is observed and after consultation 
with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer than 
84 days. 
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• Cycle may be delayed for situations other than TEAEs such as medical/surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study 
therapy within 21 days of the scheduled delay, unless otherwise discussed with the 
Sponsor (for example for national or regional emergencies). The reason for the delay 
should be documented in the participant’s study record. 
6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
not listed in Section 6.5.4 (Tables 3-8) will be required to temporarily delay the IMP. After cycle 
delay, such participants may be considered for treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline  
The dose of SAR444245 should be reduced to 
 μg/kg (with the exception of lymphocytopenia 
which is directly associated with SAR444245 mode-of-action and does not require dose 
reduction) in cases of: 
• First occurrence of Grade 3 TRAE that does not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 TRAE of any duration. 
• Grade 4 TRAE. 
• First occurrence of Grade 3 laboratory abnormality that are clinically significant per 
Section 10.3.1 of the master protocol. and that do not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 clinically significant laboratory abnormality 
of any duration. 
• Grade 4 laboratory abnormalities that are clinically significant.  
Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to be in the 
best interest of the participant, except when specified otherwise in this protocol, or if the event has 
required the IMP temporary interruption for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
Vascular Leak Syndrome (VLS) and Infusion-related reactions (IRR) are presented in 
Section 6.5.4. 
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6.5.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF. 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An 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.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 3.  
After an infusion-related reaction due to pembrolizumab infusion (Grade 3 or Grade 4), the 
SAR444245 infusion will be delayed and can be administered after resolution of symptoms. The 
Investigator should discuss with the Sponsor’s Medical Monitor if the SAR444245 infusion needs 
to be delayed more than 1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 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, please see Section 6.1.2.1 of the 
master protocol. 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics. 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
• 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (eg, from 100 mL/hr. to 
50 mL/hr.). Otherwise, dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
Epinephrine*, 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics, 
- 
Oxygen, 
- 
Pressors, 
- 
Corticosteroids. 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
• 
Hospitalization may be indicated. 
*In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
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Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise, dosing will be held 
until symptoms resolve and the participant should be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics.  
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; pressor or ventilator support 
indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 are provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
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6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and pembrolizumab being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines) 
(37, 38, 39). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 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 C-reactive protein (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 according to severity grading are provided in Table 5. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV fluids 
(care should be taken to not excessively hydrate if evidence of vascular leak), 
antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and laboratory 
monitoring should initially be performed daily, then less frequently as the 
participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring 
vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to IV fluids 
(care should be taken to not excessively hydrate if evidence of vascular leak), 
antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as medically 
indicated should be increased until the participant recovers. Transfer to ICU 
may be required. 
For participants with comorbidities, older age, or with oxygen requirement, 
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Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
hypotension, or participants in whom symptoms (eg, high grade fever) that do 
not respond to antipyretics within 72 hours treatment with corticosteroids and/or 
tocilizumab should be considered, as per guidance for Grade 3 events.  
SAR444245 may be resumed when clinical symptoms have resolved or 
improved to Grade 1 and corticosteroid taper. No dose modification is required 
but decreasing to half the infusion rate can be considered. 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a 
vasopressor with or without 
vasopressin  
• 
And/orc hypoxia requiring high-
flow nasal cannulad, face mask, 
nonrebreather mask, or Venturi 
mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding 
vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
If CRS grade 3, SAR444245 should be temporarily cycle delayed, and 
subsequent treatment should be resumed only when symptoms have resolved 
or improved to Grade 1 at
µg/kg or permanently discontinued, as clinically 
indicated. 
If CRS Grade 4, SAR444245 should be permanently discontinued as clinically 
indicated. 
If CRS Grade 3 or Grade 4, IV corticosteroids should be initiated (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, management for persistent or 
worsening CRS should be initiated. Re-evaluation for other contributing 
conditions should be done, such as infection, cardiac, thromboembolic and 
other complications. Intravenous Tocilizumab at 8 mg/kg (for participants 
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 should be discussed with 
clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
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Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the 
last dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
IrAEs are thought to be caused by unrestrained cellular immune responses directed at the normal 
host tissues. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing pembrolizumab clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and 
administer corticosteroids. 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 6. Of 
note, when study interventions are administered in combination, if the AE is considered immune-
related, both drugs in the combination should be held according to recommended dose 
modifications.  If a participant experiences several irAEs, the most conservative recommendation 
should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 6, the 
combination of SAR444245 or pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered 
after communication with the Sponsor. 
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Table 6 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE 
decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Pneumonitis  
Grade 2 
Withholda  
Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Add prophylactic antibiotics 
for opportunistic infections. 
Monitor participants for signs 
and symptoms of 
pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
Recurrent Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor participants for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinueb 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returns to 
baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Type 1 Diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholda,f 
Initiate insulin replacement 
therapy for participants with 
T1DM. 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
Hyperthyroidism  
Grade 2 
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinueb 
Myocarditis 
 
 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes. 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinueb 
All Other irAEs 
Persistent Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinueb 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 - 3.0 x ULN if baseline normal;  
>1.5 - 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; 
>3.0 - 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.  
6.5.4.5 Immune cell-associated neurotoxicity syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome 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 10.11 of the master protocol). 
Recommendations for ICANS) management mainly include the use of 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 SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement 
to Grade 1 after corticosteroid taper. Consideration for reduction of 
SAR444245 dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at
µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
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Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 4 ICANS, SAR444245 should be permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab and should be handled as described in Table 5 in 
Section 6.5.4.3. Corticosteroids can then be administered IV or orally every 
8 hours for up to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; ICANS= Immune effector 
cell associated neurotoxicity syndrome; ICE= Immune Effector Cell-Associated Encephalopathy; IV = Intravenous. 
6.5.4.6 Vascular leak syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with 
multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a balance 
between maintaining the intravascular volume to ensure organ perfusion to prevent organ failure, 
while avoiding volume overload. The management of VLS according to severity grading is 
described in Table 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 (40).  
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Table 8 - Guidelines for the management of vascular leak syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued.   
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AKI= acute kidney injury; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; MW= molecular weight; 
NCI = National Cancer Institute; VLS= vascular leak syndrome. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
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6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater. There is no 
specific antidote for overdose with pembrolizumab. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol and Section 1.3. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s) 
Please refer to the master protocol for RECIST 1.1. 
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol.  
In addition, combining SAR444245 with other anticancer therapies may increase the frequency 
and severity of immune-related adverse events related to other anticancer therapies. Immune-
mediated endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, and 
cortisol level will be monitored. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort A irAEs will be collected until 90 days following last administration of 
study treatment regardless of whether or not another anticancer therapy is initiated. 
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8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, SAEs that are considered expected will be specified in the reference safety 
information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol.  
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8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
Please refer to the master protocol. 
9.2 
SAMPLE SIZE DETERMINATION 
The plan is to treat approximately 40 participants in Cohort A. 
Table 9 lists estimated ORR and 90% exact confidence intervals (CIs) by number of responders 
from a sample size of 40 participants treated. 
Table 9 - Estimated objective response rate (ORR) depending on number of responders 
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
2 
5% (0.9% - 14.9%) 
4 
10% (3.5% - 21.4%) 
6 
15% (6.7% - 27.5%) 
8 
20% (10.4% - 33.2%) 
10 
25% (14.2% - 38.7%) 
12 
30% (18.3% - 44.0%) 
14 
35% (22.6% - 49.2%) 
CI: confidence interval; N=number. 
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 cohort. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
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9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol. 
9.4.4 Tertiary/exploratory endpoint(s)  
 
9.4.4.1 Exploratory antitumor indicators 
 
9.4.5 Other safety analysis 
Please refer to the master protocol. 
9.4.6 Other analysis 
Please refer to the master protocol.  
9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
If the predictive probability of concluding a minimum clinical meaningful effect of the study 
treatment (ORR of 5%) at the end of study is <15%, the corresponding cohort will be stopped for 
futility. To facilitate the calculation of predictive probability, a minimum informative prior of 
Beta (0.5, 0.5) is used at the time of the design of the study. However, emerging data generated 
from outside of the study may warrant a different prior to be considered before this interim 
analysis. 
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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 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
 Please refer to the master protocol.  
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol. 
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
10.1.9 Study and site start and closure 
Please refer to the master protocol. 
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10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. Cohort 
A specific evaluations are presented in Table 10. 
Table 10 - Protocol-required laboratory tests 
Laboratory tests 
Parameters 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
NOTES : 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol. 
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10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 
Please refer to the master protocol. 
10.9 
APPENDIX 9:
 
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New lesions: 
i
i
i
i
i
i
l
i
i
i
i
. 
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i
 
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. 
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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. For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be 
a potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is advised to differentiate between response or SD and PD. 
10.10 APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
10.11 APPENDIX 11: RISK ASSESSMENT  
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 11. 
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Table 11 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
 
Pembrolizumab 
Common, but infusion-related reactions 
in labeling include drug 
hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, hypersensitivity 
and cytokine release syndrome. 
Pembrolizumab 
Dose modification and treatment guidelines 
for pembrolizumab infusion associated 
reactions are provided in Table 3. 
Hypersensitivity, including anaphylaxis 
Pembrolizumab 
Not specifically reported but included 
among infusion-related reactions in 
label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
 
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master protocol.  
 
Hepatotoxicity 
Pembrolizumab 
Hepatitis occurred in 0.8% of patients, 
including Grade 2, 3 or 4 cases in 
0.1%, 0.5% and 0.1% patients, 
respectively, receiving pembrolizumab. 
The median time to onset of hepatitis 
was 3.6 months (range 8 days to 21.4 
months). The median duration was 1.1 
months (range 1 day to 20.9+ months). 
Hepatitis led to discontinuation of 
pembrolizumab in 0.3% patients. 
Hepatitis resolved in 36 patients. 
Dose modification and treatment guidelines 
for liver enzyme increase are provided under 
immune-related reactions in Table 6.   
 
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury 
 
Dose modification and treatment guidelines 
for nephrotoxicity are provided under 
immune-related reactions in  Table 6.  
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy 
peripheral, dysgeusia (very common) 
and lethargy (common) for 
pembrolizumab in combination with 
chemotherapy  
Uncommon: epilepsy.  
Dose modification and treatment guidelines 
for neurological AEs are provided under 
immune-related reactions in Table 6. 
 
Immune-mediated Adverse Events 
Pembrolizumab 
Immune-mediated adverse events are 
designated as important identified risk 
for pembrolizumab. 
Dose modification and treatment guidelines 
for immune-related reactions are provided in 
Table 6. 
Risks related to special populations 
 
 
Pregnancy and lactation exposure and 
outcomes 
Pembrolizumab 
Pembrolizumab should not be used 
during pregnancy unless the clinical 
condition of the woman requires 
treatment with pembrolizumab. 
See master protocol for exclusion of 
participants, guidance on highly effective 
contraceptive methods, and pregnancy tests 
to be performed regularly.  
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Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Drug-drug interactions 
No data available.  
Overdose and its treatment 
No specific information is available on 
the treatment of overdose of 
pembrolizumab. 
See Section 6.8 of the master protocol.  
10.12 APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol. 
10.13 APPENDIX 13: ABBREVIATIONS  
 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CPS: 
combined positive score 
CR: 
complete response 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
ESCC: 
esophageal squamous cell carcinoma 
ICANS: 
immune Cell-Associated Neurotoxicity Syndrome 
ICU: 
intensive care unit 
IRR: 
infusion-related reactions  
MSI-H: 
microsatellite instability 
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NHP: 
non-human primate  
 
PD1: 
programmed cell death protein 1 
 
PK: 
pharmacokinetic 
SAEs: 
serious adverse events 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
VLS: 
Vascular Leak Syndrome 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
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10.14.1 
Amended protocol 01 (30 August 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is to include stopping rules for futility and update the 
rules for dose modification in case of treatment-related adverse events (TRAEs) for Cohort A in 
substudy 01. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
Criteria 
I04 has been revised from “Participants should 
have received at least but no more than 2 prior 
lines of treatment…” to “Participants should have 
received at least one but no more than 2 prior 
lines of treatment…”. 
For correction. 
In I06, “- less than required number of slides or 
archival tumor tissue sample collected more than 
6 months prior to screening” has been revised to 
“-less than required number of slides or archival 
tumor tissue sample collected more than 6 months 
prior to enrollment”. 
Harmonization per program level approach. 
Section 6.5.1 General 
rules 
The following sentence has been deleted “Once 
a dose has been decreased, intra-patient 
re-escalation back to the previous dose level is 
not permitted.”, and the following sentences have 
been added “In participants who have SAR444245 
dose reduction due to SAR444245 related Grade 
≥3 TRAEs, SAR444245 dose may be 
re-escalated to 
 μg/kg if: •no SAR444245 
related Grade ≥3 TRAE or clinically significant 
laboratory abnormality within at least 
2 subsequent cycles, AND •both Investigator and 
Sponsor agree that the participant has clinical 
benefit.”. 
For clarification of how dose will be reduced 
and re-escalated for participants who 
experience any Grade ≥3 TRAEs. 
Section 6.5.3 General 
guidelines for the 
management of 
treatment-related 
adverse events 
The following sentence “Participants who 
experience Grade ≥3 TRAEs at any time of the 
study (including clinically significant Grade 3 
laboratory abnormalities as defined in Section 
10.3.1 of the master protocol) will be required to 
temporarily delay the IMP, unless specified 
For consistency and clarity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
otherwise in the protocol, and with the exception 
of the TRAEs resolving within 5 days. After cycle 
delay, such participants may be considered for 
treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline or is stable and 
manageable through supportive/medical therapy.” 
has been changed to “Participants who 
experience Grade ≥3 TRAEs at any time of the 
study (including clinically significant Grade 3 
laboratory abnormalities as defined in 
Section 10.3.1 of the master protocol) not listed in 
Section 6.5.4 (Tables 3-8) will be required to 
temporarily delay the IMP. After cycle delay, such 
participants may be considered for treatment 
resumption once the TRAE resolves or improves 
to Grade 1 or baseline”. 
Dose reduction rules have added, and the 
following sentence has been deleted “Dose 
reduction for SAR444245 from 
µg/kg to 
 
µg/kg (or another lower recommended dose) may 
be decided when specified in the protocol or 
following discussions with the Sponsor.” . 
Section 6.5.4.1 
Infusion-related 
reactions (IRR) 
In Table 4 under Grade 3 and Grade 4, 
“prematurely” has been removed from 
“prematurely permanently discontinued”. 
For clarity. 
Section 6.5.4.3 Fever, 
flu-like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 5 under Grade 3, the following sentence 
was deleted “If subsequent administration is 
tolerated, increasing the SAR444245 dose to 
µg/kg at subsequent administration can be 
considered based on the clinical judgement of the 
Investigator with the Sponsor”. 
For consistency. 
Section 9.5 Interim 
analyses 
The following sentences have been added “If the 
predictive probability of concluding a minimum 
clinical meaningful effect of the study treatment 
(ORR of 5%) at the end of study is <15%, the 
corresponding cohort will be stopped for futility. To 
facilitate the calculation of predictive probability, 
a minimum informative prior of Beta (0.5, 0.5) is 
used at the time of the design of the study. 
However, emerging data generated from outside 
of the study may warrant a different prior to be 
considered before this interim analysis.”. 
To include stopping rules for futility. 
 
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11 
REFERENCES 
  
1. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
2. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8. 
3. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for 
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol. 
2005;23(10):2346-57. 
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
2008;358(25):2698-703. 
5. Greenwald RJ, Freeman GJ,  Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
7. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
8. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol. 
2004,173(2):945-54. 
9. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41. 
10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
11. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
2005;25(21):9543-53. 
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
VV-CLIN-0617848 3.0
Page 186


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SAR444245-ACT16902-S01 
12-Jan-2022 
Version number: 1 
 
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Page 68 
13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65(3):1089-96. 
14. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the 
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
15. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9. 
16. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade 
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 
2003;63(19):6501-5. 
17. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2:3. 
18. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
19. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
20. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7. 
21.Kojima T, Doi T. Immunotherapy for Esophageal Squamous Cell Carcinoma. Curr Oncol Rep. 
2017;19(5):33. 
22. Abnet CC, Arnold M, Wei WQ. Epidemiology of Esophageal Squamous Cell Carcinoma. 
Gastroenterology. 2018;154(2):360-373. 
23. Doi T, Piha-Paul SA, Jalal SI, Saraf S, Lunceford J, Koshiji M, et al. Safety and Antitumor 
Activity of the Anti-Programmed Death-1 Antibody Pembrolizumab in Patients With 
Advanced Esophageal Carcinoma. J Clin Oncol. 2018;36(1):61-67. 
24. Shah MA, Kojima T, Hochhauser D, Enzinger P, Raimbourg J, Hollebecque A, et al. Efficacy 
and Safety of Pembrolizumab for Heavily Pretreated Patients With Advanced, Metastatic 
Adenocarcinoma or Squamous Cell Carcinoma of the Esophagus: The Phase 2 KEYNOTE-
180 Study. JAMA Oncol. 2019;5(4):546-50. 
VV-CLIN-0617848 3.0
Page 187


Amended Clinical Trial Protocol 02 (Substudy 01) 
SAR444245-ACT16902-S01 
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Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 69 
25. Kudo T, Hamamoto Y, Kato K, Ura T, Kojima T, Tsushima T, et al. Nivolumab treatment for 
oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol. 
2017;18(5):631-9. 
26. Kitagawa Y, Doki Y, Kato K, Ura T, Kojima T, Tsushima T, et al. 638PTwo year survival and 
safety update for esophageal squamous cell carcinoma treated with nivolumab 
(ATTRACTION-01/ONO-4538-07). Ann Oncol. 2017;28(suppl_5). 
27. Kojima T, Shah MA, Muro K, Francois E, Adenis A, Hsu CH, et al. on behalf of the 
KEYNOTE-181 Investigators. Randomized Phase III KEYNOTE-181 Study of 
Pembrolizumab Versus Chemotherapy in Advanced Esophageal Cancer. J Clin Oncol. 
2020;38(35):4138-48. 
28. Kato K, Cho BC, Takahashi M, Okada M, Lin CY, Chin K, et al. Nivolumab versus 
chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or 
intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-
label, phase 3 trial. Lancet Oncol. 2019;20(11):1506-17. 
29. Kato K, Sun J-M, Shah MA, Enzinger PC, Adenis A, Doi T, et al. LBA8_PR Pembrolizumab 
plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced 
esophageal cancer: The phase 3 KEYNOTE-590 study. Ann Oncol, Virtual ESMO 
2020;31(Supp 4): S1192-3. 
30. European Medicines Agency. Keytruda® European Public Assessment Report, Risk 
Management Plan Summary. [Online]. Last updated 2020 Jun 18 [cited on 2021 Jun 23]. 
Available from: URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda 
31. Diab A, Tykodi S, Daniels G, Maio M, Curti B, Lewis K, et al. 420 Progression-free survival 
and biomarker correlates of response with BEMPEG plus NIVO in previously untreated 
patients with metastatic melanoma: results from the PIVOT-02 study. J Immunother Cancer. 
2020;8(Suppl 3):A256. 
32. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line 
pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or 
metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 
Lancet Oncol. 2017;18(11):1483-92. 
33. Hoffman-Censits JH, Grivas P, Van Der Heijden MS, Dreicer R, Loriot Y, Retz M, et al. 
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally 
advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016;34 (2_suppl):355. 
34. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al. 
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, 
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 
2020;2(1):100124. 
VV-CLIN-0617848 3.0
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Amended Clinical Trial Protocol 02 (Substudy 01) 
SAR444245-ACT16902-S01 
12-Jan-2022 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 70 
35. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov. 
2020;10(8):1121-8. 
36. 
37. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
38. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18. 
39. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
40. Siddall E, Khatri M, Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, 
and management. Kidney Int. 2017;92(1):37-46.  
 
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According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 02) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab 
for the treatment of participants with advanced and 
metastatic gastric cancer or gastro-esophageal junction 
adenocarcinoma  
Protocol number: 
ACT16902-S02 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab 
for the treatment of participants with gastric cancer or 
gastro-esophageal junction adenocarcinoma  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
156424 
2021-002181-41 
NCT05104567 
U1111-1251-4981 
Date: 
12-Jan-2022 
Total number of pages: 73 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 02 
(Substudy 02) 
All 
12 January 2022, version 1 
(electronic 3.0) 
Amended Clinical Trial Protocol 01 
(Substudy 02) 
All 
30 August 2021, version 1 
(electronic 2.0) 
Clinical Trial Protocol (Substudy 02) 
 
20 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 02 (12 January 2022) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Belgian, Italian, German (Federal 
Institute for Drugs and Medical Devices [BfArM]), and South Korean Health Authorities after 
initial review. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities (SoA) 
A complete Table of SoA is provided for this 
substudy with procedures taken from the master 
protocol. And the previous footnote a for 
endocrine function tests has been renumbered as 
footnote j in the current document. 
Regulatory Authorities (BfArM) request. 
Troponin test has been added at screening, at 
C4D1, and as clinically indicated during treatment 
period until Follow-up visit 1. 
To allow assessment of any potential 
cardiotoxity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
activities (SoA) 
3 Objective and 
endpoints 
8.10 Patient-reported 
outcomes (PRO) 
9.4.4.2 Patient-reported 
outcomes 
Patient-reported outcome assessment have been 
added.  
Exploratory objective and endpoints for Patient-
reported outcomes have been added. 
New section added. 
 
Analysis for PRO endpoints has been added. 
To assess patient-reported experience of 
treatment
in an exploratory 
endpoint. 
1.4 Biomarker flowchart 
A complete Table of biomarker flowchart is 
provided for this substudy with biomarker sample 
collections taken from the master protocol. 
Regulatory Authorities (BfArM) request. 
1.5 Pharmacokinetic 
flowcharts 
A complete Table of pharmacokinetic (PK) 
flowcharts are provided for this substudy with PK 
sample collections taken from the master protocol. 
Regulatory Authorities (BfArM) request. 
5.1 Inclusion criteria 
For I07, “for whom available SOC should not be in 
their best interest” has been added. 
For clarity. 
5.1 Inclusion criteria, 
10.7 Appendix 7: 
Country-specific 
requirements 
South Korea specific requirements has been 
added for I07 and I08, to clarify that Korean 
patients will not be enrolled in Cohort B1 or Cohort 
B2 to receive SAR444245 + pembrolizumab as 
1st or 2nd line (L) treatment neither in Cohort B3 
to receive SAR444245 + pembrolizumab as 2nd L.  
Regulatory Authorities request. 
  
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 02) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 8 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 14 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 20 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 21 
1.5.1 
Participants with more intensive PK sampling ............................................................................... 21 
1.5.2 
All other participants....................................................................................................................... 22 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.2.1 
Pembrolizumab .............................................................................................................................. 23 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 23 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 24 
2.2.2 
Rationale for GC/GEJ and selected populations (Cohorts B1, B2 and B3) ................................... 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 26 
2.3.1 
Risk assessment ............................................................................................................................ 26 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 26 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 27 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 28 
2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
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3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 30 
4.2.1 
Participant input into design ........................................................................................................... 31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 31 
4.3.1 
SAR444245 dose ........................................................................................................................... 31 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 31 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 35 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 35 
5.4 
SCREEN FAILURES...................................................................................................................... 35 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 35 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 36 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 36 
6.1.1 
Investigational medicinal product (IMP) ......................................................................................... 36 
6.1.2 
Non-investigational medicinal products ......................................................................................... 37 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 37 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 37 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 37 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 37 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 37 
6.5 
DOSE MODIFICATION .................................................................................................................. 37 
6.5.1 
General rules .................................................................................................................................. 37 
6.5.2 
Cycle delay ..................................................................................................................................... 38 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 39 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 40 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 40 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 42 
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6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 43 
6.5.4.4 
Immune-related adverse events .................................................................................................... 45 
6.5.4.5 
Immune cell-associated neurotoxicity syndrome (ICANS) ............................................................. 48 
6.5.4.6 
Vascular leak syndrome (VLS) ...................................................................................................... 49 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 50 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 50 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 51 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 52 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 52 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 52 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 52 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 53 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 53 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 53 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 53 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 53 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 53 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 54 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 54 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 54 
8.3.5 
Pregnancy ...................................................................................................................................... 54 
8.3.6 
Cardiovascular and death events .................................................................................................. 54 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 54 
8.3.8 
Adverse event of special interest ................................................................................................... 54 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 54 
8.4 
PHARMACOKINETICS .................................................................................................................. 54 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 55 
8.6 
BIOMARKERS ............................................................................................................................... 55 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 55 
8.8 
HEALTH ECONOMICS .................................................................................................................. 55 
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8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 55 
8.10 
PATIENT-REPORTED OUTCOMES (PRO) ................................................................................. 55 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 57 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 57 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 57 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 57 
9.4.1 
General considerations .................................................................................................................. 58 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 58 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 58 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 58 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 58 
9.4.4.2 
Patient-reported outcomes ............................................................................................................. 58 
9.4.5 
Other safety analysis...................................................................................................................... 58 
9.4.6 
Other analysis ................................................................................................................................ 58 
9.5 
INTERIM ANALYSES .................................................................................................................... 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 59 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 59 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 59 
10.1.2 
Financial disclosure........................................................................................................................ 59 
10.1.3 
Informed consent process .............................................................................................................. 59 
10.1.4 
Data protection ............................................................................................................................... 59 
10.1.5 
Committees structure ..................................................................................................................... 59 
10.1.6 
Dissemination of clinical study data ............................................................................................... 59 
10.1.7 
Data quality assurance .................................................................................................................. 59 
10.1.8 
Source documents ......................................................................................................................... 59 
10.1.9 
Study and site start and closure ..................................................................................................... 59 
10.1.10 Publication policy ........................................................................................................................... 60 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 60 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 60 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 60 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 60 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 60 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 61 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 .......... 61 
10.9 
...................................................................................................................... 61 
10.9.1 
Response and stable disease duration (RECIST 1.1 and
) ............................................. 63 
10.9.2 
Methods of measurement .............................................................................................................. 64 
10.10 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 65 
10.11 
APPENDIX 11: RISK ASSESSMENT ............................................................................................ 65 
10.12 
APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 66 
10.13 
APPENDIX 13: ABBREVIATIONS ................................................................................................. 66 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY ................................................................ 67 
10.14.1 Amended protocol 01 (30 August 2021) ........................................................................................ 67 
11 
REFERENCES ............................................................................................................................... 70 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 29 
Table 2 - Overview of IMP administered ....................................................................................................... 36 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 40 
Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 42 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 43 
Table 6 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 46 
Table 7 - Guidelines for the management of immune cell-associated neurotoxicity syndrome (ICANS) ..... 48 
Table 8 - Guidelines for the management of vascular leak syndrome (VLS) ................................................ 49 
Table 9 - Estimated objective response rate (ORR) depending on number of responders .......................... 57 
Table 10 - Protocol-required laboratory tests ................................................................................................ 60 
Table 11 - Risk assessment .......................................................................................................................... 65 
 
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LIST OF FIGURES 
Figure 1 - Overall study schema - Substudy 02 ............................................................................................ 11 
Figure 2 - Graphical study design - Cohorts B1, B2, and B3 ........................................................................ 13 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Cohort-specific 
protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of 
participants with advanced and metastatic gastric cancer or gastro-esophageal junction 
adenocarcinoma 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of 
participants with gastric cancer or gastro-esophageal junction adenocarcinoma 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 1 
(PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in 
the syngeneic murine CT-26 colon cancer model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
High-level microsatellite instability (MSI-H) has been associated with better clinical outcomes in 
metastatic gastroesophageal cancer participants treated by PD1/PD-L1-based regimens but the 
prevalence of MSI-H in metastatic gastric cancer is low (~10%). Hence, the proposed study would 
focus on non MSI-H tumors with a large unmet need to establish proof-of-concept that combining 
the non-alpha-IL2 SAR444245 with the anti-PD1 antibody pembrolizumab will result in 
a significant increase in the percentage of patients experiencing an objective response in the 
setting of advanced unresectable or metastatic gastric cancer or gastro-esophageal junction 
adenocarcinoma (GC/GEJ), especially with low PD-L1 expression or after progression on prior 
PD1/PD-L1-based regimens.  
Objectives and endpoints  
 
Please refer to the master protocol. 
Overall design: 
Please refer to the master protocol. 
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Brief summary:  
Cohorts B1, B2 and B3 will assess SAR444245 adding on to pembrolizumab in participants with 
advanced unresectable or metastatic GC or Siewert Type 2 & 3 GEJ and for whom receiving 
standard of care (SOC) is not of best interest ( for example, participants who are not eligible, 
cannot tolerate, decline to receive, or have no access to such treatment) or where no SOC is 
established. MSI-H cases will not be eligible. HER2 + cases will not be eligible unless they have 
progressed on a trastuzumab-based treatment.   
• Cohorts B1 & B2 participants must not have received more than two prior lines of 
treatment that did not include an anti-PD1/PD-L1-based regimen. Participants will be 
assigned to one of these 2 cohorts according to the level of PD-L1 expression at baseline 
using the CPS as follow: 
- 
Cohort B1: participants with CPS ≥1 GC/GEJ 
- 
Cohort B2: participants with CPS <1 GC/GEJ 
• Cohort B3 participants are eligible regardless of the disease CPS status and must have 
received at least one and no more than three prior lines of treatment and have progressed 
after primary or secondary resistance to an anti-PD1/PD-L1-based regimen (detailed in 
Section 5.1). 
A graphical presentation of the substudy schema is shown Figure 1. 
Figure 1 - Overall study schema - Substudy 02 
 
* In 1L, when receiving standard of care (SOC) is not in the best interest of the participant 
** non-MSI-H and HER2 negative (or HER2 positive if progression is noted on trastuzumab based therapy) 
Abbreviations: 1-3L: first-line to third-line; 2-4L: second- to fourth-line; CPS: combined positive score; GC: gastric cancer; GEJ: gastro-
esophageal junction adenocarcinoma; MSI-H: high-level microsatellite instability; N=number; PD-1: programmed cell death 1; PD-L1: 
programmed cell death ligand 1 
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Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in each of Cohorts B1, B2, and 
B3. 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration for a participant 
in Cohorts B1, B2, and B3. For treatment period, the completion of Cycle 35 is applicable for all 
3 cohorts.  
Study intervention(s) 
Dosing sequence:
Investigational medicinal products 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in 
single-dose vials 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered as a dose of 200 mg using 
a 30-minute IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min). 
SAR444245 
SAR444245 formulation, route of administration, and dose regimen as described in the master 
protocol. Treatment duration for Cohorts B1, B2, and B3 is up to 35 cycles. 
Noninvestigational medicinal products 
Please refer to the master protocol. 
After 4 cycles, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, premedication no longer needs to be 
administered. 
Statistical considerations: 
Please refer to master protocol.  
Data Monitoring/Other committee: Yes
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1.2 
SCHEMA 
Figure 2 - Graphical study design - Cohorts B1, B2, and B3 
 
C=Study cycle; D=Study day; EOT=end of treatment; IMP=Investigational medicinal product; Q9W=every 9 weeks; Q12W=every 12 weeks. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
 
Inclusion and 
exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical and 
disease history  
X 
  
  
  
  
  
  
  
  
  
See Section 8 of 
the master protocol 
Body Weight / 
Heightg 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Full physical 
examination 
X 
 
 
 
 
X 
 
 
 
 
See Section 8.2.1 
of the master 
protocol  
Directed Physical 
examination 
 
X 
X 
X 
X 
 
X 
  
  
  
See Section 8.2.1 
of the master 
protocol  
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
  
  
  
See Section 8.2.2 
of the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Performance status 
(ECOG) 
X 
X  
X 
X 
X 
X 
X 
  
  
  
 
SpO2 
X 
As clinically indicated 
  
  
  
  
  
 
Laboratory and other investigations 
 
12-Lead ECG  
X 
X 
As clinically indicated 
  
  
  
See Section 8.2.3 
of the master 
protocol  
LVEF 
X 
As clinically indicated 
  
  
  
See Section 8.2.3 
of the master 
protocol  
Troponin 
X 
As clinically 
indicated 
X (Cycle 4 
Day 1) 
As clinically indicated 
 
 
 
See Section 8.2.3 
of the master 
protocol and 
Section 10.2 of the 
master protocol  
Pregnancy test  
X 
X 
  
  
X 
X 
X 
X 
  
  
See Section 8.2.5 
of the master 
protocol and 
Section 10.2 of the 
master protocol 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
Hepatitis serology, 
CD4 counts and viral 
load  
Xh 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol and 
Section 10.7 of the 
master protocol  
Hematology  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Coagulation 
X 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol  
Blood Chemistry  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Urinalysisi 
X 
X 
  
  
X 
X 
X 
  
 
 
See Section 10.2 
of the master 
protocol 
T3, FT4, TSH & 
cortisolj 
X 
   
  
  
X 
X 
X 
  
  
  
See Section 10.2 
IMP 
 
SAR444245 
 
X 
 
 
X 
 
 
 
 
 
 
Pembrolizumab 
  
X 
  
  
X 
  
  
  
  
  
  
Hospitalizationk 
  
X 
  
  
  
  
  
  
  
  
 
AE/SAE assessmentl 
X 
Continuously throughout treatment period 
 X 
  
  
  
See Section 8.3 of 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ± 7 days 
Every 
3 months+/- 
14 days 
 
the master protocol  
Prior/Concomitant 
Meds 
X 
Continuously throughout treatment period 
  
  
  
  
See Section 6.8 of 
the master protocol 
First subsequent anti-
cancer therapy 
  
  
  
  
   
X 
X 
X 
X 
X 
 
Survival status 
  
  
  
  
  
  
  
  
  
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy) / Immunogenicity assessments 
 
PK SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
ADA SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
PDy - Blood and 
tumor tissue 
collectionm,n 
See Biomarker flowchart in Section 1.4  
Tumor assessment 
 
Brain imagingo 
X 
  
  
  
  
 
 
 
 
  
See Section 8.1 of 
the master protocol  
CT/MRIp 
X 
  
  
  
X 
X 
X 
X 
X 
  
See Section 8.1 of 
the master protocol  
Patient-reported outcome assessment 
 
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a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as 
part of screening within 3 days prior to first IMP administration. During the study treatment period, all assessments must be performed, and results should be reviewed by the investigator prior to IMP administration 
at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are 
performed and can be signed more than 28 days prior to first IMP administration. Screening time indicates the maximum time frame relative to the first IMP administration in which study procedures used to support 
eligibility are done. 
b Cycle: a treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1. For participant's convenience, all 
Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and 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 study. 
e For Cycle 4 visits, please refer to PK flowchart in Section 1.5. 
f 
C1D8 and/or C1D15 visits must be performed on site for the following participants only: 1) Participants scheduled to have blood draws for biomarker assessment and/or ADA on Day 8; 2) Participants who will 
receive IMP on Day 8 and Day 15. For all other participants, these 2 on-site visits may be done remotely as appropriate based on investigator’s discretion per institutional standard and local regulations. If this is 
the case, this must be documented in the source document. Sponsor may decide to cancel safety assessment on C1D8 and C1D15 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 For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.7 of the master protocol). 
i 
Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal), will be performed every 4 cycles during Treatment Period and as 
clinically indicated. 
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated  
k Only for participants who will participate in the intensive PK sample collection. 
l 
AE/SAE assessment: 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 (1).   
m If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
n Will not be done for participants enrolled in China. 
o Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is clinically 
contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease as per protocol tumor assessment (TA) schedule. In all other cases, the lesions must be treated. Two additional scans, obtained at least 4 weeks apart, should be obtained to document disease 
stability after local treatment administration to the brain metastases has been completed. If participants receive 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 
4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or have 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. 
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p CT/MRI: The initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ± 7 days) after the date of first IMP and if clinically indicated. Imaging studies should 
follow calendar days and should not be adjusted for delays in cycle starts or extension. 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, during 
treatment period until PD. Per the primary tumor assessment criteria, after the first documentation of response or the first documentation of progression (if the participant is clinically stable), confirmatory imaging 
may be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor assessment is not needed for 
participants who start another anti-cancer therapy.  
q 
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AST=aspartate transaminase; ALT=alanine transaminase; C=Cycle; ANC=Absolute neutrophil count; AP=Alkaline phosphatase; BUN=Blood urea 
nitrogen; CRF=case report form; CRS=Cytokine release syndrome; CT=computed tomography;
 D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; e-CRF=electronic case report form; EOT=end-of-treatment; FT4=free thyroxine; FU=follow-up; HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; ICF=Informed consent form; 
IMP=investigational medicinal product; INR=international normalized ratio; LDH=Lactate hydrogenase; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA= multigated acquisition; 
PD=progressive disease; 
; PDy=pharmacodynamic; PK=pharmacokinetic; 
; PR=partial response; 
PS=Performance Status; SpO2= oxygen saturation; Q3W=every 3 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; 
WBC=White blood cells. 
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1.4 
BIOMARKER FLOWCHART 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
For participants who will undergo more intensive pharmacokinetic (PK) sampling, the schedule is shown in the flowchart in Section 1.5.1. Up to 
30 participants enrolled across cohorts treated with SAR444245 + pembrolizumab (including Cohorts B1, B2, and B3) will undergo more 
intensive PK sampling, up to 10 participants from China will undergo more intensive PK sampling. 
For all other participants, the PK sampling schedule is shown in the flowchart in Section 1.5.2. 
1.5.1 Participants with more intensive PK sampling  
 
Cycle 
 
Cycle 1 
Cycle 2, 3 
Cycle 4 
Cycles 6, 8, 
10 + every 
4th cycle 
thereafter 
EOT 
visit 
  30 (±7) 
days 
after 
last 
IMP 
admin 
Day 
D1 
D8 
D1 
D1 
 
D1 
Time after 
SAR444245 
dosing 
(EOI, 
except SOI) 
[h] 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
168 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
SOI 
EOI 
SAR444245 
PK sample ID 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08  
P00a 
P01b 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P00a 
P01b 
  
Sample time 
window 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
 
 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
  
SAR444245 
ADA sample 
IDc 
AB00a 
  
  
  
  
  
  
  
 
 AB01 
AB00a 
  
AB00a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI), 
b PK sample must be taken at EOI after flush. 
c ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
In the event the infusion is interrupted, a PK sample should be drawn immediately after interruption. If infusion is not likely to be resumed by clinical assessment, subsequent samples should be drawn at EOI + 1 h, +2 
h, +4 h, +8 h, +24 h, +48 h and +72 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent samples should be drawn at 1 h, 2 h, 4 h, 8 h, 24 h, 
48 h and 72 h after end of resumed infusion (as per protocol). 
ADA: anti-drug antibodies; EOI: End of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: Start of infusion.   
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1.5.2 All other participants  
 
Cycle 
Cycle 1 
Cycles 2, 3. 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
Day 
D1 
D8 
D1 
Time after SAR444245 dosing (EOI, 
except SOI) [h] 
SOI 
EOI 
24 
168 
SOI 
EOI 
30 (±7) days after 
last IMP admin 
SAR444245 PK sample 
 
P01b 
P06c 
 
 
P01b 
 
SAR444245 ADA sample 
AB00a 
 
AB01 
AB00a 
 
ABF00 
a Samples collected strictly before start of infusion (SOI) 
b EOI samples = end of infusion samples. Must be taken at end of infusion precisely 
c PK sample can be collected at any time during the second day of the cycle. 
ADA: anti-drug antibodies, PK: pharmacokinetic: SOI: start of infusion; EOI: end of infusion   
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2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to cohorts with advanced unresectable or metastatic GC or Siewert Type 
2 & 3 GEJ for the combination therapy with pembrolizumab. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models while anti programmed cell death-1 (anti-PD1) antibody 
prevents T cell suppression through the PD1/PD-L1 pathway. The combination of anti-PD1 
treatment with SAR444245 was tested in a syngeneic mouse CT-26 colon cancer model and 
induced enhanced anti-tumor activity as demonstrated by an increased number of CR and tumor-
free surviving animals compared to each agent in monotherapy. These data support evaluation of 
SAR444245 in combination with pembrolizumab. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across 
a number of indications. 
Refer to the country approved labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background  
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (3, 4). 
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The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (6, 8, 9, 10). The mechanism by which PD1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins (11, 12).  
2.2.1.2 Pre-clinical trials  
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(13, 14, 15, 16, 17, 18, 19). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (7, 16, 18, 19, 20). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo (18). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see pembrolizumab IB). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
2.2.2  Rationale for GC/GEJ and selected populations (Cohorts B1, B2 and B3)  
Gastric cancer (GC) is an important health problem, being the 5th most common cancer and the 
3rd leading cause of cancer death worldwide. In 2018, over 1 million new cases of GC (5.7% 
among all cancer cases diagnosed) were diagnosed with an estimated 782 685 deaths related to 
GC. It accounts for 8.2% of all deaths from cancers in 2018 (21). In the United States, 27 600 new 
cases of GC and 11,010 related death are estimated in 2020 (22). Eastern Asia is a high-risk area 
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of GC. GC is the second most common cancer in China, following lung cancer and the mortality 
is the third highest (after lung and liver cancers) (21). The GEJ is anatomically separated from 
GC, but their pathological types, molecular types, genetic variations, and therapeutic approaches 
are similar (23). First-line chemotherapy most commonly comprises platinum and 
fluoropyrimidine, which extends overall survival (OS) by approximately 6.7 months (23). Disease 
progression after 1L chemotherapy is common and 2L treatment options include docetaxel, 
paclitaxel, irinotecan as a single agent or in combination therapy.  In addition, trastuzumab for 
patients with HER-2 positive disease and anti-VEGFR2 monoclonal antibody ramucirumab are 
also approved as 2L therapies. Pembrolizumab, was approved by FDA in 2017 for its use in 
advanced, recurrent GC expressing PD-L1 (CPS ≥1), after two prior lines of treatment, which was 
based on ORR from the phase II KEYNOTE-059 clinical trial (24). The phase II trial ONO4538 
and phase III trial ATTRACTION-2 revealed that nivolumab administration to heavily pre-treated 
GC patients is associated with improved OS, compared to patients treated with placebo (25). 
These results led to the approval of nivolumab in Japan for the treatment of advanced stage GC 
patients progressing after standard systemic cytotoxic therapy, regardless of the PD-L1 status. In 
this study, PDL1 expression in tumor cells was documented only retrospectively using TPS. The 
so called combined positive score (CPS), which takes into account the PD-L1 positivity on cancer 
and infiltrating immune cells, has been shown to be a better scoring method than the percentage of 
PD-L1+ tumor. In the 2L KEYNOTE-061 trial, treatment with pembrolizumab failed to show 
a significant survival benefit when compared to paclitaxel, however, patients with higher PD-L1 
levels by CPS showed a trend towards better survival (26). Indeed, the overall survival of GC 
patients treated with pembrolizumab was longer than that of patients under chemotherapy in 
CPS ≥10, which could not be recapitulated with a CPS ≥1. There were similar findings in the 
KEYNOTE-062 randomized trial in the 1L setting, where only patients with CPS ≥1 disease were 
randomized to receive either pembrolizumab alone or in combination with chemotherapy, or 
chemotherapy alone. (pembrolizumab ± chemo versus chemotherapy). In this trial, neither the 
pembrolizumab alone nor pembrolizumab combined with chemo improved OS in the CPS ≥1 
population, but pembrolizumab with or without chemo had comparable survival and 
pembrolizumab was found noninferior to chemotherapy in that same population. Unfortunately, 
this noninferiority was associated with significantly worst outcome in terms of ORR (15%) and 
progression-free survival (PFS) (2 months) when compared to chemo alone (ORR 37% and PFS 
6.4 months). However, in patients with tumors having a CPS ≥10, pembrolizumab alone (and not 
pembrolizumab with chemotherapy) was associated with an impressive OS (median OS, 
17.4 months [HR, 0.69; 95% CI, 0.49-0.97]) which unfortunately had no α attributed and thus 
could not be considered a statistically significant result (27). As both KEYNOTE-061 and 
KEYNOTE -062 were negative studies, pembrolizumab is therefore not approved in the 1 & 2L 
settings but remained approved after two prior lines of treatment in CPS ≥1. 
Very recently, the positive results of two randomized trial for nivolumab combined with 
oxaliplatin-based chemotherapy regimens in the 1L setting were disclosed.  The CheckMate-649 
trial enrolled GC/GEJC/EAC patients regardless of CPS with a primary endpoint for OS in the 
CPS≥5 (28). The study demonstrated superior OS (14.4 versus 11.1 months, HR 0.71; p<0.0001) 
with 29% reduction in risk of death, and a 3.3 months improvement in median OS with nivolumab 
plus chemo versus chemo in patients whose tumors expressed PD-L1 CPS ≥5. This survival 
benefit was extended to all study population including PD-L1 CPS≥1, however the CPS <5 may 
have been underrepresented.  In the ATTRACTION-4 study (29), Asian patients with GC/GEJ 
were enrolled regardless of the PD-L1 status of their disease. PFS (interim analysis) was 
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significantly improved (median PFS, 10.5 versus 8.3 months, HR 0.68; p = 0.0007) in the 
experimental arm however, there was no statistically significant improvement in OS, which might 
have been due to 2L treatment containing immune checkpoint inhibitors in the control arm. 
Nivolumab plus chemo represents a new potential 1st line standard treatment for patients with 
advanced GC/GEJ cancers.   
Indeed, in non-MSI-H GC/GEJ cancer, the KEYNOTE and CheckMate studies highlights the 
importance of PD-L1 expression on the response and potential benefit in OS, even in the absence 
of chemotherapy.  Combining SAR444245 with an immune checkpoint inhibitor may allow to 
expand the population of patients who may benefit from an ICI, especially in the context of low or 
no PD-L1 expression.  Cohort B1 and B2 aims to bring evidences that the combination of 
SAR444245 with pembrolizumab can have a meaningful increase in the ORR induced by 
pembrolizumab alone in ICI-naïve patients with GC/GEJ with CPS ≥1 (Cohort B1) or 
CPS <1 (Cohort B2). Despite the important benefit of ICI or ICI-based therapy in GC/GEJ, not all 
patients respond to treatment, and some move on to progression after an initial response. As ICI- 
based treatment moves to earlier line, it will be important to explore alternative treatment to 
rescue this population for whom the prognosis is poor on chemotherapy standard of care in later 
treatment lines. In Cohort B3, the potential to rescue patients who will have progressed on prior 
ICI-based treatment will be investigated. 
2.3 
BENEFIT/RISK ASSESSMENT 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin).  
Risk assessment of SAR444245 when combined with pembrolizumab results from anticipated 
risks for SAR444245 and from the label information for Keytruda® (pembrolizumab), taking into 
account potential overlapping risks. The available safety data for pembrolizumab, along with 
proposed mitigation strategies are summarized below and also provided in Table 11. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment (TME). 
The use of pembrolizumab may cause IRRs (drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, and hypersensitivity. Pembrolizumab use may be associated with 
infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, leukopenia), 
increase in the level of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well as adverse effects 
on the functioning of nervous system (dizziness, headache, peripheral neuropathy, dysgeusia (very 
common) and lethargy). In combination therapy with other chemotherapeutic drugs, 
pembrolizumab administration is commonly associated with hypertension and cardiac arrhythmia 
(including atrial fibrillation). 
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Immune-mediated adverse events are designated as important identified risks for pembrolizumab 
(30). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in 
post-marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis.  
Please refer to the country-approved product labeling (eg, United States Package Insert [USPI], 
Summary of Product Characteristics [SmPC]) for pembrolizumab for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab 
Combining SAR444245 with pembrolizumab may lead to an increased frequency and/or severity 
of adverse events (AEs) related to immune activation or may lead to additional AEs related to 
immune system activation for each substance individually or may cause occurrences of 
qualitatively different AEs. Serious adverse drug reactions reported with agents known to increase 
immune activation include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction  
(see Section 2.3.1.1).  
As both substances are biologic agents, they may have the propensity to induce infusion-related 
reactions that may have higher rate of occurrence and severity when SAR444245 with 
pembrolizumab are used in combination. 
The maximum tolerated dose (MTD) of SAR444245 combined with the approved dosing of the 
anti PD-1 pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. 
Safety data generated from the combination of SAR444245 and pembrolizumab have informed 
the selection of the combination dose in this study.  
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
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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). 
Immune checkpoint inhibitors are approved in most of the indications proposed to be tested in this 
study (please refer to Section 2.1 - Study Rationale): ESCC, gastric and gastroesophageal, HCC. 
In gastric cancer and ESCC, the main benefit of pembrolizumab is brought to patients with 
diseases that have a relatively high expression of PD-L1 (CPS ≥10). Combining SAR444245 to 
pembrolizumab is anticipated to expand to population responding to the an anti-PD1 and to 
increase the quality of the response. Such effects have been demonstrated in the PIVOT-02 study 
for bempegaldesleukin combined with nivolumab in metastatic melanoma, achieving deep and 
durable responses with rates of CR of 34% and PFS (30.9 months) exceeding that reported in 
clinical trials for approved treatments (31). Objective responses were also documented in PDL1 
negative cases (n=13), with an ORR of 39% and 3 patients achieving 100% reduction of target 
lesions, and 2 patients achieving CR. Echoing these results are those of the same combination in 
1L metastatic urothelial carcinoma, an indication where response to immune checkpoint is linked 
to the level of expression of PD-L1.  In this study, bempegaldesleulin when combined with 
nivolumab induced significant ORR with 17% CR, with ORR similar and PD-L1 negative (50%) 
and PD-L1 positive (56%) (15), which contrast with data from Keynote-052 for pembrolizumab 
(32, 33). Combining SAR444245 with pembrolizumab is anticipated to bring benefit to patients 
with ESCC and GC/GEJ even in the context of low PD-L1 and could rescue patients who have 
progressed or relapsed following an anti-PD1/PD-L1. 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. 
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 pembrolizumab are justified by the anticipated benefits that may be afforded to 
participants with GC/GEJ.  
2.3.4 Benefit and risk assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity. 
In addition, the impact of PD-1 blockade therapy on  Coronavirus disease 2019 (COVID-19) 
severity was also explored by 2 groups and did not find a clinically meaningful signal (34, 35). 
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below.  
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Cohorts B1, B2 and B3 will assess SAR444245 adding on to pembrolizumab in participants with 
advanced unresectable or metastatic gastric cancer (GC) or Siewert Type 2 & 3 gastro-esophageal 
junction adenocarcinoma (GEJ) and for whom receiving standard of care (SOC) is not in his or 
her best interest (for example, participants who are not eligible, cannot tolerate, decline to receive, 
or have no access to such treatment) or where no SOC is established. MSI-H cases will not be 
eligible. HER2 + cases will not be eligible unless they have progressed on a trastuzumab-based 
treatment.   
•
Cohorts B1 & B2 participants must not have received more than two prior lines of
treatment that did not include an anti-PD1/PD-L1-based regimen. Participants will be
assigned to one of these 2 cohorts according to the level of PD-L1 expression at baseline
using the CPS as follow:
-
Cohort B1: participants with CPS ≥1 GC/GEJ
-
Cohort B2: participants with CPS <1 GC/GEJ
•
Cohort B3 participants are eligible regardless of the disease CPS status and must have
received at least one and no more than three prior lines of treatment and have progressed
after primary or secondary resistance to an anti-PD1/PD-L1-based regimen (detailed in
Section 5.1).
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts.   
A graphical presentation of the substudy schema is shown in Figure 1. For treatment period, the 
completion of Cycle 35 is applicable for Cohorts B1, B2, and B3. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the 
population experiencing an objective response. 
The design of the 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 RECIST 1.1 for participants with advanced unresectable and metastatic 
GC/GEJ.  
Please refer to the master protocol for more information. 
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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 
4.3.1 SAR444245 dose  
Please refer to the master protocol.   
4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is justified 
by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold exposure range 
(refer to the pembrolizumab IB). 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications. And 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
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Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, 
a PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohorts B1, B2, and B3 specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01.  Histologically or cytologically confirmed diagnosis of GC or Siewert Type 2 & 3 GEJ. 
I 02. Confirmed diagnosis at study entry of advanced unresectable or metastatic disease.  
PD-L1 expression using CPS as determined at local laboratory with an approved test (please refer 
to the lab manual for details on PD-L1 assay) 
I 03. For participants in Cohort B1: Disease with CPS scoring of ≥1. 
I 04. For participants in Cohort B2: Disease with CPS scoring of <1. 
Note: For participants in Cohort B3: Disease with any CPS scoring. No need for CPS 
determination at local laboratory. 
I 05. MSI status: Participants must have MSI status known, determined locally and must have 
non-MSI-H disease to be eligible.   
I 06. Other genetic aberrations: Participants with unknown HER2/neu status must have their 
HER2/neu status determined locally. Participants with HER2/neu negative are 
eligible. Participants with HER2/neu positive tumors must have documentation 
of disease progression on treatment containing trastuzumab to be eligible.  
Prior anticancer therapy 
I 07. For participants in Cohorts B1, and B2: Participants for whom available SOC should not 
be in their best interest and should have failed or relapsed on no more than 2 prior lines of 
treatment, and which did not include an anti-PD-1/PD-L1-based treatment. See 
instructions specific to Korea in Appendix 7 (Section 10.7). 
I 08. For participants in Cohort B3: Participants should have received at least one but no more 
than 3 prior lines of treatment, including an anti-PD-1/PDL-1 containing regimen and have 
progressed after a primary or secondary resistance to an anti-PD-1/PDL-1. See instructions 
specific to Korea in Appendix 7 (Section 10.7). 
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Note: For Cohorts B3:  
Primary resistance is defined as a patient who has experienced progressive disease (PD) or SD 
lasting <6 months of initiation of PD-1/PD-L1 inhibitor-based treatment and who received at least 
6 weeks of the PD1/PD-L1. Radiographic confirmation of the PD must be documented after 
a minimum of 4 weeks after the initial identification of progression, unless: i) investigator 
confirms clinical progression/ deterioration attributed to PD, or ii) the first radiographic 
assessment indicated critical tumor growth by imaging (size or location).   
Or 
Secondary resistance: patients must have experienced PD, either during or within 3 months of 
discontinuing treatment with anti-PD1-based therapy, occurring after previous clear benefit (any 
complete [CR] or partial response [PR]), or after previous stable disease (SD) >6 months. 
No requirement for radiographic confirmation of progression. 
I 09. An anti-PD1/PD-L1 containing regimen is defined as either an anti-PD1/PD-L1 
monotherapy, or an anti-PD1/PD-L1 agent administered in the same cycle as another 
systemic anticancer therapy. If PD1/PD-L1 was used beyond initial radiological 
progression while continuing to use the same PD1/PD-L1 agent used before PD, it is still 
considered as the same regimen. The site’s study team must have reviewed previous tumor 
assessments (including screening tumor imaging) to determine that radiographic 
progression has occurred per RECIST 1.1 following initiation of the anti-PD1/PD-L1 
containing regimen. 
I 10. Provision of tumor tissue: 
- 
Mandatory baseline biopsy for participants in Cohorts B1, B2, and B3, : minimum 
5 slides with 4-5 micron thickness for the first 20 participants who have signed ICF 
(excluding screen failure participants), minimum 10 slides with 4-5 micron thickness 
for subsequent participants in each cohort. Archival tumor tissue samples should be 
obtained from biopsies done within 6 months, and there should be no systemic 
anti-cancer therapy between collection of biopsy and enrollment. Slides specifications 
are detailed in Lab Manual.  
- 
Optional on-treatment biopsy for Cohorts B1, B2, and B3 per Investigator’s 
discretion and evaluation. 
- 
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. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
Prior/concomitant therapy 
E 01. For participants in Cohorts B1 and B2: Prior treatment with an agent (approved or 
investigational) that blocks the PD-1/PD-L1 pathway (participants who joined a study with 
an anti-PD-1/PD-L1 but have written confirmation they were on control arm are allowed).   
 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
Please refer to the master protocol. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
For study treatment duration, completion of Cycle 35 is applicable for Cohorts B1, B2, and B3. 
Dosing sequence: 
In addition, if a participant has immune unconfirmed progression of disease (iUPD) and is 
clinically stable, it is at the discretion of the Investigator to continue treating the subject with the 
assigned treatment per protocol until progression of disease is confirmed (iCPD) at least 4 weeks, 
but no longer than 8 weeks  from the date of the scan suggesting progression of disease 
(Section 10.9). 
6.1.1 Investigational medicinal product (IMP)  
Investigation medicinal product is defined as SAR444245 and pembrolizumab administered in 
combination as described in Section 4. Details of each IMP component to be administered are 
shown in Table 2.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.  
Table 2 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
100 mg/vial 
Dosage level(s)a 
24 μg/kg Q3W 
200 mg Q3W 
Route of administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
See master protocol 
IMP 
Packaging and labeling 
See master protocol 
Supplied in single dose vials containing 
100 mg/4 mL pembrolizumab labelled with 
a multilingual booklet. 1 vial per treatment box. 
Current/Former name(s) 
or alias(es) 
See master protocol 
Keytruda 
a See master protocol. 
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6.1.2 Non-investigational medicinal products 
Please refer to the master protocol. 
In case of permanent SAR444245 discontinuation and continuation of pembrolizumab treatment 
as part of AE management, SAR444245 premedication no longer needs to be administered. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modifications for SAR444245 are permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed.  
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In participants who have SAR444245 dose reduction due to SAR444245 related Grade ≥3 
treatment-related adverse events (TRAEs), SAR444245 dose may be re-escalated to
 μg/kg if:  
• no SAR444245 related Grade ≥3 TRAE or clinically significant laboratory abnormality 
within at least 2 subsequent cycles, AND  
• both Investigator and Sponsor agree that the participant has clinical benefit. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case, it is partial permanent discontinuation, and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued, it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay  
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administered ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3 and Section 6.5.4. After cycle is delayed, such participants may be 
considered for treatment resumption once the toxicity resolves or improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on the 
day of planned administration, the cycle will be delayed; restart of study IMPs could occur 
only on the initiation of the subsequent cycle. 
• In case of cycle delay for the recovery of toxicity, the following rules should be followed 
for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to restart 
the study treatment, if a clear benefit from treatment is observed and after consultation 
with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer than 
84 days. 
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• Cycle may be delayed for situations other than TEAEs such as medical/surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study 
therapy within 21 days of the scheduled delay, unless otherwise discussed with the 
Sponsor (for example for national or regional emergencies). The reason for the delay 
should be documented in the participant’s study record. 
6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
not listed in Section 6.5.4 (Tables 3-8) will be required to temporarily delay the IMP. After cycle 
delay, such participants may be considered for treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline .  
The dose of SAR444245 should be reduced to 
μg/kg (with the exception of lymphocytopenia 
which is directly associated with SAR444245 mode-of-action and does not require dose 
reduction) in cases of: 
• First occurrence of Grade 3 TRAE that does not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 TRAE of any duration. 
• Grade 4 TRAE. 
• First occurrence of Grade 3 laboratory abnormality that are clinically significant per 
Section 10.3.1 of the master protocol. and that do not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 clinically significant laboratory abnormality 
of any duration. 
• Grade 4 laboratory abnormalities that are clinically significant. 
Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to be in the 
best interest of the participant, except when specified otherwise in this protocol, or if the event has 
required the IMP temporary interruption for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
Vascular Leak Syndrome (VLS) and Infusion-related reactions (IRR) are presented in 
Section 6.5.4. 
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6.5.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF. 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An 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.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 3. 
After an infusion-related reaction due to pembrolizumab infusion (Grade 3 or Grade 4), the 
SAR444245 infusion will be delayed and can be administered after resolution of symptoms. The 
Investigator should discuss with the Sponsor’s Medical Monitor if the SAR444245 infusion needs 
to be delayed more than 1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 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, please see Section 6.1.2.1 of the 
master protocol. 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics. 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
• 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (eg, from 100 mL/hr. to 
50 mL/hr.). Otherwise, dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po 
(or equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
Epinephrine*, 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics, 
- 
Oxygen, 
- 
Pressors, 
- 
Corticosteroids. 
• 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
• 
Hospitalization may be indicated. 
*In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further study 
drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
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Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s clinical 
status. 
SAR444245 infusion may be interrupted at any time if deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the opinion of 
the investigator. 
Grade 2 
Requires therapy or infusion interruption 
but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hrs. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may be 
restarted at 50% of the original infusion rate. Otherwise dosing will be held until 
symptoms resolve and the participant should be premedicated for the next scheduled 
dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy may 
include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, narcotics.  
Increase monitoring of vital signs will be as medically indicated until the participant 
recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy may 
include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
Grade 4 
Life-threatening; pressor or ventilator 
support indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy may 
include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant recovers. 
a Information for preparation and storage of SAR444245 are provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; IV=intravenous; NCI = National Cancer 
Institute; NSAIDs: nonsteroidal anti-inflammatory drugs. 
6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and pembrolizumab being administered. 
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Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines) 
(37, 38, 39). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 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 C-reactive protein (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 according to severity grading are provided in Table 5. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV 
fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less 
frequently as the participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as 
medically indicated should be increased until the participant recovers. 
Transfer to ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, 
hypotension, or participants in whom symptoms (eg, high grade fever) that 
do not respond to antipyretics within 72 hours treatment with 
corticosteroids and/or tocilizumab should be considered, as per guidance 
for Grade 3 events.  
SAR444245 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 SAR444245  
dose modification and supportive care guidelines 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a vasopressor 
with or without vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
If CRS grade 3, SAR444245 should be temporarily delayed, and 
subsequent treatment should be resumed only when symptoms have 
resolved or improved to Grade 1.  
SAR444245 can be either restarted at 
µg/kg or permanently 
discontinued, as clinically indicated.  
If CRS Grade 4, SAR444245 should be permanently discontinued, as 
clinically indicated. 
If CRS Grade 3 or Grade 4, IV corticosteroids should be initiated (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, management for 
persistent or worsening CRS should be initiated. Re-evaluation for other 
contributing conditions should be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous Tocilizumab at 
8 mg/kg (for participants 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 should be 
discussed with clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway Pressure; CPAP= 
Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; IMP=investigational medicinal 
product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
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6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
IrAEs are thought to be caused by unrestrained cellular immune responses directed at the normal 
host tissues. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing pembrolizumab clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and 
administer corticosteroids. 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 6. Of 
note, when study interventions are administered in combination, if the AE is considered immune-
related, both drugs in the combination should be held according to recommended dose 
modifications.  If a participant experiences several irAEs, the most conservative recommendation 
should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
If the toxicities do resolve and conditions are aligned with what is defined in Table 6, the 
combination of SAR444245 and pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered 
after communication with the Sponsor. 
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Table 6 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245  
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld pembrolizumab and SAR444245 may be resumed after the irAE 
decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Pneumonitis  
Grade 2 
Withholda 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Add prophylactic antibiotics 
for opportunistic infections. 
Monitor participants for signs 
and symptoms of 
pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
Recurrent Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor participants for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinueb 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returns to 
baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Type 1 Diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholda f 
Initiate insulin replacement 
therapy for participants with 
T1DM. 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb f 
Hyperthyroidism  
Grade 2 
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb f 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinueb 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinueb 
All Other irAEs 
Persistent Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinueb 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 - 3.0 x ULN if baseline normal;  
>1.5 - 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; 
>3.0 - 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.  
6.5.4.5 Immune cell-associated neurotoxicity syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome 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 10.11 of the master protocol). 
Recommendations for ICANS management mainly include the use of 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 SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245 a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement 
to Grade 1 after corticosteroid taper. Consideration for reduction of 
SAR444245 dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
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Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 4 ICANS, SAR444245 should be permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab and should be handled as described in Table 5 in 
Section 6.5.4.3. Corticosteroids can then be administered IV or orally every 
8 hours for up to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations:  ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; ICANS= Immune effector 
cell associated neurotoxicity syndrome; ICE= Immune Effector Cell-Associated Encephalopathy; IV = Intravenous. 
6.5.4.6 Vascular leak syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with 
multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a balance 
between maintaining the intravascular volume to ensure organ perfusion to prevent organ failure, 
while avoiding volume overload. The management of VLS according to severity grading is 
described in Table 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 (1).  
Table 8 - Guidelines for the management of vascular leak syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
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Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued.   
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AKI= acute kidney injury; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; MW= molecular weight; 
NCI = National Cancer Institute; VLS= vascular leak syndrome. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater. There is no 
specific antidote for overdose with pembrolizumab. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
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6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol and Section 1.3. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s) 
Please refer to the master protocol for RECIST 1.1. 
 
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol.  
In addition, combining SAR444245 with other anticancer therapies may increase the frequency 
and severity of immune-related adverse events related to other anticancer therapies. Immune-
mediated endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, and 
cortisol level will be monitored. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort B1, B2 and B3 irAEs will be collected until 90 days following last 
administration of study treatment regardless of whether or not another anticancer therapy is 
initiated. 
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8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, SAEs that are considered expected will be specified in the reference safety 
information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol.  
8.4 
PHARMACOKINETICS 
Please refer to the master protocol.  
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8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
8.10 
PATIENT-REPORTED OUTCOMES (PRO) 
 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
 STATISTICAL HYPOTHESES  
Please refer to the master protocol. 
9.2 
SAMPLE SIZE DETERMINATION 
The plan is to treat approximately 40 participants per cohort for Cohorts B1, B2, and B3. 
Table 9 lists estimated ORR and 90% exact confidence intervals (CIs) by number of responders 
from a sample size of 40 participants treated. 
Table 9 - Estimated objective response rate (ORR) depending on number of responders  
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
2 
5% (0.9% - 14.9%) 
4 
10% (3.5% - 21.4%) 
6 
15% (6.7% - 27.5%) 
8 
20% (10.4% - 33.2%) 
10 
25% (14.2% - 38.7%) 
12 
30% (18.3% - 44.0%) 
14 
35% (22.6% - 49.2%) 
CI: confidence interval; N=number. 
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 these cohorts. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
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9.4.1 General considerations 
Please refer to the master protocol. 
In addition, efficacy analyses will be performed by pooled cohorts B1 and B2.  
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol. 
9.4.4 Tertiary/exploratory endpoint(s)  
. 
9.4.4.1 Exploratory antitumor indicators 
.  
9.4.4.2 Patient-reported outcomes 
 
9.4.5 Other safety analysis 
Please refer to the master protocol. 
9.4.6 Other analysis 
Please refer to the master protocol.  
9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
For each cohort, if the predictive probability of concluding a minimum clinical meaningful effect 
of the study treatment (ORR of 15% for cohort B1, 5% for cohort B2, 10% for cohort B3) at the 
end of study is <15%, the corresponding cohort will be stopped for futility. To facilitate the 
calculation of predictive probability, a minimum informative prior of Beta (0.5, 0.5) is used at the 
time of the design of the study. However, emerging data generated from outside of the study may 
warrant a different prior to be considered before this interim analysis. 
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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 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
Please refer to the master protocol.  
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol. 
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
10.1.9 Study and site start and closure 
Please refer to the master protocol. 
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10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. 
Cohorts B1, B2, and B3 specific evaluations are presented in Table 10. 
Table 10 - Protocol-required laboratory tests 
Laboratory tests 
Parameters 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
NOTES : 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
South Korea: 
Korean participants with gastric cancer or gastro-esophageal junction adenocarcinoma will not be 
enrolled in Cohort B1 or Cohort B2 to receive SAR444245 in combination with pembrolizumab 
as 1st or 2nd line (L) treatment neither in Cohort B3 to receive SAR444245 + pembrolizumab as 
2nd L. 
Please refer to the master protocol for additional country specific requirements. 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 
Please refer to the master protocol. 
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 or
 
(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). 
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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. For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. 
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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: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
 
10.11 APPENDIX 11: RISK ASSESSMENT  
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 11. 
Table 11 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for 
risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
 
Pembrolizumab 
Common, but infusion-related reactions 
in labeling include drug 
hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, hypersensitivity 
and cytokine release syndrome. 
Pembrolizumab 
Dose modification and treatment guidelines 
for pembrolizumab infusion-related reactions 
are provided in Table 3. 
Hypersensitivity, including anaphylaxis 
Pembrolizumab 
Not specifically reported but included 
among infusion-related reactions in 
label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
 
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master protocol.  
 
Hepatotoxicity 
Pembrolizumab 
Hepatitis occurred in 0.8% of patients, 
including Grade 2, 3 or 4 cases in 
0.1%, 0.5% and 0.1% patients, 
respectively, receiving pembrolizumab. 
The median time to onset of hepatitis 
was 3.6 months (range 8 days to 
21.4 months). The median duration 
was 1.1 months (range 1 day to 20.9+ 
months). Hepatitis led to 
discontinuation of pembrolizumab in 
0.3% patients. Hepatitis resolved in 
36 patients. 
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 
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury 
 
Dose modification and treatment guidelines 
for nephrotoxicity are provided under 
immune-related reactions in Table 6.  
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy 
peripheral, dysgeusia (very common) 
and lethargy (common) for 
pembrolizumab in combination with 
chemotherapy  
Uncommon: epilepsy.  
Dose modification and treatment guidelines 
for neurological AEs are provided under 
immune-related reactions in Table 6.  
 
Immune-mediated Adverse Events 
Pembrolizumab 
Immune-mediated adverse events are 
designated as important identified risk 
for pembrolizumab. 
 
 Dose modification and treatment guidelines 
for immune-related reactions are provided in 
Table 6. 
 
 
Risks related to special populations 
 
 
Pregnancy and lactation exposure and 
outcomes 
Pembrolizumab 
Pembrolizumab should not be used 
during pregnancy unless the clinical 
condition of the woman requires 
treatment with pembrolizumab. 
See master protocol for exclusion of 
participants, guidance on highly effective 
contraceptive methods, and pregnancy tests 
to be performed regularly.  
Drug-drug interactions 
No data available.  
Overdose and its treatment 
No specific information is available on 
the treatment of overdose of 
pembrolizumab. 
See Section 6.8 of the master protocol.  
 
10.12 APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol. 
10.13 APPENDIX 13: ABBREVIATIONS  
 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CR: 
complete response 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
GC: 
gastric cancer 
GEJ: 
gastro-esophageal junction adenocarcinoma 
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICU: 
intensive care unit 
 
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IRR: 
infusion-related reactions  
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NHP: 
non-human primate  
 
PD1: 
programmed cell death protein 1 
PK: 
pharmacokinetic 
PRO: 
patient reported outcome 
SAEs: 
serious adverse events 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
VLS: 
vascular leak syndrome 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.14.1 
Amended protocol 01 (30 August 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is to include stopping rules for futility, update the rules 
for dose modification in case of treatment-related adverse events (TRAEs), and clarify the 
population for Cohorts B1, B2 and B3 in substudy 02. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
and Section 4.1 Study 
design 
The following sentence has been added “for 
example, participants who are not eligible, cannot 
tolerate, decline to receive, or have no access to 
such treatment” to clarify the population for Cohort 
B1, B2, and B3. 
For clarity. 
Section 1.1 Synopsis 
In Figure 1, the following sentences have been 
added as footnote 
 “* In 1L, when receiving standard of care (SOC) is 
not in the best interest of the participant 
For consistency. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
** non-MSI-H and HER2 negative (or HER2 
positive if progression is noted on trastuzumab 
based therapy)”. 
Section 5.1 Inclusion 
Criteria 
In I06,  “- less than required number of slides or 
archival tumor tissue sample collected more than 
6 months prior to screening” has been revised to 
“-less than required number of slides or archival 
tumor tissue sample collected more than 6 months 
prior to enrollment”. 
Harmonization per program level approach. 
Section 6.5.1 General 
rules 
The following sentence has been deleted “Once 
a dose has been decreased, intra-patient 
re-escalation back to the previous dose level is 
not permitted.”, and the following sentences have 
been added “In participants who have SAR444245 
dose reduction due to SAR444245 related Grade 
≥3 TRAEs, SAR444245 dose may be 
re-escalated to 
 μg/kg if: •no SAR444245 
related Grade ≥3 TRAE or clinically significant 
laboratory abnormality within at least 
2 subsequent cycles, AND •both Investigator and 
Sponsor agree that the participant has clinical 
benefit.”. 
For clarification of how dose will be reduced 
and re-escalated for participants who 
experience any Grade ≥3 TRAEs. 
Section 6.5.3 General 
guidelines for the 
management of 
treatment-related 
adverse events 
The following sentence “Participants who 
experience Grade ≥3 TRAEs at any time of the 
study (including clinically significant Grade 3 
laboratory abnormalities as defined in Section 
10.3.1 of the master protocol) will be required to 
temporarily delay the IMP, unless specified 
otherwise in the protocol, and with the exception 
of the TRAEs resolving within 5 days. After cycle 
delay, such participants may be considered for 
treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline or is stable and 
manageable through supportive/medical therapy.” 
has been changed to “Participants who 
experience Grade ≥3 TRAEs at any time of the 
study (including clinically significant Grade 3 
laboratory abnormalities as defined in Section 
10.3.1 of the master protocol) not listed in Section 
6.5.4 (Tables 3-8) will be required to temporarily 
delay the IMP. After cycle delay, such participants 
may be considered for treatment resumption once 
the TRAE resolves or improves to Grade 1 or 
baseline”. 
Dose reduction rules have added, and the 
following sentence has been deleted “Dose 
reduction for SAR444245 from 
 µg/kg to 
 µg/kg (or another lower recommended dose) 
may be decided when specified in the protocol or 
following discussions with the Sponsor.” . 
For consistency and clarity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.5.4.1 
Infusion-related 
reactions (IRR) 
In Table 4 under Grade 3 and Grade 4, 
“prematurely” has been removed from 
“prematurely permanently discontinued”. 
For clarity. 
Section 6.5.4.3 Fever, 
flu-like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 5 under Grade 3, the following sentence 
was deleted “If subsequent administration is 
tolerated, increasing the SAR444245 dose to 
 µg/kg at subsequent administration can be 
considered based on the clinical judgement of the 
Investigator with the Sponsor”. 
For consistency. 
Section 9.5 Interim 
analyses 
The following sentences have been added “For 
each cohort, if the predictive probability of 
concluding a minimum clinical meaningful effect of 
the study treatment (ORR of 15% for cohort B1, 
5% for cohort B2, 10% for cohort B3) at the end of 
study is <15%, the corresponding cohort will be 
stopped for futility. To facilitate the calculation of 
predictive probability, a minimum informative prior 
of Beta (0.5, 0.5) is used at the time of the design 
of the study. However, emerging data generated 
from outside of the study may warrant a different 
prior to be considered before this interim 
analysis.”. 
To include stopping rules for futility. 
 
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11 
REFERENCES 
  
1. Siddall E , Khatri M , Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, 
and management. Kidney Int. 2017;92(1):37-46. 
2. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8. 
3. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for 
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol. 
2005;23(10):2346-57. 
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
2008;358(25):2698-703. 
5. Greenwald RJ, Freeman GJ,  Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
7. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
8. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol. 
2004,173(2):945-54. 
9. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41. 
10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
11. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
2005;25(21):9543-53. 
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
VV-CLIN-0617849 3.0
Page 260


Amended Clinical Trial Protocol 02 (Substudy 02) 
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Version number: 1 
 
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Page 71 
13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65(3):1089-96. 
14. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the 
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
15. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9. 
16. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade 
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 
2003;63(19):6501-5. 
17. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2:3. 
18. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
19. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
20. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7. 
21. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 
2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 
countries. CA Cancer J Clin. 2018;68(6):394-424. 
22. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. 
23. Chen C, Zhang F, Zhou N, Gu YM, Zhang YT, He YD, et al. Efficacy and safety of immune 
checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer: a systematic 
review and meta-analysis. Oncoimmunology. 2019;8(5):e1581547. 
24. Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, et al. Pembrolizumab alone 
or in combination with chemotherapy as first-line therapy for patients with advanced gastric or 
gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized 
KEYNOTE-059 study. Gastric Cancer. 2019;22(4):828-37. 
VV-CLIN-0617849 3.0
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Version number: 1 
 
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Page 72 
25. Kang YK, Boku N, Satoh T, Ryu MH, Chao Y, Kato K, et al. Nivolumab in patients with 
advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least 
two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461-71. 
26. Shitara K, Özgüroğlu M, Bang YJ, Di Bartolomeo M, Mandalà M, Ryu MH, et al. 
Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-
oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 
trial. Lancet. 2018;392(10142):123-33. 
27. Shitara K, Van Cutsem E, Bang YJ, Fuchs C, Wyrwicz L, Lee KW, et al. Efficacy and Safety 
of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for 
Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized 
Clinical Trial. JAMA Oncol. 2020;6(10):1571-80. 
28. Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyrwicz L, et al. LBA6_PR: 
Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for 
advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal 
adenocarcinoma (EAC): First results of the CheckMate 649 study. Ann Oncol, Virtual ESMO 
2020;31(Supp 4): S1191. 
29. Boku N, Ryu MH, Oh D, Oh SC, Chung HC, Lee  K, et al. LBA7_PR Nivolumab plus 
chemotherapy versus chemotherapy alone in patients with previously untreated advanced or 
recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-
37) study. Ann Oncol, Virtual ESMO. 2020;31(Supp 4):S1192. 
30. European Medicines Agency. Keytruda® European Public Assessment Report, Risk 
Management Plan Summary. [Online]. Last updated 2020 Jun 18 [cited on 2021 Jun 23]. 
Available from: URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda 
31. Diab A, Tykodi S, Daniels G, Maio M, Curti B, Lewis K, et al. 420 Progression-free survival 
and biomarker correlates of response with BEMPEG plus NIVO in previously untreated 
patients with metastatic melanoma: results from the PIVOT-02 study. J Immunother Cancer. 
2020;8(Suppl 3):A256. 
32. Balar AV, Castellano D, O'Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line 
pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or 
metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. 
Lancet Oncol. 2017;18(11):1483-92. 
33. Hoffman-Censits JH, Grivas P, Van Der Heijden MS, Dreicer R, Loriot Y, Retz M, et al. 
IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally 
advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol. 2016;34 (2_suppl):355. 
34. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al. 
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, 
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Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 
2020;2(1):100124. 
35. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov. 
2020;10(8):1121-8. 
36. 
 
37. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
38. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18. 
39. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
40. 
 
41. 
 
 
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Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 03) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab 
for the treatment of participants with advanced and 
metastatic hepatocellular carcinoma  
Protocol number: 
ACT16902-S03 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab 
for the treatment of participants with hepatocellular 
carcinoma  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
1 avenue Pierre Brossolette,  
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
156424 
2021-002181-41 
NCT05104567 
U1111-1251-4981 
Date: 
12-Jan-2022 
Total number of pages: 71 
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Page 2 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 02 (Substudy 03) 
All 
12 January 2022, version 1 
(electronic 3.0) 
Amended Clinical Trial Protocol 01 (Substudy 03) 
All 
30 August 2021, version 1 
(electronic 2.0) 
Clinical Trial Protocol (Substudy 03) 
20 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 02 (12 January 2022) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Belgian, Italian, German (Federal 
Institute for Drugs and Medical Devices [BfArM]), and South Korean Health Authorities after 
initial review. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities (SoA) 
A complete Table of SoA is provided for this substudy with 
procedures taken from the master protocol. And the previous 
footnote a for endocrine function tests has been renumbered 
as footnote j in the current document. 
Regulatory Authorities 
(BfArM) request. 
 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up 
Visit 1. 
To allow assessment of any 
potential cardiotoxity. 
1.4 Biomarker flowchart 
A complete Table of biomarker flowchart is provided for this 
substudy with biomarker sample collections taken from the 
master protocol. 
Regulatory Authorities 
(BfArM) request. 
1.5 Pharmacokinetic flowcharts 
Complete Tables of pharmacokinetic (PK) flowcharts are 
provided for this substudy with PK sample collections taken 
from the master protocol. 
Regulatory Authorities 
(BfArM) request. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.1.1 Assessment of objective 
response using the most 
appropriate modality according 
to the nature of the measurable 
lesion(s) 
The following sentence has been removed “To account for the 
possibility of unconventional immune responses, participants 
may continue treatment beyond progression if pseudo-
progression is ruled out.” 
For consistency. 
10.9 
. 
For correction. 
Throughout 
Minor editorial updates. 
For consistency and 
clarification. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 03) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 14 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 20 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 21 
1.5.1 
Participants with more intensive PK sampling ............................................................................... 21 
1.5.2 
All other participants....................................................................................................................... 22 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.2.1 
Pembrolizumab .............................................................................................................................. 23 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 23 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 24 
2.2.2 
Rationale for HCC and selected population (Cohort C) ................................................................. 24 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 26 
2.3.1 
Risk assessment ............................................................................................................................ 26 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 26 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 27 
2.3.2 
Benefit assessment ........................................................................................................................ 27 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 27 
2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 28 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 29 
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3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 29 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 30 
4.2.1 
Participant input into design ........................................................................................................... 30 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 30 
4.3.1 
SAR444245 dose ........................................................................................................................... 30 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 31 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 33 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 34 
5.4 
SCREEN FAILURES...................................................................................................................... 34 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 34 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 35 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 35 
6.1.1 
Investigational medicinal product (IMP) ......................................................................................... 35 
6.1.2 
Non-investigational medicinal products ......................................................................................... 36 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 36 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 36 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 36 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 36 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 36 
6.5 
DOSE MODIFICATION .................................................................................................................. 36 
6.5.1 
General rules .................................................................................................................................. 36 
6.5.2 
Cycle delay ..................................................................................................................................... 37 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 38 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 39 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 39 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 41 
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6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 42 
6.5.4.4 
Immune-related adverse events .................................................................................................... 44 
6.5.4.5 
Immune cell-associated neurotoxicity syndrome (ICANS) ............................................................. 47 
6.5.4.6 
Vascular leak syndrome (VLS) ...................................................................................................... 48 
6.5.4.7 
Hepatic Events ............................................................................................................................... 49 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 52 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 52 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 52 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 53 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 53 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 53 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 53 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 54 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 54 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 54 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 54 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 54 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 54 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 55 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 55 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 55 
8.3.5 
Pregnancy ...................................................................................................................................... 55 
8.3.6 
Cardiovascular and death events .................................................................................................. 55 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 55 
8.3.8 
Adverse event of special interest ................................................................................................... 55 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 56 
8.4 
PHARMACOKINETICS .................................................................................................................. 56 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 56 
8.6 
BIOMARKERS ............................................................................................................................... 56 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 56 
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8.8 
HEALTH ECONOMICS .................................................................................................................. 56 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 56 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 57 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 57 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 57 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 57 
9.4.1 
General considerations .................................................................................................................. 58 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 58 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 58 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 58 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 58 
9.4.5 
Other safety analysis...................................................................................................................... 58 
9.4.6 
Other analysis ................................................................................................................................ 58 
9.5 
INTERIM ANALYSES .................................................................................................................... 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 59 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 59 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 59 
10.1.2 
Financial disclosure........................................................................................................................ 59 
10.1.3 
Informed consent process .............................................................................................................. 59 
10.1.4 
Data protection ............................................................................................................................... 59 
10.1.5 
Committees structure ..................................................................................................................... 59 
10.1.6 
Dissemination of clinical study data ............................................................................................... 59 
10.1.7 
Data quality assurance .................................................................................................................. 59 
10.1.8 
Source documents ......................................................................................................................... 59 
10.1.9 
Study and site start and closure ..................................................................................................... 59 
10.1.10 Publication policy ........................................................................................................................... 60 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 60 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 60 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 60 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 60 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 60 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 60 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 .......... 61 
10.9 
APPENDIX 9: 
 .............................................................................. 61 
10.10 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 62 
10.11 
APPENDIX 11: RISK ASSESSMENT ............................................................................................ 63 
10.12 
APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 65 
10.13 
APPENDIX 13: ABBREVIATIONS ................................................................................................. 65 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY ................................................................ 65 
10.14.1 Amended protocol 01 (30 August 2021) ........................................................................................ 65 
11 
REFERENCES ............................................................................................................................... 68 
 
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LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 29 
Table 2 - Overview of IMP administered ....................................................................................................... 35 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 39 
Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 41 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 42 
Table 6 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 45 
Table 7 - Guidelines for the management of immune cell-associated neurotoxicity syndrome (ICANS) ..... 47 
Table 8 - Guidelines for the management of vascular leak syndrome (VLS) ................................................ 49 
Table 9 - Management of HE associated with Pembrolizumab and SAR444245 ......................................... 50 
Table 10 - Estimated objective response rate (ORR) depending on number of responders ........................ 57 
Table 11 - Protocol-required laboratory tests ................................................................................................ 60 
Table 12 -
.......................... 62 
Table 13 - Risk assessment .......................................................................................................................... 64 
 
LIST OF FIGURES 
Figure 1 - Overall study schema - Substudy 03 ............................................................................................ 11 
Figure 2 - Graphical study design - Cohort C ................................................................................................ 13 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Cohort-specific 
protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of 
participants with advanced and metastatic hepatocellular carcinoma 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of 
participants with hepatocellular carcinoma 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 1 
(PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in the 
syngeneic murine CT-26 colon cancer model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
PD1/PD-L1-based regimens have been approved as 1L or 2L therapy for advanced unresectable or 
metastatic hepatocellular carcinoma (HCC). Rescue of patients who will have failed 
ICI-containing regimens is crucial for later line therapies. This proposed study aims to establish 
proof-of-concept that combining the non-alpha-IL2 SAR444245 with the anti-PD1 antibody 
pembrolizumab will result in a significant increase in the percentage of patients experiencing an 
objective response in participants with advanced unresectable or metastatic HCC who relapsed on 
prior PD1/PD-L1-based regimens.  
Objectives and endpoints  
Please refer to the master protocol.  
Overall design: 
Please refer to the master protocol. 
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Brief summary:  
Cohort C will assess SAR444245 adding on to pembrolizumab in participants with advanced 
unresectable or metastatic HCC who relapsed on prior PD1/PD-L1-based regimens, with at least 
SD as best response and with no more than 2 prior lines of treatment. 
A graphical presentation of the substudy schema is shown in Figure 1. 
Figure 1 - Overall study schema - Substudy 03 
 
Abbreviations: 2-3L: second-line or third-line; HCC: hepatocellular carcinoma; N=number; PD-1: programmed cell death 1; PD-L1: programmed 
cell death ligand 1  
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in Cohort C. 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration for a participant 
in Cohort C. For treatment period, the completion of Cycle 35 is applicable for Cohort C.  
Study intervention(s) 
Dosing sequence:
Investigational medicinal products 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in 
single-dose vials 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered as a dose of 200 mg using 
a 30-minute IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min). 
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SAR444245 
SAR444245 formulation, route of administration, and dose regimen as described in the master 
protocol. Treatment duration for Cohort C is up to 35 cycles. 
Noninvestigational medicinal products 
Please refer to the master protocol. 
After 4 cycles, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, premedication no longer needs to be 
administered. 
Statistical considerations: 
Please refer to master protocol.  
Data Monitoring/Other committee: Yes 
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1.2 
SCHEMA 
Figure 2 - Graphical study design - Cohort C 
 
C=Study cycle; D=Study day; EOT=end of treatment; IMP=Investigational medicinal product; Q9W=every 9 weeks; Q12W=every 12 weeks. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to 
D-1 
D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ±7 days 
Every 
3 months+/- 
14 days 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
 
Inclusion and 
exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical and 
disease history  
X 
  
  
  
  
  
  
  
  
  
See Section 8 of 
the master protocol 
Body Weight/Heightg 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Full physical 
examination 
X 
 
 
 
 
X 
 
 
 
 
See Section 8.2.1 
of the master 
protocol  
Directed Physical 
examination 
 
X 
X 
X 
X 
 
X 
  
  
  
See Section 8.2.1 
of the master 
protocol  
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
  
  
  
See Section 8.2.2 
of the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to 
D-1 
D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ±7 days 
Every 
3 months+/- 
14 days 
 
Performance status 
(ECOG) 
X 
X  
X 
X 
X 
X 
X 
  
  
  
 
SpO2 
X 
As clinically indicated 
  
  
  
  
  
 
Laboratory and other investigations 
 
12-Lead ECG  
X 
X 
As clinically indicated 
  
  
  
See Section 8.2.3 
of the master 
protocol  
LVEF 
X 
As clinically indicated 
  
  
  
See Section 8.2.3 
of the master 
protocol  
Troponin 
X 
As clinically 
indicated 
X (Cycle 4 
Day 1) 
As clinically indicated 
 
 
 
See Section 8.2.3 
of the master 
protocol and 
Section 10.2 of the 
master protocol  
Pregnancy test  
X 
X 
  
  
X 
X 
X 
X 
  
  
See Section 8.2.5 
of the master 
protocol and 
Section 10.2 of the 
master protocol 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to 
D-1 
D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ±7 days 
Every 
3 months+/- 
14 days 
 
Hepatitis serology, 
CD4 counts and viral 
load  
Xh 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol and 
Section 10.7 of the 
master protocol  
Hematology  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Coagulation 
X 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol  
Blood Chemistry  
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
Urinalysisi 
X 
X 
  
  
X 
X 
X 
  
 
  
See Section 10.2 
of the master 
protocol  
T3, FT4, TSH & 
cortisolj 
X 
   
  
  
X 
X 
X 
  
  
  
See Section 10.2 
AFP 
X 
 
 
 
 
 
 
 
 
 
 
IMP 
 
SAR444245 
 
X 
 
 
X 
 
 
 
 
 
 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 
and 
beyonde 
EOT Visit 
Follow-Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day (Visit 
window in Days) 
D-28 to 
D-1 
D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
30 days (+/- 7 days) 
after last IMP or at 
initiation of further 
therapy 
3 months 
after last 
IMP admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU Visit 
2 ±7 days 
Every 
3 months+/- 
14 days 
 
Pembrolizumab 
  
X 
  
  
X 
  
  
  
  
  
  
Hospitalizationk 
  
X 
  
  
 
  
  
  
  
  
 
AE/SAE assessmentl 
X 
Continuously throughout treatment period 
 X 
  
  
  
See Sectio 8.3 of 
the master protocol  
Prior/Concomitant 
Meds 
X 
Continuously throughout treatment period 
  
  
  
  
See Section 6.8 of 
the master protocol 
First subsequent anti-
cancer therapy 
  
  
  
  
  
X 
X 
X 
X 
X 
 
Survival status 
  
  
  
  
  
  
  
  
  
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy) / Immunogenicity assessments 
 
PK SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
ADA SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
PDy - Blood and 
tumor tissue 
collectionm,n  
See Biomarker flowchart in Section 1.4 
Tumor assessment 
 
Brain imagingo 
X 
  
  
  
 
 
 
 
 
  
See Section 8.1 of 
the master protocol  
CT/MRIp 
X 
  
  
  
X 
X 
X 
X 
X 
  
See Section 8.1 of 
the master protocol  
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a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as 
part of screening within 3 days prior to first IMP administration. During the study treatment period, all assessments must be performed, and results should be reviewed by the investigator prior to IMP administration 
at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are 
performed and can be signed more than 28 days prior to first IMP administration. Screening time indicates the maximum time frame relative to the first IMP administration in which study procedures used to support 
eligibility are done. 
b Cycle: a treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1 For participant's convenience, all 
Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and 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 study. 
e For Cycle 4 visits, please refer to PK flowchart in  Section 1.5. 
f 
C1D8 and/or C1D15 visits must be performed on site for the following participants only: 1) Participants scheduled to have blood draws for biomarker assessment and/or ADA on Day 8; 2) Participants who will 
receive IMP on Day 8 and Day 15. For all other participants, these 2 on-site visits may be done remotely as appropriate based on investigator’s discretion per institutional standard and local regulations. If this is 
the case, this must be documented in the source document. Sponsor may decide to cancel safety assessment on C1D8 and C1D15 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 For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.7 of the master protocol). 
i 
Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal), will be performed every 4 cycles during Treatment Period and as 
clinically indicated. 
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated  
k Only for participants who will participate in the intensive PK sample collection. 
l 
AE/SAE assessment: 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 (1).  
m If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
n Will not be done for participants enrolled in China. 
o Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is clinically 
contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease as per protocol tumor assessment (TA) schedule. In all other cases, the lesions must be treated. Two additional scans, obtained at least 4 weeks apart, should be obtained to document disease 
stability after local treatment administration to the brain metastases has been completed. If participants receive 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 
4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or have 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. 
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p CT/MRI: The initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP and if clinically indicated. Imaging studies should 
follow calendar days and should not be adjusted for delays in cycle starts or extension. 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, during treatment 
period until PD. Per the primary tumor assessment criteria, after the first documentation of response or the first documentation of progression (if the participant is clinically stable), confirmatory imaging may be 
performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor assessment is not needed for participants who 
start another anti-cancer therapy.  
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AFP: alpha fetoprotein; AST=aspartate transaminase; ALT=alanine transaminase; C=Cycle; ANC=Absolute neutrophil count; AP=Alkaline phosphatase; 
BUN=Blood urea nitrogen; CRF=case report form; CRS=Cytokine release syndrome; CT=computed tomography; 
; D=Day; ECG=electrocardiogram; ECOG=Eastern 
Cooperative Oncology Group; e-CRF=electronic case report form; EOT=end-of-treatment; FT4=free thyroxine; FU=follow-up; HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; ICF=Informed consent form; 
IMP=investigational medicinal product; INR=international normalized ratio; LDH=Lactate hydrogenase; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA= multigated acquisition; 
PD=progressive disease;
 PDy=pharmacodynamic; PK=pharmacokinetic; PR=partial response; PS=Performance Status; SpO2= oxygen saturation; Q3W=every 3 weeks; 
RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; WBC=White blood cells. 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
For participants who will undergo more intensive pharmacokinetic (PK) sampling, the schedule is shown in the flowchart in Section 1.5.1. Up to 
30 participants enrolled across cohorts treated with SAR444245 + pembrolizumab (including Cohort C) will undergo more intensive PK sampling, 
up to 10 participants from China will undergo intensive PK sampling. 
For all other participants, the PK sampling schedule is shown in the flowchart in Section 1.5.2. 
1.5.1 Participants with more intensive PK sampling  
 
Cycle 
Cycle 1 
Cycle 2, 3 
Cycle 4 
Cycles 6, 8, 
10 + every 
4th cycle 
thereafter 
EOT 
visit 
  30 (±7) 
days 
after 
last 
IMP 
admin 
Day 
D1 
D8 
D1 
D1 
D1 
Time after 
SAR444245 
dosing 
(EOI,except 
SOI) [h] 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
168 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
SOI 
EOI 
SAR444245 
PK sample ID 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08  
P00a 
P01b 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P00a 
P01b 
  
Sample time 
window 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
 
 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
  
SAR444245 
ADA sample 
IDc 
AB00a 
  
  
  
  
  
  
  
 
 AB01 
AB00a 
  
AB00a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI), 
b PK sample must be taken at EOI after flush. 
c ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
In the event the infusion is interrupted, a PK sample should be drawn immediately after interruption. If infusion is not likely to be resumed by clinical assessment, subsequent samples should be drawn at EOI +1 h, 
+2 h, +4 h, +8 h, +24 h, +48 h and +72 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent samples should be drawn at 1 h, 2 h, 4 h, 8 h, 
24 h, 48 h and 72 h after end of resumed infusion (as per protocol). 
ADA: anti-drug antibodies; EOI: End of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: Start of infusion.   
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1.5.2 All other participants  
 
Cycle 
Cycle 1 
Cycles 2, 3. 4, 6, 8, 10 + 
every 4th cycle thereafter 
EOT visit 
Day 
D1 
D8 
D1 
Time after SAR444245 dosing 
(EOI, except SOI) [h] 
SOI 
EOI 
24  
168 
SOI 
EOI 
30 (±7) days 
after last IMP 
admin 
SAR444245 PK sample 
 
P01b 
P06c 
 
 
P01b 
 
SAR444245 ADA sample 
AB00a 
 
 
AB01 
AB00a 
 
ABF00 
a Samples collected strictly before start of infusion (SOI) 
b EOI samples = end of infusion samples. Must be taken at end of infusion precisely 
c PK sample can be collected at any time during the second day of the cycle. 
ADA: anti-drug antibodies, PK: pharmacokinetic: SOI: start of infusion; EOI: end of infusion   
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2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to cohort with advanced unresectable or metastatic HCC for the 
combination therapy with pembrolizumab. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models while anti-PD1 antibody prevents T cell suppression 
through the PD1/PD-L1 pathway. The combination of anti-PD1 treatment with SAR444245 was 
tested in a syngeneic mouse CT-26 colon cancer model and induced enhanced anti-tumor activity 
as demonstrated by an increased number of CR and tumor-free surviving animals compared to 
each agent in monotherapy. These data support evaluation of SAR444245 in combination with 
pembrolizumab. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across 
a number of indications. 
Refer to the country approved labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background  
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (3, 4). 
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The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (6, 8, 9, 10). The mechanism by which PD1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins (11, 12). 
2.2.1.2 Pre-clinical trials  
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities 
(13, 14, 15, 16, 17, 18, 19). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (7, 16, 18, 19, 20). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo (18). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see pembrolizumab IB). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2.  
2.2.2 Rationale for HCC and selected population (Cohort C)  
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Worldwide, 
liver cancers are the 4th most common cause of cancer-related death and rank 6th in terms of 
incident cases (21). In Asia the global burden of HCC is declining, it is still increasing in the US 
and Europe (22). Liver cancer is the second most lethal tumor. More than half of patients present 
with advanced-stage tumor and ultimately receive palliative therapies.  
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Up to recently, sorafenib has been the mainstay of 1L HCC treatment. Several tyrosine kinase 
inhibitors (TKIs) have become available in the last few years. Lenvatinib was approved as 1L 
treatment for HCC in 2018 by demonstrating non-inferiority to sorafenib. In the 2L setting, 
regorafenib has become the first drug approved by the FDA for second-line treatment because it 
decreased the death risk by 37% as compared to the placebo (23). Cabozantinib and ramucirumab 
also received FDA approval as second-line treatment because of promising efficacy and 
manageable safety profile based on two RCTs (CELESTIAL and REACH-2) (24, 25). In this 
setting, the TKI are the current treatment options but inducing limited response rates (~4 -7%). 
Otherwise, HCC is characterized by immune tolerance, with a complex array of immune cells 
populating the tumor microenvironment that are inactivated by local immune-suppressive 
signals (26), it is why Immunotherapy has become a promising therapeutic approach for HCC. 
The FDA has granted accelerated approval for nivolumab and pembrolizumab monotherapy for 
patients with HCC who have been previously been treated with sorafenib based on two studies 
(CheckMate-040 and KEYNOTE-224) (27, 1). Although ICI monotherapy had achieved clinically 
meaningful ORRs, these ORRs are still modest (15-18%) and did not translate into survival 
benefit. In the Phase 3 trial of KEYNOTE-240, despite an ORR of 18.3% as achieved for 
pembrolizumab vs. 4.4% for placebo, pembrolizumab versus placebo failed to demonstrate 
significant improvements in overall survival (OS) or overall survival (PFS) as these primary 
endpoints did not reach statistical significance per prespecified criteria (28). Furthermore, 
nivolumab monotherapy failed to achieve a significant primary endpoint (OS) as the 1L treatment 
of HCC (CheckMate 459).  
Efforts have intensified to develop strategies to enhance the immune response and overall efficacy 
of ICIs, including combination regimens with agents that target pathways involved in tumor 
progression and process immunomodulatory properties (29) and these led to further investigations 
of combinations of immunotherapy with other modalities to increase durable responses and 
survival. Nivolumab combined with ipilimumab (Phase 1/2 CheckMate-040) received accelerated 
approval because of promising ORR (32%) and durable responses (at least 24 months over 30% 
of responders) in the early Phase 1/2 CheckMate-040 (30).  
More recently, FDA approved atezolizumab in combination with bevacizumab as the new SoC in 
1L based on the data from Phase-3 RCT (IMbrave150) where a significant improvement in both 
OS and PFS was observed in the atezolizumab-bevacizumab arm compared to the sorafenib arm 
(OS: NE versus 13.2 months; PFS: 6.8 versus 4.3 months) (29).  
In summary, TKIs are main treatment options in this population, inducing very limited ORR 
(~5%). ICI-based regimen (atezolizumab + bevacizumab) has become the new SoC in 1L, 
therefore, most patients will have received an ICI before later line therapies. Rescue of patients 
who will have failed ICI-containing regimen in 1L will be evaluated to establish PoC of 
SAR444245 when combined with pembrolizumab in 2L+ HCC. 
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2.3 
BENEFIT/RISK ASSESSMENT 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin).  
Risk assessment of SAR444245 when combined with pembrolizumab results from anticipated 
risks for SAR444245 and from the label information for Keytruda® (pembrolizumab), taking into 
account potential overlapping risks. The available safety data for pembrolizumab, along with 
proposed mitigation strategies are summarized below and also provided in Table 13. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment (TME). 
The use of pembrolizumab may cause IRRs (drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, and hypersensitivity). Pembrolizumab use may be associated with 
infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, leukopenia), 
increase in the level of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well as adverse effects 
on the functioning of nervous system (dizziness, headache, peripheral neuropathy, dysgeusia (very 
common) and lethargy). In combination therapy with other chemotherapeutic drugs, 
pembrolizumab administration is commonly associated with hypertension and cardiac arrhythmia 
(including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risks for pembrolizumab 
(31). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in 
post-marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
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Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis.  
Please refer to the country-approved product labeling (eg, United States Package Insert [USPI], 
Summary of Product Characteristics [SmPC]) for pembrolizumab for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab 
Combining SAR444245 with pembrolizumab may lead to an increased frequency and/or severity 
of adverse events (AEs) related to immune activation or may lead to additional AEs related to 
immune system activation for each substance individually or may cause occurrences of 
qualitatively different AEs. Serious adverse drug reactions reported with agents known to increase 
immune activation include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction 
(see Section 2.3.1.1).  
As both substances are biologic agents, they may have the propensity to induce infusion-related 
reactions that may have higher rate of occurrence and severity when SAR444245 with 
pembrolizumab are used in combination. 
The maximum tolerated dose (MTD) of SAR444245 combined with the approved dosing of the 
anti PD-1 pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. 
Safety data generated from the combination of SAR444245 and pembrolizumab have informed 
the selection of the combination dose in this study.  
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of 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). 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. 
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 pembrolizumab are justified by the anticipated benefits that may be afforded to 
participants with HCC.  
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2.3.4 Benefit and risk assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity. 
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was also explored by 2 groups and did not find a clinically meaningful signal (32, 33).  
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Exploratory 
 
 
 
 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Cohort C will assess SAR444245 adding on to pembrolizumab in participants with advanced 
unresectable or metastatic hepatocellular carcinoma (HCC) who relapsed on prior PD1/PD-L1-
based regimens, with at least SD as best response and with no more than 2 prior lines of treatment. 
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts.   
A graphical presentation of the substudy schema is shown in Figure 1. For treatment period, the 
completion of Cycle 35 is applicable for Cohort C. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with the anti-PD1 antibody pembrolizumab will result in a significant increase in the 
population experiencing an objective response. 
The design of the 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 RECIST 1.1 for participants with advanced and metastatic HCC.  
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol.  
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4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is justified 
by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold exposure range 
(refer to the pembrolizumab IB). 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications. And 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, 
a PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
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Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort C specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Histologically or cytologically confirmed diagnosis of HCC, or clinically by AASLD 
criteria in cirrhotic patients (patients without cirrhosis must have had histological 
confirmation of diagnosis).  
I 02. Confirmed diagnosis at study entry of advanced unresectable or metastatic disease. 
Note: For participants in Cohort C: Disease with any CPS scoring. No need for CPS 
determination at local laboratory. 
I 03. Prior anticancer therapy: Participants must have received 1 or 2 prior lines of treatment per 
local standard of care, including an anti-PD-1/PDL-1 treatment, have progressed on or 
after an anti-PD-1/PD-L1 treatment and have had at least stable disease (SD) as best 
response on this anti-PD-1/PD-L1-based treatment.  
I 04. Provision of tumor tissue: 
- 
Optional baseline biopsy per Investigator’s discretion and evaluation of participants 
in Cohort C. 
- 
Optional on-treatment biopsy for Cohort C per Investigator’s discretion and 
evaluation. 
- 
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. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
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Medical conditions 
E 01. Participants with Child-Pugh class B or C.   
 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
Please refer to the master protocol. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
For study treatment duration, completion of Cycle 35 is applicable for Cohort C. 
Dosing sequence: 
6.1.1 Investigational medicinal product (IMP)  
Investigation medicinal product is defined as SAR444245 and pembrolizumab administered in 
combination as described in Section 4. Details of each IMP component to be administered are 
shown in Table 2.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.  
Table 2 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
100 mg/vial 
Dosage level(s)a 
24 μg/kg Q3W 
200 mg Q3W 
Route of administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
See master protocol 
IMP 
Packaging and labeling 
See master protocol 
Supplied in single dose vials containing 100 mg/4 mL 
pembrolizumab labelled with a multilingual booklet. 1 vial 
per treatment box. 
Current/Former name(s) or alias(es) 
See master protocol 
Keytruda 
a See master protocol. 
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6.1.2 Non-investigational medicinal products 
Please refer to the master protocol. 
In case of permanent SAR444245 discontinuation and continuation of pembrolizumab treatment 
as part of AE management, SAR444245 premedication no longer needs to be administered. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modifications for SAR444245 are permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
interrupted or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed.  
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In participants who have SAR444245 dose reduction due to SAR444245 related Grade ≥3 
treatment-related adverse events (TRAEs), SAR444245 dose may be re-escalated to
 μg/kg if:  
• no SAR444245 related Grade ≥3 TRAE or clinically significant laboratory abnormality 
within at least 2 subsequent cycles, AND  
• both Investigator and Sponsor agree that the participant has clinical benefit. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case, it is partial permanent discontinuation, and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued, it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF).  
6.5.2 Cycle delay  
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administered ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3 and Section 6.5.4. After cycle is delayed, such participants may be 
considered for treatment resumption once the toxicity resolves or improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on 
the day of planned administration, the cycle will be delayed; restart of study IMPs could 
occur only on the initiation of the subsequent cycle. 
• In case of cycle delay for the recovery of toxicity, the following rules should be followed 
for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to restart 
the study treatment, if a clear benefit from treatment is observed and after consultation 
with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer than 
84 days. 
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• Cycle may be delayed for situations other than TEAEs such as medical/surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study 
therapy within 21 days of the scheduled delay, unless otherwise discussed with the 
Sponsor (for example for national or regional emergencies). The reason for the delay 
should be documented in the participant’s study record. 
6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
not listed in Section 6.5.4 (Tables 3-8) will be required to temporarily delay the IMP. After cycle 
delay, such participants may be considered for treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline.  
The dose of SAR444245 should be reduced to 
 μg/kg (with the exception of lymphocytopenia 
which is directly associated with SAR444245 mode-of-action and does not require dose 
reduction) in cases of: 
• First occurrence of Grade 3 TRAE that does not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 TRAE of any duration. 
• Grade 4 TRAE. 
• First occurrence of Grade 3 laboratory abnormality that are clinically significant per 
Section 10.3.1 of the master protocol. and that do not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 clinically significant laboratory abnormality 
of any duration. 
• Grade 4 laboratory abnormalities that are clinically significant. 
Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to be in the 
best interest of the participant, except when specified otherwise in this protocol, or if the event has 
required the IMP temporary interruption for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
Vascular Leak Syndrome (VLS) and Infusion-related reactions (IRR) are presented in 
Section 6.5.4. 
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6.5.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF. 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An 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.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 3.  
After an infusion-related reaction due to pembrolizumab infusion (Grade 3 or Grade 4), the 
SAR444245 infusion will be delayed and can be administered after resolution of symptoms. The 
Investigator should discuss with the Sponsor’s Medical Monitor if the SAR444245 infusion needs 
to be delayed more than 1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 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, please see Section 6.1.2.1 of the 
master protocol. 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
• 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
None 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics. 
• 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• 
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr. to 50 mL/hr.). 
Otherwise, dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Participant may be premedicated 1.5 h 
(±30 minutes) prior to infusion of 
pembrolizumab with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
Epinephrine*, 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics, 
- 
Oxygen, 
- 
Pressors, 
- 
Corticosteroids. 
• 
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator. 
• 
Hospitalization may be indicated. 
*In cases of anaphylaxis, epinephrine should be used 
immediately. 
Participant is permanently discontinued from further 
study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
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Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise, dosing will be held 
until symptoms resolve and the participant should be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics.  
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; pressor or ventilator support 
indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 are provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; IV=intravenous; NCI = National Cancer 
Institute; NSAIDs: nonsteroidal anti-inflammatory drugs. 
6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and pembrolizumab being administered. 
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Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines) (35, 
36, 37). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 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 C-reactive protein (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 according to severity grading are provided in Table 5. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not limited to IV fluids 
(care should be taken to not excessively hydrate if evidence of vascular leak), 
antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less frequently 
as the participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring 
vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interrupt SAR444245 if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as 
medically indicated should be increased until the participant recovers. Transfer 
to ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, 
hypotension, or participants in whom symptoms (eg, high grade fever) that do 
not respond to antipyretics within 72 hours treatment with corticosteroids 
and/or tocilizumab should be considered, as per guidance for Grade 3 events.  
SAR444245 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 SAR444245  
dose modification and supportive care guidelines 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a 
vasopressor with or without 
vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi 
mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding 
vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
If CRS Grade 3, SAR444245 should be temporarily cycle delayed, and 
subsequent treatment should be resumed only when symptoms have resolved 
or improved to Grade 1 at 
 µg/kg or permanently discontinued, as clinically 
indicated.  
If CRS Grade 4, SAR444245 should be permanently discontinued, as clinically 
indicated. 
If CRS Grade 3 or Grade 4, IV corticosteroids should be initiated (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, management for persistent 
or worsening CRS should be initiated. Re-evaluation for other contributing 
conditions should be done, such as infection, cardiac, thromboembolic and 
other complications. Intravenous Tocilizumab at 8 mg/kg (for participants 
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 should be discussed 
with clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway Pressure; CPAP= 
Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; IMP=investigational medicinal 
product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
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6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
IrAEs are thought to be caused by unrestrained cellular immune responses directed at the normal 
host tissues. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing pembrolizumab clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab and/or SAR444245, administration of 
corticosteroids and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 6. Of 
note, when study interventions are administered in combination, if the AE is considered immune-
related, both drugs in the combination should be held according to recommended dose 
modifications.  If a participant experiences several irAEs, the most conservative recommendation 
should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 6, the 
combination of SAR444245 or pembrolizumab may be restarted at the discretion of the 
investigator. In these cases where the toxicity is attributed to the combination or to 
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered 
after communication with the Sponsor. 
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Table 6 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245  
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE 
decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and follow-up 
Pneumonitis  
Grade 2 
Withholda  
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Add prophylactic antibiotics 
for opportunistic infections. 
Monitor participants for signs and 
symptoms of pneumonitis. 
Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment. 
Recurrent 
Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor participants for signs and 
symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
Participants with ≥Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis. 
Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinueb 
AST or ALT 
elevation or 
Increased 
Bilirubin/hepatitis 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returns to baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
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irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and follow-up 
Type 1 Diabetes 
Mellitus (T1DM) 
or 
Hyperglycemia 
New onset T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure 
Withholda, f 
Initiate insulin replacement 
therapy for participants with 
T1DM. 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb, f 
Hyperthyroidism  
Grade 2 
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb, f 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid replacement 
hormones 
(eg, levothyroxine or 
liothyronine) per standard of 
care. 
Monitor for signs and symptoms of 
thyroid disorders. 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal function. 
Grade 3 or 4 
Permanently 
discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinueb 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinueb 
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irAEs 
Toxicity 
grade 
(CTCAE 
V5.0) 
Action with 
pembrolizumab 
and 
SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and follow-up 
All Other irAEs 
Persistent 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinueb 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 - 3.0 x ULN if baseline normal;  
>1.5 - 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; 
>3.0 - 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
6.5.4.5 Immune cell-associated neurotoxicity syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment 
of cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.11 
of the master protocol). Recommendations for ICANS management mainly include the use of 
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 SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
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Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245 a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement to 
Grade 1 after corticosteroid taper. Consideration for reduction of SAR444245 
dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on EEG 
that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and unable 
to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
If Grade 4 ICANS, SAR444245 should be permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS may 
require tocilizumab and should be handled as described in Table 5 in 
Section 6.5.4.3. Corticosteroids can then be administered IV or orally every 
8 hours for up to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; ICANS= Immune effector 
cell associated neurotoxicity syndrome; ICE= Immune Effector Cell-Associated Encephalopathy; IV = Intravenous. 
6.5.4.6 Vascular leak syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with 
multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a balance 
between maintaining the intravascular volume to ensure organ perfusion to prevent organ failure, 
while avoiding volume overload. The management of VLS according to severity grading is 
described in Table 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 (1).  
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Table 8 - Guidelines for the management of vascular leak syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
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 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued.   
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AKI= acute kidney injury; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; MW= molecular weight; 
NCI = National Cancer Institute; VLS= vascular leak syndrome. 
6.5.4.7 Hepatic Events 
Hepatic events (HEs) as described in Section 8.3.8. All these HEs will require holding study 
intervention with an immediate assessment: 
All participants should be considered for evaluation according to the directions below within 
72 hours of the alert for AESI. 
• Procedures: 
- 
Consider obtaining a consultation with a hepatologist 
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- 
Obtain a work-up for hepatitis if there is no underlying hepatitis, including hepatitis A, 
B, C, D, E, Epstein-Barr virus, and cytomegalovirus 
- 
Assess for ingestion of drugs/supplements with hepatotoxic potential 
- 
Assess for alcohol ingestion 
- 
Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal 
bleeding 
- 
Repeat ALT, AST, total bilirubin, direct bilirubin, alkaline phosphatase, -glutamyl 
transpeptidase, INR, and complete blood count with differential 
- 
Measure HCV RNA viral load (applies only for participants who have current active 
HCV infection or had infection in the past) 
- 
HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs 
regardless of prior HBV status (Note: participants should be questioned about 
compliance with the use of antiviral agents) 
- 
Other laboratories or imaging studies as clinically indicated 
- 
Consider liver biopsy if indicated 
HCC patients are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation. Those with a history of chronic HCV or 
HBV infection also have the potential to experience virologic flares. Immune-related hepatitis has 
been observed in approximately 1-2% of participants who received pembrolizumab. The 
following section provides further guidance on the diagnosis and management of potential hepatic 
complications among HCC participants in this study. The recommendation is to hold study 
interventions (cycle delay when SAR444245 is withhold + pembrolizumab is withhold). If 
toxicity does not improve within 1 to 2 days or worsens, follow “Management of HE for 
Pembrolizumab/SAR4444245” below.  
Table 9 - Management of HE associated with Pembrolizumab and SAR444245 
 
Diagnosis 
Management 
Hepatitis B consider flare or 
change in HBV 
immunologic status 
Rapid elevation of ALT to 
>5 × ULN and/or >3 × 
baseline 
Interrupt pembrolizumab and SAR444245 interventions for up to 
12 weeks. 
Start antiviral therapy or check for compliance if HBV is detectable. 
Measure safety labs for AST, ALT, ALP, T Bili, D Bili, and INR on 
weekly basis. 
Measure HBsAg and HBV DNA on weekly basis (if detected at the 
time of onset of ECI). 
Evaluate the following every 2-3 weeks: 
anti-HBe, HBe antigen, anti-HBs, and HBV DNA levels (if not 
detected at the onset of ECI) 
Restart pembrolizumab and SAR444245 intervention only if ALT 
returns to normal or Grade 1 (if normal at baseline), or to baseline 
grade (if Grade 2 at baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should have permanent full 
discontinuation of study interventions  
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Diagnosis 
Management 
Hepatitis C exacerbation in 
participants with HCV RNA 
positive 
Rapid elevation of ALT to 
>5 × ULN and/or >3x 
baseline  
Interrupt pembrolizumab and SAR444245 interventions for up to 
12 weeks. 
Assess use of injection or inhalation drugs. 
Recheck HCV genotype at the time of relapse of HCV RNA to rule out 
new infection. 
Measure safety labs for AST, ALT, ALP, T Bili, D Bili, and INR on 
weekly basis 
Measure HCV RNA levels every 2 weeks. 
Please discuss risk benefit with Sponsor prior to starting HCV antiviral 
therapy. 
Restart pembrolizumab and SAR444245 interventions only if ALT 
returns to normal or Grade 1 (if normal at baseline), or to baseline 
grade (if Grade 2 at baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should have a permanent 
full discontinuation of study interventions. 
Relapse of HCV infection 
for participants with 
successfully treated or new 
HCV infection 
If HCV RNA was TND at 
baseline, and now has 
confirmed detectable HCV 
RNA (2 specimens, 
1 week apart) 
Immune-related Hepatitis 
If any of the HECI criteria 
is met as defined in the 
protocol Section 8.3.8 
Note:  
Immune-related hepatitis 
is a diagnosis made after 
excluding other possible 
etiologies such as viral 
flare, biliary or vascular 
obstruction, infection, 
medications, and alcohol 
use usually immune-
related hepatitis response 
to dechallenge and/or 
steroids and re-occurs 
with rechallenge 
Interrupt pembrolizumab and SAR444245 interventions for up to 
12 weeks. 
Start IV corticosteroid 60 mg/day of prednisone or equivalent followed 
by oral corticosteroid. 
Monitor with biweekly laboratory tests, including AST, ALT, T Bili, 
D Bili, ALP, and INR. 
Restart pembrolizumab and SAR444245 intervention only if:  
Abnormal laboratory values resolve to Grade ≤1 or baseline (if 
abnormal at baseline) 
Taper steroid over 28 days 
Steroid treatment is tapered to prednisone <10 mg/day or equivalent 
Permanently fully Discontinue pembrolizumab and SAR444245 
intervention if: 
Laboratory abnormalities do not resolve within 3 weeks 
Steroids cannot be lowered to ≤10 mg/day (or prednisone equivalent) 
within 12 weeks 
Decompensation to CP-C status 
Other Causes 
Rule out infection with 
blood, urine, and ascites 
culture - antibiotics should 
be started if infection is 
found 
If total bilirubin is elevated, 
imaging should be 
obtained to rule out 
vascular compromise, 
biliary obstruction, and/or 
tumor progression by 
imaging 
Ruled out alcohol use and 
hepatotoxic drugs 
including herbal and 
alternative medications 
Restart pembrolizumab and SAR444245 only if laboratory values 
have returned to Grade 1 or baseline (if normal or Grade 1 at start) or 
to baseline grade within 3 weeks. 
If biliary obstruction is present, consultation with a gastroenterologist 
and/or an interventional radiologist should be obtained to see if the 
obstruction may be relieved. 
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Abbreviations: ALT= alanine aminotransferase; ALP=alkaline phosphatase; AST=aspartate aminotransferase; D Bili=direct bilirubin, HBe= 
hepatitis B e antigen; HBs= hepatitis B surface antigen; HBV= hepatitis B virus; HCV= hepatitis C virus; HECI= Hepatic Events of Clinical 
Interest; INR= international normalized ratio, IV=intravenous; T Bili=total bilirubin, TND= target not detected. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater. There is no 
specific antidote for overdose with pembrolizumab. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol and Section 1.3. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol.  
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s) 
Please refer to the master protocol for RECIST 1.1. 
  
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol.  
In addition, combining SAR444245 with other anticancer therapies may increase the frequency 
and severity of immune-related adverse events related to other anticancer therapies. Immune-
mediated endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, and 
cortisol level will be monitored. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort C irAEs will be collected until 90 days following last administration of 
study treatment regardless of whether or not another anticancer therapy is initiated. 
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8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, SAEs that are considered expected will be specified in the reference safety 
information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
Hepatic Events (HEs) include any of the following events if the events are considered not due to 
disease progression as judged by the investigator 
• ALT: 
a) Among subjects with Baseline ALT <2 × ULN:  ALT ≥5 × ULN 
b) Among subjects with Baseline ALT ≥2 × ULN:  ALT >3 × the Baseline level 
c) ALT >500 U/L regardless of baseline level 
• Total Bilirubin: 
a) Total bilirubin >3.0 mg/dL 
• Regardless of laboratory values, hepatic decompensation diagnosed clinically, including: 
- 
New onset clinically detectable ascites requiring intervention for >3 days 
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- 
Hepatic Encephalopathy 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol.  
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
For participants to Cohort C (HCC), tumor biopsy is optional. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
 STATISTICAL HYPOTHESES  
Please refer to the master protocol. 
9.2 
SAMPLE SIZE DETERMINATION 
The plan is to treat approximately 40 participants in Cohort C. 
Table 10 lists estimated ORR and 90% exact confidence intervals (CIs) by number of responders 
from a sample size of 40 participants treated. 
Table 10 - Estimated objective response rate (ORR) depending on number of responders  
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
2 
5% (0.9% - 14.9%) 
4 
10% (3.5% - 21.4%) 
6 
15% (6.7% - 27.5%) 
8 
20% (10.4% - 33.2%) 
10 
25% (14.2% - 38.7%) 
12 
30% (18.3% - 44.0%) 
14 
35% (22.6% - 49.2%) 
CI: confidence interval; N=number. 
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 cohort. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
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9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol. 
9.4.4 Tertiary/exploratory endpoint(s)  
. 
9.4.4.1 Exploratory antitumor indicators 
9.4.5 Other safety analysis 
Please refer to the master protocol. 
9.4.6 Other analysis 
Please refer to the master protocol.  
9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
If the predictive probability of concluding a minimum clinical meaningful effect of the study 
treatment (ORR of 5%) at the end of study is <15%, the corresponding cohort will be stopped for 
futility. To facilitate the calculation of predictive probability, a minimum informative prior of 
Beta (0.5, 0.5) is used at the time of the design of the study. However, emerging data generated 
from outside of the study may warrant a different prior to be considered before this interim 
analysis. 
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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 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol. 
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
10.1.9 Study and site start and closure 
Please refer to the master protocol. 
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10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. Cohort 
C specific evaluations are presented in Table 11. 
Table 11 - Protocol-required laboratory tests 
Laboratory tests 
Parameters 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
Cortisol (preferably in the morning) 
NOTES : 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol. 
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10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 
Please refer to the master protocol. 
10.9 
APPENDIX 9:
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10.10 APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
 
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10.11 APPENDIX 11: RISK ASSESSMENT  
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 13. 
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Table 13 - Risk assessment  
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
Pembrolizumab 
Common, but infusion-related reactions in labeling 
include drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, hypersensitivity and cytokine 
release syndrome. 
Pembrolizumab 
Dose modification and treatment 
guidelines for pembrolizumab infusion 
associated reactions are provided in 
Table 4. 
Hypersensitivity, including 
anaphylaxis 
Pembrolizumab 
Not specifically reported but included among infusion-
related reactions in label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
 
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master 
protocol. 
Hepatotoxicity 
Pembrolizumab 
Hepatitis occurred in 0.8% of patients, including 
Grade 2, 3 or 4 cases in 0.1%, 0.5% and 0.1% 
patients, respectively, receiving pembrolizumab. The 
median time to onset of hepatitis was 3.6 months 
(range 8 days to 21.4 months). The median duration 
was 1.1 months (range 1 day to 20.9+ months). 
Hepatitis led to discontinuation of pembrolizumab in 
0.3% patients. Hepatitis resolved in 36 patients. 
Dose modification and treatment 
guidelines for liver enzyme increase 
are provided under immune-related 
reactions in Table 6.   
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury 
Dose modification and treatment 
guidelines for nephrotoxicity are 
provided under immune-related 
reactions in Table 6.  
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy (common) for 
pembrolizumab in combination with chemotherapy  
Uncommon: epilepsy.  
Dose modification and treatment 
guidelines for neurological AEs are 
provided under immune-related 
reactions in Table 6. 
Immune-mediated Adverse 
Events 
Pembrolizumab 
Immune-mediated adverse events are designated as 
important identified risk for pembrolizumab. 
Dose modification and treatment 
guidelines for immune-related 
reactions are provided in Table 6. 
Risks related to special populations 
Pregnancy and lactation 
exposure and outcomes 
Pembrolizumab 
Pembrolizumab should not be used during pregnancy 
unless the clinical condition of the woman requires 
treatment with pembrolizumab. 
 
See master protocol for exclusion of 
participants, guidance on highly 
effective contraceptive methods, and 
pregnancy tests to be performed 
regularly.  
Drug-drug interactions 
No data available.  
Overdose and its treatment 
No specific information is available on the treatment 
of overdose of pembrolizumab. 
See Section 6.8 of the master protocol.  
 
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10.12 APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol. 
10.13 APPENDIX 13: ABBREVIATIONS  
 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CR: 
complete response 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
HCC: 
hepatocellular carcinoma  
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICU: 
intensive care unit 
IRR: 
infusion-related reactions  
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NHP: 
non-human primate  
 
PD1: 
programmed cell death protein 1 
PK: 
pharmacokinetic 
SAEs: 
serious adverse events 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
VLS: 
vascular leak syndrome 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.14.1 
Amended protocol 01 (30 August 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is include stopping rules for futility and update the rules 
for dose modification in case of treatment-related adverse events (TRAEs) for Cohort C in 
substudy 03. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 2.3.2 Benefit 
assessment 
The following sentences have been deleted “Non-MSI-H mCRC are known to 
not respond to immune checkpoint inhibitors, being qualified as immune 
excluded or restricted tumors. Combining SAR444245 may unleash 
inflammatory response in the tumor microenvironment and sensitize CRC to 
anti-PD1.” 
Correction for 
consistency. 
Section 5.1 Inclusion 
Criteria 
In I06, “- less than required number of slides or archival tumor tissue sample 
collected more than 6 months prior to screening” has been revised to “-less 
than required number of slides or archival tumor tissue sample collected more 
than 6 months prior to enrollment”. 
Harmonization per 
program level 
approach 
Section 6.5.1 General 
rules 
The following sentence has been deleted “Once a dose has been decreased, 
intra-patient re-escalation back to the previous dose level is not permitted.”, 
and the following sentences have been added “In participants who have 
SAR444245 dose reduction due to SAR444245 related Grade ≥3 TRAEs, 
SAR444245 dose may be re-escalated to
 μg/kg if: no SAR444245 related 
Grade ≥3 TRAE or clinically significant laboratory abnormality within at least 
2 subsequent cycles, AND both Investigator and Sponsor agree that the 
participant has clinical benefit.”. 
For clarification of how 
dose will be reduced 
and re-escalated for 
participants who 
experience any Grade 
≥3 TRAEs. 
Section 6.5.3 General 
guidelines for the 
management of 
treatment-related 
adverse events 
The following sentence “Participants who experience Grade ≥3 TRAEs at any 
time of the study (including clinically significant Grade 3 laboratory 
abnormalities as defined in Section 10.3.1 of the master protocol) will be 
required to temporarily delay the IMP, unless specified otherwise in the 
protocol, and with the exception of the TRAEs resolving within 5 days. After 
cycle delay, such participants may be considered for treatment resumption 
once the TRAE resolves or improves to Grade 1 or baseline or is stable and 
manageable through supportive/medical therapy.” has been changed to 
“Participants who experience Grade ≥3 TRAEs at any time of the study 
(including clinically significant Grade 3 laboratory abnormalities as defined in 
Section 10.3.1 of the master protocol) not listed in Section 6.5.4 (Tables 3-8) 
will be required to temporarily delay the IMP. After cycle delay, such 
participants may be considered for treatment resumption once the TRAE 
resolves or improves to Grade 1 or baseline”. 
Dose reduction rules have added, and the following sentence has been deleted 
“Dose reduction for SAR444245 from 
 µg/kg to 
 µg/kg (or another lower 
recommended dose) may be decided when specified in the protocol or 
following discussions with the Sponsor.” 
For consistency and 
clarity. 
Section 6.5.4.1 
Infusion-related 
reactions (IRR) 
In Table 4 under Grade 3 and Grade 4, “prematurely” has been removed from 
“prematurely permanently discontinued”. 
For clarity 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.5.4.3 
Fever, flu-like 
symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 5 under Grade 3, the following sentence was deleted “If subsequent 
administration is tolerated, increasing the SAR444245 dose to 
 µg/kg at 
subsequent administration can be considered based on the clinical judgement 
of the Investigator with the Sponsor”. 
For consistency. 
Section 9.5 Interim 
analyses 
The following sentences have been added “If the predictive probability of 
concluding a minimum clinical meaningful effect of the study treatment (ORR of 
5%) at the end of study is <15%, the corresponding cohort will be stopped for 
futility. To facilitate the calculation of predictive probability, a minimum 
informative prior of Beta (0.5, 0.5) is used at the time of the design of the study. 
However, emerging data generated from outside of the study may warrant 
a different prior to be considered before this interim analysis.”. 
To include stopping 
rules for futility. 
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11 
REFERENCES 
  
1. Zhu AX, Finn RS, Edeline J, Cattan S, Ogasawara S, Palmer D, et al. Pembrolizumab in 
patients with advanced hepatocellular carcinoma previously treated with sorafenib 
(KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940-
52. 
2. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8. 
3. Dudley ME, Wunderlich JE, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for 
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol. 
2005;23(10):2346-57. 
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
2008;358(25):2698-703. 
5. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
7. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
8. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
T Cell Stimulation, but Only Receptor Ligation Prevents T Cell Activation. J Immunol. 
2004;173(2):945-54. 
9. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574(1-3):37-41. 
10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
11. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al. 
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
2005;25(21):9543-53. 
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
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13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
2005;65(3):1089-96. 
14. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the 
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
15. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer-preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9. 
16. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade 
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 
2003;63(19):6501-5. 
17. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2:3. 
18. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
19. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
20. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7. 
21. Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450-62. 
22. Kulik L, El-Serag HB. Epidemiology and Management of Hepatocellular Carcinoma. 
Gastroenterology. 2019;156(2):477-91. 
23. Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with 
hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, 
double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56-66. 
24. Abou-Alfa GK, Meyer T, Cheng AL, El-Khoueiry AB, Rimassa L, Ryoo BY, et al. 
Cabozantinib in Patients with Advanced and Progressing Hepatocellular Carcinoma. N Engl J 
Med. 2018;379(1):54-63. 
25. Zhu AX, Kang YK, Yen CJ, Finn RS, Galle PR, Llovet JM, et al. Ramucirumab after 
sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein 
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concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial. 
Lancet Oncol. 2019;20(2):282-96. 
26. Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and 
current immunotherapeutic strategies for hepatocellular carcinoma. Journal of experimental & 
clinical cancer research : CR. 2019;38(1):396. 
27. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients 
with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, 
phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-502. 
28. Finn RS, Ryoo BY, Merle P, Kudo M, Bouattour M, Lim HY, et al. Pembrolizumab As 
Second-Line Therapy in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-
240: A Randomized, Double-Blind, Phase III Trial. J clin Oncol: official journal of the 
American Society of Clinical Oncology. 2020;38(3):193-202. 
29. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim TY, et al. Atezolizumab plus 
Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-
905. 
30. Yau T, Kang YK, Kim TY, El-Khoueiry AB, Santoro A, Sangro B, et al. Efficacy and Safety 
of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma 
Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA 
Oncol. 2020;6(11):e204564. 
31. European Medicines Agency. Keytruda® European Public Assessment Report, Risk 
Management Plan Summary. [Online]. Last updated 2020 Jun 18 [cited on 2021 Jun 23]. 
Available from: URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda 
32. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al. 
Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, 
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 
2020;2(1):100124. 
33. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov. 
2020;10(8):1121-8. 
34. 
35. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
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36. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18. 
37. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
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Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
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According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 04) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab 
or cetuximab for the treatment of participants with 
advanced and metastatic colorectal cancer 
Protocol number: 
ACT16902-S04 
Amendment number: 
02  
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 combined with pembrolizumab 
or cetuximab for the treatment of participants with 
colorectal cancer  
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
1 avenue Pierre Brossolette,  
91380 Chilly-Mazarin,  
France 
Monitoring team’s 
representative name and 
contact information 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
NCT: 
WHO: 
156424 
2021-002181-41 
NCT05104567 
U1111-1251-4981 
Date: 
12-Jan-2022 
Total number of pages: 82 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 02 (Substudy 04) 
All 
12 January 2022, version 1 
(electronic 3.0) 
Amended Clinical Trial Protocol 01 (Substudy 04) 
All 
30 August 2021, version 1 
(electronic 2.0) 
Clinical Trial Protocol (Substudy 04) 
20 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 02 (12 January 2022) 
This amended protocol (Amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main rationale for this amendment is to address requests from the French (National Agency 
for the Safety of Medicines and Health Products [ANSM]), Belgian, Italian, German (Federal 
Institute for Drugs and Medical Devices [BfArM]), and South Korean Health Authorities after 
initial review. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of activities 
(SoA) 
A complete Table of SoA is provided for this substudy with 
procedures taken from the master protocol. And the previous 
footnote a for endocrine function tests has been renumbered as 
footnote j in the current document. 
Regulatory Authorities (BfArM) 
request. 
 
Troponin test has been added at screening, at C4D1, and as 
clinically indicated during treatment period until Follow-up 
Visit 1. 
To allow assessment of any 
potential cardiotoxity. 
1.4 Biomarker flowchart 
A complete Table of biomarker flowchart is provided for this 
substudy with biomarker sample collections taken from the 
master protocol. 
Regulatory Authorities (BfArM) 
request. 
1.5 Pharmacokinetic 
flowcharts 
A complete Table of pharmacokinetic (PK) flowcharts is 
provided for this substudy with PK sample collections taken 
from the master protocol. 
Regulatory Authorities (BfArM) 
request. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.4.1 Infusion-related 
reactions (IRR) 
In Table 7, pembrolizumab was removed for Grade 3 or 4. 
For consistency since Table 7 
describes cetuximab infusion-
related reaction dose 
modification and treatment 
guidelines. 
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome (CRS) 
The following sentence has been added “Cetuximab may be 
associated with CRS. CRS typically occurs within one hour 
after infusion and is less commonly associated with 
bronchospasm and urticaria.  CRS is normally most severe in 
relation to the first infusion of cetuximab. Cetuximab related 
IRR’s, including CRS, are discussed in Section 6.5.4.1.  Please 
refer to Table 7 for Cetuximab IRR dose modifications and 
treatment guidelines.” 
To include information on 
cytokine-release syndrome 
reported with cetuximab and 
providing recommended 
guidelines for management. 
Table 8 has been updated with Recommended Cetuximab dose 
modifications and supportive care guidelines. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 (SUBSTUDY 04) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 23 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 24 
1.5.1 
Participants with more intensive PK sampling ............................................................................... 24 
1.5.2 
All other participants....................................................................................................................... 25 
2 
INTRODUCTION ............................................................................................................................ 26 
2.1 
STUDY RATIONALE...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.2.1 
Pembrolizumab .............................................................................................................................. 26 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 27 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 27 
2.2.2 
Cetuximab ...................................................................................................................................... 28 
2.2.3 
Rationale for mCRC and selected populations and experimental SAR444245-based 
regimens (Cohorts D1 and D2) ...................................................................................................... 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Risk assessment ............................................................................................................................ 29 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 29 
2.3.1.2 
Cetuximab ...................................................................................................................................... 30 
2.3.1.3 
SAR444245 combined with pembrolizumab or cetuximab ............................................................ 31 
2.3.2 
Benefit assessment ........................................................................................................................ 32 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 32 
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2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 33 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 34 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
4 
STUDY DESIGN ............................................................................................................................ 35 
4.1 
OVERALL DESIGN ........................................................................................................................ 35 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 35 
4.2.1 
Participant input into design ........................................................................................................... 35 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 35 
4.3.1 
SAR444245 dose ........................................................................................................................... 35 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 36 
4.3.3 
Cetuximab dose ............................................................................................................................. 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 
5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 39 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 39 
5.4 
SCREEN FAILURES...................................................................................................................... 39 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION ................ 39 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 40 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 40 
6.1.1 
Investigational medicinal product (IMP) ......................................................................................... 40 
6.1.2 
Non-investigational medicinal products ......................................................................................... 42 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 42 
6.1.2.2 
Premedication for cetuximab ......................................................................................................... 42 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 42 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 42 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 42 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 42 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 43 
6.5 
DOSE MODIFICATION .................................................................................................................. 43 
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6.5.1 
General rules .................................................................................................................................. 43 
6.5.2 
Cycle delay ..................................................................................................................................... 43 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 45 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 46 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 46 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 49 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 50 
6.5.4.4 
Immune-related adverse events .................................................................................................... 52 
6.5.4.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 56 
6.5.4.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 57 
6.5.4.7 
Dermatologic toxicity ...................................................................................................................... 58 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 59 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 59 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 59 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 60 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 60 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 60 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 60 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 61 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 61 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 61 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 61 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 61 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 61 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 62 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 62 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 62 
8.3.5 
Pregnancy ...................................................................................................................................... 62 
8.3.6 
Cardiovascular and death events .................................................................................................. 62 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 62 
8.3.8 
Adverse event of special interest ................................................................................................... 62 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 62 
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8.4 
PHARMACOKINETICS .................................................................................................................. 63 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 63 
8.6 
BIOMARKERS ............................................................................................................................... 63 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 63 
8.8 
HEALTH ECONOMICS .................................................................................................................. 63 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 63 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 64 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 64 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 64 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 64 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 64 
9.4.1 
General considerations .................................................................................................................. 65 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 65 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 65 
9.4.3.1 
Other secondary endpoints ............................................................................................................ 65 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 65 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................... 65 
9.4.5 
Other safety analysis...................................................................................................................... 65 
9.4.6 
Other analysis ................................................................................................................................ 65 
9.5 
INTERIM ANALYSES .................................................................................................................... 65 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 66 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 66 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 66 
10.1.2 
Financial disclosure........................................................................................................................ 66 
10.1.3 
Informed consent process .............................................................................................................. 66 
10.1.4 
Data protection ............................................................................................................................... 66 
10.1.5 
Committees structure ..................................................................................................................... 66 
10.1.6 
Dissemination of clinical study data ............................................................................................... 66 
10.1.7 
Data quality assurance .................................................................................................................. 66 
10.1.8 
Source documents ......................................................................................................................... 66 
10.1.9 
Study and site start and closure ..................................................................................................... 66 
10.1.10 Publication policy ........................................................................................................................... 67 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 67 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 67 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 67 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 67 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 67 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 68 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 .......... 68 
10.9 
APPENDIX 9: 
 ...................................................................................................................... 68 
10.9.1 
Response and stable disease duration (RECIST 1.1 and
) ............................................. 70 
10.9.2 
Methods of measurement .............................................................................................................. 70 
10.10 
APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 71 
10.11 
APPENDIX 11: RISK ASSESSMENT ............................................................................................ 72 
10.12 
APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 76 
10.13 
APPENDIX 13: ABBREVIATIONS ................................................................................................. 76 
10.14 
APPENDIX 14: PROTOCOL AMENDMENT HISTORY ................................................................ 77 
10.14.1 Amended protocol 01 (30 August 2021) ........................................................................................ 77 
11 
REFERENCES ............................................................................................................................... 79 
 
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LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 11 
Table 2 - Objectives and endpoints ............................................................................................................... 34 
Table 3 - Overview of IMP administered ....................................................................................................... 41 
Table 4 - Dose levels for cetuximab dose reduction ..................................................................................... 45 
Table 5 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 47 
Table 6 - SAR444245 infusion-related reaction dose modification and treatment guidelines ...................... 48 
Table 7 - Cetuximab infusion-related reaction dose modification and treatment guidelines ......................... 49 
Table 8 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 50 
Table 9 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 53 
Table 10 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) . 56 
Table 11 - Guidelines for the management of Vascular Leak Syndrome (VLS) ........................................... 58 
Table 12 - Cetuximab dose modification for dermatologic toxicities ............................................................. 59 
Table 13 - Estimated objective response rate (ORR) depending on number of responders ........................ 64 
Table 14 - Protocol-required laboratory tests ................................................................................................ 67 
Table 15 - Risk assessment .......................................................................................................................... 72 
 
LIST OF FIGURES 
Figure 1 - Overall study schema - Substudy 04 ............................................................................................ 11 
Figure 2 - Graphical study design - Cohort D1 and D2 ................................................................................. 15 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Cohort-specific 
protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab or cetuximab for the 
treatment of participants with advanced and metastatic colorectal cancer 
Brief title: 
A study of SAR444245 combined with pembrolizumab or cetuximab for the 
treatment of participants with colorectal cancer 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti-PD1 antibody prevents 
T cell suppression through the programmed cell death-1/programmed cell death-ligand 
1 (PD1/PD-L1) pathway. The combination of anti-PD1 treatment with SAR444245 was tested in 
the syngeneic murine CT-26 colon cancer model and induced enhanced anti-tumor activity as 
demonstrated by an increased number of complete responses (CR) and tumor-free surviving 
animals compared to each agent in monotherapy. These data support evaluation of SAR444245 in 
combination with an anti-PD1 antibody. 
Clinical data from the on-going monotherapy dose escalation of SAR444245 (HAMMER study) 
has indicated a peripheral increase in the number of NK cells.  NK cells are important effector 
cells which mediate antibody-dependent cellular cytotoxicity (ADCC) for IgG1 antibodies such as 
cetuximab. In vitro data where NK cells pretreated with SAR444245 and then co-cultured with 
the EGFR-expressing A431 cancer cells improved the ADCC function of cetuximab in 
a dose-dependent fashion. These data support the evaluation of SAR444245 in combination with 
cetuximab. 
The proposed study aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 
antibody cetuximab will result in a significant increase in the percentage of patients experiencing 
an objective response in the setting of advanced unresectable or metastatic colorectal cancer 
(mCRC). 
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Objectives and endpoints  
Please refer to the master protocol for description of common objectives and endpoints. 
Substudy-specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
 
Objectives 
Endpoints 
Secondary 
 
• 
To assess active concentrations of cetuximab when 
given in combination with SAR444245 
• 
Ctrough and Cend of infusion of cetuximab 
Overall design: 
Please refer to the master protocol. 
Brief summary:  
Cohorts D1 and D2 will assess SAR444245 adding on to either pembrolizumab or cetuximab, 
respectively, in participants with advanced unresectable or mCRC who have progressed on prior 
regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, with either bevacizumab or 
cetuximab, and with no more than 5 prior lines of treatments. Patients are not eligible if MSI-H. 
Patients with RASmut are not eligible for enrollment in Cohort D2. 
A graphical presentation of the substudy schema is shown in Figure 1. 
Figure 1 - Overall study schema - Substudy 04 
 
Abbreviations: 3-6L: third-line to sixth-line; CRC: colorectal carcinoma; MSI-H: high-level microsatellite instability; N=number; PD-1: programmed 
cell death 1; PD-L1: programmed cell death- ligand 1. 
Number of participants: 
Overall, approximately 40 participants will be enrolled and treated in each cohort for Cohorts D1 
and D2. 
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Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration for a participant 
in Cohorts D1 and D2. For treatment period, the completion of Cycle 35 is only applicable for 
Cohort D1. 
Study intervention(s) 
Cohort D1 (SAR444245 + pembrolizumab)  
Dosing sequence:
Investigational medicinal products 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in 
single-dose vials 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered as a dose of 200 mg using 
a 30-minute IV infusion on Day 1 of each 3-week treatment cycle for up to 35 cycles. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes -5 min/+10 min). 
SAR444245 
SAR444245 formulation, route of administration, and dose regimen as described in the master 
protocol. Treatment duration for Cohort D1 is up to 35 cycles. 
Noninvestigational medicinal products 
Please refer to the master protocol. 
After 4 cycles, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, premedication no longer needs to be 
administered.  
Cohort D2 (SAR444245 + cetuximab) 
Dosing sequence:
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Investigational medicinal products 
. 
Cetuximab 
Cetuximab will be administered 
 
. 
• Formulation:  
- 
a clear, colorless solution for injection provided as 100 mg/50 mL (2 mg/mL) or 
200 mg/100 mL in a single-dose vial  
or  
- 
100 mg/20 mL or 500 mg/100 mL 
or 
- 
any other cetuximab formulation approved locally. 
• Route of administration: IV infusion  
Dose regimen: Cetuximab will be given on Cycle 1 Day 1 as an initial loading dose of 400 mg/m2 
infused over 120 minutes (maximum infusion rate 10 mg/min, or as per local practice and labels) 
followed by 250 mg/m² infused over 60 minutes (maximum infusion rate 10 mg/min) for all 
subsequent doses starting with the Cycle 1 Day 8 administration, until PD. 
Noninvestigational medicinal products 
Premedication for SAR444245 as described in the master protocol. 
Premedication for cetuximab 
All participants who will receive cetuximab should be premedicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior infusion reactions (IRs). 
Each dose of cetuximab will be followed by a 1-2 hours observation period. If there are no 
reported infusion-related reactions (IRRs) during this observation period, then the SAR444245 
dose may be administered at applicable dosing visits. 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication. 
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Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. Substudy-
specific analyses are summarized below. 
• Active concentrations of cetuximab when given in combination with SAR444245 will be 
analyzed with descriptive statistics. 
Data Monitoring/Other committee: Yes 
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1.2 
SCHEMA 
Figure 2 - Graphical study design - Cohort D1 and D2 
 
C=Study cycle; D=Study day; EOT=end of treatment; IMP=Investigational medicinal product; Q9W= every 9 weeks; Q12W=every 12 weeks. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-
Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day 
(Visit window 
in Days) 
D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 days (+/-7 days) 
after last IMP or 
at initiation of 
further therapy 
3 months 
after last 
IMP 
admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU 
Visit 2 
±7 days 
Every 
3 months  
+/-14 days 
 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion and 
exclusion criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Demography, 
medical/surgical 
and disease history  
X 
  
  
  
  
  
  
  
  
  
  
  
See Section 8 of 
the master 
protocol 
Body Weight/ 
Heightg 
X 
X 
X 
X 
X 
  
  
X 
X 
  
  
  
 
Full physical 
examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
See 
Section 8.2.1 of 
the master 
protocol  
Directed Physical 
examination 
 
X 
X 
X 
X 
  
  
 
X 
  
  
  
See 
Section 8.2.1 of 
the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-
Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day 
(Visit window 
in Days) 
D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 days (+/-7 days) 
after last IMP or 
at initiation of 
further therapy 
3 months 
after last 
IMP 
admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU 
Visit 2 
±7 days 
Every 
3 months  
+/-14 days 
 
Vital Signs 
X 
X 
X 
X 
X 
  
  
X 
X 
  
  
  
See 
Section 8.2.2 of 
the master 
protocol  
Performance status 
(ECOG) 
X 
X  
X 
X 
X 
  
  
X 
X 
  
  
  
 
SpO2 
X 
As clinically indicated 
  
  
  
  
  
 
Laboratory and other investigations 
 
12-Lead ECG  
X 
X 
As clinically indicated 
  
  
  
See 
Section 8.2.3 of 
the master 
protocol  
LVEF 
X 
As clinically indicated 
  
  
  
See 
Section 8.2.3 of 
the master 
protocol  
Troponin 
X 
As clinically 
indicated 
X (Cycle 4 Day 1) 
As clinically indicated 
 
 
 
See 
Section 8.2.3 of 
the master 
protocol and 
Section 10.2 of 
the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-
Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day 
(Visit window 
in Days) 
D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 days (+/-7 days) 
after last IMP or 
at initiation of 
further therapy 
3 months 
after last 
IMP 
admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU 
Visit 2 
±7 days 
Every 
3 months  
+/-14 days 
 
Pregnancy test  
X 
X 
  
  
X 
  
  
X 
X 
X 
  
  
See 
Section 8.2.5 of 
the master 
protocol and 
Section 10.2 of 
the master 
protocol 
Hepatitis serology, 
CD4 counts and 
viral load  
Xh 
As clinically indicated 
  
  
  
See Section 10.2 
of the master 
protocol and 
Section 10.7 of 
the master 
protocol  
Hematology  
X 
X 
X 
X 
X 
  
 
X 
X 
 
 
 
See Section10.2 
of the master 
protocol  
Coagulation 
X 
As clinically indicated 
  
  
  
See Section10.2 
of the master 
protocol  
Blood Chemistry  
X 
X 
X 
X 
X 
  
 
X 
X 
 
 
 
See Section 10.2 
of the master 
protocol  
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-
Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day 
(Visit window 
in Days) 
D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 days (+/-7 days) 
after last IMP or 
at initiation of 
further therapy 
3 months 
after last 
IMP 
admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU 
Visit 2 
±7 days 
Every 
3 months  
+/-14 days 
 
Urinalysisi 
X 
X 
  
  
X 
  
 
X 
X 
  
 
  
See Section 10.2 
of the master 
protocol  
T3, FT4, TSH & 
cortisol (Cohort D1 
only)j 
X 
   
  
  
X 
  
  
X 
X 
  
  
  
See Section 10.2 
Electrolytes (Cohort 
D2 only) 
 
weekly under treatment and then at the end of treatment, at FU Visit 1 and as 
clinically indicated 
 
 
 
 
IMP 
 
SAR444245 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Pembrolizumab 
(Cohort D1 only) 
  
X 
  
  
X 
  
  
  
  
  
  
  
  
Cetuximab 
(Cohort D2 only) 
  
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
Hospitalizationk 
  
X 
  
  
  
  
  
  
  
  
  
  
 
AE/SAE 
assessmentl 
X 
Continuously throughout treatment period 
 X 
  
  
  
See Section 8.3 
of the master 
protocol  
Prior/Concomitant 
Meds 
X 
Continuously throughout treatment period 
  
  
  
  
See Section 6.8 
of the master 
protocol 
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Evaluationa 
Screening  
Treatment Periodb 
End of Treatment 
Observation Periodc 
Survival 
Phone Call 
Follow-upd 
Notes 
 
Cycle 1 
Cycle 2 and 
beyonde 
EOT Visit 
Follow-
Up 
Follow-Up 
Follow-Up 
Phone Call 
FU 
 
Visit 1 
Visit 2 
Visit 3+ 
Cycle Day 
(Visit window 
in Days) 
D-28 to D-1 D1 D8f 
(±1) 
D15f  
(±1) 
D1 
(±3) 
D8 
(±1) 
D15 
(±1) 
30 days (+/-7 days) 
after last IMP or 
at initiation of 
further therapy 
3 months 
after last 
IMP 
admin 
±7 days 
6 months 
after last 
IMP admin 
±7 days 
Every 
3 months 
after FU 
Visit 2 
±7 days 
Every 
3 months  
+/-14 days 
 
First subsequent 
anti-cancer therapy 
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
 
Survival status 
  
  
  
  
  
  
  
  
  
  
  
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy) / Immunogenicity assessments 
 
PK SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
PK Cetuximab 
See PK flowcharts in Section 1.5 
ADA SAR444245  
See PK flowcharts in Section 1.5.1 and Section 1.5.2 
PDy - Blood and 
tumor tissue 
collectionm,n 
See Biomarker flowchart in Section 1.4 
Tumor assessment 
 
Brain imagingo 
X 
  
  
  
 
  
  
 
 
 
 
  
See Section 8.1 
of the master 
protocol  
CT/MRIp 
X 
  
  
  
X 
  
  
X 
X 
X 
X 
  
See Section 8.1 
of the master 
protocol 
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a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed as 
part of screening within 3 days prior to first IMP administration. During the study treatment period, all assessments must be performed, and results should be reviewed by the investigator prior to IMP administration 
at that visit. After Cycle 1, samples for laboratory assessments (excluding PK & biomarker) can be collected up to 3 days prior to IMP administration. ICF must be signed before any study-specific procedures are 
performed and can be signed more than 28 days prior to first IMP administration. Screening time indicates the maximum time frame relative to the first IMP administration in which study procedures used to support 
eligibility are done. 
b Cycle: a treatment cycle is 21 days. See details in Section 6.1 for IMP administration. If treatment cycles are adjusted, all procedures except tumor assessment imaging will be completed according to the cycle 
number. Tumor assessment imaging will be performed at fixed time points from C1D1 regardless of any treatment delays. 
c Observation Period: Participants who enter the Observation period will be followed differently depending on the reason leading to permanent IMP discontinuation. See Section 4.1. For participant's convenience, all 
Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and 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 study. 
e For Cycle 4 visits, please refer to PK flowchart in Section 1.5. 
f 
C1D8 and/or C1D15 visits must be performed on site for the following participants only: 1) Participants scheduled to have blood draws for biomarker assessment and/or ADA on Day 8; 2) Participants who will 
receive IMP on Day 8 and Day 15. For all other participants, these 2 on-site visits may be done remotely as appropriate based on investigator’s discretion per institutional standard and local regulations. If this is 
the case, this must be documented in the source document. Sponsor may decide to cancel safety assessment on C1D8 and C1D15 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 For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in Germany and Italy (see details and specific instructions in 
Section 10.2 and Section 10.7 of the master protocol). 
i 
Urinalysis using dipstick for glucose, blood, pH, protein, ketones, leukocytes and microscopic examination (if blood or protein is abnormal), will be performed every 4 cycles during Treatment Period and as 
clinically indicated. 
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated  
k Only for participants who will participate in the intensive PK sample collection. 
l 
AE/SAE assessment: 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 (1).   
m If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan.  
n Will not be done for participants enrolled in China. 
o Brain imaging: For participants with no previous history of brain metastases, screening brain imaging will need to be obtained. MRI is the preferred imaging modality however CT is acceptable if an MRI is clinically 
contraindicated. Patients with asymptomatic brain metastases (ie, no neurological symptoms, no requirements for corticosteroids, and no lesion >1.5 cm) may participate but will require regular imaging of the brain 
as a site of disease as per protocol tumor assessment (TA) schedule. In all other cases, the lesions must be treated. Two additional scans, obtained at least 4 weeks apart, should be obtained to document disease 
stability after local treatment administration to the brain metastases has been completed. If participants receive 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 
4 weeks apart. Stability as defined above should be documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or have 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. 
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p CT/MRI: The initial tumor imaging will be performed within 28 days prior to C1D1. Scans performed as part of routine clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 28 days prior to the date of enrollment. On study imaging will be performed every 9 weeks (63 ±7 days) after the date of first IMP and if clinically indicated. Imaging studies should 
follow calendar days and should not be adjusted for delays in cycle starts or extension. 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, during 
treatment period until PD. Per the primary tumor assessment criteria, after the first documentation of response or the first documentation of progression (if the participant is clinically stable), confirmatory imaging 
may be performed no fewer than 28 days later. Alternately, the scan performed at the next scheduled time point (eg, every 63 ±7 days) may be used as confirmation. Tumor assessment is not needed for 
participants who start another anti-cancer therapy.  
Abbreviations: ADA=anti-drug antibodies; AE=adverse event; AST=aspartate transaminase; ALT=alanine transaminase; C=Cycle; ANC=Absolute neutrophil count; AP=Alkaline phosphatase; BUN=Blood urea 
nitrogen; CRF=case report form; CRS=Cytokine release syndrome; CT=computed tomography; 
; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; e-CRF=electronic case report form; EOT=end-of-treatment; FT4=free thyroxine; FU=follow-up; HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; ICF=Informed consent form; 
IMP=investigational medicinal product; INR=international normalized ratio; LDH=Lactate hydrogenase; LVEF=left ventricular ejection fraction; MRI=magnetic resonance imaging; MUGA= multigated acquisition; 
PD=progressive disease; 
; PDy=pharmacodynamic; PK=pharmacokinetic; PR=partial response; PS=Performance Status; SpO2= oxygen saturation; Q3W=every 3 weeks; 
RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; T3=tri-iodothyronine; TSH=thyroid stimulating hormone; WBC=White blood cells. 
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1.4 
BIOMARKER FLOWCHART 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
For participants who will undergo more intensive pharmacokinetic (PK) sampling, the schedule is shown in the flowchart in Section 1.5.1. Up to 
30 participants enrolled across cohorts treated with SAR444245 + pembrolizumab (including Cohort D1) will undergo more intensive PK 
sampling, up to 10 participants from China will undergo intensive PK sampling.  
For all other participants, the PK sampling schedule is shown in the flowchart in Section 1.5.2. 
1.5.1 Participants with more intensive PK sampling  
 
Cycle 
Cycle 1 
Cycle 2, 3 
Cycle 4 
Cycles 6, 8, 
10 + every 
4th cycle 
thereafter 
EOT 
visit 
  30 (±7) 
days 
after 
last 
IMP 
admin 
Day 
D1 
D8 
D1 
D1 
D1 
Time after 
SAR44424
5 dosing 
(EOI, 
except 
SOI) [h] 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
168 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
24 
48 
72 
SOI 
EOI 
SAR444245 
PK sample ID 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08  
P00a 
P01b 
P00a 
P01b 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P00a 
P01b 
  
Sample time 
window 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
 
 
 
 
±15 
min 
±30 
min 
±30 
min 
±30 
min 
±4 h ±6 h ±8 h  
  
SAR444245 
ADA sample 
IDc 
AB00a 
  
  
  
  
  
  
  
 
 AB01 
AB00a 
  
AB00a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI), 
b PK sample must be taken at EOI after flush. 
c ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
In the event the infusion is interrupted, a PK sample should be drawn immediately after interruption. If infusion is not likely to be resumed by clinical assessment, subsequent samples should be drawn at EOI + 1 h, 
+2 h, +4 h, +8 h, +24 h, +48 h and +72 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent samples should be drawn at 1 h, 2 h, 4 h, 8 h, 
24 h, 48 h and 72 h after end of resumed infusion (as per protocol). 
ADA: anti-drug antibodies; EOI: End of infusion; EOT: end of treatment; PK: pharmacokinetic; SOI: Start of infusion.   
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1.5.2 All other participants  
 
Cycle 
Cycle 1 
Cycles 2, 3, 4, 6, 8, 10 + every 
4th cycle thereafter 
EOT visit 
Day 
D1 
D8 
D1 
Time after SAR444245 dosing (EOI, 
except SOI) [h] 
SOI 
EOI 
24 
168 
SOI 
EOI 
30 (±7) days after 
last IMP admin 
SAR444245 PK sample 
 
P01b  
P06 
 
 
P01b  
 
SAR444245 ADA sample 
AB00a  
 
AB01 
AB00a  
 
ABF00 
Time after cetuximab dosing (EOI, 
except SOI) [h] 
SOI 
EOI 
24 
168 
SOI 
EOI 
 
Cetuximab PK sample 
PC00a  
PC01b  
 
PC00a 
PC01b 
 
a Samples collected strictly before start of infusion (SOI) 
b EOI samples = end of infusion samples. Must be taken at end of infusion precisely 
c PK sample can be collected at any time during the second day of the cycle. 
ADA: anti-drug antibodies, PK: pharmacokinetic: SOI: start of infusion; EOI: end of infusion   
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2 
INTRODUCTION 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to cohorts with advanced unresectable or metastatic colorectal cancer for 
the combination therapy with pembrolizumab or cetuximab. 
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models while anti-PD1 antibody prevents T cell suppression 
through the PD1/PD-L1 pathway. The combination of anti-PD1 treatment with SAR444245 was 
tested in a syngeneic mouse CT-26 colon cancer model and induced enhanced anti-tumor activity 
as demonstrated by an increased number of CR and tumor-free surviving animals compared to 
each agent in monotherapy. These data support evaluation of SAR444245 in combination with 
pembrolizumab. 
Clinical data from the on-going monotherapy dose escalation of SAR444245 (HAMMER study) 
has indicated a peripheral increase in the number of NK cells. NK cells are important effector 
cells which mediate antibody-dependent cellular cytotoxicity (ADCC) for IgG1 antibodies such as 
cetuximab. In vitro data where NK cells pretreated with SAR444245 and then co-cultured with 
the EGFR-expressing A431 cancer cells improved the ADCC function of cetuximab in 
a dose-dependent fashion. These data support the evaluation of SAR444245 in combination with 
cetuximab. 
2.2 
BACKGROUND 
2.2.1 Pembrolizumab  
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the PD1 receptor, thus inhibiting its interaction with PD-L1 and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has 
high affinity and potent receptor blocking activity for PD1. Pembrolizumab has an acceptable 
preclinical safety profile and is in clinical development as an IV immunotherapy for advanced 
malignancies. Keytruda (pembrolizumab) is indicated for the treatment of patients across 
a number of indications.  
Refer to the country approved labeling for detailed background information on pembrolizumab. 
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2.2.1.1 Pharmaceutical and therapeutic background  
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2). Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and RCC. Tumor-infiltrating lymphocytes can be expanded 
ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (3, 4). 
The PD1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control. The normal function of PD1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD1 has been resolved (7). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable-type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following 
T-cell stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade (6, 8, 9, 10). The mechanism by which PD1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins (11, 12). 
2.2.1.2 Pre-clinical trials  
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T cells and ultimately leads 
to tumor rejection, either as a monotherapy or in combination with other treatment modalities  
(13, 14, 15, 16, 17, 18, 19). Anti-mouse PD1 or anti-mouse PD-L1 antibodies have demonstrated 
antitumor responses in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
acute myeloid leukemia and colorectal carcinoma (7, 16, 18, 19, 20). In such studies, tumor 
infiltration by CD8+ T cells and increased IFN-γ, granzyme B and perforin expression were 
observed, indicating that the mechanism underlying the antitumor activity of PD1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo (18). 
Experiments have confirmed the in vivo efficacy of anti-mouse PD1 antibody as a monotherapy, 
as well as in combination with chemotherapy, in syngeneic mouse tumor models 
(see pembrolizumab IB). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
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2.2.2 Cetuximab 
Cetuximab is an IgG1 monoclonal antibody against the ligand binding domain of epidermal 
growth factor receptor (EGFR), which is abnormally activated in many epithelial cancers 
including colorectal cancer (21). The mechanism of action of cetuximab appears to include 
antibody dependent cell mediated cytotoxicity (22) in addition to EGFR blockade, which may 
contribute to its efficacy and may be further exploited. Erbitux (cetuximab) is indicated for the 
treatment of KRAS wild-type, EGFR-expressing, metastatic colorectal cancer (mCRC) as 
determined by an FDA-approved test, as a single agent in patients who have failed oxaliplatin- 
and irinotecan-based chemotherapy or who are intolerant to irinotecan, or in combination with 
FOLFIRI (irinotecan, fluorouracil, leucovorin) as the first line treatment, or in combination with 
irinotecan for patients who are refractory to irinotecan-based chemotherapy. More recently, the 
BRAF inhibitor encorafenib was approved when combined with cetuximab, for the treatment of 
mCRC with a BRAF V600E mutation, after prior therapy. 
2.2.3 Rationale for mCRC and selected populations and experimental SAR444245-based 
regimens (Cohorts D1 and D2)  
Colorectal cancer remains the second leading cause of cancer death, with an estimated 8.7% of 
cancer-related deaths annually in 2020, and although overall mortality from CRC continues to 
decline, survival remains poor for advanced disease (23, 24, 25). Chemotherapy and targeted 
therapies remain the main modalities of treatment. 
An increasing number of patients with metastatic colorectal cancer (mCRC) are able to receive 
3 or more lines of therapy. Treatments in this setting can include regorafenib (an oral multikinase 
inhibitor), trifluridine/tipiracil hydrochloride (TAS-102), antibodies that target epidermal growth 
factor receptor (EGFR) for patients with RAS wild-type tumors (if no prior exposure), and, where 
approved, ICI for patients with microsatellite instability-high (MSI-H) mCRC (26).  
While ICI induce 33%-55% ORR (up to ~65% with nivolumab + ipilimumab in the MSI-H), this 
population represents <10% of metastatic disease (27), non-MSI-H mCRC remain the majority of 
the cases and are typically refractory to ICI, being either so-called “cold” [CRC molecular 
sub-group CMS2&3 - “immune-excluded”] or “immune-restricted” [molecular sub-group CMS4] 
(28). So beyond the 2L, in non-MSI-H setting, regorafenib and TAS-102 are the two main 
treatment options. Both regorafenib and TAS-102 have marginal improvement of overall survival 
(OS_ (6.4 to 8.8 months versus 5.0 to 6.3 months) over BSC or placebo, with minimal impact on 
PFS (1.9 to 3.2 months versus 1.7 months) and minimal ORR (1-4%) and despite the fact that they 
have their respective safety profile, they are overall poorly tolerated (29, 30, 31). 
Not only is there a strong medical need in that 3L+ mCRC, non-MSI-H population, but it is 
an opportunity to bring IO in this indication which is known to be refractory to 
immunomodulatory treatments.  Our two hypotheses (exploitation of T cells and NK cells) can be 
tested in 1) 3L+ patients treated with SAR444245 + pembrolizumab and 2) in 3L+ patients, 
RASwt (post-cetuximab), treated with SAR444245 + the anti-EGFR IgG1 mAb cetuximab. 
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2.3 
BENEFIT/RISK ASSESSMENT 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the 
new-generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin).  
Risk assessment of SAR444245 when combined with either pembrolizumab or cetuximab results 
from anticipated risks for SAR444245 and from the label information for Keytruda® 
(pembrolizumab) and Erbitux® (cetuximab), taking into account potential overlapping risks. The 
available safety data for pembrolizumab and cetuximab, along with proposed mitigation strategies 
are summarized below and also provided in Table 15. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment (TME). 
The use of pembrolizumab may cause IRRs (drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, and hypersensitivity). Pembrolizumab use may be associated with 
infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, leukopenia), 
increase in the level of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well as adverse effects 
on the functioning of nervous system (dizziness, headache, peripheral neuropathy, dysgeusia (very 
common) and lethargy). In combination therapy with other chemotherapeutic drugs, 
pembrolizumab administration is commonly associated with hypertension and cardiac arrhythmia 
(including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risks for pembrolizumab 
(32). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related AEs (irAEs) associated with pembrolizumab are: immune-related 
pneumonitis, immune-related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in 
post-marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
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Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis.  
Please refer to the country-approved product labeling (eg, United States Package Insert [USPI], 
Summary of Product Characteristics [SmPC]) for pembrolizumab for more detailed information. 
2.3.1.2 Cetuximab  
The important identified risks for cetuximab include, but are not limited to: infusion reactions 
(including anaphylaxis on the first dose); interstitial lung disease, severe adverse skin reactions 
(with increased risk of secondary bacterial infection), electrolyte disturbances (hypomagnesemia, 
hypokalemia, hypocalcemia) cardiac adverse events (including cardiopulmonary arrest/sudden 
death), and eye disorders (including ulcerative keratitis).  
The most common adverse reactions (incidence ≥25%) are: cutaneous adverse reactions 
(including rash, pruritus, and nail changes), headache, diarrhea, and infection.  
The following precautions and warnings are to be acknowledged: 
Cetuximab can cause serious and fatal infusion reactions. Infusion reactions of any grade occurred 
in 8.4% of patients who received cetuximab across clinical trials. Grades 3 and 4 infusion 
reactions occurred in 2.2% of patients. Signs and symptoms included rapid onset of airway 
obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, 
myocardial infarction, and/or cardiac arrest. The risk of anaphylactic reactions may be increased 
in patients with a history of tick bites, red meat allergy, or in the presence of IgE antibodies 
directed against galactose-α-1,3-galactose. Approximately 90% of severe infusion reactions 
occurred with the first infusion despite premedication with antihistamines. Infusion reactions may 
occur during or several hours following completion of the infusion. Premedication with 
a histamine-1 (H1) receptor antagonist is recommended together with monitor patients for at least 
1 hour following each infusion.  
Cardiopulmonary arrest or sudden death have occurred in 2-3% patients with squamous cell 
carcinoma of the head and neck receiving cetuximab with radiation therapy or a cetuximab 
product with platinum-based therapy and fluorouracil. A history of coronary artery disease, 
congestive heart failure, or arrhythmias and abnormal serum electrolytes may be predisposing 
factors.  
Interstitial lung disease (ILD) that may be fatal has occurred in <0.5% of patients receiving 
cetuximab in clinical trials.  
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. Acneiform rash occurred in 82% of patients across clinical trials. 
Grades 3 or 4 acneiform rash occurred in 9.7% of patients. Acneiform rash usually developed 
within the first two weeks of therapy; the rash lasted more than 28 days after stopping treatment in 
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most patients. Life-threatening and fatal bullous mucocutaneous disease with blisters, erosions, 
and skin sloughing, has been observed. It could not be determined whether these mucocutaneous 
adverse reactions were directly related to EGFR inhibition or to idiosyncratic immune-related 
effects (eg, Stevens-Johnson syndrome or toxic epidermal necrolysis).  
Cetuximab can cause hypomagnesemia which occurred in 55% patients in various clinical trials, 
including Grades 3 and 4 in 6% to 17%. Hypomagnesemia and accompanying electrolyte 
abnormalities can occur days to months after initiating treatment. It is recommended to monitor 
patients weekly during treatment for hypomagnesemia, hypocalcemia, and hypokalemia, and for 
at least 8 weeks following the completion of treatment and to replete electrolytes as necessary. 
Based on animal data and its mechanism of action, cetuximab can cause fetal harm when 
administered to a pregnant woman. There are no available data for cetuximab exposure in 
pregnant women. In an animal reproduction study, intravenous administration of cetuximab once 
weekly to pregnant cynomolgus monkeys resulted in an increased incidence of embryo-lethality 
and abortion. Disruption or depletion of EGFR in animal models results in impairment of 
embryo-fetal development including effects on placental, lung, cardiac, skin, and neural 
development. 
The safety and effectiveness of cetuximab in pediatric patients have not been established. The 
pharmacokinetics of cetuximab, in combination with irinotecan, were evaluated in pediatric 
patients with refractory solid tumors in an open-label, single-arm, dose-finding study. Cetuximab 
was administered once weekly, at doses up to 250 mg/m2, to 27 patients ranging from 1 to 
12 years old; and in 19 patients ranging from 13 to 18 years old. No new safety signals were 
identified in pediatric patients. The pharmacokinetics of cetuximab between the two age groups 
were similar following a single dose of 75 mg/m2 and 150 mg/m2. The volume of the distribution 
appears to be independent of dose and approximates the vascular space of 2 L/m2 to 3 L/m2. 
Following a single dose of 250 mg/m2, the mean AUC0-inf (CV%) was 17.7 mg*h/mL (34%) in 
the younger age group (1-12 years, n=9) and 13.4 mg*h/mL (38%) in the adolescent group 
(13-18 years, n=6). The mean half-life of cetuximab was 110 hours (69 to 188 hours) in the 
younger group and 82 hours (55 to 117 hours) in the adolescent group. 
Of the 1662 patients with advanced colorectal cancer who received cetuximab with irinotecan, 
with FOLFIRI or as monotherapy in six studies, 35% of patients were 65 years of age or older. 
No overall differences in safety or efficacy were observed between these patients and younger 
patients. 
Please refer to the country-approved cetuximab labeling (eg, USPI, SmPC) for more detailed 
prescribing information. 
2.3.1.3 SAR444245 combined with pembrolizumab or cetuximab 
Combining SAR444245 with pembrolizumab or cetuximab may lead to an increased frequency 
and/or severity of adverse events (AEs) related to immune activation or may lead to additional 
AEs related to immune system activation for each substance individually or may cause 
occurrences of qualitatively different AEs. Serious adverse drug reactions reported with agents 
known to increase immune activation include pneumonitis, hepatitis, nephritis, colitis, and 
hormonal dysfunction (see Section 2.3.1.1). SAR444245 could also increase the incidence of 
cetuximab-induced cutaneous toxicities. 
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As all three substances are biologic agents, they may have the propensity to induce infusion-
related reactions that may have higher rate of occurrence and severity when SAR444245 with 
pembrolizumab or cetuximab are used in combination. 
The maximum tolerated dose (MTD) of SAR444245 combined with the approved dosing of the 
anti PD-1 pembrolizumab or cetuximab is under assessment in the HAMMER study using a Q3W 
schedule. Safety data generated from the combination of SAR444245 and pembrolizumab or 
cetuximab have informed the selection of the combination dose in this study.  
2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab or cetuximab are provided 
below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of 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). 
Non-MSI-H mCRC are known to not respond to immune checkpoint inhibitors, being qualified as 
immune excluded or restricted tumors. Combining SAR444245 may unleash inflammatory 
response in the tumor microenvironment and sensitize CRC to anti-PD1. Preclinical and 
preliminary clinical data indicates that SAR444245 expands NK cells which are important 
effector cells mediating antibody-dependent cellular cytotoxicity (ADCC) for IgG1 antibodies 
such as cetuximab. In vitro experiments show that SAR444245 improved the ADCC function of 
cetuximab in a dose-dependent fashion. The expansion of NK cells induced by SAR444245 may 
also rescue the activity of cetuximab in KRASwt mCRC. In 3L+ mCRC, the benefit of SoC 
remains marginal, and the proposed SAR444245-based combination may bring improved benefit 
compared to SoC. 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. 
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 pembrolizumab or cetuximab are justified by the anticipated benefits that may 
be afforded to participants with colorectal cancer.  
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2.3.4 Benefit and risk assessment in the context of COVID-19 pandemic  
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity. 
In addition, the impact of PD-1 blockade therapy on Coronavirus disease 2019 (COVID-19) 
severity was also explored by 2 groups and did not find a clinically meaningful signal (33, 34).  
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below.  
Table 2 - Objectives and endpoints 
Objectives 
Endpoints 
Secondary 
 
• 
To assess active concentrations of cetuximab when 
given in combination with SAR444245 
• 
Ctrough and Cend of infusion of cetuximab 
Exploratory 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
Cohorts D1 and D2 will assess SAR444245 adding on to either pembrolizumab or cetuximab, 
respectively, in participants with advanced unresectable or metastatic colorectal cancer (mCRC) 
who have progressed on prior regimens having contained fluoropyrimidine, oxaliplatin, 
irinotecan, with either bevacizumab or cetuximab, and with no more than 5 prior lines of 
treatments. Patients are not eligible if MSI-H. Patients with RASmut are not eligible for enrollment 
in Cohort D2. 
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts.   
A graphical presentation of the substudy schema is shown in Figure 1. For treatment period, the 
completion of Cycle 35 is only applicable for Cohort D1. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed substudy aims to establish proof-of-concept that combining the non-alpha-IL2 
SAR444245 with either the anti-PD1 antibody pembrolizumab or with the anti-EGFR IgG1 
antibody cetuximab will result in a significant increase in the population experiencing 
an objective response. 
The design of the 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, or anti-EGFR therapy as a benchmark to show outstanding objective 
response rate. The ORR will be assessed using RECIST 1.1 for participants with advanced and 
metastatic colorectal cancer.  
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
There was no participant input into design of the trial. 
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol. 
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4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is justified 
by: 
• Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold exposure range 
(refer to the pembrolizumab IB). 
• Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications. And 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, 
a PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
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these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.3.3 Cetuximab dose 
This study proposes to evaluate the clinical benefit of 24 µg/kg SAR444245 Q3W combined with 
the approved dose of 400 mg/m² cetuximab as an IV infusion on day 1 of the study followed by 
subsequent doses of 250 mg/m² cetuximab IV QW.  
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohorts D1 and D2 specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply 
(in addition to the criteria listed presented in the master protocol): 
Type of participant and disease characteristics 
I 01. 
Histologically or cytologically confirmed diagnosis of colorectal cancer. Only patients 
with non-MSI-H disease are eligible.  
I 02. 
Confirmed diagnosis at study entry of advanced unresectable or metastatic disease. 
Note: For participants in Cohort D1 and D2: Disease with any CPS scoring. No need for 
CPS determination at local laboratory. 
I 03. 
MSI status: Participants must have MSI status known or determined locally and must have 
non-MSI-H disease to be eligible.  Other genetic aberrations: Participants in Cohort D2 
must have RAS wild-type disease. 
I 04. 
Prior anticancer therapy: Participants should have failed or relapsed on at least 2 but 
no more than 5 prior regimens having contained fluoropyrimidine, oxaliplatin, irinotecan, 
with bevacizumab and/or cetuximab. 
I 05. 
Provision of tumor tissue: 
- 
Mandatory baseline biopsy for participants in Cohorts D1, and D2: minimum 
5 slides with 4-5 micron thickness for the first 20 participants who have signed ICF 
(excluding screen failure participants), minimum 10 slides with 4-5 micron thickness 
for subsequent participants in each cohort. Archival tumor tissue samples should be 
obtained from biopsies done within 6 months, and there should be no systemic 
anti-cancer therapy between collection of biopsy and enrollment. Slides specifications 
are detailed in Lab Manual. 
- 
Mandatory on-treatment biopsy for at least 20 participants in each of Cohort D1 
and Cohort D2, if clinically feasible. On-treatment biopsies are otherwise optional 
per Investigator’s discretion and evaluation of all other participants. 
- 
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. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
Medical conditions 
E 01. Electrolyte (magnesium, calcium, potassium) levels outside of normal ranges for 
participants in Cohort D2. 
Prior/concomitant therapy 
E 02. For participants in Cohort D1. - Prior treatment with an agent (approved or 
investigational) that blocks the PD-1/PD-L1 pathway (participants who joined a study with 
an anti-PD-1/PD-L1 but have written confirmation they were on control arm are allowed).  
 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
Please refer to the master protocol. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
For study treatment duration, completion of Cycle 35 is only applicable for Cohort D1. 
Dosing sequence for Cohort D1: 
Enrolled participants in Cohort D2 will receive treatment with both SAR444245 and cetuximab 
until PD. 
Dosing sequence for Cohort D2:
In addition, if a participant has immune unconfirmed progression of disease (iUPD) and is 
clinically stable, it is at the discretion of the Investigator to continue treating the subject with the 
assigned treatment per protocol until progression of disease is confirmed (iCPD) at least 4 weeks, 
but no longer than 8 weeks  from the date of the scan suggesting progression of disease 
(Section 10.9). 
6.1.1 Investigational medicinal product (IMP)  
Investigation medicinal product is defined as SAR444245, pembrolizumab, and cetuximab 
administered in combination as described in Section 4. Details of each IMP component to be 
administered are shown in Table 3.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3 of the 
master protocol.  
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Table 3 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Cetuximab 
Type 
See master protocol 
Biologic 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Solution for injection 
Unit dose strength(s) 
See master protocol 
100 mg/vial 
As per locally approved 
formulation 
Dosage level(s)a 
24 μg/kg Q3W 
200 mg Q3W 
An initial loading dose of 
400 mg/m2 on C1D1, followed by 
250 mg/m2 once weekly 
Route of administration 
See master protocol 
IV infusion 
IV infusion 
Use 
See master protocol 
Treatment of cancer 
(combination) 
Treatment of cancer 
(combination) 
IMP or NIMP 
See master protocol 
IMP 
IMP 
Packaging and labeling 
See master protocol 
Supplied in single dose vials 
containing 100 mg/4 mL 
pembrolizumab labelled with 
a multilingual booklet. 1 vial per 
treatment box. 
To be locally sourced as locally 
available/marketed where 
possible. Central sourcing (EU 
sourced and clinically labeled 
only for the countries where local 
sourcing is not possible) 
Current/Former name(s) or 
alias(es) 
See master protocol 
Keytruda 
As per locally approved 
formulation 
a See master protocol. 
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6.1.2 Non-investigational medicinal products 
Non-investigational medicinal products include the premedication administered for SAR444245 
and cetuximab. 
For Cohort D1, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, SAR444245 premedication no longer needs 
to be administered. 
6.1.2.1 Premedication for SAR444245  
Please refer to the master protocol. 
6.1.2.2 Premedication for cetuximab 
All participants who will receive cetuximab should be premedicated with diphenhydramine 25 to 
50 mg IV (or equivalent) prior to the first dose of cetuximab or any other recommended 
premedication as per local requirements. Premedication for subsequent doses of cetuximab should 
be given per medical judgment and history of prior infusion reactions (IRs). 
When SAR444245 and cetuximab are given on the same day, participants who have received 
diphenhydramine as cetuximab premedication may skip the diphenhydramine as SAR444245 
premedication. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
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6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modifications for SAR444245 and cetuximab are permitted. according to the guidelines 
described in this section. Pembrolizumab dose reductions are not permitted. Pembrolizumab 
treatment may be interrupted or discontinued due to toxicity.  
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed.  
In participants who have SAR444245 dose reduction due to SAR444245 related Grade ≥3 
treatment-related adverse events (TRAEs), SAR444245 dose may be re-escalated to 
 μg/kg if:  
• no SAR444245 related Grade ≥3 TRAE or clinically significant laboratory abnormality 
within at least 2 subsequent cycles, AND  
• both Investigator and Sponsor agree that the participant has clinical benefit. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case, it is partial permanent discontinuation, and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued, it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF).  
6.5.2 Cycle delay  
The treatment window is ±3 days for each of the Q3W administrations. The treatment window is 
±1 day for cetuximab administration on Day 8 and Day 15 of each cycle.  
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A cycle is deemed to have been delayed if the treatment is administered ≥4 days beyond the 
theoretical day of Q3W IMP administration. The participant may receive the next dose after 
recovery from the toxicity as described in Section 6.5.3 and Section 6.5.4. After cycle is delayed, 
such participants may be considered for treatment resumption once the toxicity resolves or 
improves to Grade 1 or baseline. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on 
the day of planned administration, the cycle will be delayed; restart of study IMPs could 
occur only on the initiation of the subsequent cycle. 
• For cetuximab Day 8 and Day 15 administration in each cycle: if toxicity occurs and the 
patient does not recover on the day of planned infusion or within the following 3 days, 
infusion may be omitted. 
• In case of cycle delay or dose omissions for the recovery of toxicity, the following rules 
should be followed for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days or a dose omission, it is per Investigator’s 
decision to restart the study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, or 2 to 4 consecutive dose omissions, it 
is per Investigator’s decision to restart the study treatment or the IMP that is omitted, if 
a clear benefit from treatment is observed and after consultation with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer than 
84 days, or if the participant has more than 4 consecutive dose omissions. 
- 
For any delayed cetuximab treatment, do not repeat the initial dose of 400 mg/m². At 
the restart of cetuximab treatment, all subsequent infusions will be at the appropriate 
dose level according to Table 4. 
• Cycle delay or dose omission may be considered for situations other than TEAEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 21 days of the scheduled delay or omission, 
unless otherwise discussed with the Sponsor (for example for national or regional 
emergencies). The reason for the delay or omission should be documented in the 
participant’s study record. 
Modification of dose levels in case of dose reduction 
Dose reduction steps for cetuximab are shown in Table 4. One or several doses of cetuximab can 
be omitted. 
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Table 4 - Dose levels for cetuximab dose reduction 
 
Starting dose 
Dose level 1 
Dose level 2 
400 mg/m2 then 
250 mg/m2 
200 mg/m2 
(20% decrease) 
150 mg/m2 
(20% decrease) 
6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 TRAEs at any time of the study (including clinically 
significant Grade 3 laboratory abnormalities as defined in Section 10.3.1 of the master protocol) 
not listed in Section 6.5.4 (Tables 5-11) will be required to temporarily cycle delay the IMP. After 
cycle delay, such participants may be considered for treatment resumption once the TRAE 
resolves or improves to Grade 1 or baseline.  
The dose of SAR444245 should be reduced to 
μg/kg (with the exception of lymphocytopenia 
which is directly associated with SAR444245 mode-of-action and does not require dose 
reduction) in cases of: 
• First occurrence of Grade 3 TRAE that does not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 TRAE of any duration. 
• Grade 4 TRAE. 
• First occurrence of Grade 3 laboratory abnormality that are clinically significant per 
Section 10.3.1 of the master protocol. and that do not resolve to Grade 1 or baseline within 
72 hours, and second occurrence of Grade 3 clinically significant laboratory abnormality 
of any duration. 
• Grade 4 laboratory abnormalities that are clinically significant. 
Treatment resumption is at the discretion of the Investigator and Sponsor, if thought to be in the 
best interest of the participant, except when specified otherwise in this protocol, or if the event has 
required the IMP temporary interruption for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
Vascular Leak Syndrome (VLS) and Infusion-related reactions (IRR) are presented in 
Section 6.5.4. 
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6.5.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interest (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
e-CRF. 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An 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.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 5. 
After an infusion-related reaction due to pembrolizumab infusion (Grade 3 or Grade 4), the 
SAR444245 infusion will be delayed and can be administered after resolution of symptoms. The 
Investigator should discuss with the Sponsor’s Medical Monitor if the SAR444245 infusion needs 
to be delayed more than 1 day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 6. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
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Table 5 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication 
at subsequent 
dosing 
Grade 1 
Mild transient reaction; 
infusion interruption not 
indicated; intervention not 
indicated 
• 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(eg, antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs. 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may include but is not 
limited to: 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics. 
• 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
• 
If symptoms resolve within 1 hour of stopping drug infusion, the 
infusion may be restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr. to 50 mL/hr.). Otherwise, dosing will be 
held until symptoms resolve and the participant should be 
premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug treatment 
Participant may be 
premedicated 1.5 h 
(±30 minutes) prior 
to infusion of 
pembrolizumab with: 
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may include but is not 
limited to: 
- 
Epinephrine*, 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
- 
Acetaminophen, 
- 
Narcotics, 
- 
Oxygen, 
- 
Pressors, 
- 
Corticosteroids. 
• 
Increase monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the opinion of the 
investigator. 
• 
Hospitalization may be indicated. 
*In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent 
dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov. 
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Table 6 - SAR444245 infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs as 
medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise, dosing will be held 
until symptoms resolve and the participant should be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics.  
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; pressor or ventilator support 
indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be permanently 
discontinued. The participant can continue treatment with the other anti-cancer 
therapy in combination 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 are provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
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Participants who experience cetuximab-related infusion reactions should have cetuximab reduced 
according to Table 7 and continue to receive antihistamine premedication prior to administration. 
Once the cetuximab infusion rate has been decreased due to an allergic/hypersensitivity reaction, 
it should remain decreased for all subsequent infusions. If the participant experiences a second 
infusion reaction at the decreased rate, cetuximab should be permanently discontinued. If any 
Grade 3-4 infusion reaction occurs, cetuximab treatment should be discontinued immediately. 
Severe infusion-related reactions, including anaphylactic reactions, may commonly occur, in 
some cases with fatal outcome. Occurrence of a severe infusion-related reaction requires 
immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency 
treatment. Some of these reactions may be anaphylactic or anaphylactoid in nature or represent 
a cytokine release syndrome (CRS). Symptoms may occur during the first infusion and for up to 
several hours afterwards or with subsequent infusions. 
Table 7 - Cetuximab infusion-related reaction dose modification and treatment guidelines 
NCI CTCAE Grade 
Dose modification 
Grade 1 
Mild reaction; infusion interruption not indicated; intervention 
not indicated 
Decrease the cetuximab infusion rate by 50% and monitor closely 
for any worsening. 
Grade 2 
Requires therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hrs 
Stop cetuximab infusion and administer bronchodilators, oxygen, 
etc. as medically indicated. 
Resume infusion at 50% of previous rate once 
allergic/hypersensitivity reaction has resolved or decreased to 
Grade 1 in severity and monitor closely for any worsening. 
Grades 3 or 4 
Grade 3: 
Prolonged (ie, not rapidly responsive to symptomatic 
medication and/or brief interruption of infusion); recurrence 
of symptoms following initial improvement; hospitalization 
indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilator support indicated 
Stop the cetuximab infusion immediately, administer epinephrine, 
bronchodilators, antihistamines, glucocorticoids, intravenous 
fluids, vasopressor agents, oxygen, etc., as medically indicated. 
Cetuximab should permanently discontinued. The participant can 
continue treatment with SAR444245. 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion related reaction; NCI = National Cancer Institute. 
6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of SAR444245, pembrolizumab and cetuximab being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines)  
(36, 1, 37). 
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6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cetuximab may be associated with CRS. CRS typically occurs within one hour after infusion and 
is less commonly associated with bronchospasm and urticaria.  CRS is normally most severe in 
relation to the first infusion of cetuximab. Cetuximab related IRR’s, including CRS, are discussed 
in Section 6.5.4.1. Please refer to Table 7 for Cetuximab IRR dose modifications and treatment 
guidelines. 
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 8. 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 C-reactive protein (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 according to severity grading are provided in Table 8. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 8 - Guidelines for the management of suspected cytokine release syndrome (CRS) 
Event severity (ASTCT 
CRS Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care 
guidelines 
Recommended 
Cetuximab dose 
modifications and 
supportive care 
guidelines 
Grade 1 
• 
Fever (Temperature 
≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a 
Appropriate symptomatic treatment may include but is not 
limited to IV fluids (care should be taken to not excessively 
hydrate if evidence of vascular leak), antihistamines, 
NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. 
Clinical and laboratory monitoring should initially be 
performed daily, then less frequently as the participant 
improves. 
Decrease the cetuximab 
infusion rate by 50% and 
monitor closely for any 
worsening. 
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Event severity (ASTCT 
CRS Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care 
guidelines 
Recommended 
Cetuximab dose 
modifications and 
supportive care 
guidelines 
Grade 2 
• 
Feverb (Temperature 
≥38°C) 
• 
Hypotension not 
requiring vasopressors  
• 
and/orc hypoxia 
requiring low-flow nasal 
cannulad or blow-by. 
Temporarily interrupt SAR444245 if event occurs during 
infusion 
Additional appropriate medical therapy may include but is 
not limited to IV fluids (care should be taken to not 
excessively hydrate if evidence of vascular leak), 
antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions 
closely as medically indicated should be increased until the 
participant recovers. Transfer to ICU may be required. 
For participants with comorbidities, older age, or with 
oxygen requirement, hypotension, or participants in whom 
symptoms (eg, high grade fever) that do not respond to 
antipyretics within 72 hours treatment with corticosteroids 
and/or tocilizumab should be considered, as per guidance 
for Grade 3 events.  
SAR444245 may be resumed when clinical symptoms have 
resolved or improved to Grade 1 and corticosteroid taper. 
No dose modification is required but decreasing to half the 
infusion rate can be considered. 
Stop cetuximab infusion and 
administer bronchodilators, 
oxygen, etc., as medically 
indicated.  
 
Resume infusion at 50% of 
previous rate once 
allergic/hypersensitivity 
reaction has resolved or 
decreased to Grade 1 in 
severity and monitor closely 
for any worsening. 
Grade 3 
• 
Feverb (Temperature 
≥38°C)  
• 
Hypotension requiring a 
vasopressor with or 
without vasopressin  
• 
And/orc hypoxia 
requiring high-flow nasal 
cannulad, face mask, 
nonrebreather mask, or 
Venturi mask 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
• 
Feverb (Temperature 
≥38°C) 
• 
Hypotension requiring 
multiple vasopressors 
(excluding vasopressin) 
• 
And/orc hypoxia 
requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation and 
mechanical ventilation) 
If CRS grade 3, SAR444245 should be temporarily cycle 
delayed, and subsequent treatment should be resumed only 
when symptoms have resolved or improved to Grade 1 at 
 µg/kg or permanently discontinued, as clinically 
indicated.  
If CRS Grade 4, SAR444245 should be permanently 
discontinued, as clinically indicated. 
If CRS Grade 3 or Grade 4, IV corticosteroids should be 
initiated (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. 
Stop the cetuximab infusion 
immediately, administer 
epinephrine, bronchodilators, 
antihistamines, 
glucocorticoids, intravenous 
fluids, vasopressor agents, 
oxygen, etc., as medically 
indicated.  
 
Cetuximab should 
permanently discontinued. 
The participant can continue 
treatment with SAR444245. 
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Event severity (ASTCT 
CRS Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care 
guidelines 
Recommended 
Cetuximab dose 
modifications and 
supportive care 
guidelines 
 
If no clinical improvement in oxygenation, hypotension, 
fever, and other CRS manifestations is observed within 
24 to 72 hours, management for persistent or worsening 
CRS should be initiated. Re-evaluation for other contributing 
conditions should be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous 
Tocilizumab at 8 mg/kg (for participants 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 should be discussed with clinical site 
specialists 
 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by 
hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (irAEs) may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than one body system simultaneously. 
IrAEs are thought to be caused by unrestrained cellular immune responses directed at the normal 
host tissues. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing pembrolizumab clinical study data, most irAEs were reversible 
and could be managed with interruptions of pembrolizumab, administration of corticosteroids 
and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and 
administer corticosteroids. 
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SAR444245 may increase the incidence and severity of these events. 
Dose modification and toxicity management guidelines for irAEs are provided in Table 9. Of 
note, when study interventions are administered in combination, if the AE is considered immune-
related, both drugs in the combination should be held according to recommended dose 
modifications.  If a participant experiences several irAEs, the most conservative recommendation 
should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When pembrolizumab can be restarted, it should be administered at the initial planned dose and 
schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 9, the 
combination of SAR444245 and pembrolizumab or cetuximab may be restarted at the 
discretion of the investigator. In these cases where the toxicity is attributed to the 
combination or to SAR444245 alone, re-initiation of pembrolizumab as a monotherapy 
may be considered after communication with the Sponsor. 
Table 9 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245   
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE 
decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Pneumonitis  
Grade 2 
Withholda  
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Add prophylactic antibiotics 
for opportunistic infections. 
Monitor participants for signs 
and symptoms of 
pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
Recurrent Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor participants for signs 
and symptoms of 
enterocolitis (ie, diarrhea, 
abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinueb 
perforation (ie, peritoneal 
signs and ileus). 
Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returns to 
baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Type 1 Diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholda,f 
Initiate insulin replacement 
therapy for participants with 
T1DM. 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism 
and adrenal insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
Hyperthyroidism  
Grade 2 
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as appropriate. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinueb,f 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid and/or 
other therapies 
Monitoring and 
follow-up 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinueb 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinueb 
All Other 
immune-related 
AEs 
Persistent Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinueb 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 - 3.0 x ULN if baseline normal;  
>1.5 - 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; 
>3.0 - 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and/or SAR444245 is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
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6.5.4.5 Immune Cell-Associated Neurotoxicity Syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment 
of cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.11 
of the master protocol). Recommendations for ICANS management mainly include the use of 
steroids, whereas tocilizumab should only be used in the context of CRS, as outlined in Table 10. 
The proposed management should be considered only as recommendations and in light of 
recommendations from site specialist. 
Table 10 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS) 
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or improvement 
to Grade 1 after corticosteroid taper. Consideration for reduction of 
SAR444245 dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
If Grade 4 ICANS, both SAR444245 and pembrolizumab should be 
permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab and should be handled as described in Table 8 in 
Section 6.5.4.3. Corticosteroids can then be administered IV or orally every 
8 hours for up to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; ICANS= Immune effector 
cell associated neurotoxicity syndrome; ICE= Immune Effector Cell-Associated Encephalopathy; IV = Intravenous. 
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6.5.4.6 Vascular Leak Syndrome (VLS)  
Vascular leak syndrome is a disorder characterized by leakage of intravascular fluids into the 
extravascular space and can lead to generalized edema and multiple organ failure. This syndrome 
is observed in patients who demonstrate a state of generalized leaky capillaries following shock 
syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, medications, or poisoning. 
In various human diseases, an increase in capillary permeability to proteins leads to the loss of 
protein-rich fluid from the intravascular to the interstitial space manifested by any of the 
following clinical presentations: diffuse pitting edema, exudative serous cavity effusions, 
noncardiogenic pulmonary edema, hypotension, and, in some cases, hypovolemic shock with 
multiple-organ failure. Fluid management is the cornerstone of VLS management; it is a balance 
between maintaining the intravascular volume to ensure organ perfusion to prevent organ failure, 
while avoiding volume overload. The management of VLS according to severity grading is 
described in Table 11. 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 (38).  
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Table 11 - Guidelines for the management of Vascular Leak Syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure together 
with a fluid-restrictive strategy is advocated to limit interstitial fluid volume 
expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently discontinued.   
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain with 
refractory shock in the setting of low filling pressures, high molecular weight 
starches such as hetastarch (MW 450 kDa) and pentastarch (MW 264 kDa) 
may be effective in expanding the intravascular volume. Supportive care with 
invasive and noninvasive ventilation as well as renal replacement may be 
necessary in severe cases. When available, disease-specific therapy should be 
initiated as soon as possible to facilitate recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in stabilization 
of blood pressure, at which time fluid overload symptoms and signs may 
predominate (eg, pulmonary edema, pleural effusions, acute respiratory distress 
syndrome, systemic edema, ascites). Volume removal with loop diuretics is the 
first-line therapy in these patients. In those with marginal blood pressure and 
fluid overload, the combination of loop diuretics and 25% albumin IV may 
facilitate volume removal. Patients with AKI refractory to diuretics will require 
renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AKI= acute kidney injury; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; MW= molecular weight; 
NCI = National Cancer Institute; VLS= vascular leak syndrome. 
6.5.4.7 Dermatologic toxicity 
Cetuximab can cause dermatologic toxicities, including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative keratitis with decreased visual acuity, 
cheilitis), and hypertrichosis. 
The dosing of cetuximab will be omitted 1 to 2 weeks in the case of severe (Grade 3 or 4) 
acneiform rash. If acneiform rash improves during this time, then the dose of cetuximab should be 
reduced as indicated in Table 12. The dose modification guidelines as per  the current local label 
should be followed for dermatologic toxicities other than acneiform rash.  
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If acneiform rash does not improve during this time, cetuximab will be permanently discontinued.  
Participant who have held cetuximab therapy for more than 2 consecutive infusions due to 
acneiform rash, and upon resolution of the toxicity are still felt to be benefiting from cetuximab 
treatment may resume cetuximab with Sponsor approval. 
Table 12 - Cetuximab dose modification for dermatologic toxicities 
Dermatologic toxicities and infectious 
sequelae (eg, acneiform rash, 
mucocutaneous disease) 
Recommended cetuximab  
dose modification 
1st occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, continue at 
the same dose of 250 mg/m2. If no improvement, discontinue cetuximab. 
2nd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently 
reduce at 200 mg/m2. If no improvement, discontinue cetuximab. 
3rd occurrence; Grade 3 or 4 
Day 1 of cycle: delay cycle until condition improves 
Within cycle: Omit infusion 1 to 2 weeks; if condition improves, permanently 
reduce at 150 mg/m2. If no improvement, discontinue cetuximab. 
4th occurrence; Grade 3 or 4 
 Permanently discontinue cetuximab. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater. There is no 
specific antidote for overdose with pembrolizumab, or cetuximab. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol.  
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol and Section 1.3. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol. 
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s) 
Please refer to the master protocol for RECIST 1.1. 
   
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol.  
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
In addition, combining SAR444245 with other anticancer therapies may increase the frequency 
and severity of immune-related adverse events related to other anticancer therapies. Immune-
mediated endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, and 
cortisol level will be monitored for participants in Cohort D1. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and serious adverse events (SAEs) collection. For 
participants in Cohort D1 irAEs will be collected until 90 days following last administration of 
study treatment regardless of whether or not another anticancer therapy is initiated. 
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8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab and cetuximab, SAEs that are considered expected will be specified in the 
reference safety information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
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8.4 
PHARMACOKINETICS 
Please refer to the master protocol for a description of common PK evaluations. Substudy specific 
evaluations are summarized below.  
PK parameters (eg, maximum concentration, area under the concentration time curve) will be 
generated in patients undergoing intensive PK sampling (as in Section 1.5.1 of the master 
protocol). Samples collected for analyses of cetuximab concentration may also be used to evaluate 
safety or efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant.  
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.6 
BIOMARKERS 
Please refer to the master protocol. 
8.7 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.8 
HEALTH ECONOMICS 
Please refer to the master protocol. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
 STATISTICAL HYPOTHESES  
Please refer to the master protocol. 
9.2 
SAMPLE SIZE DETERMINATION 
The plan is to treat approximately 40 participants per cohort for Cohorts D1 and D2. 
Table 13 lists estimated ORR and 90% exact confidence intervals (CIs) by number of responders 
from a sample size of 40 participants treated. 
Table 13 - Estimated objective response rate (ORR) depending on number of responders  
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
2 
5% (0.9% - 14.9%) 
4 
10% (3.5% - 21.4%) 
6 
15% (6.7% - 27.5%) 
8 
20% (10.4% - 33.2%) 
10 
25% (14.2% - 38.7%) 
12 
30% (18.3% - 44.0%) 
14 
35% (22.6% - 49.2%) 
CI: confidence interval; N=number. 
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 these cohorts. 
9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
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9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
Please refer to the master protocol. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol for description of common objectives and endpoints. 
Substudy-specific objectives and endpoints are summarized below. 
9.4.3.1 Other secondary endpoints  
Plasma concentrations (or where applicable PK parameters) of cetuximab will be summarized 
with descriptive statistics.  
9.4.4 Tertiary/exploratory endpoint(s)  
. 
9.4.4.1 Exploratory antitumor indicators 
 
9.4.5 Other safety analysis 
Please refer to the master protocol. 
9.4.6 Other analysis 
Please refer to the master protocol.  
9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
For each cohort, if the predictive probability of concluding a minimum clinical meaningful effect 
of the study treatment (ORR of 5% for both cohorts) at the end of study is <15%, the 
corresponding cohort will be stopped for futility. To facilitate the calculation of predictive 
probability, a minimum informative prior of Beta (0.5, 0.5) is used at the time of the design of the 
study. However, emerging data generated from outside of the study may warrant a different prior 
to be considered before this interim analysis. 
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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 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
Please refer to the master protocol.  
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol. 
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
10.1.9 Study and site start and closure 
Please refer to the master protocol. 
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10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Clinical laboratory tests that are common to all cohorts are detailed in the master protocol. 
Cohort D1 and D2 specific evaluations are presented in Table 14. 
Table 14 - Protocol-required laboratory tests 
Endocrine function testsa 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
 
Cortisol (preferably in the morning) 
NOTES : 
a Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT in cohorts receiving 
pembrolizumab. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed as clinically 
indicated. 
In addition, for participants in Cohort D2, electrolytes to be done weekly under treatment and then 
at the end of treatment, at FU visit 1 and as clinically indicated. After last IMP administration, 
additional electrolytes monitoring for Cohort D2, outside the visits, may be done according to the 
local standard institutional care.  
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol. 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 
Please refer to the master protocol. 
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 or 
(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.” 
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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. For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to 
a diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as 
a method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be 
a potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is advised to differentiate between response or SD and PD. 
10.10 APPENDIX 10: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
 
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10.11 APPENDIX 11: RISK ASSESSMENT  
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab and cetuximab is shown in Table 15. 
Table 15 - Risk assessment  
Potential risk of 
clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion reactions 
Pembrolizumab 
Common, but infusion-related reactions in labeling 
include drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, hypersensitivity and cytokine 
release syndrome. 
Cetuximab 
Severe infusion-related reactions, including 
anaphylactic reactions, may commonly occur, in 
some cases with fatal outcome. Symptoms may 
occur during the first infusion and for up to several 
hours afterwards or with subsequent infusions. 
Symptoms may include bronchospasm, urticaria, 
increase or decrease in blood pressure, loss of 
consciousness or shock. In rare cases, angina 
pectoris, myocardial infarction or cardiac arrest have 
been observed. 
Anaphylactic reactions may occur as early as within a 
few minutes of the first infusion and can occur 
despite the use of premedication. 
The risk for anaphylactic reactions is much increased 
in patients with a history of allergy to red meat or tick 
bites or positive results of tests for IgE antibodies 
against cetuximab  
(α-1-3-galactose). In these patients cetuximab should 
be administered only after a careful assessment of 
benefit/risk, including alternative treatments, and only 
under close supervision of well-trained personnel with 
resuscitation equipment ready. 
A cytokine release syndrome (CRS) typically occurs 
within one hour after infusion and is less commonly 
associated with bronchospasm and urticaria. CRS is 
normally most severe in relation to the first infusion. 
Mild or moderate infusion-related reactions are very 
common comprising symptoms such as fever, chills, 
dizziness, or dyspnea that occur in a close temporal 
relationship mainly to the first cetuximab infusion 
Pembrolizumab 
Dose modification and treatment guidelines for 
pembrolizumab infusion associated reactions 
are provided in Table 5. 
Cetuximab 
Occurrence of a severe infusion-related 
reaction requires immediate and permanent 
discontinuation of cetuximab therapy and may 
necessitate emergency treatment. 
It is recommended to warn patients of the 
possibility of such a late onset and instruct 
them to contact their physician if symptoms or 
signs of an infusion-related reaction occur. 
The first dose should be administered slowly 
and the speed must not exceed 5 mg/min 
whilst all vital signs are closely monitored for 
at least two hours. If during the first infusion, 
an infusion-related reaction occurs within the 
first 15 minutes, the infusion should be 
stopped. A careful benefit/risk assessment 
should be undertaken including consideration 
whether the patient may have performed IgE 
antibodies before a subsequent infusion is 
given. 
Premedicate with a histamine-1 (H1) receptor 
antagonist prior to cetuximab administration. 
Monitor patients for at least 1 hour following 
each cetuximab infusion, in a setting with 
resuscitation equipment and other agents 
necessary to treat anaphylaxis. Initiate 
SAR444245 infusion only when no infusion 
reaction has occurred after 1-2 hours of 
observation. In patients requiring treatment for 
infusion reactions, use recommended per the 
country-approved product labeling (eg, USPI, 
SmPC) for cetuximab. 
 
If an infusion-related reaction develops later 
during the infusion or at a subsequent infusion 
further management will depend on its 
severity: 
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a) Grade 1: 
continue slow infusion under close supervision 
b) Grade 2: 
continue slow infusion and immediately 
administer treatment for symptoms 
c) Grade 3 and 4: 
stop infusion immediately, treat symptoms 
vigorously and contraindicate further use of 
cetuximab 
 
If the patient experiences a mild or moderate 
infusion-related reaction, the infusion rate may 
be decreased. It is recommended to maintain 
this lower infusion rate in all subsequent 
infusions. 
 
A close monitoring of patients, particularly 
during the first administration, is required. 
Special attention is recommended for patients 
with reduced performance status and pre-
existing cardio-pulmonary disease 
Immunogenicity (Anti-
drug antibodies) 
Cetuximab 
The development of human anti-chimeric antibodies 
(HACA) is a class effect of monoclonal chimeric 
antibodies. Current data on the development of 
HACAs is limited. Overall, measurable HACA titers 
were noted in 3.4% of the patients studied, with 
incidences ranging from 0% to 9.6% in the target 
indication studies. No conclusive data on the 
neutralizing effect of HACAs on cetuximab is 
available to date. The appearance of HACA did not 
correlate with the occurrence of hypersensitivity 
reactions or any other undesirable effect to 
cetuximab. 
 
Hypersensitivity, 
including anaphylaxis 
Pembrolizumab 
Not specifically reported but included among infusion-
related reactions in label. 
Cetuximab 
Please see above within Infusion reactions 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
Also, see specific instructions for cetuximab. 
Infections 
Pembrolizumab 
Common: pneumonia. 
Cetuximab 
Patients who receive cetuximab in combination with 
platinum-based chemotherapy are at an increased 
risk for the occurrence of severe neutropenia, which 
may lead to subsequent infectious complications 
such as febrile neutropenia, pneumonia or 
sepsis. Careful monitoring is recommended in such 
patients, in particular in those who experience skin 
See routine mitigation in the master protocol.  
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lesions, mucositis or diarrhea that may facilitate the 
occurrence of infections. 
Further, the risk for secondary infections (mainly 
bacterial) of adverse skin reactions is increased and 
cases of staphylococcal scalded skin syndrome, 
necrotizing fasciitis and sepsis, in some cases with 
fatal outcome, have been reported 
Hepatotoxicity 
Pembrolizumab 
Hepatitis occurred in 0.8% of patients, including 
Grade 2, 3 or 4 cases in 0.1%, 0.5% and 0.1% 
patients, respectively, receiving pembrolizumab. The 
median time to onset of hepatitis was 3.6 months 
(range 8 days to 21.4 months). The median duration 
was 1.1 months (range 1 day to 20.9+ months). 
Hepatitis led to discontinuation of pembrolizumab in 
0.3% patients. Hepatitis resolved in 36 patients. 
Cetuximab 
Increase in liver enzymes is very common 
Exclusion of participants with impaired liver 
functions. 
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 9.   
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury 
Cetuximab 
Not reported in the SmPC 
Dose modification and treatment guidelines for 
nephrotoxicity are provided under immune-
related reactions in Table 9.  
Hypomagnesaemia 
Cetuximab 
 
Hypomagnesaemia is very common 
Exclusion of participants with electrolytes 
(magnesium, calcium, potassium) outside the 
normal ranges. 
Monitor electrolytes regularly as per protocol. 
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy (common) for 
pembrolizumab in combination with chemotherapy  
Uncommon: epilepsy.  
Cetuximab: 
Headaches are common 
Dose modification and treatment guidelines for 
neurological AEs are provided under immune-
related reactions in Table 9. 
 
 
 
Analgesics as clinically indicated 
Cardiovascular effects, 
including QT interval 
prolongation 
Cetuximab 
Cardiopulmonary arrest or sudden death have 
occurred in 2-3% patients with squamous cell 
carcinoma of the head and neck receiving cetuximab 
with radiation therapy or a cetuximab product with 
platinum-based therapy and fluorouracil cetuximab. A 
history of coronary artery disease, congestive heart 
failure, or arrhythmias and abnormal serum 
electrolytes may be predisposing factors.  
Specifically, for patients receiving cetuximab, 
exclude patients with electrolytes (magnesium, 
calcium and potassium) <LLN and monitor 
serum electrolytes weekly during and for at 
least 8 weeks after last cetuximab 
administration. 
Immune-mediated 
Adverse Events 
Pembrolizumab 
Immune-mediated adverse events are designated as 
important identified risk for pembrolizumab. 
Cetuximab 
Not reported as such in the SmPC. 
Dose modification and treatment guidelines for 
immune-related reactions are provided 
in Table 9. 
Patients treated with cetuximab: 
If a diagnosis of ulcerative keratitis is 
confirmed, treatment with cetuximab should be 
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Patients presenting with signs and symptoms 
suggestive of keratitis such as acute or worsening: 
eye inflammation, lacrimation, light sensitivity, blurred 
vision, eye pain and/or red eye should be referred 
promptly to an ophthalmology specialist. 
Very rarely, Stevens-Johnson syndrome/toxic 
epidermal necrolysis may occur in patients treated 
with cetuximab. 
interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing 
treatment should be carefully considered. 
Cetuximab should be used with caution in 
patients with a history of keratitis, ulcerative 
keratitis or severe dry eye. Contact lens use is 
also a risk factor for keratitis and ulceration. 
Interstitial lung disease 
Cases of interstitial lung disease (ILD), including fatal 
cases, have been reported, with the majority of 
patients from the Japanese population. 
Confounding or contributing factors, such as 
concomitant chemotherapy known to be associated 
with ILD, and pre-existing pulmonary diseases were 
frequent in fatal cases. 
Patients treated with cetuximab: Patients 
should be closely monitored for ILD. In the 
event of symptoms (such as dyspnoea, cough, 
fever) or radiographic findings suggestive of 
ILD, prompt diagnostic investigation should 
occur. 
Dermatological 
toxicities 
Pembrolizumab: 
Refer to immune-related adverse events 
Cetuximab: 
Cetuximab can cause dermatologic toxicities, 
including acneiform rash, skin drying and fissuring, 
paronychial inflammation, infectious sequelae (for 
example, S. aureus sepsis, abscess formation, 
cellulitis, blepharitis, conjunctivitis, keratitis/ulcerative 
keratitis with decreased visual acuity, cheilitis), and 
hypertrichosis. Acneiform rash occurred in 82% of 
patients across clinical trials. Grades 3 or 4 acneiform 
rash occurred in 9.7% of patients. Acneiform rash 
usually developed within the first two weeks of 
therapy; the rash lasted more than 28 days after 
stopping treatment in most patients. Life-threatening 
and fatal bullous mucocutaneous disease with 
blisters, erosions, and skin sloughing, has been 
observed. It could not be determined whether these 
mucocutaneous adverse reactions were directly 
related to EGFR inhibition or to idiosyncratic immune-
related effects (eg, Stevens-Johnson syndrome or 
toxic epidermal necrolysis). 
For cetuximab: 
Monitor patients for dermatologic toxicities and 
infectious sequelae. Instruct patients to limit 
sun exposure during cetuximab therapy. 
Withhold, reduce dose or permanently 
discontinue cetuximab based on severity of 
acneiform rash or mucocutaneous disease 
Risks related to special populations 
Pregnancy and 
lactation exposure and 
outcomes 
Pembrolizumab 
Pembrolizumab should not be used during pregnancy 
unless the clinical condition of the woman requires 
treatment with pembrolizumab. 
Cetuximab 
EGFR is involved in foetal development. Limited 
observations in animals are indicative of a placental 
transfer of cetuximab, and other IgG1 antibodies 
have been found to cross the placental barrier. 
Animal data revealed no evidence of teratogenicity. 
However, dependent on the dose, an increased 
See master protocol for exclusion of 
participants, guidance on highly effective 
contraceptive methods, and pregnancy tests to 
be performed regularly.  
It is recommended that women do not breast-
feed during treatment with cetuximab and for 
2 months after the last dose, because it is not 
known whether cetuximab is excreted in 
breast milk. 
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incidence of abortion was observed. Sufficient data 
from pregnant or lactating women are not available. 
It is strongly recommended that cetuximab be given 
during pregnancy or to any woman not employing 
adequate contraception only if the potential benefit 
for the mother justifies a potential risk to the foetus. 
Breast-feeding 
It is recommended that women do not breast-feed 
during treatment with cetuximab and for 2 months 
after the last dose, because it is not known whether 
cetuximab is excreted in breast milk. 
Fertility 
There are no data on the effect of cetuximab on 
human fertility. Effects on male and female fertility 
have not been evaluated within formal animal 
studies. 
Drug-drug interactions 
No data available.  
Overdose and its 
treatment 
No specific information is available on the treatment 
of overdose of pembrolizumab. 
See Section 6.8 of the master protocol.  
 
 
10.12 APPENDIX 12: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol. 
10.13 APPENDIX 13: ABBREVIATIONS  
 
AESIs: 
adverse events of special interest 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CR: 
complete response 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
ICANS: 
immune Cell-Associated Neurotoxicity Syndrome 
ICU: 
intensive care unit 
 
IRR: 
infusion-related reactions  
mCRC: 
metastatic colorectal cancer 
NCI-CTCAE: 
National Cancer Institute- Common Terminology Criteria for Adverse Event 
NHP: 
non-human primate  
 
PD1: 
programmed cell death protein 1 
PK: 
pharmacokinetic 
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SAEs: 
serious adverse events 
TEAE: 
treatment-emergent adverse event 
TIL: 
tumor infiltrating lymphocytes 
VLS: 
Vascular Leak Syndrome 
 
10.14 APPENDIX 14: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.14.1 
Amended protocol 01 (30 August 2021) 
This amended protocol (Amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The overall rationale for the amendment is to include stopping rules for futility and update the 
rules for dose modification in case of treatment-related adverse events (TRAEs) for Cohorts D1 
and D2 in substudy 04. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.5 
Pharmacokinetics 
flowcharts 
The frequency of sampling for cetuximab PK sample has been 
increased to obtain data every cycle for the first 3 cycles, every 
other cycle for 4 cycles, then every 4th cycle.  
Regulatory Authorities (FDA) 
request to generate more 
comprehensive evidence 
Section 5.1 Inclusion 
Criteria 
For I03, “Participants in Cohort D2” has been added to clarify 
that the genetic aberration of the RAS wild type disease is only 
applicable on the D2 cohort. 
For clarity 
In I06, “- less than required number of slides or archival tumor 
tissue sample collected more than 6 months prior to screening” 
has been revised to “-less than required number of slides or 
archival tumor tissue sample collected more than 6 months prior 
to enrollment”. 
Harmonization per program level 
approach 
Section 6.5.1 General 
rules 
The following sentence has been deleted “Once a dose has 
been decreased, intra-patient re-escalation back to the previous 
dose level is not permitted.”, and the following sentences have 
been added “In participants who have SAR444245 dose 
reduction due to SAR444245 related Grade ≥3 TRAEs, 
SAR444245 dose may be re-escalated to
 μg/kg if: •no 
SAR444245 related Grade ≥3 TRAE or clinically significant 
laboratory abnormality within at least 2 subsequent cycles, AND 
•both Investigator and Sponsor agree that the participant has
For clarification of how dose will be 
reduced and re-escalated for 
participants who experience any 
Grade ≥3 TRAEs 
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Section # and 
Name 
Description of Change 
Brief Rationale 
clinical benefit.”. 
Section 6.5.3 General 
guidelines for the 
management of 
treatment-related 
adverse events 
The following sentence “Participants who experience Grade ≥3 
TRAEs at any time of the study (including clinically significant 
Grade 3 laboratory abnormalities as defined in Section 10.3.1 of 
the master protocol) will be required to temporarily delay the 
IMP, unless specified otherwise in the protocol, and with the 
exception of the TRAEs resolving within 5 days. After cycle 
delay, such participants may be considered for treatment 
resumption once the TRAE resolves or improves to Grade 1 or 
baseline or is stable and manageable through 
supportive/medical therapy.” has been changed to “Participants 
who experience Grade ≥3 TRAEs at any time of the study 
(including clinically significant Grade 3 laboratory abnormalities 
as defined in Section 10.3.1 of the master protocol) not listed in 
Section 6.5.4 (Tables 5-11) will be required to temporarily delay 
the IMP. After cycle delay, such participants may be considered 
for treatment resumption once the TRAE resolves or improves 
to Grade 1 or baseline”. 
Dose reduction rules have added, and the following sentence 
has been deleted “Dose reduction for SAR444245 from 
µg/kg to 
 µg/kg (or another lower recommended dose) 
may be decided when specified in the protocol or following 
discussions with the Sponsor.” 
For consistency and clarity 
Section 6.5.4.1 Infusion-
related reactions (IRR) 
In Table 6 under Grade 3 and Grade 4, and in Table 7 under 
Grade 3 or 4, “prematurely” has been removed from 
“prematurely permanently discontinued”. 
For clarity 
Section 6.5.4.3 Fever, 
flu-like symptoms and 
cytokine-release 
syndrome (CRS) 
In Table 5 under Grade 3, the following sentence was deleted “If 
subsequent administration is tolerated, increasing the 
SAR444245 dose to
µg/kg at subsequent administration can 
be considered based on the clinical judgement of the 
Investigator with the Sponsor”. 
For consistency 
Section 6.5.4.7 
Dermatologic toxicity  
The following sentence “The dose modification guidelines in 
Table 4 should be followed…” has been changed to “The dose 
modification guidelines as per current local label should be 
followed…”. 
For clarity 
Section 6.5.4.7 
Dermatologic toxicity 
In Table 12, “dose level 1” has been changed to “200 mg/m2”, 
“dose level 2” has been changed to “150 mg/m2”.  
In Table 12 under Grade 3 or 4, “prematurely” has been 
removed from “prematurely permanently discontinue 
cetuximab”. 
For clarity 
Section 9.5 Interim 
analyses 
The following sentences have been added “For each cohort, if 
the predictive probability of concluding a minimum clinical 
meaningful effect of the study treatment (ORR of 5% for both 
cohorts) at the end of study is <15%, the corresponding cohort 
will be stopped for futility. To facilitate the calculation of 
predictive probability, a minimum informative prior of Beta (0.5, 
0.5) is used at the time of the design of the study. However, 
emerging data generated from outside of the study may warrant 
a different prior to be considered before this interim analysis.” 
To include stopping rules for futility 
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11 
REFERENCES 
  
1. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol.
2017;28(suppl 4):iv100-18.
2. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8.
3. Dudley ME, Wunderlich JE, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive
cell transfer therapy following non-myeloablative but Lymphodepleting chemotherapy for the
treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-57.
4. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med.
2008;358(25):2698-703.
5. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol.
2005;23(1):515-48.
6. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71.
7. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and functional
analysis of the costimulatory receptor programmed Death-1. Immunity. 2004;20(3):337-47.
8. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T
cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004,173
(2):945-54.
9. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooter J, et al. PD-1 inhibits T-cell
receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream
signaling to PKCtheta. FEBS Lett. 2004;574(1-3)37-41.
10. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25.
11. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, et al.
CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol.
2005;25(21):9543-53.
12. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity.
Immunol Rev. 2010;236:219-42.
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Page 80 
13. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res.
2005;65(3):1089-96.
14. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, et al. PD-L1/B7H-1 inhibits the
effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer
Res. 2004;64(3):1140-5.
15. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9.
16. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, et al. B7-H1 blockade
augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res.
2003;63(19):6501-5.
17. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored
IL-2 production and proliferation of CD8(+) T cells directly within the tumor
microenvironment. J Immunother Cancer. 2014;2:3.
18. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80.
19. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J
Immunol. 2010;184(7):3442-9.
20. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in
human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-7.
21. Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology
and treatment of cancer. J Clin Oncol. 2003;21(14):2787-99.
22. Iannello A, Ahmad A. Role of antibody-dependent cell-mediated cytotoxicity in the efficacy
of therapeutic anti-cancer monoclonal antibodies. Cancer Metastasis Rev. 2005;24(4):487-99.
23. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
24. Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, et al. Annual report to
the nation on the status of cancer, part I: National cancer statistics. Cancer.
2018;124(13):2785-2800.
25. Goodwin RA, Asmis TR. Overview of systemic therapy for colorectal cancer. Clin Colon
Rectal Surg. 2009;22(4):251-6.
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SAR444245-ACT16902-S04 
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Page 81 
26. Bekaii-Saab T, Kim R, Kim TW, O'Connor JM, Strickler JH, Malka D, et al. Third- or later-
line therapy for metastatic colorectal cancer: Reviewing best practice. Clin Colorectal Cancer.
2019;18(1):e117-e129.
27. Lumish MA, Cercek A. Immunotherapy for the treatment of colorectal cancer. Journal of
surgical oncology. 2021;123(3):760-74.
28. Roelands J, Kuppen PJK, Vermeulen L, Maccalli C, Decock J, Wang E, et al.
Immunogenomic classification of colorectal cancer and therapeutic implications. Int J Mol Sci.
2017;18(10):2229.
29. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib
monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international,
multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-12.
30. Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, et al. Regorafenib plus best supportive care versus
placebo plus best supportive care in Asian patients with previously treated metastatic
colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol. 2015;16(6):619-29.
31. Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al.
Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med.
2015;372(20):1909-19.
32. European Medicines Agency. Keytruda® European Public Assessment Report, Risk
Management Plan Summar. [Online]. Last updated 2020 Jun 18 [cited 2021 Jun 23]. Available
from: URL:https://www.ema.europa.eu/en/medicines/human/EPAR/keytruda
33. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov.
2020;10(8):1121-8.
34. Piper-Vallillo AJ, Mooradian MJ, Meador CB, Yeap BY, Peterson J, Sakhi M, et al.
Coronavirus disease 2019 infection in a patient population with lung cancer: Incidence,
presentation, and alternative diagnostic considerations. JTO Clin Res Rep. 2021;2(1):100124.
35. 
36. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al.
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis
Network symposium. J Allergy Clin Immunol. 2006;117:391-7.
37. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al.
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology.
Allergy. 2014;69(8):1026-45.
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38. Siddall E, Khatri M , Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology,
and management. Kidney Int. 2017;92(1):37-46.
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Signature Page for VV-CLIN-0617851 v3.0
act16902-16-1-1-amended-protocol02-substudy04
Approve & eSign
Clinical
Approve & eSign
Clinical
VV-CLIN-0617851 3.0
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SAP_001.pdf: 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
 
According to template: Sanofi eSAP Version 1.0, dated 24-MAR-2021 
Page 1 
 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with other 
anticancer therapies for the treatment of participants 
with advanced and metastatic gastrointestinal cancer  
Protocol number: 
ACT16902 
Compound number 
(INN/Trademark): 
SAR444245 
  
Study phase: 
Phase 2 
Short Title: 
A study of SAR444245 combined with other anticancer 
therapies for the treatment of participants with 
gastrointestinal cancer (Master protocol) 
Acronym 
Pegasus Gastrointestinal 203 
Statistician: 
(contractor, Aixial) 
Statistical project leader: 
 
Date of issue: 
26-Sep-2022 
Regulatory agency identifier number(s): 
IND: 
156424 
EudraCT: 
2021-002181-41 
NCT: 
NCT05104567 
WHO: 
U1111-1251-4981 
EUDAMED: 
Not applicable 
Other: 
Merck MK3475-B78 
 
Date: 
26-Sep-2022 
Total number of pages: 41 
 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
ANALYSIS POPULATIONS .......................................................................................................... 10 
3 
STATISTICAL ANALYSES ........................................................................................................... 11 
3.1 
GENERAL CONSIDERATIONS .................................................................................................... 11 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 12 
3.2.1 
Definition of endpoint(s) ................................................................................................................. 12 
3.2.2 
Main analytical approach ............................................................................................................... 12 
3.2.3 
Sensitivity analysis ......................................................................................................................... 12 
3.2.4 
Supplementary analyses ................................................................................................................ 12 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 13 
3.3.1 
Efficacy secondary endpoint(s) ...................................................................................................... 13 
3.3.1.1 
Definition of endpoint(s) ................................................................................................................. 13 
3.3.1.2 
Main analytical approach ............................................................................................................... 13 
3.3.2 
Supportive secondary endpoint(s) ................................................................................................. 15 
3.4 
EXPLORATORY ENDPOINT(S) ANALYSIS ................................................................................. 15 
3.4.1 
Definition of endpoint(s) ................................................................................................................. 15 
3.4.2 
Main analytical approach ............................................................................................................... 16 
3.5 
MULTIPLICITY ISSUES ................................................................................................................ 16 
3.6 
SAFETY ANALYSES ..................................................................................................................... 16 
3.6.1 
Extent of exposure ......................................................................................................................... 16 
3.6.1.1 
Overall exposure ............................................................................................................................ 16 
3.6.1.2 
SAR444245 exposure .................................................................................................................... 17 
3.6.1.3 
Pembrolizumab exposure .............................................................................................................. 18 
3.6.1.4 
Cetuximab exposure ...................................................................................................................... 19 
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3.6.2 
Adverse events .............................................................................................................................. 21 
3.6.3 
Additional safety assessments ....................................................................................................... 24 
3.6.3.1 
Laboratory variables and vital signs............................................................................................... 24 
3.7 
OTHER ANALYSES....................................................................................................................... 25 
3.7.1 
Other variables and/or parameters ................................................................................................ 25 
3.7.1.1 
PK analyses ................................................................................................................................... 25 
3.7.1.2 
Immunogenicity analyses ............................................................................................................... 26 
3.7.1.3 
Quality of life analyses ................................................................................................................... 28 
3.7.1.4 
Biomarker analyses........................................................................................................................ 28 
3.7.2 
Subgroup analyses ........................................................................................................................ 29 
3.8 
INTERIM ANALYSES .................................................................................................................... 29 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES .................................................................... 30 
4 
SAMPLE SIZE DETERMINATION ................................................................................................ 34 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 35 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 35 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS .............................................................................. 35 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 37 
5.4 
APPENDIX 4 SANOFI SPONSOR RANGES ................................................................................ 39 
5.5 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 40 
6 
REFERENCES ............................................................................................................................... 41 
 
 
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LIST OF TABLES  
Table 1 - Overview of study cohorts ................................................................................................................ 6 
Table 2 - Objectives and endpoints - master protocol .................................................................................... 7 
Table 3 - Objectives and endpoints - substudies ............................................................................................ 8 
Table 4 - Summary of primary estimand for main endpoints .......................................................................... 9 
Table 5 - Populations for analyses ................................................................................................................ 10 
Table 6 - Censoring rules for DOR and PFS ................................................................................................ 14 
Table 7 - SAR444245 dose reduction criteria ............................................................................................... 18 
Table 8 - Cetuximab dose reduction criteria.................................................................................................. 20 
Table 9 - Sorting of AE tables ....................................................................................................................... 21 
Table 10 - Analyses of adverse events ......................................................................................................... 22 
Table 11 - List of PK parameters and definitions .......................................................................................... 25 
Table 12 - Subgroup analyses ...................................................................................................................... 29 
Table 13 - Minimum clinical meaningful effect .............................................................................................. 30 
Table 14 - Estimated objective response rate (ORR) depending on number of responders ........................ 34 
 
 
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Page 5 
VERSION HISTORY  
This statistical analysis plan (SAP) for study ACT16902 is based on the amended protocol 02 
dated 21-Jan-2022. 
The first participant was enrolled on 10-Jan-2022. This SAP is approved before the first analysis 
is conducted.  
Major changes in statistical analysis plan 
SAP 
Version 
Approval 
Date 
Changes 
Rationale 
Change 
from 
1 
Current 
version 
• Interim analyses section: removed 
“without enrollment hold”  
• The enrollment hold was based on 
a recommendation from the 
first program-level Data Monitoring 
Committee (DMC) meeting held on 
18 May 2022, to assesses totality of 
benefit/risk profile based on both 
efficacy and safety data extracted from 
clinical database 
Amended 
protocol 02 
 
 
• Estimand framework has been 
added for the primary and main 
secondary efficacy endpoints. 
• To further characterize the antitumor 
activity effect that will be estimated. 
 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with advanced or metastatic gastrointestinal cancer. 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with various anticancer therapies by identifying early efficacy signals. 
The information that is introductory and common to all cohorts is included in the master protocol, 
and cohort-specific elements are contained in individual substudy protocols. Table 1 presents 
an overview of substudies and cohorts.  
Table 1 - Overview of study cohorts 
Substudy 
Cohort 
Study intervention 
Disease 
01 
A 
SAR444245 + pembrolizumab 
2-3L ESCC - Regardless of CPS 
Post-PD1/PDL1 
02 
B1 
SAR444245 + pembrolizumab 
1-3L GC/GEJ non-MSI-H 
CPS ≥1 
PD-1/PD-L1 Naïve 
02 
B2 
SAR444245 + pembrolizumab  
1-3L GC/GEJ non-MSI-H 
CPS <1 
PD-1/PD-L1 Naïve 
02 
B3 
SAR444245 + pembrolizumab 
2-4L GC/GEJ non-MSI-H - Regardless of CPS  
Post-PD1/PDL1 
03 
C 
SAR444245 + pembrolizumab  
2-3Lpost PD1/PDL1 HCC 
04 
D1 
SAR444245 + pembrolizumab 
3-6L mCRC non-MSI-H  
Any RAS 
04 
D2 
SAR444245 + cetuximab 
3-6L mCRC non-MSI-H  
RASwt 
ESCC: esophageal squamous cell carcinoma; CPS: combined positive score; GC: gastric cancer; GEJ: gastro-esophageal junction 
adenocarcinoma, HCC: hepatocellular carcinoma; 1-3L: first to third line; 2-4L: second- to fourth-line; 2-3L: second to third line; 3-6L: third to 
sixth line;  mCRC: metastatic colorectal cancer; MSI-H: high-level microsatellite instability; PD1/PDL1: programmed cell death 1 or 
programmed cell death-ligand 1; RASwt: RAS wild-type  RECIST: response evaluation criteria in solid tumors; 
 
After a screening period of up to 28 days, participants will receive treatment until progressive 
disease (PD), unacceptable adverse event (AE) or other full permanent discontinuation criteria 
(described in Section 7 of the master protocol) or completion of Cycle 35 (if applicable). 
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1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints - master protocol  
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of SAR444245 
in combination with other anticancer therapies   
• 
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  
Secondary 
• 
To assess the safety of SAR444245 in combination 
with other anticancer therapies 
• 
Incidence of treatment emergent adverse events 
(TEAEs), serious adverse events (SAEs), laboratory 
abnormalities according to National Cancer Institute 
Common Terminology Criteria for Adverse Events 
(NCI CTCAE) V5.0 and American Society for 
Transplantation and Cellular Therapy (ASTCT) 
consensus grading  
• 
To assess other indicators of antitumor activity 
• 
Time to response (TTR)  defined as the time from 
the first administration of investigational medicinal 
product (IMP) to the first tumor assessment at 
which the overall response was recorded as PR or 
CR that is subsequently confirmed and determined 
by Investigator per RECIST 1.1 
• 
Duration of response (DoR), defined as the time 
from first documented 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 
death from any cause, whichever occurs first 
• 
Clinical benefit rate (CBR) including confirmed CR 
or PR at any time or stable disease (SD) of at least 
6 months determined by Investigator per RECIST 
1.1. 
• 
Progression-free survival (PFS), defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by Investigator as per RECIST 1.1 or 
death due to any cause, whichever occurs first 
• 
To assess the pharmacokinetics of SAR444245 in 
combination with other anticancer therapies 
• 
Plasma concentrations and where applicable PK 
parameters of SAR444245 
• 
To assess the immunogenicity of SAR444245 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245 
Exploratory 
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Objectives 
Endpoints 
 
 
 
 
Table 3 - Objectives and endpoints - substudies  
Substudy 
Objectives 
Endpoints 
 
Secondary 
04 (cohort D2) 
• To assess active 
concentrations of cetuximab 
when given in combination with 
SAR444245 
• 
Ctrough and Cend of infusion of cetuximab 
 
Exploratory 
 
1.2.1 Estimands  
Primary estimand defined for main efficacy endpoints are summarized in below Table 4. More 
details are provided in Section 3. 
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Table 4 - Summary of primary estimand for main endpoints 
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) (IE) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary objective: To determine the antitumor activity of SAR444245 in combination with other anticancer therapies 
Primary endpoint 
(estimand 1) 
Objective Response 
(OR) (confirmed CR or 
PR)  
Efficacy 
• 
While not initiating new anti-cancer therapy 
(NAT)  
• 
Regardless of early IMP discontinuation 
(treatment policy strategy) 
ORR, defined as the percentage of the participants 
with objective response (CR or PR) as best overall 
response. Confidence interval will be calculated using 
Clopper Pearson methods. 
Secondary objective: To assess other indicators of antitumor activity of SAR444245 in combination with other anticancer therapies 
Secondary endpoint 
(estimand 2) 
DOR 
Responders from 
efficacy population 
• 
Had NAT not been initiated (hypothetical 
strategy) 
• 
Regardless of early IMP discontinuation 
(treatment policy strategy) 
• 
Had two or more consecutive tumor 
assessments not been missed/unevaluable 
immediately before documented 
progression or death (hypothetical strategy) 
The Kaplan Meier estimate and corresponding 
confidence interval of DOR at specified time points. 
The quantiles of DOR and corresponding confidence 
interval from Kaplan Meier method.  
Secondary endpoint 
(estimand 3) 
PFS 
Efficacy  
• 
Had NAT not been initiated (hypothetical 
strategy) 
• 
Regardless of early IMP discontinuation 
(treatment policy strategy) 
• 
Had two or more consecutive tumor 
assessments not been missed/unevaluable 
immediately before documented 
progression or death (hypothetical strategy) 
The Kaplan Meier estimate and corresponding 
confidence interval of PFS at specified time points. 
The quantiles of PFS and corresponding confidence 
interval from Kaplan Meier method.  
 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined.  
Table 5 - Populations for analyses 
Population 
Description 
Screened 
All participants who have given their informed consent.  
Enrolled 
All participants who have given their informed consent and have been allocated to 
an intervention (by IRT) regardless of whether the intervention was received or not.  
Exposed 
All participants who have given their informed consent and received at least one 
dose (even incomplete) of IMP (SAR444245 or other anticancer therapies).  
Population without trial impact 
(disruption) due to COVID-19 
All exposed participants: 
• 
without any critical or major deviation related to COVID-19 
• 
and who did not permanently discontinue treatment due to COVID-19  
• 
and who did not permanently discontinue study due to COVID-19 
Efficacy 
All participants from the exposed population with at least one evaluable post-
baseline tumor assessment or who permanently discontinued study treatment. 
Response-evaluable 
All participants from efficacy population with an evaluable baseline and at least one 
evaluable post-baseline tumor assessments. Participants who died from disease 
progression before any TA will also be response-evaluable. 
Pharmacokinetic (PK) 
All participants from exposed population with at least 1 PK concentration available 
after the first dose of study intervention. 
ADA 
All participants from exposed population with at least 1 ADA result (positive, 
negative or inconclusive) after the first dose of study intervention. 
Pharmacodynamics (PDy) 
All participants from the exposed population with at least 1 PDy 
parameter assessed after the first dose of study intervention. 
Participants exposed to study intervention before or without being enrolled will not be considered 
enrolled and will not be included in any analysis population. The safety experience of these 
participants will be reported separately. 
For any participant enrolled and treated more than once, only the data associated with the 
first enrollment will be used in any analysis population. The safety experience associated with any 
later enrollment will be reported separately 
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
The baseline value is defined as the last available value before the first administration of any of 
the IMPs in combination (refer to Table 1). For participants enrolled but not treated, the baseline 
value is defined as the last available value before enrollment. 
Unless otherwise specified, analyses will be performed by cohort and overall (if applicable). 
All efficacy analyses will be performed on the efficacy population and analyzed by cohort and 
pooled cohorts (B1 and B2) if relevant.  
Objective response rate, as well as all other response-related efficacy endpoints will be primarily 
derived using the local radiologist’s/Investigator’s assessment and according to criteria RECIST 
1.1. 
Central imaging may be done retrospectively if significant activity is observed  
(See Section 3.2.3 sensitivity analysis). 
Confidence intervals will be two-sided 90% CI for efficacy analyses. CI will be used for 
descriptive purposes only, without inference. 
The BOR is defined as the best overall response observed from the date of first IMP until disease 
progression, death, cut-off date or initiation of subsequent anti-cancer therapy, whichever occurs 
first.  
• A PR or a CR must be confirmed on a second examination done at least 4 weeks apart, in 
order to confirm the antitumoral response. 
• A SD response must be assessed at least 6 weeks after the first IMP administration to be 
considered as evaluable. 
All safety analyses will be performed on the exposed population. 
Analysis period  
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 first administration of the IMP. 
• The on-treatment period (ie, treatment-emergent (TE) 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 end of the on-treatment period, 
ie, 31 days after the last administration of IMP.  
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3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
3.2.1 Definition of endpoint(s)  
The primary endpoint is the ORR.  
The ORR is defined as the proportion of participants who have a BOR (see Section 3.1) as 
confirmed CR or PR.  
3.2.2 Main analytical approach  
The primary endpoint, ORR, will be analyzed with the Estimand 1, introduced in Section 1.2.1, 
and defined according to the following attributes: 
• The endpoint is confirmed objective response (confirmed CR or PR) 
• The treatment condition is SAR444245 in combination (refer to Table 1) 
• The analysis population is the efficacy population 
• Intercurrent events (IE): 
- 
The new anticancer therapy IE will be handled with the “while not initiating new 
anti-cancer therapy” strategy; confirmed objective response will be assessed based 
on tumor assessments up to the time of new anticancer therapy. 
- 
The early IMP discontinuation IE will be handled with the “treatment policy” 
strategy; confirmed objective response will be assessed based on tumor assessments 
irrespective of IMP discontinuation. 
• Population-level summary will include the ORR and confidence interval using the 
Clopper-Pearson method. In absence of confirmed OR, participants will be considered as 
non-responders, whatever the reason (including participants with missing or non-evaluable 
BOR).  
3.2.3 Sensitivity analysis  
Central imaging reading may be done retrospectively if significant activity is observed. ORR may 
be presented based on central imaging assessment, using the same estimand as for the primary 
analysis.  
3.2.4 Supplementary analyses  
ORR will be presented for the response-evaluable population. 
This supplementary analysis will be provided using an estimand defined according to the 
following attributes: 
• The endpoint is ORR. 
• The treatment condition is SAR444245 in combination (refer to Table 1). 
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• The analysis population is the response-evaluable population. 
• Intercurrent events and their handling strategy will be the same as for ORR estimand 
defined in Section 3.2.2. 
• Population-level summary will be the same as for ORR estimand defined in Section 3.2.2. 
In addition, the BOR will be summarized with descriptive statistics. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are the efficacy endpoints. Other secondary 
endpoints analyses are defined in Section 3.6 (safety), Section 3.7.1 (PK) and Section 3.7.1.2 
(immunogenicity). 
3.3.1  Efficacy secondary endpoint(s)   
3.3.1.1 Definition of endpoint(s)  
The time to response is 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. 
The duration of response (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 until 
documented PD before the initiation of any subsequent anti-cancer therapy or death due to any 
cause, whichever occurs first.  
The clinical benefit rate (CBR) is defined as the proportion of participants with clinical benefit: 
confirmed CR or PR as BOR, or SD lasting at least 6 months (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). 
The progression-free survival (PFS) is defined as the time from the date of first IMP 
administration to the date of the first documentation of objective PD, or death due to any cause, 
whichever occurs first. 
3.3.1.2 Main analytical approach  
The time to response will be assessed on the subgroup of participants who have achieved 
confirmed OR and summarized using descriptive statistics. 
The analyses of DOR and PFS will be based on estimands 2 and 3 introduced in Section 1.2.1 and 
defined according to the following attributes: 
• The endpoints are DOR and PFS. 
• The treatment condition is SAR444245 in combination (refer to Table 1). 
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• The analysis population for DOR corresponds to all participants from the efficacy 
population who achieve either confirmed PR or confirmed CR. 
• The analysis population for PFS corresponds to all participants from the efficacy 
population. 
• Intercurrent events: 
- 
The new anticancer therapy IE will be handled with the hypothetical strategy: DOR 
and PFS will be assessed based on tumor assessments had a new anticancer therapy 
not being taken. DOR and PFS will be assessed based on tumor assessments up to the 
time of new anticancer therapy. 
- 
The early IMP discontinuation IE will be handled with the treatment policy strategy: 
DOR and PFS will be assessed based on tumor assessments irrespective of IMP 
discontinuation. 
- 
Two or more consecutive missing/unevaluable tumor assessments immediately before 
documented progression or death will be handled with the hypothetical strategy: DOR 
and PFS will be assessed based on tumor assessments had two consecutive tumor 
assessments not been missed immediately before documented progression or death. 
• Population-level summary will include the Kaplan Meier estimate of DOR and PFS and 
corresponding CI at specified time points. CIs for KM estimates will be estimated using 
the Kaplan Meier method and log-log approach based on a normal approximation 
following the Greenwood’s formula. The quantiles of DOR and PFS and corresponding CI 
from Kaplan Meier method will also be provided. CI will be constructed using a log-log 
transformation of the survival function and the methods of Brookmeyer and Crowley. In 
the absence of disease progression or death before the cut-off date, DOR and PFS will be 
censored as indicated in Table 6. 
Table 6 - Censoring rules for DOR and PFS  
Situation 
Date of progression or 
censoring 
Outcome 
Category 
No baseline tumor assessmentsa 
Date of first treatment intake 
Censored 
No baseline 
tumor 
assessments 
No evaluableb post-baseline tumor 
assessmentsa 
Date of first treatment intake  
Censored 
No evaluable 
post-baseline 
tumor 
assessments 
Progression documented at or between 
scheduled visits 
Date of the first tumor assessment 
documenting progression 
Event 
Documented 
progression 
New anticancer treatment before 
documented progression 
Date of the last evaluable tumor 
assessment before new treatment 
Censored 
New anticancer 
treatment 
Death prior to the first planned post-
baseline tumor assessmenta 
Date of death 
Event 
Death 
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Situation 
Date of progression or 
censoring 
Outcome 
Category 
Death at or between scheduled visits 
Date of death 
Event 
Death 
Death or documented progression 
immediately after twoc or more missed or 
non-evaluable tumor assessments 
Date of the last evaluable tumor 
assessment documenting no progression 
Censored 
Death or 
progression 
after two or 
more 
missed/unevalu
able tumor 
assessments 
Alive and no documented progression 
Date of the last evaluable tumor 
assessment 
Censored 
Alive without 
documented 
progression 
a Not applicable for DOR. 
b Evaluable TA means an evaluation different from non-evaluable. 
c Two consecutive tumor assessments are considered as missed/non-evaluable if the duration between two consecutive tumor 
assessments done (non-missing) and evaluable is strictly longer than 20 weeks. 
The clinical benefit rate will be summarized using the same estimand as for the primary endpoint. 
3.3.2 Supportive secondary endpoint(s)  
Not applicable. 
3.4 
EXPLORATORY ENDPOINT(S) ANALYSIS  
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3.5 
MULTIPLICITY ISSUES  
No formal testing will be performed. Therefore, no multiplicity issues need to be addressed. 
3.6 
SAFETY ANALYSES  
The analysis of the safety variables will be descriptive, and no testing is planned.  
3.6.1 Extent of exposure  
If applicable, summaries will be provided by trial impact (disruption) due to COVID-19. 
3.6.1.1 Overall exposure  
The dose information will be assessed by the following variables: 
• Overall number of cycles started, defined by the number of cycles in which at least 
one dose of any study interventions is administered. 
• Duration of IMP exposure (in months) is defined as (Last day of exposure – first day of 
exposure +1)/30.4375. 
• The first day of exposure is defined as the first administration date with non-zero dose for 
at least one of the IMP (refer to Table 1).  
The last day of exposure is the day before the theoretical date of the next administration 
(after the last administration), defined as the maximum between: 
- 
The last administration date + 20 for SAR444245, 
- 
The last administration date + 20 for pembrolizumab or the last administration date 
+ 6 for cetuximab according to the cohort (refer to Table 1). 
The total number of cycles started and number of cycles started by participants will be 
summarized by category. The duration of overall exposure will be summarized quantitatively.  
The following variable will be computed to describe overall dose modification (cycle delay): 
• Cycle delay: A cycle is deemed as delayed if the start date of the current cycle - theoretical 
duration of a cycle - start date of the previous cycle is ≥4 days. Cycle delay is not defined 
for the first cycle. 
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Cycle delay will be analyzed at the participant (with number of participants used as denominator) 
and cycle (with number of cycles used as denominator) levels, as follows: 
• Number (%) of participants with at least 1 cycle delayed 
- 
Number (%) of participants with a cycle delayed between 4 and 7 days (using 
maximum delay across all cycles)  
- 
Number (%) of participants with a cycle delayed more than 7 days (using maximum 
delay across all cycles) 
• Number (%) of cycles delayed 
- 
Number (%) of cycles delayed between 4 and 7 days 
- 
Number (%) of cycles delayed more than 7 days 
3.6.1.2 SAR444245 exposure  
The dose information will be assessed by the following: 
• Total number of cycles started per participant  
• Duration of SAR444245 exposure (in months) is defined by (date of last administration of 
SAR444245 + 21 – date of first administration of SAR444245)/30.4375. 
• Actual dose (μg/kg)  
• Cumulative dose (μg/kg): the cumulative dose is the sum of all actual doses of 
SAR444245, given from first to last administration  
• Actual dose intensity (ADI in μg/kg/week): defined as the cumulative dose divided by the 
duration of SAR444245 exposure (in weeks) 
• Planned dose intensity (PDI in μg/kg/week): corresponds to the planned dose at C1D1 
divided by the theoretical cycle duration expressed in weeks (i.e. 3 weeks) 
• Relative dose intensity (RDI, in %):100 ×
ADI (μg/kg/week) 
PDI (μg/kg/week)  
The total number of cycles started, number of cycles started by participant will be summarized by 
category. Duration of SAR444245 exposure, cumulative dose, ADI and RDI will be summarized 
quantitatively and by category if relevant. 
The following variables will be derived to describe dose modifications and dose interruptions:  
• Dose reduction: The first administration will not be counted as a dose reduction. For the 
second and subsequent SAR444245 administrations, dose reduction will be determined 
using the dose level intervals provided in Table 7, by comparing the current dose level to 
the previous dose level. If the current dose level is below the dose level interval of the 
previous dose administration, then the current dose level is considered reduced. 
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Table 7 - SAR444245 dose reduction criteria 
Actual dose level 
Dose level interval 
8 μg/kg 
16 μg/kg  
24 μg/kg 
• Dose omission is defined as a dose not administered at the scheduled visit. 
• Dose interruption: A dose will be considered as interrupted if SAR444245 administration 
is stopped during an infusion regardless of whether it is restarted or not.  
Dose modifications and dose interruptions will be analyzed by participant and dose as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with at least 1 dose interruption  
- 
Number (%) of participants with at least 1 dose interrupted and restarted 
- 
Number (%) of participants with at least 1 dose interrupted and not restarted 
- 
Number (%) of participants with at least 2 dose interruptions 
• Dose (number of doses started will be used as denominator)  
- 
Number of doses 
- 
Number (%) of dose interruptions 
- 
Number (%) of doses interrupted and re-started 
- 
Number (%) of doses interrupted and not re-started 
- 
Number (%) of doses interrupted more than once, 
- 
Number (%) of doses interrupted at 1st dose, 2nd dose, subsequent doses, 
- 
Time from dose start to first interruption in minutes summarized as a continuous 
variable and by category.  
3.6.1.3 Pembrolizumab exposure  
The dose information will be assessed by the following: 
• Total number of cycles started per participant 
• Duration of pembrolizumab exposure (in months) is defined by (date of last administration 
of pembrolizumab + 21 – date of first administration of pembrolizumab)/30.4375. 
• Actual dose (mg)  
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• Cumulative dose (mg): the cumulative dose is the sum of all actual doses of 
pembrolizumab, given from first to last administration  
• Actual dose intensity (ADI in mg/week): defined as the cumulative dose divided by the 
duration of pembrolizumab exposure (in weeks) 
• Planned dose intensity (PDI in mg/week): corresponds to the planned dose at C1D1 and 
divided by the theoretical cycle duration expressed in weeks (ie, 3 weeks) 
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/week) 
PDI (mg/week) 
The total number of cycles started, number of cycles started by participants will be summarized 
by category. Duration of pembrolizumab exposure, cumulative dose, ADI and RDI will be 
summarized quantitatively and by category if relevant. 
The following variables will be derived to describe dose modifications and dose interruptions:  
• Dose omission is defined as a dose not administered at the scheduled visit. 
• Dose interruption: A dose will be considered as interrupted if pembrolizumab 
administration is stopped during an infusion regardless of whether the infusion is restarted 
or not. 
Dose modifications and dose interruptions will be analyzed by participant as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with at least 1 dose interruption  
- 
Number (%) of participants with at least 1 dose interrupted and re-started 
- 
Number (%) of participants with at least 1 dose interrupted and not re-started 
- 
Number (%) of participants with at least 2 dose interruptions  
3.6.1.4 Cetuximab exposure  
The dose information will be assessed by the following: 
• Total number of cycles started 
• Number of cycles started per participant 
• Duration of cetuximab exposure (in months) is defined by (date of last administration of 
cetuximab + 7 – date of first administration of cetuximab)/30.4375. 
• Actual dose (mg/m²)  
• Cumulative dose (mg/m²): the cumulative dose is the sum of all actual doses of cetuximab, 
given from first to last administration  
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• Actual dose intensity (ADI in mg/m²/week): defined as the cumulative dose divided by the 
duration of cetuximab exposure (in weeks) 
• Planned dose intensity (PDI in mg/m²/week): corresponds to the sum of planned dose 
started divided by theoretical duration of cetuximab exposure (in weeks)  
• Relative dose intensity (RDI, in %):100 ×
ADI (mg/m²/week) 
PDI (mg/m²/week) 
The total number of cycles started, number of cycles started by participants will be summarized 
by category. Duration of cetuximab exposure, cumulative dose, ADI and RDI will be summarized 
quantitatively and by category if relevant. 
The following variables will be derived to describe dose modifications and dose interruptions:  
• Dose reduction: The first and second administration will not be counted as a dose 
reduction. For the third and subsequent cetuximab administrations, dose reduction will be 
determined using the dose level intervals provided in Table 8, by comparing the current 
dose level to the previous dose level. If the current dose level is below the dose level 
interval of the previous dose administration, then the current dose level is considered 
reduced. 
Table 8 - Cetuximab dose reduction criteria 
Actual dose level 
Dose level interval 
250 mg/m² 
> 225 mg/m² 
Dose level -1 (200 mg/m²) 
>175 mg/m² and ≤225 mg/m² 
Dose level -2 (150 mg/m²) 
>0 mg/m² and ≤175 mg/m² 
• Dose omission is defined as a dose not administered at the scheduled visit. 
• Dose interruption: A dose will be considered as interrupted if cetuximab administration is 
stopped during an infusion regardless of whether the infusion is restarted or not. 
Dose modifications and dose interruptions will be analyzed by participant as follows:  
• Participant (number of participants treated will be used as denominator) 
- 
Number (%) of participants with at least 1 dose modification 
- 
Number (%) of participants with at least 1 dose reduction 
- 
Number (%) of participants with at least 1 dose omission 
- 
Number (%) of participants with at least 1 dose interruption  
- 
Number (%) of participants with at least 1 dose interrupted and re-started 
- 
Number (%) of participants with at least 1 dose interrupted and not re-started 
- 
Number (%) of participants with at least 2 dose interruptions  
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3.6.2 Adverse events  
General common rules for adverse events 
All AEs will be graded according to National Cancer Institute Common Terminology for Adverse 
Events (NCI-CTCAE version 5.0) and coded to a lower-level term (LLT), preferred term (PT), 
high-level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. Cytokine Release Syndrome (CRS) and Immune 
effector cell associated neurotoxicity syndrome (ICANS) will be graded using ASTCT consensus 
grading. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs occurring during the pre-treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened (according to 
the Investigator’s opinion) or became serious during the treatment-emergent period 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period.  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The primary AE analyses will be on TEAEs. Pre-treatment and post-treatment AEs will be 
described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is 
a pre-treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. Missing grade will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase, using the maximum (worst) grade by treatment phase. Summaries 
will be provided for all grades combined and for grade ≥3 (including Grade 5). Missing grades, if 
any, will be included in the “all grades” category.  
The AE tables will be sorted as indicated in Table 9. 
Table 9 - Sorting of AE tables 
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTs a, b 
PT 
By decreasing frequency of PTsa 
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a Sorting will be based on the AE incidence. 
b The table of all TEAEs presented by primary SOC and PT will define the presentation order for all other tables (eg, treatment-emergent 
SAE) presented by SOC and PT, unless otherwise specified.  
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any grade ≥3 TEAE   
• Any treatment-emergent SAE 
• Treatment related TEAEs 
• Treatment related TEAE of grade ≥3 
• Serious treatment related TEAEs 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period) 
• Any TEAE leading to permanent full intervention discontinuation  
• Any TEAE leading to permanent partial intervention discontinuation (discontinuation of 
each individual drug) 
The AE summaries of Table 10 will be generated with number (%) of participants experiencing at 
least one event. The analyses will be performed for all grades combined and for grades ≥3. The all 
TEAE summary by Primary SOC and PT (and other safety summaries (eg, SAEs, deaths), if 
deemed needed after TEAE evaluation) will be performed by trial impact (disruption) due to 
COVID-19.  
Table 10 - Analyses of adverse events 
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HLGT, HLT and PT 
Primary SOC and PT 
TEAE related to IMP (overall) as per Investigator’s judgment 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC and PT  
Treatment emergent SAE related to IMP (overall) as per 
Investigator’s judgment 
Primary SOC and PT 
TEAE leading to permanent full intervention discontinuation 
Primary SOC and PT 
TEAE leading to permanent partial intervention discontinuation (for 
each individual drug) 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
AE leading to deatha 
• 
In context of disease progressionb 
• 
In context other than disease progressionc 
Primary SOC and PT 
Pre-treatment AE 
Primary SOC and PT 
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Type of AE 
MedDRA levels 
Post-treatment AE 
Primary SOC and PT 
TEAE leading to dose interruption 
Primary SOC and PT 
TEAE leading to dose modification (including dose reduction, dose 
omission and cycle delay) 
Primary SOC and PT 
a Death as an outcome of the AE as reported by the Investigator in the AE page 
b Death within 30 days from last IMP administration and the cause of death is disease progression 
c Death within 30 days from last IMP administration and for whom cause of death is not disease progression or the death occurred more 
than 30 days from last IMP administration and the cause of death is AE 
Analysis of deaths 
In addition to the analyses of deaths included in Table 10 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by main reason for death  
• An overview of Grade 5 AEs will be provided with the following categories: 
- 
Grade 5 AE (TEAE and post-treatment). 
- 
Fatal TEAE (regardless of date of death/period). 
- 
Grade 5 TEAE with a fatal outcome during the treatment-emergent period,  
- 
Any Grade TEAE with a fatal outcome during the post-treatment period.  
- 
Post-treatment Grade 5 AE (excluding a TEAE that worsened to Grade 5 during the 
post-treatment period). 
Analysis of adverse events of special interest (AESIs) 
Number (%) of participants experiencing at least one adverse event of special interest will be 
provided, by SOC and PT. The selection will be made using the eCRF specific AESI tick box. 
Tables will be sorted as indicated in Table 9.  
In addition, the following analyses will be done for infusion reaction category (selected by eCRF 
specific form) which are infusion related reactions (IRRs), cytokine release syndrome (CRS), 
flu-like symptoms (FLS) and anaphylaxis: 
• Description of the infusion reaction category by predefined grouping and other reported 
PT.  
• Worst grade 
• Action taken for each IMP 
• Corrective treatment given (Yes, No) 
• Number (%) of participants with only 1 episode, ≥2, ≥3, ≥4 and ≥5 episodes 
• Onset of first episode of infusion reactions (at the first infusion and subsequent infusions) 
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• Number (%) of participants with infusion reactions (any episode) at the first and 
subsequent infusions 
• Number (%) of participants with at least one infusion with two episodes of infusion 
reactions 
• Total number of infusion reaction episodes 
• Time to onset from infusion (by category: Infusion day/1 day after infusion/ 2 to 3 days 
from infusion/ More than 3 days from infusion when applicable) 
• Duration of infusion reaction (in days) (by category 1 day/ 2 to 3 days/ More than 
3 days/Not recovered) 
• Number (%) of participants with infusion reactions symptoms (as reported by investigator) 
by SOC and PT. 
3.6.3 Additional safety assessments  
3.6.3.1 Laboratory variables and vital signs  
The following laboratory variables and vital signs variables will be analyzed. They will be 
converted into standard international units. 
• Hematology:  
- 
Red blood cells and platelets: hemoglobin, hematocrit, platelet count 
- 
White blood cells: leukocytes, neutrophils, lymphocytes, monocytes, basophils, 
eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, albumin, lipase, amylase 
- 
Electrolytes: sodium, potassium, chloride, calcium corrected, bicarbonate, magnesium  
Calcium Corrected (mmol/L) = Total calcium (mmol/L) + 0.8 * 0.25 * [4 – Serum 
albumin (g/L) * 0.1] 
- 
Renal function: creatinine, eGFR, blood urea nitrogen 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, lactate dehydrogenase, bilirubin 
- 
Vital signs: heart rate, systolic and diastolic blood pressure, respiratory rate, 
temperature, ECOG Performance status  
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification will be replaced by ULOQ value. 
For hematological parameters and some selected biochemistry parameters, Sanofi sponsor generic 
ranges (LLN, ULN) are defined and will be used for grading (see list of parameters in 
Section 5.4). For other biochemistry parameters, grading will be derived using local laboratory 
normal ranges. 
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Analyses according to PCSA and NCI grading 
For laboratory variables, analyses according to NCI grading will be made based on NCI-CTCAE 
version 5.0. In addition, for eGFR, blood urea nitrogen, hematocrit, monocytes, basophils and 
chloride, PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at 
the time of the database lock. 
Analyses according to PCSA and NCI grading will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables and vital signs above, the incidence of participants with at least one 
PCSA during the treatment-emergent period will be summarized regardless of the baseline level 
and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
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.  
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 PK analyses  
PK parameters will include but may not be limited to those listed in Table 11, depending on the 
IMP and type of PK. The intensive PK parameters will be calculated using non-compartmental 
method from SAR444245 concentrations.  
Table 11 - List of PK parameters and definitions 
Parameters 
Definition 
Intensive PK 
SAR444245 
Sparse PK 
SAR444245 
Sparse PK 
cetuximab 
Ctrough 
Concentration observed just before intervention 
administration during repeated dosing 
 
 
X 
CEOI 
Concentration at end of infusion 
 
X 
X 
Cmax 
Maximum concentration observed 
X 
 
 
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Parameters 
Definition 
Intensive PK 
SAR444245 
Sparse PK 
SAR444245 
Sparse PK 
cetuximab 
Clast 
Last concentration observed above the lower limit 
of quantification 
X 
 
 
tlast 
Time of the last concentration observed above the 
lower limit of quantification (ie, Clast) 
X 
 
 
AUClast 
Area under the plasma concentration versus time 
curve calculated using the trapezoidal method from 
time zero to tlast 
X 
 
 
AUC 
Area under the concentration versus time curve 
extrapolated to infinity 
X 
 
 
Rac 
Observed accumulation ratio calculated using the 
following equation : Rac = 
𝐴𝑈𝐶 𝑎𝑡 𝐶𝑦𝑐𝑙𝑒 4 𝐷𝑎𝑦 1
𝐴𝑈𝐶 𝑎𝑡 𝐶𝑦𝑐𝑙𝑒 1 𝐷𝑎𝑦 1 
X 
 
 
Rac,Cmax 
Observed accumulation ratio calculated using the 
following equation : Rac, Cmax = 
𝐶max 𝑎𝑡 𝐶𝑦𝑐𝑙𝑒 4 𝐷𝑎𝑦 1
𝐶𝑚𝑎𝑥 𝑎𝑡 𝐶𝑦𝑐𝑙𝑒 1 𝐷𝑎𝑦 1 
X 
 
 
These PK parameters will be summarized as indicated in following sections on the PK population. 
Sparse and intensive PK of SAR444245 will be analyzed separately.   
All concentration values below the lower limit of quantitation (LLOQ) will be treated as zero in 
all summary statistics. Geometric mean will not be computed in case at least one concentration is 
below LLOQ.  
 Descriptive statistics  
The PK variables defined above will be summarized by cycle separate for Chinese and 
non-Chinese subjects, as well as pooling all subjects, using the following descriptive statistics: 
mean, median, standard deviation, coefficient of variation, minimum, and maximum. In addition, 
geometric mean and geometric standard deviation will be calculated for concentration parameters. 
These analyses will be performed by specific subgroups (eg, gender, BMI, age) if appropriate. 
3.7.1.2 Immunogenicity analyses  
Participant’s ADA status, response variable and kinetics of ADA responses (see definitions 
below) will be summarized on the ADA population. 
Kinetics of ADA responses will be described for participants with treatment-induced ADA and 
for participants with treatment-boosted ADA, separately. Time to ADA onset and duration of 
ADA will be described with minimum, Q1, median, Q3 and maximum statistics. 
Peak titer will be described with minimum, Q1, median, Q3 and maximum statistics for 
participants with treatment-induced ADA and for participants with treatment-boosted ADA, 
separately. 
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ADAs against SAR444245 (negative, positive, inconclusive) and corresponding titers, ADAs 
directed against PEG moiety of SAR444245 status (negative, positive) and ADAs cross-reacting 
with endogenous IL-2 status (negative, positive) will also be described overtime using descriptive 
statistics. ADAs directed against PEG moiety of SAR444245 status and ADAs cross-reacting with 
endogenous IL-2 status will only be determined if the status of ADAs against SAR444245 is 
positive.  
The impact of positive immune response on efficacy, PK and safety variables may be further 
explored, depending on ADA incidence. 
Participant’s ADA status against SAR444245 
• Participants with pre-existing ADAs correspond to participants with ADAs present in 
samples drawn before first administration of intervention. Participants with missing ADA 
sample at baseline will be considered as without pre-existing ADA. 
• Participants with treatment-emergent ADA correspond to participants with at least one 
treatment-induced/boosted ADA. 
- 
Participants with treatment-induced ADAs correspond to participants with ADAs 
that developed during the treatment-emergent (TE) period and without pre-existing 
ADA (including participants without pre-treatment samples). 
- 
Participants with treatment-boosted ADAs correspond to participants with 
pre-existing ADAs that are boosted during the TE period to a significant higher titer 
than the baseline. A 2-fold serial dilution schema is used during titration, so at least 
a 4-fold increase will be considered as significant. 
• Participants with unclassified ADA correspond to participants with pre-existing ADAs 
that cannot be classified as treatment-boosted ADA because of missing titer(s)  
(ie, a positive ADA sample during the TE period in a participant with pre-existing ADA 
but with missing titer at this sample or at baseline). 
• Participants without treatment-emergent ADA correspond to participants without 
treatment-induced/boosted ADA and without any inconclusive sample nor unclassified 
ADA during the TE period. 
• Participants with inconclusive ADA are defined as participants which cannot irrefutably 
be classified as with or without treatment-emergent ADA. 
Kinetics of ADA response 
Kinetics of ADA response will be derived for participants with treatment-induced/boosted ADA 
considering ADA samples collected during the TE period and post-treatment period. 
• Time to onset of ADA response is defined as the time period between the first IMP 
administration and the first treatment-induced/boosted ADA.  
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• Duration of ADA response is defined as the time between the first treatment-induced/ 
boosted ADA and the last treatment-induced/boosted ADA, irrespective of negative 
samples or positive samples not reaching the boosted threshold in-between. ADA duration 
will be summarized only for participants with persistent ADA response.  
- 
A positive sample (boosted positive sample for participants with pre-existing ADA) 
occurring after the TE period will be considered as treatment-induced/boosted ADA if 
a previous treatment-induced/boosted ADA occurred during the TE period and less 
than 16 weeks before this sample 
• Persistent ADA response is defined by treatment-induced/boosted ADA with a duration 
of ADA response of at least 16 weeks.  
• Transient ADA response is defined by treatment-induced/boosted ADA with a duration 
of ADA response of less than 16 weeks and the last sample of the TE period is not 
treatment-induced/boosted.  
• Indeterminate ADA response is defined by treatment-induced/boosted ADA that are 
neither persistent nor transient. 
ADA response variable: 
• ADA incidence is defined as the proportion of participants found to have seroconverted 
(treatment-induced ADAs) or boosted their pre-existing ADA response (treatment-boosted 
ADAs) at any time point during the TE period. 
• Incidence of ADAs directed against PEG moiety of SAR444245 is defined as the 
proportion of participants with ADAs directed against PEG moiety of SAR444245 during 
the TE period among evaluable participants. Participants from ADA population are 
evaluable for ADAs directed against PEG moiety except if ADAs directed against PEG 
moiety status is not determined on an ADA against SAR444245 positive sample 
• Incidence of ADAs cross-reacting with endogenous IL-2 is defined as the proportion of 
participants with ADAs directed against endogenous IL-2 during the TE period among 
evaluable participants. Participants from ADA population are evaluable for ADAs directed 
against endogenous IL-2 except if their status is not determined on an ADA against 
SAR444245 positive sample. 
3.7.1.3 Quality of life analyses  
Quality of life analyses of 
 will be described in separated document.  
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3.7.2 Subgroup analyses  
Analyses will be performed on the primary endpoint across the following subgroups (categories 
with fewer than 5 participants may be combined with other categories): 
Table 12 - Subgroup analyses  
 
ESCC 
GC/GEC 
HCC 
CRC 
 
A 
B1 
B2 
B3 
C 
D1 
D2 
Number of prior systemic therapy regimens 
 
 
 
 
 
 
 
1 vs >=2 
Yes 
 
 
Yes 
Yes 
 
 
0 vs >=1 
 
Yes 
Yes 
 
 
 
 
2 vs >=3 
 
 
 
 
 
Yes 
Yes 
Disease status at entry (locally advanced vs metastatic) 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
PD-L1 status at baseline (<1 vs >=1%) 
Yes 
 
 
Yes 
Yes 
Yes 
Yes 
 
The ORR will be provided, as well as the corresponding 90% CI, for each subgroup, using the 
same method as applied to the primary analysis.  
3.8 
INTERIM ANALYSES  
No formal interim analyses are planned. However, for each cohort, in order to support project 
strategic planning and design of future studies, informal interim analyses will be conducted during 
the study (eg, after half of the planned number of participants have undergone two post-baseline 
tumor assessment or have discontinued study treatment, whichever is earlier). 
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If the predictive probability of concluding a minimum clinical meaningful effect of the study 
treatment (ORR) at the end of study is <15%, the corresponding cohort will be stopped for futility. 
Minimum clinical meaningful effect for each cohort is in Table 13. To facilitate the calculation of 
predictive probability, a minimum informative prior of Beta (0.5, 0.5) is used at the time of the 
design of the study. However, emerging data generated from outside of the study may warrant 
a different prior to be considered before this interim analysis. 
Table 13 - Minimum clinical meaningful effect  
 
ESCC 
GC/GEC 
HCC 
CRC 
 
A 
B1 
B2 
B3 
C 
D1 
D2 
ORR 
5% 
15% 
5% 
10% 
5% 
5% 
5% 
In addition, the cumulative safety data for each study intervention across cohorts will be reviewed 
periodically by the Data Monitoring Committee (DMC). The enrollment will not be paused or 
stopped during the safety monitoring unless severe safety concern arises. 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. Occurrence of any 
treatment related G3 or higher AE (excluding lymphocyte count decrease) not resolving within 
72 hours in >25% of participants will trigger ad hoc DMC. The DMC procedures will be detailed 
in the DMC charter and approved by the DMC members. 
The cohort cut-off for the primary ORR endpoint analysis is estimated to be approximately 
9 months from the date of the last participant first infusion. This would allow the possibility to 
observe the response of the last participant for 6 months, assuming there is a response at first 
treatment assessment. 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of primary objective) will be 18 months from cohort LPI. After this cut-off date for the 
final analysis, the participants still receiving study treatment in that specific cohort will be 
followed up as the cohorts after early termination described in Section 10.1.9 of the master 
protocol. 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
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Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
02  
Master protocol 
21-Jan-2022 
1.1 Synopsis, 3 Objectives and Endpoints, and 
9.4.3 Secondary endpoint(s) 
Definitions of Time to response and Duration 
of response have been revised as follows: 
• Time to response (TTR) defined as the time 
from the first administration of investigational 
medicinal product (IMP) to the first tumor 
assessment at which the overall response was 
recorded as PR or CR that is subsequently 
confirmed and determined by Investigator per 
RECIST 1.1. 
• Duration of response (DoR), defined as the 
time from first tumor assessment at which the 
overall response was recorded as CR or PR 
that is subsequently confirmed until 
documented progressive disease (PD) 
determined by Investigator per RECIST 1.1 or 
death from any cause, whichever occurs first. 
For clarification. 
02 
Master protocol 
21-Jan-2022 
1.1 Synopsis and 9.4.3.5 Adverse events 
Treatment-related TEAEs will be analyzed 
overall, regardless of the drug 
To assess treatment-related AE of the 
regimen as whole (SAR444245 with 
other anticancer therapies). 
02 
Master protocol 
21-Jan-2022 
9.3 Population of analyses 
Update of Efficacy population definition 
To characterize efficacy excluding 
participants newly enrolled. 
02 
Master protocol 
21-Jan-2022 
9.5 Interim analysis 
The following sentence has been added 
“Occurrence of any treatment related G3 or 
higher AE (excluding lymphocyte count 
decrease) not resolving within 72 hours 
in >25% of participants will trigger ad hoc 
DMC.” 
For clarity. 
02 
Substudy 02 
12-Jan-2022 
1.3 Schedule of activities (SoA) ; 3 Objective 
and endpoints ; 8.10 Patient-reported 
outcomes (PRO) 
9.4.4.2 Patient-reported outcomes ; 
Patient-reported outcome assessment have 
been added. 
Exploratory objective and endpoints for 
Patientreported outcomes have been added. 
New section added. 
Analysis for PRO endpoints has been added. 
To assess patient-reported experience 
of treatment 
 in 
an exploratory endpoint. 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
01 
Master protocol 
30-Aug-
2021 
Section 1.1 Synopsis, Section 4.1 Overall 
design 
The follow sentence has been deleted “or until 
start of another anticancer therapy or final 
cohort cut-off, whichever comes first” for the 
reason leading to EOT for the participants who 
discontinue study treatment with PD 
For consistency and clarification 
01 
Substudy 01 
30-Aug-
2021 
Section 9.5 Interim Analyses 
The following sentences have been added “If 
the predictive probability of concluding 
a minimum clinical meaningful effect of the 
study treatment (ORR of 5%) at the end of 
study is <15%, the corresponding cohort will 
be stopped for futility. To facilitate the 
calculation of predictive probability, a minimum 
informative prior of Beta (0.5, 0.5) is used at 
the time of the design of the study. 
However, emerging data generated from 
outside of the study may warrant a different 
prior to be considered before this interim 
analysis.” 
To include stopping rules for futility. 
01 
Substudy 02 
30-Aug-
2021 
Section 9.5 Interim Analyses 
The following sentences have been added 
“For each cohort, if the predictive probability of 
concluding a minimum clinical meaningful 
effect of the study treatment (ORR of 15% for 
cohort B1, 5% for cohort B2, 10% for cohort 
B3) at the end of study is <15%, the 
corresponding cohort will be stopped for 
futility. To facilitate the calculation of predictive 
probability, a minimum informative prior of 
Beta (0.5, 0.5) is used at the time of the design 
of the study. However, emerging data 
generated from outside of the study may 
warrant a different prior to be considered 
before this interim analysis.”. 
To include stopping rules for futility. 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
01 
Substudy 03 
30-Aug-
2021 
Section 9.5 Interim Analyses 
The following sentences have been added “If 
the predictive probability of concluding a 
minimum clinical meaningful effect of the study 
treatment (ORR of 5%) at the end of study is 
<15%, the corresponding cohort will be 
stopped for futility. To facilitate the calculation 
of predictive probability, a minimum 
informative prior of Beta (0.5, 0.5) is used at 
the time of the design of the study. 
However, emerging data generated from 
outside of the study may warrant a different 
prior to be considered before this interim 
analysis.”. 
To include stopping rules for futility. 
01 
Substudy 04 
30-Aug-
2021 
The following sentences have been added 
“For each cohort, if the predictive probability of 
concluding a minimum clinical meaningful 
effect of the study treatment (ORR of 5% for 
both cohorts) at the end of study is <15%, the 
corresponding cohort will be stopped for 
futility. To facilitate the calculation of predictive 
probability, a minimum informative prior of 
Beta (0.5, 0.5) is used at the time of the design 
of the study. However, emerging data 
generated from outside of the study may 
warrant a different prior to be considered 
before this interim analysis.” 
To include stopping rules for futility. 
 
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4 
SAMPLE SIZE DETERMINATION  
As the study is not intended to explicitly test a hypothesis, calculations of power and Type I error 
were not considered in the study design. 
The plan is to treat approximately 40 participants in each cohort.  
Table 14 lists estimated ORR and 90% exact confidence intervals (CIs) by number of responders 
from a sample size of 40 participants treated. 
Table 14 - Estimated objective response rate (ORR) depending on number of responders  
Number of Responders 
(N=40) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
2 
5% (0.9% - 14.9%) 
4 
10% (3.5% - 21.4%) 
6 
15% (6.7% - 27.5%) 
8 
20% (10.4% - 33.2%) 
10 
25% (14.2% - 38.7%) 
12 
30% (18.3% - 44.0%) 
14 
35% (22.6% - 49.2%) 
CI: confidence interval 
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 each cohort. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADAs: 
anti-drug antibodies 
ADI: 
actual dose intensity 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CBR: 
clinical benefit risk 
DMC: 
data monitoring committee 
DoR: 
duration of response 
ECG: 
electrocardiogram 
IE: 
intercurrent event 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
NAT: 
new anti-cancer therapy 
NCI-CTCAE: 
National Cancer Institute Common Terminology for Adverse Events 
ORR: 
objective response rate 
PDI: 
planned dose intensity 
 
PFS: 
progression-free survival 
PK: 
pharmacokinetic 
RDI: 
relative dose intensity 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
TEAE: 
treatment-emergent adverse event 
TTR: 
time to response 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 5 will 
be summarized. Reasons for exclusion from the population without trial impact (disruption) due to 
COVID-19 will be summarized. 
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Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled. The number (%) of screen failures and reasons for screen failures will be 
provided in the screened population. 
Regarding intervention discontinuation, the following definitions will be used: 
• Permanent partial intervention discontinuation is defined as the discontinuation of one of 
the study drugs but at least one is continued  
• Permanent full intervention discontinuation is defined as the discontinuation of all the 
study drugs 
The number (%) of participants in the following categories will be provided:  
• Enrolled participants 
• Enrolled but not exposed participants  
• Exposed participants 
• Participants still on study intervention 
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent full intervention discontinuation. 
• Participants who did not complete the study treatment period as per protocol for 
SAR444245 and main reason for permanent partial intervention discontinuation 
(discontinuation of SAR444245). 
• Participants who completed the study period as per protocol. 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and “other 
reasons” will be split as related versus not related to COVID-19, if applicable. 
In addition, the number (%) of participants screened, screened-failed, enrolled, with permanent 
full intervention discontinuation and with early study discontinuation will be provided by country 
and site. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the enrolled 
population as well as displayed separately as related versus not related to COVID-19 if applicable. 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline will be summarized using descriptive statistics in the exposed 
population. 
Demographic and baseline characteristics  
• age in years as quantitative variable and in categories (<65, 65 to <75, ≥75) 
• gender (Male, Female) 
• race: 
- 
White 
- 
Black/Black or African American 
- 
Asian 
- 
Native Hawaiian or Other Pacific Islander 
- 
American Indian or Alaska Native 
- 
Not reported 
- 
Unknown 
• ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown) 
• BMI (kg/m²) 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Medical (or surgical) history includes relevant history of previous pathologies and smoking status. 
Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, and associated primary 
SOC using the MedDRA version currently in effect at Sanofi at the time of database lock.  
Specific disease characteristics at diagnosis includes: 
• Time from initial diagnosis of cancer to first study treatment infusion (in years), 
• Histology type, 
• Location, 
• Stage of the disease  
Specific disease status at study entry includes: 
• Extent of the disease 
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• Number of organ(s) involved 
• Type of organ(s) involved  
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant used prior to first IMP intake.  Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant concomitantly to 
any IMP(s) from the first administration of IMP to the last IMP intake + 30 days. 
• Post-treatment medications are those the participant took in the period after the end of the 
concomitant medications period.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether 
a given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant medications will be summarized for the exposed population, by 
anatomic and therapeutic level. The summaries will be sorted by decreasing frequency of 
anatomic category (ATC). In case of equal frequency, alphabetical order will be used. Participants 
will be counted once in each ATC category (anatomic or therapeutic) linked to the medication.  
Anticancer therapies  
Prior anticancer therapies will be described, including several characteristics such as: 
• Therapy type 
• Number of prior regimens  
• Intent of prior regimens 
• Best response to last regimen 
• Intent of last regimen 
• Reason for discontinuation of the last regimen 
• Time from completion of last regimen of treatment to first study treatment (months) 
• Duration of last regimen (months) 
Subsequent therapies after discontinuation of intervention will be summarized based on 
WHO-DD coding. 
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Statistical Analysis Plan 
26-Sep-2022 
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Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 39 
Pre-medications 
Number (%) of patients with the following pre-medications will be provided. Number (%) of 
patients with pre-medications will be provided by infusions at Cycle 1, Cycle 2, Cycle 3 and 
Cycle 4. Number (%) of infusions with pre-medications will be provided overall for subsequent 
cycles. 
Categories of pre-medication are: 
• Acetaminophen (paracetamol)  
• Diphenhydramine (or equivalent eg, cetirizine, promethazine, dexchlorpheniramine, 
according to local approval and availability)  
• Others 
5.4 
APPENDIX 4 SANOFI SPONSOR RANGES  
 
Test 
Gender 
Unit 
Lower/upper limit of 
normal 
Basophils 
 
10^9/L 
0 - 0.15 
Eosinophils 
 
10^9/L 
0 - 0.4 
Erythrocytes 
Male 
10^12/L 
4.5 - 5.9 
Erythrocytes 
Female 
10^12/L 
4 - 5.2 
Hemoglobin 
Male 
g/L 
135 - 175 
Hemoglobin 
Female 
g/L 
120 - 160 
Hematocrit 
Male 
v/v 
0.41 - 0.53 
Hematocrit 
Female 
v/v 
0.36 - 0.46 
Leukocytes 
 
10^9/L 
4.5 - 11 
Lymphocytes 
 
10^9/L 
1 - 2 
Monocytes 
 
10^9/L 
0.18 - 0.5 
Neutrophils 
 
10^9/L 
1.8 - 3.15 
Platelets 
 
10^9/L 
150 - 350 
Albumin 
 
g/L 
35 - 55 
Urea Nitrogen 
 
mmol/L 
3.6 - 7.1 
Chloride 
 
mmol/L 
80 - 115 
Glucose 
 
mmol/L 
3.900001 - 6.999999 
Bicarbonate (HCO3) 
 
mmol/L 
22 - 29 
Potassium 
 
mmol/L 
3.5 - 5 
Magnesium 
 
mmol/L 
0.8 - 1.2 
Sodium 
 
mmol/L 
136 - 145 
VV-CLIN-0636106 1.0


Statistical Analysis Plan 
26-Sep-2022 
SAR444245 - ACT16902 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 40 
Test 
Gender 
Unit 
Lower/upper limit of 
normal 
Phosphate 
 
mmol/L 
1 - 1.4 
Protein 
 
g/L 
55 - 80 
Urea 
 
mmol/L 
3.6 - 7.1 
INR 
 
Ratio 
0.8 - 1.2 
Calcium corrected 
 
mmol/L 
2.2 - 2.6 
 
 
5.5 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs and ADA will be used for 
computation of baseline, the worst on-treatment value, analysis according to PCSAs/NCI grade, 
and the shift summaries for safety.  
VV-CLIN-0636106 1.0


Statistical Analysis Plan 
26-Sep-2022 
SAR444245 - ACT16902 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 41 
6 
REFERENCES  
Not applicable. 
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