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 Lung Cancer or Pleural Mesothelioma
Phase: PHASE2
Conditions: Pleural Mesothelioma, Non-small Cell Lung Cancer
Sponsor: Sanofi

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Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
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AMENDED CLINICAL TRIAL PROTOCOL 03 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with other anticancer 
therapies for the treatment of participants with lung 
cancer or pleural mesothelioma 
Protocol number: 
Amendment number: 
ACT16849 
03 
Compound number 
(INN/Trademark): 
SAR444245  
(Not applicable) 
Brief title: 
A study of SAR444245 combined with other anticancer 
therapies for the treatment of participants with lung 
cancer or mesothelioma 
Acronym 
Pegathor Lung 202 
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: 
153864 
2020-005331-78 
NCT04914897 
U1111-1254-0107 
Date: 
20-Oct-2021
Total number of pages: 176 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 03 
ALL 
20 Oct 2021, version 1 (electronic 8.0) 
Amended Clinical Trial Protocol 02 
ALL 
05 May 2021, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 01 
ALL 
19 Mar 2021, version 1 (electronic 1.0) 
Original Protocol 
  
23 Feb 2021, version 1 (electronic 2.0) 
Amended protocol 03 (20 Oct 2021) 
This amended protocol for Review (amendment 03) is considered to be substantial based on the 
criteria set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the 
Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reason for the amendment is in response to Health Authorities’ (HAs) requests for 
correction and clarification. Instructions regarding participant enrollment specific to France as 
requested by the French HA (ANSM) have been added. 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 
The study acronym “Pegathor Lung 202” was added.  
For consistency across the program. 
1.1 Synopsis: Table 2 
Objectives and 
Endpoints,  
3 Objectives and 
Endpoints,  
9.4.3.1 Time to 
response, and 9.4.3.2 
Duration of response  
Definitions of secondary endpoints “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 (for NSCLC) or mRECIST (for mesothelioma). 
• Duration of response (DoR), defined as the time from 
first tumor assessment at which the overall response was 
recorded as PR or CR that is subsequently confirmed 
until progressive disease (PD) determined by investigator 
per RECIST 1.1 (for NSCLC) or mRECIST (for 
For clarification 
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Section # and 
Name 
Description of Change 
Brief Rationale 
mesothelioma) or death from any cause, whichever 
occurs first. 
1.1 Synopsis, 4.1 Overall 
Design, 
9.4.3.3 Progression-free 
survival, and 9.5 Interim 
analyses 
The cut-off date for the final analysis was defined. 
The study cut-off date has been replaced by cohort cut-
off for final analysis.  
 
 For clarification 
1.1 Synopsis, Figure 1, 
1.3 Schedule of Activities 
(SoA), 4.1 Overall 
Design 
The “Study Committee” has been renamed as “Study 
Board” and its composition and role have been clarified in 
Section 4.1. 
For consistency with Sanofi standard 
terminology 
1.1 Synopsis, 
6.1.2.1 Premedication for 
SAR444245, Table 23 
Risk assessment 
1.1 Synopsis, 
6.1.2.1 Premedication for 
SAR444245 
Oral administration of diphenhydramine is now permitted, 
in addition to IV administration. 
Intravenous administration of acetaminophen is now 
permitted, in addition to oral administration. 
To allow local approved administration 
route to be used. 
1.3 Schedule of Activities 
(SoA) 
Footnote f now applies only to C1D15 and was changed 
from:  
C1D8 and/or C1D15 visits must be performed on site 
only for participants enrolled in the Safety run-in, 
participants scheduled to have blood draws for biomarker 
assessment on Day 8 or ADA on Day 15, and 
participants in Cohort B2 who will receive nab-paclitaxel 
administration on Day 8. 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. The Study 
Committee may decide to cancel safety assessment on 
C1D8 and C1D15, upon agreement with Sponsor, and if 
justified by safety data.  
to 
C1D15 visits must be performed for participants enrolled 
in the safety run-in. For all other participants, the Study 
Board may decide to cancel safety assessment on 
C1D15, upon agreement with Sponsor, and if justified by 
safety data. 
To limit visits and operational 
procedures for participants’ comfort.  
1.3 Schedule of Activities 
(SoA) 
Footnote r was added: For carboplatin/cisplatin dosing, 
only in Cycles 3 and 4. 
For clarification 
1.5.1 All cohorts 
The ADA sample at C1D15 was replaced with a sample 
at C1D8. 
The C1D15 visit may be cancelled by 
the study board as described above, 
and a sample at C1D8 is considered 
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Section # and 
Name 
Description of Change 
Brief Rationale 
sufficient to detect the potential early 
onset of an ADA response. 
2.3.1.5 SAR444245 
combined with 
pembrolizumab and 
SAR444245 combined 
with pembrolizumab and 
chemotherapy regimen, 
2.3.2 Benefit 
assessment 
A description of the benefit-risk assessment of 
SAR444245 combined with pembrolizumab and 
chemotherapy has been added. The section title was 
changed from "SAR444245 combined with 
pembrolizumab" to "SAR444245 combined with 
pembrolizumab and SAR444245 combined with 
pembrolizumab and chemotherapy regimen". 
To complete the benefit-risk 
assessment and to respond to HA 
request (Italy) 
4.3.1 SAR444245 dose 
This section was updated with the most recent data 
available from Phase 1 Hammer study.  
To include all available data in support 
of the safety of the recommended 
phase 2 dose. 
5 Study population 
The following text has been added “For participants 
enrolled in France and Japan please refer to 
Section 10.7”. 
To address HA requests (France and 
Japan) 
5.1 Inclusion Criteria 
In I 04 the timeline for the archival tumor tissue sample 
was changed from “collected more than 6 months prior to 
screening” to “collected more than 6 months prior to first 
IMP administration”. 
For clarification 
5.1 Inclusion Criteria 
In I 06, for participants in Cohorts B1 and B2, the wording 
has been changed to; 
-Patients with metastatic NSCLC should have progressed 
after having received prior benefit from an anti-PD1/PD-
L1* containing regimen (SD, partial response [PR], or 
CR).  Patients must have received prior anti-PD1/PD-L1 
containing regimen given concurrently or sequentially 
with a platinum-based chemotherapy.  Patients who 
received concurrent anti-PD1/PD-L1 chemotherapy 
combination are allowed to receive one additional 
chemotherapy.  Platinum ineligible patients can enroll 
after anti-PD1/PD-L1 monotherapy, or anti-PD1/PD-L1 
monotherapy followed by a non-platinum form of 
chemotherapy.  
*If anti-PD1/PD-L1 was used beyond initial radiological 
progression while continuing to use the same anti-
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. 
To clarify requirements for the prior 
lines of treatment for Cohorts B1 and 
B2 
5.1 Inclusion criteria, 
8.2.5 Pregnancy testing, 
8.3.5 Pregnancy, Table 
21 footnote e 
In I 08, the recommended duration for continuing 
contraception after last dose of study intervention in 
Cohort A3 was changed from 420 days to 330 days for 
male participants and from 330 days to 420 days for 
female participants. 
For female participants in cohorts A1, A2, B1, B2 and C1 
(SAR444245 plus pembrolizumab), the recommended 
For correction, as the original 
presentation inadvertently reversed 
the information for males and females. 
 
 
 
For correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
duration for continuing contraception after last dose of study 
intervention was changed from 180 days to 150 days. 
5.2 Exclusion criteria 
E 04 was changed from “History of allogenic or solid 
organ transplant” to “History of allogenic tissue/solid 
organ transplant”. 
For clarification 
5.2 Exclusion criteria 
E 21 was changed from “Known hypersensitivity to or 
contraindication for the use of any study intervention, 
including premedication to be administered in this study, 
as well as PEG or any pegylated drug” to “Known 
hypersensitivity to or contraindication for the use of any 
study intervention or components thereof, including 
premedication to be administered in this study, as well as 
PEG or any pegylated drug and E. coli-derived protein”. 
To clarify that patients with known 
hypersensitivity to any excipient of the 
study interventions or to E. coli-
derived protein must be excluded 
5.2 Exclusion criteria and 
6.5.2 Prohibited 
concomitant 
medications, 
Appendix 12 Risk 
assessment Table 23 
E 25 
” has been 
deleted.  
The following sentence in Section 6.5.2 has been 
deleted: “
i
l.” 
In Table 23, the row for 
 was 
deleted. 
Based on new de-risking in-vitro data 
5.2 Exclusion criteria 
E 29 was changed from: Participation in a concurrent 
clinical study in the treatment period 
To  
Current enrollment or past participation in a study of an 
investigational treatment or has used an investigational 
device within 28 days prior to the first dose of study 
treatment.  
Note:  Participants who have entered the follow-up phase 
of an investigational study may participate as long as it 
has been 28 days after the last dose of the previous 
investigational treatment. 
For clarification 
5.4 Screen failures 
The following text was added “A participant may be 
rescreened only once”. 
For clarity 
6.2 Preparation/handling/ 
storage/accountability 
The following text regarding DTP shipment of IMP was 
deleted: “(except for DTP shipment, for which a courier 
company has been approved by the Sponsor)”.  
Direct-to-patient shipment of IMP is 
not possible in this study.  
6.6.2 Cycle delay and 
dose omission and 
6.6.3 General guidelines 
for the management of 
The following text regarding the treatment resumption 
after cycle delay/treatment withhold was deleted: “or is 
stable and manageable through supportive/medical 
therapy”. 
For correction 
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Section # and 
Name 
Description of Change 
Brief Rationale 
treatment-related adverse 
events 
6.6.4.2 Dose 
modification for nab-
paclitaxel 
Table 11 - Recommended nab-paclitaxel dose reductions 
for non-hematological toxicities, was added 
To comply with nab-paclitaxel dosing 
instructions and to respond to HA 
request (Italy) 
6.6.5.1 Infusion-related 
reactions (IRR) 
In Table 13, the language regarding SAR444245 dose 
modification guidelines was modified as follows: 
For Grade 2 events 
“SAR444245 infusion should be interrupted if applicable” 
was changed to “Interrupt SAR444245 infusion” 
For Grade 3 and 4 events: 
“SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, permanently 
discontinue SAR444245.” was changed to “Permanently 
discontinue SAR444245.” 
For clarification 
 
6.6.5.3 Fever, flu-like 
symptoms and cytokine-
release syndrome (CRS) 
In Table 14, the dose modification instructions for events 
of CRS were modified as follows:  
For Grade 3 events the following text was deleted:
j
 
For Grade 4 events, the following text was deleted: “as 
clinically indicated”. 
For consistency with instructions 
given in Section 6.6.1 General rules 
6.6.5.5 Immune cell-
associated neurotoxicity 
syndrome (ICANS) 
In Table 16, instructions for treatment with IV 
corticosteroids were added for Grade 3 events.  
For consistency with instructions for 
Grade 4 events.  
6.6.5.6 Vascular leak 
syndrome 
The literature reference cited was changed to: Siddall E, 
Khatri M, Radhakrishnan J. Capillary leak syndrome: 
etiologies, pathophysiology, and management. Kidney 
Int. 2017 Jul;92(1):37-46. Crossreferences to articles 
cited thereafter have been renumbered accordingly. 
For correction 
8.3.1 Time period and 
frequency for collecting 
AE and SAE information 
The instruction to stop collecting AE and SAE information 
should the participant initiate another anticancer therapy 
was removed. All AEs and SAEs are to be collected until 
30 days and 90 days, respectively, following cessation of 
study treatment. 
For consistency with Sanofi standards 
standards 
9.3 Populations for 
Analyses 
The efficacy population description was revised to 
“Efficacy population will include all participants from the 
exposed population with at least one evaluable post-
To characterize efficacy excluding 
newly enrolled participants 
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Section # and 
Name 
Description of Change 
Brief Rationale 
baseline tumor assessment or who permanently 
discontinued study treatment”. 
9.4.1 General 
considerations 
“By dose (as applicable)” has been added to efficacy 
analyses. 
For clarification 
9.4.3.6 Clinical 
laboratory evaluations 
and 9.4.5 Other safety 
analyse(s) 
Descriptive statistics for laboratory variables and vital 
signs will be performed only when relevant. The following 
text was deleted: “These analyses will be performed 
using local measurements for laboratory variables”. 
These analyses will be done as 
needed following analyses of 
abnormalities according to NCI-
CTCAE grade 
9.4.5 Other safety 
analyse(s) 
“ECG” was removed from quantitative analyses. 
ECG data are not collected 
systematically during the treatment 
period 
Appendix 10.1.3 
Informed Consent 
Process 
Minor revisions were made to the paragraph describing 
consent for the use of participants’ data or biological 
samples for future research.  
For clarification and closer alignment 
with the informed consent form 
i
Appendix 10.7 Country 
specific requirements 
Instructions regarding participant enrollment specific to 
France were added. 
 
Specific tests for early detection of interstitial lung disease 
have been added at Screening for participants in Japan. 
To respond to HA requests (France) 
 
To respond to HA requests (Japan)  
10.8 Appendix 8: 
Response evaluation 
criteria in solid tumors 
(RECIST) 1.1 
In the following sentence “Confirmatory scans should 
also be obtained at least 4 weeks following initial 
documentation of objective response or progressive 
disease”, the text “or progressive disease” was deleted. 
To correct a typographical error 
10.12 Appendix 12 Risk 
assessment 
The following text was added “For pembrolizumab, the 
information below is per currently available USPI and EU 
SmPC. Please always refer to the latest version of the 
SAR444245 IB and pembrolizumab local label for the 
most up-to-date safety data”. 
For clarification 
10.12 Appendix 12 Risk 
assessment, Table 23 
In Table 23, assessment for hepatoxicity with 
pembrolizumab was revised to be aligned with the latest 
version of USPI warnings and precautions for 
pembrolizumab.  
For consistency with latest available 
information 
Throughout the 
document 
The term "Infusion-associated reaction (IAR)” was 
changed to “infusion-related reaction (IRR)” 
For consistency with MedDRA 
definition 
Throughout the 
document 
Minor editorial updates. 
For clarity and consistency 
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TABLE OF CONTENT  
AMENDED CLINICAL TRIAL PROTOCOL 03 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENT .................................................................................................................................... 8 
LIST OF TABLES ......................................................................................................................................... 14 
LIST OF FIGURES ........................................................................................................................................ 14 
1 
PROTOCOL SUMMARY ............................................................................................................... 15 
1.1 
SYNOPSIS ..................................................................................................................................... 15 
1.2 
SCHEMA ........................................................................................................................................ 28 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 29 
1.4 
BIOMARKER FLOWCHART .......................................................................................................... 35 
1.5 
PHARMACOKINETIC FLOWCHART ............................................................................................ 36 
1.5.1 
All cohorts ...................................................................................................................................... 36 
2 
INTRODUCTION ............................................................................................................................ 37 
2.1 
STUDY RATIONALE...................................................................................................................... 37 
2.2 
BACKGROUND ............................................................................................................................. 38 
2.2.1 
Pembrolizumab .............................................................................................................................. 38 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 38 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 39 
2.2.2 
Rationale for NSCLC and selected participant population (Cohorts A1, A2, A3, B1 and B2) ....... 39 
2.2.3 
Current standard of care in NSCLC ............................................................................................... 39 
2.2.3.1 
PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as first-line therapy ...... 39 
2.2.3.2 
Second- or third-line treatment options for patients who have progressed on or after 
PD1/PD-L1-based therapy ............................................................................................................. 40 
2.2.3.3 
Nab-Paclitaxel as second-line therapy........................................................................................... 40 
2.2.3.4 
Interleukin-2 as a treatment option for NSCLC .............................................................................. 41 
2.2.3.5 
Rationale for combining SAR444245 with pembrolizumab or with pembrolizumab plus 
chemotherapy ................................................................................................................................ 41 
2.2.4 
Rationale for malignant pleural mesothelioma and selected participant population (Cohort 
C1).................................................................................................................................................. 42 
2.2.4.1 
PD1/PD-L1 inhibitors as treatment options .................................................................................... 42 
2.2.4.2 
Interleukin-2 as a treatment option for MPM (Cohort C1) .............................................................. 43 
2.2.4.3 
Rationale for combining SAR444245 with pembrolizumab ........................................................... 43 
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2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 43 
2.3.1 
Risk assessment ............................................................................................................................ 43 
2.3.1.1 
Aldesleukin experience .................................................................................................................. 44 
2.3.1.2 
SAR444245 .................................................................................................................................... 45 
2.3.1.3 
NKTR-214 (bempegaldesleukin) clinical data ................................................................................ 46 
2.3.1.4 
Pembrolizumab .............................................................................................................................. 47 
2.3.1.5 
SAR444245 combined with pembrolizumab and SAR444245 combined with 
pembrolizumab and chemotherapy regimen ................................................................................. 48 
2.3.2 
Benefit assessment ........................................................................................................................ 48 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 49 
2.3.4 
Benefit and risk assessment in the context of COVID-19 pandemic ............................................. 50 
2.3.4.1 
Risks in the context of COVID-19 .................................................................................................. 50 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 52 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 53 
4 
STUDY DESIGN ............................................................................................................................ 54 
4.1 
OVERALL DESIGN ........................................................................................................................ 54 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 59 
4.2.1 
Participant input into design ........................................................................................................... 60 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 60 
4.3.1 
SAR444245 dose ........................................................................................................................... 60 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 62 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 63 
5 
STUDY POPULATION .................................................................................................................. 64 
5.1 
INCLUSION CRITERIA .................................................................................................................. 64 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 67 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 71 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 71 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 71 
5.3.3 
Activity ............................................................................................................................................ 71 
5.3.4 
Hydration ........................................................................................................................................ 72 
5.4 
SCREEN FAILURES...................................................................................................................... 72 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
SCREENING/ENROLLMENT/ADMINISTRATION OF STUDY INTERVENTION ......................... 72 
6 
STUDY INTERVENTION AND CONCOMITANT THERAPY ........................................................ 73 
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6.1 
STUDY INTERVENTIONS ADMINISTERED ................................................................................ 73 
6.1.1 
Investigational medicinal product ................................................................................................... 73 
6.1.2 
Non-investigational medicinal products ......................................................................................... 74 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 74 
6.1.2.2 
Premedication for pemetrexed ....................................................................................................... 75 
6.1.2.3 
Premedication for cisplatin ............................................................................................................. 75 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 75 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 76 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 76 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 77 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 77 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 77 
6.5.1 
Acceptable concomitant medications ............................................................................................. 78 
6.5.2 
Prohibited concomitant medications .............................................................................................. 78 
6.6 
DOSE MODIFICATION .................................................................................................................. 79 
6.6.1 
General rules .................................................................................................................................. 79 
6.6.2 
Cycle delay and dose omission ..................................................................................................... 80 
6.6.3 
General guidelines for the management of treatment-related adverse events ............................. 81 
6.6.4 
Dose modification for chemotherapy ............................................................................................. 81 
6.6.4.1 
Dose modification for cisplatin, carboplatin and pemetrexed ........................................................ 82 
6.6.4.2 
Dose modification for nab-paclitaxel .............................................................................................. 83 
6.6.5 
Guidelines for the management of specific adverse events .......................................................... 84 
6.6.5.1 
Infusion-related reactions (IRR) ..................................................................................................... 84 
6.6.5.2 
Anaphylaxis .................................................................................................................................... 87 
6.6.5.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 87 
6.6.5.4 
Immune-related adverse events .................................................................................................... 89 
6.6.5.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 92 
6.6.5.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 93 
6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 95 
6.8 
TREATMENT OF OVERDOSE ...................................................................................................... 95 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 96 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 96 
7.1.1 
Permanent discontinuation ............................................................................................................ 96 
7.1.1.1 
Unacceptable adverse events leading to permanent intervention discontinuation ........................ 97 
7.1.2 
Temporary discontinuation ............................................................................................................. 97 
7.1.3 
Rechallenge ................................................................................................................................... 98 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 98 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 99 
8 
STUDY ASSESSMENTS AND PROCEDURES ......................................................................... 100 
8.1 
EFFICACY ASSESSMENTS ....................................................................................................... 100 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) .............................................................................................. 101 
8.2 
SAFETY ASSESSMENTS ........................................................................................................... 102 
8.2.1 
Physical examinations ................................................................................................................. 103 
8.2.2 
Vital signs ..................................................................................................................................... 103 
8.2.3 
Electrocardiograms and LVEF ..................................................................................................... 103 
8.2.4 
Clinical safety laboratory assessments ........................................................................................ 104 
8.2.5 
Pregnancy testing ........................................................................................................................ 104 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................. 105 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................. 105 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................. 106 
8.3.3 
Follow-up of AEs and SAEs ......................................................................................................... 106 
8.3.4 
Regulatory reporting requirements for SAEs ............................................................................... 106 
8.3.5 
Pregnancy .................................................................................................................................... 106 
8.3.6 
Cardiovascular and death events ................................................................................................ 107 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ......... 107 
8.3.8 
Adverse event of special interest ................................................................................................. 107 
8.3.9 
Guidelines for reporting product complaints ................................................................................ 109 
8.4 
PHARMACOKINETICS ................................................................................................................ 109 
8.5 
PHARMACODYNAMICS ............................................................................................................. 109 
8.6 
GENETICS AND/OR PHARMACOGENOMICS .......................................................................... 109 
8.7 
BIOMARKERS ............................................................................................................................. 110 
8.8 
IMMUNOGENICITY ASSESSMENTS ......................................................................................... 111 
8.9 
HEALTH ECONOMICS ................................................................................................................ 111 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH .............................. 111 
9 
STATISTICAL CONSIDERATIONS ............................................................................................ 113 
9.1 
STATISTICAL HYPOTHESES ..................................................................................................... 113 
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9.2 
SAMPLE SIZE DETERMINATION ............................................................................................... 113 
9.3 
POPULATIONS FOR ANALYSES ............................................................................................... 114 
9.4 
STATISTICAL ANALYSES .......................................................................................................... 115 
9.4.1 
General considerations ................................................................................................................ 115 
9.4.2 
Primary endpoint(s) ...................................................................................................................... 116 
9.4.3 
Secondary endpoint(s) ................................................................................................................. 116 
9.4.3.1 
Time to response ......................................................................................................................... 116 
9.4.3.2 
Duration of response .................................................................................................................... 116 
9.4.3.3 
Clinical benefit rate....................................................................................................................... 116 
9.4.3.4 
Progression-free survival ............................................................................................................. 117 
9.4.3.5 
Adverse events ............................................................................................................................ 117 
9.4.3.6 
Clinical laboratory evaluations ..................................................................................................... 118 
9.4.3.7 
Other secondary endpoints .......................................................................................................... 119 
9.4.4 
Tertiary/exploratory endpoint(s) ................................................................................................... 119 
9.4.4.1 
Exploratory antitumor indicators .................................................................................................. 119 
9.4.4.2 
Biomarker endpoints .................................................................................................................... 119 
9.4.5 
Other safety analyse(s) ................................................................................................................ 119 
9.4.6 
Other analyse(s) ........................................................................................................................... 120 
9.5 
INTERIM ANALYSES .................................................................................................................. 120 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 121 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS .... 121 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 121 
10.1.2 
Financial disclosure...................................................................................................................... 122 
10.1.3 
Informed consent process ............................................................................................................ 122 
10.1.4 
Data protection ............................................................................................................................. 123 
10.1.5 
Committees structure ................................................................................................................... 125 
10.1.6 
Dissemination of clinical study data ............................................................................................. 125 
10.1.7 
Data quality assurance ................................................................................................................ 126 
10.1.8 
Source documents ....................................................................................................................... 127 
10.1.9 
Study and site start and closure ................................................................................................... 127 
10.1.10 Publication policy ......................................................................................................................... 128 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 128 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 130 
10.3.1 
Definition of AE ............................................................................................................................ 130 
10.3.2 
Definition of SAE .......................................................................................................................... 132 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 133 
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10.3.4 
Reporting of SAEs........................................................................................................................ 135 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 135 
10.4.1 
Definitions .................................................................................................................................... 135 
10.4.2 
Contraception guidance ............................................................................................................... 136 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 138 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 139 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 139 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1 ........ 141 
10.9 
 .................................................................................................................... 146 
10.9.1 
Response and stable disease duration (RECIST 1.1
) ........................................... 148 
10.9.2 
Methods of measurement ............................................................................................................ 148 
10.10 
APPENDIX 10: MODIFIED RECIST CRITERIA FOR MESOTHELIOMA ................................... 149 
10.10.1 Target lesion measurements ....................................................................................................... 149 
10.10.2 Non-target lesion measurements ................................................................................................. 150 
10.10.3 Definitions of response ................................................................................................................ 150 
10.10.4 Pseudo-progression ..................................................................................................................... 150 
10.11 
APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 150 
10.11.1 Informed consent ......................................................................................................................... 151 
10.11.2 Study procedures ......................................................................................................................... 151 
10.11.3 Statistical analysis ........................................................................................................................ 151 
10.11.4 Temporary discontinuation ........................................................................................................... 152 
10.12 
APPENDIX 12: RISK ASSESSMENT .......................................................................................... 152 
10.13 
APPENDIX 13: ASTCT ASSESSMENT FOR ICANS AND CRS ................................................ 157 
10.14 
APPENDIX 14: ABBREVIATIONS ............................................................................................... 159 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 161 
11 
REFERENCES ............................................................................................................................. 166 
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LIST OF TABLES  
Table 1 - Overview of study cohorts .............................................................................................................. 15 
Table 2 - Objectives and endpoints ............................................................................................................... 16 
Table 3 - Objectives and endpoints ............................................................................................................... 52 
Table 4 - Overview of cohorts ....................................................................................................................... 55 
Table 5 - Dose escalation rule of the modified toxicity probability interval-2 method ................................... 56 
Table 6 - Overview of IMP administered ....................................................................................................... 73 
Table 7 - Dose modification for chemotherapy agents ................................................................................. 82 
Table 8 - Recommended dose modifications for chemotherapy hematological toxicity ............................... 82 
Table 9 - Recommended dose modifications for chemotherapy non-hematological toxicity ........................ 82 
Table 10 - Recommended dose modifications for chemotherapy hematological and neurological toxicity .. 83 
Table 11 - Recommended dose modifications for chemotherapy non-hematological toxicity ...................... 83 
Table 12 - Pembrolizumab infusion reaction dose modification and treatment guidelines ........................... 85 
Table 13 - SAR444245 Infusion-related reaction dose modification and treatment guidelines .................... 86 
Table 14 - Guidelines for the management of suspected cytokine release syndrome (CRS) ...................... 87 
Table 15 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 90 
Table 16 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) . 93 
Table 17 - Guidelines for the management of Vascular Leak Syndrome (VLS) ........................................... 94 
Table 18 - Estimated objective response rate (ORR) and 90% CI for core phase ..................................... 113 
Table 19 - Estimated objective response rate (ORR) and 95% CI for Cohorts B1 and B2 (combining core 
and expansion phases) ............................................................................................................................... 114 
Table 20 - Populations for analyses ............................................................................................................ 114 
Table 21 - Protocol-required laboratory assessments ................................................................................ 129 
Table 22 - Japanese participants enrolled in either Cohorts B1 or C1 ....................................................... 140 
Table 23 - Risk assessment ........................................................................................................................ 152 
Table 24 - Encephalopathy assessment ICE tool for ICANS Grading ........................................................ 157 
Table 25 - ASTCT ICANS consensus grading for adults ............................................................................ 157 
Table 26 - ASTCT CRS consensus grading ............................................................................................... 158 
 
LIST OF FIGURES  
Figure 1 - Overall study schema ................................................................................................................... 20 
Figure 2 - Graphical study design ................................................................................................................. 28 
 
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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 lung cancer or pleural 
mesothelioma 
Brief title: 
A study of SAR444245 combined with other anticancer therapies for the 
treatment of participants with lung cancer or mesothelioma 
Rationale: 
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the interleukin (IL)-2 α receptor, while retaining stimulatory activity for cells expressing the 
moderate affinity IL-2 βγ receptor. Preclinical studies demonstrated that treatment with 
SAR444245 leads to polyclonal expansion of CD8+ T cells in murine and non-human primate 
(NHP) models while anti-PD1 antibody prevents T cell suppression through the programmed cell 
death-1/programmed cell death-ligand 1 (PD1/PD-L1) pathway. The combination of anti-PD1 
treatment with SAR444245 was tested in the syngeneic murine colon cancer Ct-26 model and 
induced enhanced anti-tumor activity 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 anti-PD1 monoclonal 
antibody pembrolizumab with the non-alpha IL-2 SAR444245, with or without chemotherapy, 
will result in a significant increase in the percentage of patients with lung cancer or pleural 
mesothelioma experiencing an objective response rate (ORR). 
Table 1 provides an overview by study intervention, disease type, and primary tumor assessment 
criteria of the different cohorts that will be assessed in the study.   
Table 1 - Overview of study cohorts  
Cohort 
Study intervention 
Disease 
Primary tumor 
assessment criteria 
A1 
SAR444245 + pembrolizumab as 1L therapy  
NSCLC, PD-L1 TPS ≥50% 
RECIST 1.1 
A2 
SAR444245 + pembrolizumab as 1L therapy 
NSCLC, PD-L1 TPS 1%-49% 
RECIST 1.1 
A3 
SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin as 1L therapy 
Non-squamous NSCLC 
RECIST 1.1 
B1 
SAR444245 + pembrolizumab as 2/3L therapy 
NSCLC 
RECIST 1.1 
B2 
SAR444245 + pembrolizumab 
+ nab-paclitaxel as 2/3L therapy 
NSCLC 
RECIST 1.1 
C1 
SAR444245 + pembrolizumab as 2/3L therapy 
Mesothelioma 
mRECIST 
1L = First-line; 2/3L = Second- or third-line; mRECIST  = Modified response evaluation criteria in solid tumors; NSCLC = Non-small cell lung 
cancer; PD-L1 = Programmed cell death-ligand 1; RECIST = Response evaluation criteria in solid tumors; TPS = Tumor proportion score. 
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Objectives and endpoints 
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the antitumor activity of SAR444245 
in combination with other anticancer therapies 
(see Table 1 for the description of study cohorts).  
• 
Objective response rate defined as the proportion of 
participants who have a confirmed CR or partial 
response (PR) determined by investigator, per 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 (1) for Cohort A1, Cohort A2, Cohort A3, 
Cohort B1 and Cohort B2; per modified RECIST 
(mRECIST) (2) for Cohort C1. 
Secondary 
• 
To confirm the dose and to assess the safety 
profile of SAR444245 when combined with other 
anticancer therapies. 
• 
Incidence of TEAEs, dose-limiting toxicities (DLT), 
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 gradings (3). 
• 
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 (for NSCLC) or mRECIST 
(for mesothelioma). 
• 
Duration of response (DoR), defined as the time from 
first tumor assessment at which the overall response 
was recorded as PR or CR that is subsequently 
confirmed until progressive disease (PD) determined 
by investigator per RECIST 1.1 (for NSCLC) or 
mRECIST (for mesothelioma) 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 
for NSCLC or mRECIST for mesothelioma). 
• 
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 (for NSCLC) or 
mRECIST (for mesothelioma) or death due to any 
cause, whichever occurs first. 
• 
To assess the plasma concentrations of 
SAR444245 when given in combination with 
pembrolizumab. 
• 
Plasma concentrations of SAR444245. 
• 
To assess the immunogenicity of SAR444245.  
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245. 
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Objectives 
Endpoints 
Exploratory 
Overall design: 
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245 combined with other anticancer 
therapies in participants with lung cancer or mesothelioma.  
Brief summary 
Cohort A1, Cohort A2 and Cohort A3 will assess the antitumor efficacy and safety of adding 
SAR444245 to therapeutic approaches with documented efficacy profile as 1L non-small cell lung 
cancer (NSCLC) therapy. Participants with previously untreated Stage IV NSCLC will be 
enrolled sequentially based on histology and PD-L1 tumor proportion score (TPS) to Cohort A1, 
Cohort A2 and Cohort A3.  
• Cohort A1: participants with PD-L1 TPS ≥50% NSCLC, to receive SAR444245 
+ pembrolizumab as 1L therapy. 
• Cohort A2: participants with PD-L1 TPS 1%-49% NSCLC, to receive SAR444245 
+ pembrolizumab as 1L therapy. 
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• Cohort A3: participants with non-squamous NSCLC, to receive SAR444245 
+ pembrolizumab + pemetrexed + carboplatin/cisplatin as 1L therapy. 
Cohort B1 and Cohort B2 will assess SAR444245-based therapies as 2/3L NSCLC therapy when 
receiving standard of care (SOC) is not in the best interest of participants or where no SOC is 
established. 
• Cohort B1: participants with NSCLC, to receive SAR444245 + pembrolizumab as 
2/3L therapy. 
• Cohort B2: participants with NSCLC, to receive SAR444245 + pembrolizumab 
+ nab-paclitaxel as 2/3L therapy. 
Cohort C1 will evaluate SAR444245-based therapy as 2/3L mesothelioma treatment where no 
SOC is well established. Participants with mesothelioma who have experienced disease 
progression during or after at least 1 but no more than 2 prior regimens (detailed in Section 5.1 
Inclusion Criteria I 06) will be enrolled  
• Cohort C1: participants with mesothelioma, to receive SAR444245 + pembrolizumab as 
2/3L therapy. 
The study consists of a safety run-in and core phase for all 6 cohorts, and an expansion phase for 
Cohorts B1 and/or B2. In the core phase approximately 40 participants at the confirmed safe dose 
will be enrolled per cohort. The results of an interim analysis will decide if the expansion phase 
will be opened for Cohorts B1 and/or B2. Approximately 57 additional participants are planned to 
be enrolled in each cohort in the expansion phase in order to better assess antitumor activity. 
A graphical presentation of the study schema is shown in Figure 1.  
A safety run-in will confirm the dose of SAR444245 in each regimen tested in this study, 
namely: SAR444245 + pembrolizumab; SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin; SAR444245 + pembrolizumab + nab-paclitaxel. Participants who 
fulfill the eligibility criteria of any cohort testing the regimen may be enrolled to the safety run-in 
of that regimen. Participants will be enrolled across Cohorts A1, A2, B1 and C1 to receive 
SAR444245 and pembrolizumab. Enrollment will be paused once at least 6 participants are 
evaluable for DLT. Safety data for these participants will be reviewed by a Study Board (SB) 
comprising Investigators or designees participating in the safety run-in part of applicable cohorts 
and the Sponsor clinical team members. DLT-evaluable participants include all treated 
participants in the safety run-in who have been observed for at least 21 days. Any participant who 
experienced a DLT during the first 21 days will also be DLT-evaluable. If no safety concerns are 
identified by the SB, participant enrollment will continue for the 4 cohorts. If after recruiting the 
first 10 participants there are fewer than 6 participants evaluable for DLT, more participants will 
be enrolled to ensure at least 6 DLT evaluable participants after agreement from SB. Participants 
who are enrolled in the safety run-in and treated at the confirmed safe dose will be included in the 
total number of participants in the core phase for that specific cohort (for example, if 3 Cohort A1 
participants are enrolled in the safety run-in and treated at the confirmed safe dose, approximately 
37 additional participants will be enrolled into Cohort A1 to have the total number of 
40 participants). 
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The safety run-in for other regimens (ie, SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin; and SAR444245 + pembrolizumab + nab-paclitaxel) will not be 
opened until the SAR444245 + pembrolizumab dose is confirmed, and enrollment of Cohort A2 
and Cohort B1, respectively, is completed. Details of the opening sequence of the different 
cohorts are described below. 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an IV infusion over 
30 minutes every 3 weeks on Day 1 of each cycle (21 days per cycle). Overall safety monitoring 
will be performed throughout the study. If recommended by the SB, SAR444245 dose level may 
be reduced to 
 or another lower dose level which will be explored following the 
same process described in the safety run-in for 24 μg/kg dose level.  
The DLT observation period is 21 days and will take into account the occurrence of DLT. The dose 
confirmation will follow modified toxicity probability interval 2 (mTPI2) design. 
Dose limiting toxicity: Selected events occurring during the DLT observation period (21 days of 
first cycle) are considered as DLT unless due to disease progression or to a cause obviously 
unrelated to SAR444245. Please refer to the full list of events in Section 4.1. Based on the 
occurrence of DLT and overall assessment of safety data supplemented with data from other 
SAR444245 studies, the SB will determine if the dose of SAR444245 needs to be reduced to 
 or another lower dose level, in agreement with the Sponsor.  
Safety run-in and core phase enrollment sequence 
SAR444245 and pembrolizumab - Cohorts A1, A2, B1 and C1 
As the safety run-in of this regimen is opened first, Cohorts A1, A2, B1 and C1 will be the initial 
cohorts to enroll. 
SAR444245, pembrolizumab, pemetrexed, and carboplatin/cisplatin - Cohort A3  
Once enrollment is completed for Cohort A2, the safety run-in of Cohort A3 can be conducted, 
with up to 10 participants enrolled to receive SAR444245, pembrolizumab, pemetrexed, and 
carboplatin/cisplatin prior to an enrollment pause. If Cohort A1 is still enrolling when Cohort A3 
is opened, a participant who is eligible for both Cohorts A1 and A3 should be enrolled in Cohort 
A1 until Cohort A1 enrollment is completed. 
SAR444245, pembrolizumab, and nab-paclitaxel - Cohort B2  
Once enrollment is completed for Cohort B1, the safety run-in of Cohort B2 can be conducted, 
with up to 10 participants enrolled to receive SAR444245, pembrolizumab, and nab-paclitaxel 
prior to an enrollment pause.   
Additional cohorts with different regimens or indications may be added to this protocol. 
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Figure 1 - Overall study schema  
  
*Total number in Core Phase including patients in Safety Run-in at the confirmed safe dose 
1L: First-line; 2/3L: Second- or third-line; NSCLC: Non-small cell lung cancer; NSq: Non-squamous; pembro: pembrolizumab; PD1/PD-L1: Programmed cell death 1/ ligand 1; Plt: carboplatin/cisplatin; 
peme: pemetrexed; SB: Study Board; SAR: SAR444245; TPS: Tumor proportion score. 
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Special considerations pertaining to methodology  
Interactive Response Technology will be used to control recruitment, assignment per site and 
facilitate drug supply. 
Number of participants: 
Overall in the core phase (all cohorts), approximately 40 participants will be enrolled and treated 
at the confirmed safe dose per cohort. 
In the expansion phase (Cohorts B1 and/or B2), approximately 57 participants will be enrolled 
and treated at the confirmed safe dose per cohort. 
Note: Enrolled participants are all participants from screened participants who have been 
allocated to an intervention regardless of whether the intervention was received or not.  
Intervention groups and duration: 
The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment Period: enrolled participants will receive continuous treatment until PD, 
unacceptable adverse event (AE), other full permanent discontinuation criteria as 
described in Section 7, or completion of Cycle 35 (for Cohorts, A1, A2, B1, B2 and C1).  
• End of Treatment and Follow-up: End of Treatment Visit will occur 30 days ±7 days 
from last IMP administration or prior to initiation of further therapy. Participants will then 
enter the Observation period and will be followed differently depending on the reason 
leading to End of Treatment (EOT): 
1. Participants who discontinue study treatment without radiological or clinical PD or 
who complete 35 cycles of treatment without PD (per RECIST 1.1 or mRECIST), 
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 radiological or clinical PD (per 
RECIST 1.1 or mRECIST) or
 (
) will be followed in the Follow-Up 
Visit 1 occurring 3 months ±7 days from last IMP administration before moving to the 
Survival Phone Call Follow-Up Period.  
Participants who move into the Survival Phone Call Follow-Up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Information on the first subsequent 
anticancer treatment, best reported response, and date of progression will also be collected. Updated 
survival status may be requested by the Sponsor at any time during the study. Survival Phone Call 
Follow up will continue until death, participant request to discontinue from follow-up, or final 
cohort cut-off, or upon cancellation of Survival Follow-up at the discretion of the Sponsor at any 
prior timepoint.  
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For Cohort A1, Cohort A2, Cohort A3 and Cohort C1, the cohort cut-off for the primary ORR 
endpoint analyses is estimated to be approximately 9 months from the date of the last participant’s 
first infusion in the core phase (to document that last participant response is maintained for 
6 months in the core phase). 
For Cohort B1 and Cohort B2, the cohort cut-offs for the analyses are as follows: 
• Interim analysis cut-off: the date on which all participants in the core phase have at least 
2 post-baseline tumor assessments with response durability demonstrated or discontinue 
study treatment (whichever occurs first).  
• Primary analysis cut-off: the date on which the last participant response is maintained for 
6 months in the expansion phase (approximately 9 months from last participant’s first 
infusion in the expansion phase). 
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 will be 3 years from the date of cohort last- 
patient-in, or when all patients within the cohort have completed the study.   
Study interventions 
Cohort A1 (NSCLC PD-L1 TPS ≥50%, SAR444245 + pembrolizumab as 1L therapy) 
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 
• Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion 
in a single-use vial with an extractable volume of 1mL. 
• Route of administration : IV infusion.  
• Dose regimen: 24 μg/kg (or reduced to 
 or another lower dose level 
recommended by SB) administered as an IV infusion over 30 minutes every 3 weeks on 
Day 1 of each cycle (21 days per cycle) for up to 35 cycles. 
Study sites should make every effort to target infusion duration to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted. 
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, preferably 30 to 60 minutes prior to 
SAR444245 infusion (ideally no longer than 60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or oral route (PO), 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 the next cycle. If no IRR is observed for the next cycle without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during the next cycle without premedication the participant 
experiences an IRR (any grade), premedication must be restarted for all subsequent cycles. 
• In case of permanent SAR444245 discontinuation and continuation of pembrolizumab 
treatment as part of AE management, premedication no longer needs to be administered. 
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Cohort A2 (PD-L1 TPS 1%-49% NSCLC, SAR444245 + pembrolizumab as 1L therapy) 
Dosing sequence: 
 
Investigational medicinal products 
Pembrolizumab and SAR444245, as described for Cohort A1. 
Noninvestigational medicinal products 
Premedication for SAR444245, as described for Cohort A1. 
Cohort A3 (non-squamous NSCLC, SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin as 1L therapy) 
Dosing sequence: 
For timing of pemetrexed premedication, please refer to the specific section below. 
Investigational medicinal products 
Pembrolizumab and SAR444245, as described for Cohort A1. 
Pemetrexed 
Pemetrexed will be administered 
• Formulation: pemetrexed is a concentrate for solution for infusion supplied in 
100 mg/4 mL (25 mg/mL) solution in single-dose vials (or any other formulation approved 
locally). 
• Route of administration: IV infusion. 
• Dose regimen: pemetrexed will be administered on Day 1 of each 21-day cycle as a 
500 mg/m2 IV infusion over approximately 10 mins until PD or unacceptable toxicity. 
Cisplatin 
Cisplatin will be administered
and administered according to local practice and labels. 
• Formulation: cisplatin 1 mg/mL sterile concentrate for solution for infusion supplied in 
single-dose vials (or any other formulation approved locally).  
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• Route of administration : IV infusion. 
• Dose regimen: 75 mg/m2 IV infusion administered according to locally approved label for 
4 cycles on Day 1 of each cycle. 
Carboplatin 
Carboplatin will be administered
 as per local 
practice and labels. 
• Formulation: carboplatin 10 mg/mL (or any other formulation approved locally). 
• Route of administration : IV infusion. 
• Dose regimen: AUC of 5 IV infusion over 15-60 min on Day 1 for 4 cycles on Day 1 of 
each cycle. 
Noninvestigational medicinal products 
Premedication for SAR444245, as described for Cohort A1. 
Premedication for pemetrexed 
All participants should receive the appropriate supplementation of vitamin B12 and folic acid and 
corticosteroid prophylaxis as listed below:  
• Folic acid 350-1000 μg oral: At least 5 daily doses of folic acid must be taken during the 
7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed. 
• Vitamin B12 1000 μg intramuscular injection in the week preceding the first dose of 
pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be 
given the same day as pemetrexed administration. 
• Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during Cycles 1-4 but not to exceed doses in MASCC 
(Multinational Association for Supportive Care in Cancer) guidelines (5). 
Cohort B1 (NSCLC, SAR444245 + pembrolizumab as 2/3L therapy) 
Dosing sequence:
 
Investigational medicinal products 
Pembrolizumab and SAR444245, as described for Cohort A1. 
Noninvestigational medicinal products 
Premedication for SAR444245, as described for Cohort A1. 
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Cohort B2 (NSCLC, SAR444245 + pembrolizumab + nab-paclitaxel as 2/3L therapy) 
Dosing sequence:
  
Investigational medicinal products 
Pembrolizumab and SAR444245, as described for Cohort A1. 
Nab-paclitaxel  
• Formulation: nab-paclitaxel (powder for suspension for infusion [or any other formulation 
approved locally]). 
• Route of administration: IV infusion. 
• Dose regimen: nab-paclitaxel will be administered as a 100 mg/m2 IV infusion over 
30 mins on Days 1 and 8 of each cycle for 6 cycles. 
Noninvestigational medicinal products 
Premedication for SAR444245, as described for Cohort A. 
Cohort C1 (mesothelioma, SAR444245 + pembrolizumab as 2/3L therapy) 
Dosing sequence:
Investigational medicinal products 
Pembrolizumab and SAR444245, as described for Cohort A1.  
Noninvestigational medicinal products 
Premedication for SAR444245, as described for Cohort A1. 
Statistical considerations: 
• Analysis of primary endpoint:  
- 
Objective response rate (ORR) and best overall response (BOR) will be summarized 
for the efficacy population with descriptive statistics. In addition, two-sided 90% CIs 
for ORR will be computed using the Clopper-Pearson method. 
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• Analysis of secondary efficacy endpoints:  
- 
The TTR will be summarized on the subgroup of participants who have achieved 
confirmed objective response in the efficacy population.  
- 
The DoR will only be summarized on the subgroup of participants who have achieved 
confirmed objective response in the efficacy population. 
- 
The CBR will be estimated by dividing the number of participants with clinical benefit 
by the number of participants in the efficacy population. 
- 
The PFS will be summarized on the efficacy population using Kaplan-Meier methods. 
The median PFS times and associated 90% CI will be provided. 
• Analysis of secondary safety endpoints: 
- 
Number and percentage of participants experiencing treatment-emergent adverse 
events (TEAEs) by primary System Organ Class and Preferred Term (PT) will be 
summarized by NCI-CTCAE V5.0 grade (all grades and Grade ≥3) for the exposed 
population. Similar summaries will be prepared for TEAEs related to SAR444245 and 
those related to other IMP components, TEAEs leading to permanent partial 
intervention discontinuation (any of the IMP components), TEAEs leading to full 
intervention discontinuation, TEAEs leading to dose modification, serious TEAEs, 
TEAEs with fatal outcome, adverse events of special interest (AESIs), and AEs/SAEs 
occurring during the post-treatment period. In addition, the number (%) of participants 
with any Grade 5 AE (TEAE and post-treatment) and participants who died by study 
period (treatment, post-treatment) 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 V5.0, when applicable. Number and percentage of participants with 
laboratory abnormalities (all grades and by grade) using the worst grade during the on-
treatment period will be provided for the exposed population. 
• Analysis of other secondary endpoints: 
- 
Plasma concentrations of SAR444245 will be summarized with descriptive statistics 
by each cohort.  
Independent Data Monitoring Committee: Yes (see Section 10.1.5 for details) 
 
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1.2 
SCHEMA  
Figure 2 - Graphical study design  
 
C = Study cycle (1 cycle = 21 days); D = Study day; EOT End of treatment; FU = Follow up; Q9W = Every 9 weeks; Q12W = Every 12 weeks; IMP = Investigational product. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
  
Screening 
Treatment periodb  
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Evaluationa  
  
Cycle 1 
Cycle 2 Cycle 3-6 Cycle 
7-35 
Cycle 36 
and 
beyond 
EOT Visit 
Follow- 
up 
Visit 1 
Follow- 
up 
Visit 2 
Follow-
up Visit 3 
and 
beyond 
Phone call 
Follow-up 
Cycle day 
(Visit window in 
Days) 
D-28 to D-1 D1 D2 D3e D8 
(±1) 
D15f 
(±1) 
D1 
(±3)  
D8g 
(±1)  
D1 
(±3) 
D8g 
(±1)  
D1 
(±3) D1 (±3) 
30 (±7) days 
after last 
IMP admin 
or prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin  
6 
months 
(±7 days) 
from last 
IMP 
admin  
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Informed consent/ 
Inclusion/Exclusion 
criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
IRT contact 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical 
and disease history 
X 
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
See Section 8 
Performance status 
(ECOG)  
X 
X 
  
  
X 
 X 
X 
  
X 
  
X 
X 
X 
X 
  
  
  
 
Body weight/ 
Heighth 
X 
X 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
Full physical 
examination 
X 
  
  
  
   
  
  
  
  
  
  
  
X 
  
  
  
  
 
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Screening 
Treatment periodb  
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Evaluationa  
  
Cycle 1 
Cycle 2 Cycle 3-6 Cycle 
7-35 
Cycle 36 
and 
beyond 
EOT Visit 
Follow- 
up 
Visit 1 
Follow- 
up 
Visit 2 
Follow-
up Visit 3 
and 
beyond 
Phone call 
Follow-up 
Cycle day 
(Visit window in 
Days) 
D-28 to D-1 D1 D2 D3e D8 
(±1) 
D15f 
(±1) 
D1 
(±3)  
D8g 
(±1)  
D1 
(±3) 
D8g 
(±1)  
D1 
(±3) D1 (±3) 
30 (±7) days 
after last 
IMP admin 
or prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin  
6 
months 
(±7 days) 
from last 
IMP 
admin  
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Directed physical 
examination 
 
X  X 
X  
 X 
 X 
X 
 Xf 
X 
 Xf 
X 
X 
 
X 
  
  
  
See 
Section 8.2.1 
Vital signs 
X 
X X  
 X 
X 
 X 
X 
 Xf 
X 
 Xf 
X 
X 
X 
X 
  
  
  
See 
Section 8.2.2 
SpO2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory and other investigations 
 
12-Lead ECG 
X 
As clinically indicated 
 
 
 
See 
Section 8.2.3 
LVEF 
X 
As clinically indicated 
 
 
 
See 
Section 8.2.3 
Pregnancy test 
 X 
X    
  
   
  
X 
  
X 
  
X 
X 
X 
 X 
 X 
  
  
See 
Section 8.3.5 
and 
Section 10.2 
Blood chemistry/ 
hematology 
X 
X X  
 X 
X 
X  
X 
  
X 
  
X 
X 
X 
X 
  
  
  
See 
Section 10.2 
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Screening 
Treatment periodb  
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Evaluationa  
  
Cycle 1 
Cycle 2 Cycle 3-6 Cycle 
7-35 
Cycle 36 
and 
beyond 
EOT Visit 
Follow- 
up 
Visit 1 
Follow- 
up 
Visit 2 
Follow-
up Visit 3 
and 
beyond 
Phone call 
Follow-up 
Cycle day 
(Visit window in 
Days) 
D-28 to D-1 D1 D2 D3e D8 
(±1) 
D15f 
(±1) 
D1 
(±3)  
D8g 
(±1)  
D1 
(±3) 
D8g 
(±1)  
D1 
(±3) D1 (±3) 
30 (±7) days 
after last 
IMP admin 
or prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin  
6 
months 
(±7 days) 
from last 
IMP 
admin  
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
T3, FT4, TSH and 
cortisoli 
X 
  
  
  
  
  
X 
  
X 
  
X 
X 
X 
X 
  
  
  
See 
Section 10.2 
Coagulation 
X 
As clinically indicated 
 
  
  
  
See 
Section 10.2 
Urinalysisj 
X 
X 
  
  
  
  
  
  
X 
  
X 
X 
X 
X 
  
  
  
See 
Section 10.2 
Hepatitis serology, 
CD4 counts and 
viral load 
 X 
As clinically indicated 
 
 
 
See 
Section 10.2 
IMP  
  
X 
  
  
 Xk  
  
X 
 Xk  
Xr 
Xk  
X 
Xl 
  
 
 
 
 
 
Prior Medication 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalizationm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE/SAE 
assessmentn 
X 
Continuous throughout treatment period 
X 
 
 
 
See 
Section 8.3 
Concomitant Meds 
X 
Continuous throughout treatment period 
 
 
 
 
See 
Section 6.5 
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Screening 
Treatment periodb  
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Evaluationa  
  
Cycle 1 
Cycle 2 Cycle 3-6 Cycle 
7-35 
Cycle 36 
and 
beyond 
EOT Visit 
Follow- 
up 
Visit 1 
Follow- 
up 
Visit 2 
Follow-
up Visit 3 
and 
beyond 
Phone call 
Follow-up 
Cycle day 
(Visit window in 
Days) 
D-28 to D-1 D1 D2 D3e D8 
(±1) 
D15f 
(±1) 
D1 
(±3)  
D8g 
(±1)  
D1 
(±3) 
D8g 
(±1)  
D1 
(±3) D1 (±3) 
30 (±7) days 
after last 
IMP admin 
or prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin  
6 
months 
(±7 days) 
from last 
IMP 
admin  
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
First subsequent 
anticancer therapy  
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PDy)/Immunogenicity assessments 
 
PK 
See PK Flow-Chart in Section 1.5 
 
ADA 
 
PDy - Blood and 
tumor tissue 
collectiono  
See Biomarkers Flow-Chart in Section 1.4 
 
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Screening 
Treatment periodb  
End of 
treatment 
Observation periodc 
Survival 
phone call 
follow-up 
periodd 
Notes 
Evaluationa  
  
Cycle 1 
Cycle 2 Cycle 3-6 Cycle 
7-35 
Cycle 36 
and 
beyond 
EOT Visit 
Follow- 
up 
Visit 1 
Follow- 
up 
Visit 2 
Follow-
up Visit 3 
and 
beyond 
Phone call 
Follow-up 
Cycle day 
(Visit window in 
Days) 
D-28 to D-1 D1 D2 D3e D8 
(±1) 
D15f 
(±1) 
D1 
(±3)  
D8g 
(±1)  
D1 
(±3) 
D8g 
(±1)  
D1 
(±3) D1 (±3) 
30 (±7) days 
after last 
IMP admin 
or prior to 
initiation of 
further 
therapy 
3 months 
(±7 days) 
from last 
IMP 
admin  
6 
months 
(±7 days) 
from last 
IMP 
admin  
Every 
3 months 
±7 days 
Every 
3 months 
±14 days 
 
Tumor assessment 
 
CT/MRIp  
X 
  
  
  
   
  
  
  
X 
  
X 
X 
X 
X 
X 
X 
  
See 
Section 8.1.1  
Brain imagingq 
X 
  
  
  
   
  
  
  
  
  
  
  
  
  
  
  
  
See 
Section 8.1.1 
a Evaluation: Screening assessments to be performed prior to first IMP administration unless otherwise indicated. Baseline evaluations should be completed within 7 days prior to the first dose of IMP, except for 
tumor assessment that may be performed within 28 days prior to IMP administration, and unless specified otherwise. There is no need to perform Cycle 1 Day 1 laboratory assessments that have been performed 
as part of screening within 3 days prior to 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. Information on the first subsequent anticancer treatment, best reported response, and date of progression will also be 
collected. Updated survival status may be requested by the Sponsor at any time during the study. 
e Visit and assessments on C1D3 are only for participants in the safety run-in. 
f 
 C1D15 visits must be performed for participants enrolled in the safety run-in. For all other participants, the Study Board may decide to cancel safety assessment on C1D15, upon agreement with Sponsor, and if 
justified by safety data. 
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g Only for Cohort B2. 
h 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. 
i 
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. 
j 
Urinalysis will be performed every 4 cycles during Treatment Period and as clinically indicated.  
k Nab-paclitaxel dosing on Days 1 and 8 of each cycle for 6 cycles, only for Cohort B2. 
l 
Only for pemetrexed. 
m Only for safety run-in participants. See requirements specific to Japan in Section 10.7. 
n 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 (3). 
 
o If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. Tumor biopsy during treatment period should be limited to non-target lesions or new 
lesions if their pathologic etiology is ambiguous. 
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. 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. 
q 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. Participants 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. 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 prior anti-cancer therapy. Participants with 
previously treated brain metastases may participate provided they are stable, which is defined as lack of progression on two sets of imaging obtained at least 4 weeks apart. Stability as defined above should be 
documented prior to the first dose of trial treatment. In addition, any neurologic symptoms must have returned to baseline or resolved, and the participant is not using steroids for at least 14 days prior 
to study treatment. The screening brain scan may be collected up to 42 days prior to enrollment.  
r 
For carboplatin/cisplatin dosing, only in Cycles 3 and 4. 
Abbreviations: ADA = anti-drug antibodies; AE = adverse event; ASTCT = American Society for Transplantation and Cellular Therapy; C = Cycle; CT = computed tomography; D = Day; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = End-of-treatment;  FT4 = free thyroxine; FU = Follow-up visit; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency 
virus; ICANS = immune effector cell-associated neurotoxicity syndrome; ICF = informed consent form; IMP = investigational medicinal product; LVEF = left ventricular ejection fraction; MRI = magnetic resonance 
imaging;  NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSCLC = non-small cell lung cancer; PD = progressive disease; PDy = pharmacodynamic;  
PK = pharmacokinetic; PR = partial response; Q3W = every 3 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; i
; mRECIST = Modified RECIST;  
SAE = serious adverse event; SpO2: oxygen saturation; TSH = thyroid stimulating hormone. 
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1.4 
BIOMARKER FLOWCHART  
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1.5 
PHARMACOKINETIC FLOWCHART  
The sampling time-points for PK and ADA for/against SAR444245 and/or other IMPs may be 
updated during the course of the study based on the updated knowledge of drug behavior and 
upon notification from the Sponsor. See requirements specific to Japan in Section 10.7. 
1.5.1 All cohorts  
 
Cycle 
Treatment Cycle 1 
Treatment Cycle 2, 4, 
7, 10 + every 5th cycle EOT visit 
Day 
D1 
D2 
D3a 
D8 
D1 
Time after start of 
SAR444245 dosing 
SOI 
EOI 
At any time 
At any time At any time 
SOI 
EOI 
30 (±7) days 
after last IMP 
administration  
SAR444245 PK sample 
ID 
 
P00b 
P01 
P02 
 
 
P00b 
 
SAR444245 ADA 
sample ID 
AB00c 
 
 
 
AB01 
AB00c 
 
ABF00 
a Day 3 sampling only for participants in the safety run-in who have a Day 3 visit 
b PK sample must be taken at EOI after flush 
c Samples collected strictly before start of infusion (SOI) 
Abbreviations: ADA: anti-drug antibodies; D: day; EOT: end of treatment; PK: pharmacokinetic. 
 
 
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2 
INTRODUCTION  
SAR444245 is a recombinant human IL-2 with a site-specific substitution of a non-native azido 
lysine amino acid residue which is bio-conjugated to a single linear 30 kDa PEG. SAR444245 is 
being developed as an immuno-oncology treatment to be administered every 2 weeks (Q2W) or 
less frequently (every 3 weeks [Q3W] in the present study) in patients with cancer.
. The site-specific pegylation of IL-2 in SAR444245 provides a 
“non alpha” pharmacologic profile for SAR444245 that is designed to prevent engagement of the 
high affinity IL-2Rα, while maintaining CD8+ T cell anti-tumor activity and resulting in an 
improved safety profile relative to aldesleukin. Aldesleukin is approved in the United States (US) 
for the following indications: the treatment of metastatic renal cell carcinoma (RCC) and 
metastatic melanoma, with the same or limited approval status in other countries. Its use has 
resulted in durable CR in some patients with anti-tumor effects via elevations in CD8+ T cells 
(naïve, effector, and memory T cells). However, widespread use of aldesleukin is limited by its 
low response rate, short half-life (t1/2), and severe toxicities including primarily vascular leak 
syndrome (VLS), and cytokine release syndrome (CRS). 
In contrast to native IL-2 and aldesleukin, SAR444245 does not have high potency at the 
IL-2Rα/β/γ receptor expressed on Treg cells because the site-specific pegylation blocks IL-2Rα 
engagement. Due to this re-programmed receptor bias, SAR444245 induces proliferation of 
peripheral CD8+ T and natural killer (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 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 demonstrated enhanced anti-tumor 
activity and prolonged survival compared to each monotherapy. These data support evaluation of 
SAR444245 in combination with pembrolizumab. 
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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. For more details on specific indications refer to the pembrolizumab 
Investigator’s Brochure (IB). 
Refer to the 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 (6). 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, and 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 (7, 8). 
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) (9, 10). 
The structure of murine PD1 has been resolved (11). 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 (10, 12, 13, 14). 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 (15, 16). 
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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 
(17, 18, 19, 20, 21, 22, 23). 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 (11, 20, 22, 23, 24). 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 (22). 
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 the pembrolizumab IB). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.1. 
2.2.2 Rationale for NSCLC and selected participant population (Cohorts A1, A2, A3, 
B1 and B2)  
Worldwide, lung cancer remains the leading cause of cancer incidence and its mortality is 
projected to reach 2.45 million worldwide by 2030, a 39% increase in just over a decade (25). 
NSCLC accounts for approximately 85% of all lung cancer cases, with 2 broad histologic 
subtypes, squamous cell carcinoma and non-squamous cell carcinoma (majority is 
adenocarcinoma) (26).  
2.2.3 Current standard of care in NSCLC  
2.2.3.1 PD1/PD-L1 inhibitor monotherapy or in combination with chemotherapy as 
first-line therapy  
Prominent adaptive antitumor immune responses have been documented by direct analysis of 
immune cell populations and indirectly by measuring tumor PD-L1 expression, interferon 
gamma–related signatures, or multimarker transcriptomic profiles (27, 28, 29, 30). Using 
immunohistochemistry (IHC), PD-L1 expression in greater than or equal to 1% of tumor cells has 
been reported in approximately 60% of advanced NSCLC and with high levels (eg, ≥50% of 
tumor cells) in 25% to 30% of cases (31, 32). Analysis of specific T-cell populations reveals that 
NSCLC tumors contain higher CD3+ TILs, CD8+ cytotoxic cells, and CD8+/CD45R0+ effector 
memory cells than non-tumor lung (33, 34, 35, 36, 37). Elevated levels of these T-cell subsets have 
been consistently associated with better outcomes, confirming their antitumor nature (38, 39).   
The KEYNOTE 024 trial reported a significant improvement in overall survival (OS) for 
pembrolizumab monotherapy in an equally selected population, mostly generated in the subgroup 
of patients with high PD-L1 expression (≥50%) (40). In the KEYNOTE 042 trial, a significant 
benefit with 1L pembrolizumab compared with platinum-based chemotherapy was revealed by 
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using a lower selection threshold, PD-L1 ≥1% (41). The KEYNOTE 021 trial was the first 
Phase 2 randomized study reporting improved outcome (ORR: 56.7% versus 30.2%; 
PFS: 24.0 months versus 9.3 months; and OS: not reached versus 21.0 months) with upfront 
pembrolizumab-chemotherapy combinations in unselected patients with non-squamous advanced 
NSCLC compared with chemotherapy alone (platinum plus pemetrexed) (42). These results were 
confirmed by the Phase 3 KEYNOTE 189 trial (43) in all PD-L1 subsets, even PD-L1-negative 
tumors (44). Pembrolizumab is therefore approved in combination with platinum and pemetrexed 
as the first-line therapy for non-squamous NSCLC in both the EU (45) and the US (46). 
Pembrolizumab monotherapy is also approved as the first-line therapy to treat patients with 
TPS ≥1% NSCLC in the US, and to treat patients with NSCLC TPS ≥50% in the EU. 
2.2.3.2 Second- or third-line treatment options for patients who have progressed on or 
after PD1/PD-L1-based therapy  
According to the American Society of Clinical Oncology (ASCO) and European Society for 
Medical Oncology (ESMO) clinical practice guidelines (47, 48), following disease progression 
after PD1/PD-L1-based therapy (which may include chemotherapy) as 1L or 2L therapy, patients 
without driver gene mutations may receive a variety of combinations of cytotoxic chemotherapies, 
pemetrexed (for non-squamous histology), docetaxel, or docetaxel plus ramucirumab as 
second- or third-line therapy depending on prior chemotherapies received, contraindications and 
patients’ decision. Clinical studies may be offered to patients who are ineligible or decline further 
chemotherapy. 
Despite the progress made in the clinical management of advanced NSCLC with 
PD1/PD-L1-based therapies, prognosis of the disease has not improved substantially. Early 
success with PD1 axis inhibitors has improved 5-year long-term survival rates from 9%-13% to 
approximately 15%-23% of patients with advanced NSCLC (49, 50, 51, 52, 53, 54). The 
treatment of NSCLC remains a highly unmet medical need. 
2.2.3.3 Nab-Paclitaxel as second-line therapy  
Despite the availability of second- or third-line therapy, the trend of increased use of pemetrexed 
in 1L and maintenance settings potentially limits the available second- or third-line treatment 
options for many patients. Furthermore, not all patients are able to tolerate docetaxel or 
combination chemotherapies. Nab-Paclitaxel exhibits a 10-fold mean increase of the Cmax of free 
paclitaxel and delivers a 33% higher drug concentration to tumors in preclinical xenograft models 
(55, 56). When administered (without steroid premedication) with carboplatin in the first-line 
setting, weekly nab-paclitaxel has demonstrated a more favorable efficacy and safety profile 
compared to Q3W schedule. Recently published data have demonstrated efficacy of 
nab-paclitaxel as monotherapy in the second-line setting in advanced non-squamous NSCLC with 
16.3% response rate (57). One of the regimens this study will assess is weekly nab-paclitaxel, 
administered on Days 1 and 8 of each 21-day cycle. The allowance of a one-week rest period in 
this study (ie, no treatment on Day 15), takes into account research findings from other taxanes, 
whereby patients in the second-line setting are unlikely to tolerate the same dose-intensity 
compared to chemo-naïve patients (eg, sharper dose reduction in the second-line setting). 
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2.2.3.4 Interleukin-2 as a treatment option for NSCLC  
In contrast to agents that block immune checkpoints, IL-2-based cytokine treatments target the 
IL-2Rβγ pathway, thereby augmenting lymphocyte responses. For more than 20 years, 
single-agent IL-2 (aldesleukin) treatment has shown efficacy in metastatic melanoma and RCC, 
but there have been only anecdotal reports of efficacy in other cancers including NSCLC. 
Moreover, effective aldesleukin treatment requires doses that invariably generate substantial 
toxicity, necessitating inpatient administration and intensive supportive care, restricting its 
widespread use (58).  
Bempegaldesleukin (NKTR-214) is an investigational engineered IL-2 cytokine prodrug that 
provides sustained activation of the IL-2 pathway with a bias to IL-2Rβ. It has been shown to 
increase TILs, T-cell clonality, and PD-L1 expression (59, 60). The safety and clinical activity of 
bempegaldesleukin plus the immune checkpoint inhibitor (ICI) nivolumab were evaluated in 
PIVOT-02, a multicenter Phase 1/2 study in various advanced solid tumors (61, 62, 63, 64, 65). 
The combination was tolerable and showed encouraging clinical activity, regardless of baseline 
PD-L1 status (64) with durable responses that deepened over time (65). Bempegaldesleukin plus 
nivolumab was shown to convert baseline tumors from PD-L1(-) to PD-L1(+) (61, 62, 63, 64) 
which was associated with clinical benefit (61). Based on these data, bempegaldesleukin plus 
nivolumab received Breakthrough Therapy Designation from the US Food and Drug 
Administration for patients with previously untreated, unresectable or metastatic melanoma. 
Two multiple-cohort early phase clinical studies assessing efficacy of bempegaldesleukin with ICI 
monotherapy, ICI-CTLA4 combination, or ICI-chemotherapy combination in NSCLC in addition 
to other solid tumors, are currently enrolling globally (PIVOT-02 NCT02983045 and 
PROPEL NCT03138889). Preliminary data from PIVOT-02 showed that 3 out of 
6 NSCLC patients responded to BEMPEG with nivolumab as 1 L or 2 L therapy. Five out of 
6 NSCLC patients had known PD-L1 status and all were negative. All 3 responders were PD-L1 
negative (61). 
2.2.3.5 Rationale for combining SAR444245 with pembrolizumab or with pembrolizumab 
plus chemotherapy  
SAR444245 is a non-alpha IL-2 that 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. Combining SAR444245 with either pembrolizumab or pembrolizumab plus 
chemotherapy may increase the anti-tumor immune response through the complementary immune 
modulatory effects of pembrolizumab, chemotherapy and SAR444245. In vitro studies 
demonstrated that SAR444245 in the presence of an anti-PD1 antibody increased T cell receptor 
(TCR) dependent IFN- secretion (Synthorx Report No. NCLN-707-010 Evaluation of Antigen 
Presenting Cell-mediated T Cell Activation by THOR-707 and in Combination with Nivolumab 
Employing an Allogeneic Human Mixed Lymphocyte Reaction (MLR) Assay System). These 
findings suggest that in the tumor microenvironment (TME) and draining lymph nodes, this 
combination treatment can potentially facilitate TCR-driven activation of lymphocytes to activate 
both effector memory (in the tumor) and naïve (in the draining lymph node) CD8+ T cells and 
exert cytolytic activity. This hypothesis is further supported by in vivo studies in a mouse 
CT-26 colon cancer model of anti-tumor activity of SAR444245 as monotherapy and in 
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combination with an anti-PD1 antibody. Notably, the combination treatment of anti-PD1 and 
SAR444245 prolonged survival compared to each monotherapy (Synthorx Report 
No. NCLN-707-007. Efficacy of THOR-707 as a single agent and in combination with an 
anti-PD1 antibody in CT-26 colon tumor-bearing Balb/c mice).  
Accumulating evidence suggests that immune activation plays an important role in the efficacy of 
chemotherapy (66). The immunological effects of chemotherapy are complex and can be 
influenced by many different factors, but generally chemotherapy is thought to modulate the TME 
through the release of tumor antigens, activation of antigen presenting cells and depletion of 
immunosuppressive regulatory T and myeloid cells (67, 68, 69, 70, 71, 72, 73). The addition of an 
immunotherapy to platinum chemotherapy was assessed in KEYNOTE-189 (43) and 
KEYNOTE-407 (74) which successfully demonstrated prolonged overall survival with the 
combination of pembrolizumab and chemotherapy vs chemotherapy for patients with 
non-squamous NSCLC and squamous NSCLC, respectively. These studies established the 
therapeutic potential of combining an immunotherapy (anti-PD1) with platinum- or taxane-based 
chemotherapies. 
Therefore, this Phase 2 study will further assess the potential synergistic activity of SAR444245 with 
pembrolizumab or pembrolizumab plus chemotherapy in first-line and second/third-line treatment in 
different cohorts of participants with advanced NSCLC, from an antitumor activity and safety 
standpoint. Cohort B1 and Cohort B2 will enroll patients who progressed on prior ICI therapy (eg, as 
their first-line or second-line therapy) as it is hypothesized that the combination of SAR444245, or 
SAR444245 plus nab-paclitaxel may re-sensitize the disease to allow the patient to respond. 
2.2.4 Rationale for malignant pleural mesothelioma and selected participant population 
(Cohort C1)  
Previously considered to be rare, malignant pleural mesothelioma (MPM) is a highly aggressive 
tumor that has become a very important issue over recent years. Asbestos exposure is the main 
factor involved in pathogenesis, which can explain the rise in incidence of MPM since the 1970s 
(75, 76). A combination of cisplatin (or carboplatin if necessary) and pemetrexed is currently the 
standard of treatment as first-line chemotherapy for patients with MPM (77, 78). No 
chemotherapy can be recommended as second-line after failure of chemotherapy including 
cisplatin, except pemetrexed if the patient did not have tumor progression at least 3 to 6 months 
after the end of pemetrexed-based first-line chemotherapy (77, 78). However, ultimately all 
patients experience disease progression. Therapeutic options in second or third-line are limited, 
and currently there is no standard recommended therapy in such setting (77, 78, 79). 
2.2.4.1 PD1/PD-L1 inhibitors as treatment options  
Malignant pleural mesothelioma is characterized by multiple histology patterns, and 
molecular/immunophenotypes. Using a 1% tumor cell positivity threshold, PD-L1 expression has 
been recognized in 14% to 72.4% of MPMs and reveals consistent association with non-epithelioid 
histology (eg, sarcomatoid/biphasic) and elevated TILs (80, 81, 82, 83, 84, 85, 86). Cases with 
PD-L1 expression revealed a higher fraction of Tregs and effector T cells positive for immune 
inhibitory receptors (87).  
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Promising activity has been observed with different agents targeting the PD-L1 axis when 
administered as a single agent after first-line CT failure (88, 89, 90, 91, 92, 93). Nevertheless, 
these encouraging results have not been confirmed in a recent Phase 3 trial, comparing 
pembrolizumab with second-line standard chemotherapy, which failed to reveal any survival 
differences between the two treatment arms (94). Combining ICI with anti-CTLA-4 emerged as 
an effective and tolerable strategy in the salvage setting, as documented in the MAPS2 trial with 
one-third of patients receiving nivolumab plus ipilimumab alive at 2 years (92). 
2.2.4.2 Interleukin-2 as a treatment option for MPM (Cohort C1)  
Many studies have evaluated cytokine therapy in the treatment of MPM. Intravenous, 
subcutaneous and intrapleural administrations of IL-2 have shown some effects on tumor 
regression in MPM and were tolerable. Intrapleural administration of IL-2 in patients with earlier 
stage generally resulted in 15% to 25% response (95, 96, 97). However IV and subcutaneous 
administration of IL-2 from a Phase 2 study showed only limited activity (98).  
2.2.4.3 Rationale for combining SAR444245 with pembrolizumab  
The antitumor activity observed in in vitro studies and in vivo mouse studies of SAR444245 in the 
presence of an anti-PD1 antibody is described in Section 2.2.3.5. 
2.3 
BENEFIT/RISK ASSESSMENT  
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SAR444245 may be found in the Investigator’s Brochure. 
2.3.1 Risk assessment  
Safety data from clinical studies conducted with SAR444245 in humans is currently limited to 
available data from the Phase 1/2 first-in-human (HAMMER) study. Consequently, the 
assessment of the risks associated to SAR444245 is also based on existing preclinical data, and 
takes into consideration the known safety profile of the structurally similar product aldesleukin 
(Proleukin®) and current knowledge of the new-generation, investigational IL-2 analog 
NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with pembrolizumab results therefore from anticipated 
risks for SAR444245 and from the label information for pembrolizumab, taking into account 
potential overlapping risks. 
Table 23 summarizes potential risks for SAR444245 identified from preclinical experience and 
from the Phase 1/2 first-in-human (HAMMER) study, as well as available safety data for 
pembrolizumab, along with proposed mitigation strategies. 
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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 (99), 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 (100). 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. 
High doses of aldesleukin (IL-2) were associated with decreased expression of enzymes of hepatic 
metabolism (101). As SAR444245 also exercises IL-2 activity, the Investigator should monitor 
clinical effects of narrow therapeutic index drugs that are hepatically metabolized.  
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Please refer to Proleukin Label and Summary of Product Characteristics (SmPC) for more 
detailed information. 
2.3.1.2 SAR444245  
2.3.1.2.1 Preclinical data  
Among the potential risks, preclinical data for SAR444245 are lacking for infusion-related 
reactions (IRRs), immunogenicity (anti-drug antibodies), hypersensitivity, and immune-mediated 
adverse events. Those are, however, typical effects associated with the use of biologic drugs in 
oncology and should be considered for SAR444245. 
Further, preclinical data for SAR444245 do not indicate the potential for nephrotoxicity, 
neurotoxicity, or pulmonary toxicity, which are known adverse effects for aldesleukin. However, 
mitigation strategies for these risks are also proposed in the protocol. 
Preclinical data for SAR444245 do not indicate higher risk for infections. However, infections are 
typically associated with the use of aldesleukin and are to be expected. 
There are no preclinical data for tumor lysis syndrome (TLS) associated with the use of 
SAR444245, but it is known to occur when aldesleukin is combined with cisplatinum, vinblastine 
and dacarbazine (refer to Proleukin SmPC). The participants at greatest risk of TLS are those with 
high tumor burden prior to treatment, elevated uric acid level, poor hydration or tumor infiltration 
of the kidney, or receiving intensive cytoreductive therapy. 
Cytokine release syndrome is a potentially life-threatening toxicity that has been described in the 
setting of immunotherapy with T cell engagement. It is characterized by a variety of symptoms 
including high fevers, hypotension, rigors and malaise, and may progress to cytokine storm 
(uncontrolled immune hyperactivation involving myriad cytokines) with more severe and 
potentially life-threatening manifestations. As SAR444245 mediates immune activation, it may 
induce adverse events related to cytokine release (eg, fatigue, fever, chills, muscle pain, rash, 
nausea, symptoms of autoimmune disease). Furthermore, SAR444245-related increases of plasma 
monocyte chemoattractant protein-1 (MCP-1), IL-2, and IL-1RA were observed in non-human 
primates, indicating that SAR444245 administration may be associated with CRS. 
No manifestations of VLS have been reported in pre-clinical toxicity studies with SAR444245. 
Although there is a theoretical risk of VLS occurring in an immunotherapy setting, it has not been 
observed for IL-2 variants with ‘non alpha’ profiles. Being a “non alpha” IL-2, SAR444245 is not 
anticipated to cause VLS. 
No data pertaining to pregnancy and lactation exposure and outcomes are available for 
SAR444245. Due to the missing information for this important risk, detailed mitigation measures 
will be introduced. Conditions for eligibility of women of reproductive potential and male 
subjects with female partners of childbearing potential are detailed in Section 5.1. Also, since 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-2Rβγ receptor.  
In the first-in-human Phase 1 study, NKTR-214 was administered as an outpatient regimen and 
was well tolerated. Twenty-eight patients with advanced or locally advanced solid tumor 
malignancies were enrolled in the study. Grade 3 treatment-related adverse events (TRAEs) were 
reported by 21.4% of patients; there were no Grade 4 TRAEs or any treatment related deaths. The 
most common TRAEs included fatigue (71%), flu-like symptoms (68%), pruritus (64%), 
hypotension (57%), rash (50%), decreased appetite (46%), arthralgia and cough (each 32%). The 
majority of these events coincided with the peak plasma concentrations of the active cytokine and 
resolved spontaneously or were mitigated by nonprescription oral or topical treatments. There was 
one reported immune-related adverse event (irAE) of hypothyroidism associated with NKTR-214, 
which was treated with replacement therapy. All Grade 3 hypotension events (18%) were rapidly 
reversed with IV fluid administration and did not require treatment discontinuation. 
NKTR-214-related hypotension was predictable, manageable, and reversible and the incidence of 
Grade 3 hypotension was reduced once hypotension risk mitigation strategies were implemented. 
The maximum tolerated dose (MTD) was determined to be 0.009 mg/kg Q3W. This new 
generation, IL-2Rβγ-biased IL2 could be safely administered as outpatient basis, and there was no 
report of capillary leak syndrome (CLS) or VLS (60). 
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 
NSCLC). Several treatment regimens were explored. The dose of 0.009 mg/kg had excessive 
toxicity (2 of 3 patients with DLT: Gr 3 hypotension [n=1] & Gr 4 hyperglycemia + metabolic 
acidosis [n=1]) when combined with 360 mg of nivolumab. All 38 patients had TEAEs that were 
considered related to the study combination. The MTD of the combination was defined as 
NKTR-214 0.006 mg/kg + nivolumab 360 mg Q3W and this dose was selected as the 
recommended Phase 2 dose (RP2D). The most common TRAEs (≥30%) at the RP2D were 
flu-like symptoms (80%), rash (80%), fatigue (76%), pruritis (48%), arthralgia (44%), headache 
and diarrhea (40%), nausea (40%), decreased appetite (36%) and peripheral edema (36%), 
myalgia (32%), and nasal congestion (32%). Grade ≥3 TRAEs occurred in 16% of patients at the 
RP2D (hyperglycemia, lipase increase, rash, cerebrovascular accident, hyponatremia, infectious 
pleural effusion, syncope). Immune-mediated AEs were observed in 31.6% overall: 
hypothyroidism (11), hyperthyroidism (2), hyperglycemia (2). Cytokine-related symptoms were 
observed primarily in Cycles 1 & 2 and significantly reduced thereafter. There were no 
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treatment-related deaths and generally, Grade ≥3 TRAEs were manageable using standard 
guidelines. Tumor responses were observed regardless of baseline PD-L1 status and baseline 
levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor 
prognostic risk factors for response to PD1/PD-L1 blockade. These data demonstrated that 
NKTR-214 can be safely combined with a checkpoint inhibitor as dual immunotherapy for the 
treatment of a range of advanced solid tumors (102). 
2.3.1.4 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment. 
The use of pembrolizumab is commonly associated with infusion-related reactions (drug 
hypersensitivity, anaphylactic reaction, anaphylactoid reaction, hypersensitivity and CRS), 
infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, leukopenia), 
increase in the level of hepatic enzymes (alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well as adverse effects 
on the functioning of nervous system (dizziness, headache, peripheral neuropathy, dysgeusia (very 
common) and lethargy). In combination therapy with other chemotherapeutic drugs, 
pembrolizumab administration is commonly associated with hypertension and cardiac arrhythmia 
(including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risk for pembrolizumab (45). 
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 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, USPI, SmPC) for pembrolizumab for 
more detailed information. 
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2.3.1.5 SAR444245 combined with pembrolizumab and SAR444245 combined with 
pembrolizumab and chemotherapy regimen 
SAR444245 combined with pembrolizumab 
Due to synergistic action of SAR444245 and pembrolizumab, combining these two substances 
may lead to an increased frequency and/or severity of AEs related to immune activation for each 
substance individually or may cause occurrences of qualitatively different AEs. Serious adverse 
drug reactions reported with agents known to increase immune activation include pneumonitis, 
hepatitis, nephritis, colitis, and hormonal dysfunction (see Section 2.3.1.4). 
The maximum tolerated dose of SAR444245 combined with the approved dosing of the anti-PD1 
pembrolizumab is under assessment in the HAMMER study using a Q3W schedule. Safety data 
generated from the combination of SAR444245 and pembrolizumab have informed the selection 
of the combination dose in this study (see Section 4.3 for details). 
SAR444245 combined with pembrolizumab and chemotherapy regimen 
Safety data from KEYNOTE-189 (pembrolizumab + pemetrexed and platinum) (43), KEYNOTE-
407 (pembrolizumab + carboplatin and paclitaxel or nab-paclitaxel) (74) with non-squamous 
NSCLC and squamous NSCLC, respectively, clearly demonstrated that combinations of standard 
dosing of pembrolizumab with chemotherapy are achievable with a manageable toxicity profile. 
Updated analysis of KEYNOTE-189 safety and tolerability results after a median follow-up of 
approximately 2 years continue to show results comparable with the first interim analysis of 
10.5 months medium follow-up (44).The most common adverse events in the pembrolizumab 
combination group versus placebo group were nausea (56.8% versus 53.0%),  
anemia (47.4% versus 48.5%) and fatigue (42.5% versus 38.6%).  The most common immune-
mediated adverse events in the pembrolizumab combination group were hypothyroidism (7.9%), 
hyperthyroidism (4.9%), pneumonitis (4.9%), colitis (3%) and infusion reactions (2.7%).   
The combination of SAR444245, pembrolizumab and chemotherapy (pemetrexed, platinum, nab-
paclitaxel) are expected to have overlapping toxicities based on each drug’s toxicity profile. 
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. 
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Both NSCLC and mesothelioma are tumor types that are benefiting from ICI treatment. The 
companion ICI (anti-PD1) pembrolizumab to be combined with SAR444245 in this study is 
approved to treat various disease settings of NSCLC, and few other anti-PD1/PD-L1 (for 
example, nivolumab and atezolizumab) are approved for the treatment of similar disease settings 
of NSCLC. For pleural mesothelioma, nivolumab is accelerated approved in Japan for this tumor 
type. In April 2020, interim analysis of Phase 3 confirmatory trial in patients with unresectable 
pleural mesothelioma met the primary end point of the OS (CheckMate-743). 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of complete responses and 
prolonged survival which was durable as demonstrated by the failure of the tumor to grow upon 
re-engraftment on the tumor free animals, indicating the establishment of durable memory T-cell 
population in response to the initial treatment (see SAR444245 IB). Furthermore, preliminary 
clinical data from another new generation IL-2, NKTR-214, induced an increase in ORR and 
better quality of response than historical data for anti-PD1 treatment alone in ICI-naïve NSCLC 
patients (41). Two out of 5 treated patients achieved CR, and 1 patient achieved PR.  Among the 
5 patients, 3 were PD-L1 negative (<1%) and 2 were PD-L1 positive (>1%). 
The combination regimens of SAR444245 plus pembrolizumab and SAR444245 plus 
pembrolizumab plus chemotherapy (pemetrexed, platinum, nab-paclitaxel), proposed to be 
evaluated in this study, are anticipated to benefit participants in the ICI-naïve NSCLC and 
mesothelioma cohorts. For the ICI-treated NSCLC cohorts, clinical benefit may be observed 
based on preclinical data.  
2.3.3 Overall benefit: risk conclusion  
SAR444245, with its site-specific pegylation, was designed to substantially reduce association with 
the IL-2 α receptor, while retaining stimulatory activity for cells expressing the moderate affinity 
IL-2 βγ receptor. These design features are anticipated to minimize safety liability associated with 
Proleukin® by avoiding expansion of immunosuppressive immune cell populations (regulatory 
T cells) and off-target complications such as vascular leak syndrome, while still promoting 
expansion of immune populations that can support anti-tumor immune responses. 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with this new generation IL-2 SAR444245 combined with the 
anti-PD1 inhibitor pembrolizumab and other anticancer treatments are justified by the anticipated 
benefits that may be afforded to participants with NSCLC or pleural mesothelioma. 
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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  
Participants potentially eligible for this study have advanced or metastatic NSCLC or 
mesothelioma. Patients with lung cancer may be particularly vulnerable to complications from 
COVID-19. In an initial retrospective analysis of COVID-19 outcomes among 105 patients with 
cancer in Wuhan, People’s Republic of China, patients with lung cancer had the second highest 
rates of mortality from COVID-19, behind only those with hematologic malignancies (103). More 
recent studies have confirmed the high rates of hospitalization and death within thoracic oncology 
populations affected by COVID-19. For example, in the Thoracic Cancers International 
COVID-19 Collaboration (TERAVOLT) registry (104), which pooled data from 200 patients with 
lung cancer (including 8 patients with mesothelioma) across 42 institutions and eight countries, 
76% of the patients of thoracic oncology with COVID-19 required hospitalization and 33% died. 
Importantly, recent data from Luo et al. (105, 106) suggest that patient-specific factors, such as 
smoking status and chronic obstructive pulmonary disease, rather than disease-specific factors 
(eg, previous surgery, systemic therapy) are the major determinants of COVID-19 infection 
severity among patients with lung cancer. 
There are no evidence-based guidelines for the management of lung cancer in the era of 
COVID-19. However, several guidelines designed to help make clinical decisions have been 
published. These include the ESMO Guidelines (107), and the National Comprehensive Cancer 
Network recommendation (108). ESMO Guidelines indicate that, in order to limit cancer-related 
mortality in patients with a new diagnosis of metastatic NSCLC, all standard options for first-line 
systemic therapy should be envisaged unaltered, including chemotherapy and immunotherapy. 
Discontinuation of ICIs after 2 years should be discussed. 
Testing for severe acute respiratory syndrome coronavirus 2 (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. 
During the study, if a participant is diagnosed with SARS-CoV-2, dose modification of study 
intervention should be based on the recommendations provided in Section 6.6. In addition, all 
Investigators are instructed to consult official COVID-19 clinical research guidance from their 
local hospital/institution along with other relevant resources, such as the American Society of 
Clinical Oncology (ASCO) (109) or ESMO (110). 
2.3.4.1.2 Risks related to study treatment  
The treatment regimen under evaluation in the study includes the anti-PD1 pembrolizumab and 
the non-alpha IL-2 SAR444245.  
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The impact of PD-1 blockade therapy on COVID-19 severity is also explored by 2 groups and did 
not find a clinically meaningful signal (111, 105). 
SAR444245 has the potential to induce CRS which could exacerbate the manifestations of 
COVID-19 infection. It is, however, worth noting that pegylated IL-2 bempegaldesleukin is 
currently being evaluated for the treatment of patients with mild COVID-19 in a Phase 1b study 
(NCT04646044). 
2.3.4.1.3 Risks related to study-related activity  
It is important to minimize the risk of exposure of patients to COVID-19. In addition to the 
contingency measures described in Section 10.11, the following prevention and mitigation plans 
could be implemented at clinical sites: 
• All participating sites should have implemented measures according to regional/local 
Health Authorities, European Medicines Agency (EMA), ESMO, ASCO guidelines 
including but not limited to restrictions of access to the hospitals for visitors, physical 
distancing and personal protective equipment.  
• 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 NSCLC and 
mesothelioma 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 3 - 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 CR or 
partial response (PR), determined by investigator per 
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 (1) for Cohort A1, Cohort A2, Cohort A3, 
Cohort B1 and Cohort B2; per modified RECIST 
(mRECIST) (2) for Cohort C1. 
Secondary 
• 
To confirm the dose and to assess the safety 
profile of SAR444245 when combined with other 
anticancer therapies. 
• 
Incidence of TEAEs, DLTs, SAEs, laboratory 
abnormalities according to NCI CTCAE V5.0 and 
ASTCT consensus gradings (3). 
• 
To assess other indicators of antitumor activity. 
• 
Time to response defined as the time from the first 
administration of IMP to the first tumor assessment at 
which the overall response was recorded as PR or CR 
that is subsequently confirmed and determined by 
investigator per RECIST 1.1 (for NSCLC) or mRECIST 
(for mesothelioma). 
• 
Duration of response (DoR), defined as the time from 
first tumor assessment at which the overall response 
was recorded as PR or CR that is subsequently 
confirmed until progressive disease (PD) determined 
by investigator per RECIST 1.1 (for NSCLC) or 
mRECIST (for mesothelioma) or death from any 
cause, whichever occurs first. 
• 
Clinical benefit rate (CBR) including CR or PR at any 
time plus stable disease (SD) of at least  
6 months (determined by investigator per RECIST 1.1 
[for NSCLC] or mRECIST [for mesothelioma]).  
• 
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 for NSCLC) or 
mRECIST (for mesothelioma) or death due to any 
cause, whichever occurs first. 
• 
To assess the plasma concentrations  of 
SAR444245 when given in combination with 
pembrolizumab. 
• 
Plasma concentrations of SAR444245. 
• 
To assess the immunogenicity of SAR444245.  
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245. 
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Objectives 
Endpoints 
Exploratory 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study is considered well 
established and relevant in an oncology study setting.  
In addition, suitable steps have been built into each of these assessments to ensure their reliability 
and accuracy and to minimize any risks to participant safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2, multi-cohort, un-controlled, non-randomized, open-label, multi-center study 
assessing the antitumor activity and safety of SAR444245-based therapies in participants with 
NSCLC or mesothelioma.  
Cohort A1, Cohort A2 and Cohort A3 will assess the antitumor efficacy and safety of 
SAR444245 adding on to therapeutic approaches with documented efficacy profile as 1L NSCLC 
therapy. Participants with previously untreated Stage IV NSCLC will be enrolled sequentially 
based on histology and PD-L1 tumor proportion score (TPS) to Cohort A1, Cohort A2 and 
Cohort A3.  
• Cohort A1: participants with PD-L1 TPS ≥50% NSCLC, to receive SAR444245 
+ pembrolizumab as 1L therapy. 
• Cohort A2: participants with PD-L1 TPS 1%-49% NSCLC, to receive SAR444245 
+ pembrolizumab as 1L therapy. 
• Cohort A3: participants with non-squamous NSCLC, to receive SAR444245 
+ pembrolizumab + pemetrexed + carboplatin/cisplatin as 1L therapy. 
Cohort B1 and Cohort B2 will assess SAR444245-based therapies as 2/3L NSCLC therapy when 
receiving SOC is not in the best interest of participants or where no SOC is established.  
• Cohort B1: participants with NSCLC, to receive SAR444245 + pembrolizumab as 
2/3L therapy. 
• Cohort B2: participants with NSCLC, to receive SAR444245 + pembrolizumab 
+ nab-paclitaxel as 2/3L therapy. 
Cohort C1 will evaluate SAR444245-based therapy as 2/3L mesothelioma treatment where no 
SOC is well established. Participants with mesothelioma who have experienced disease 
progression during or after at least 1 but no more than 2 prior regimens (detailed in Section 5.1 
Inclusion Criteria I 06) will be enrolled  
• Cohort C1: participants with mesothelioma, to receive SAR444245 + pembrolizumab as 
2/3L therapy. 
The study consists of a safety run-in and a core phase for all 6 cohorts and an expansion phase for 
Cohorts B1 and/or B2. In the core phase approximately 40 participants will be treated at 
confirmed safe dose per cohort. The results of an interim analysis will decide if the expansion 
phase will be opened for Cohorts B1 and/or B2. Approximately 57 additional participants are 
planned to be enrolled in each of these cohorts for the expansion phase in order to better assess 
antitumor activity. A graphical presentation of the study is shown in Figure 1. An overview of the 
study intervention and disease being treated for each cohort is provided in Table 4. 
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Table 4 - Overview of cohorts  
Cohort 
Study intervention 
Disease 
Primary tumor 
assessment criteria 
A1 
SAR444245 + pembrolizumab as 1L therapy 
NSCLC, PD-L1 TPS ≥50% 
RECIST 1.1 
A2 
SAR444245 + pembrolizumab as 1L therapy 
NSCLC, PD-L1 TPS 1%-49% 
RECIST 1.1 
A3 
SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin as 1L therapy 
non-squamous NSCLC 
RECIST 1.1 
B1 
SAR444245 + pembrolizumab as 2/3L therapy 
NSCLC 
RECIST 1.1 
B2 
SAR444245 + pembrolizumab 
+ nab-paclitaxel as 2/3L therapy 
NSCLC 
RECIST 1.1 
C1 
SAR444245 + pembrolizumab as 2/3L therapy 
mesothelioma 
mRECIST 
1L = First-line; 2/3L = Second- or third-line; mRECIST = Modified response evaluation criteria in solid tumors; NSCLC = Non-small cell lung 
cancer; PD-L1 = Programmed cell death-ligand 1; RECIST = Response evaluation criteria in solid tumors; TPS = Tumor proportion score. 
A safety run-in will confirm the dose of SAR444245 in each regimen tested in this study, 
namely: SAR444245 + pembrolizumab; SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin; SAR444245 + pembrolizumab + nab-paclitaxel. Participants who 
fulfill the eligibility criteria of any cohorts testing the regimen may be enrolled to the safety run-in 
of that regimen. Participants will be enrolled across Cohorts A1, A2, B1 and C1 to receive 
SAR444245 and pembrolizumab. Enrollment will be paused once at least 6 participants are 
evaluable for DLT. Safety data for these participants will be reviewed by a Study Board (SB), 
comprising Investigators or designees participating in the safety run-in part of applicable cohorts 
and the Sponsor clinical team members. DLT-evaluable participants include all treated 
participants in the safety run-in who have been observed for at least 21 days. Any participant who 
experienced a DLT during the first 21 days will also be DLT-evaluable. If no safety concerns are 
identified by the SB, participant enrollment will continue for the 4 cohorts. If after recruiting the 
first 10 participants there are fewer than 6 participants evaluable for DLT, more participants will 
be enrolled to ensure at least 6 DLT evaluable participants after agreement from SB. Participants 
who are enrolled in the safety run-in and treated at the confirmed safe dose will be included in the 
total number of participants in the core phase for that specific cohort (for example, if 3 Cohort A1 
participants are enrolled in the safety run-in and treated at the confirmed safe dose, approximately 
37 additional participants will be enrolled into Cohort A1 to have the total number of 
40 participants). 
The safety run-in for other regimens ie, SAR444245 + pembrolizumab + pemetrexed 
+ carboplatin/cisplatin; and SAR444245 + pembrolizumab + nab-paclitaxel will not be 
opened until SAR444245 + pembrolizumab dose is confirmed, and enrollment of Cohort A2 and 
Cohort B1, respectively, is stopped. Details of the opening sequence of the different cohorts are 
described below. 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an IV infusion over 
30 minutes every 3 weeks on Day 1 of each cycle (21 days per cycle). Overall safety monitoring 
will be performed throughout the study.  If recommended by the SB, SAR444245 dose level may 
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be reduced to
 or another lower dose level which will be explored following the 
same process described in the safety run-in for 24 μg/kg dose level. 
The DLT observation period is 21 days and will take into account the occurrence of DLT. The 
Modified Toxicity Probability Interval 2 (mTPI2) design will be used in the safety run-in part. 
The mTPI2 design is a Bayesian interval design that can be implemented in a simple fashion as 
the traditional 3+3 design, but it is more flexible and possesses superior operating characteristics. 
The target toxicity rate for the MTD is 0.3, with the acceptable toxicity probability interval of 
(0.25,0.35). The dose decision (stay at 24 µg/kg dose or reduce the dose) will be made by the SB 
and will be guided by the decision rules from the mTPI2 design. The mTPI2 decision rules are 
based on calculating the unit probability mass (UPM) of intervals as follows: (0, 0.05), 
(0.05, 0.15), (0.15, 0.25), (0.25, 0.35), (0.35, 0.45) …… (0.85, 0.95), (0.95, 1). In the mTPI2 
method, intervals that are lower than 0.25 indicate dose escalation, equivalence interval 
(0.25,0.35) indicates staying at the current dose level, and intervals that are higher than 
0.35 indicate dose de-escalation. The interval with the largest UPM is the winning interval and 
implies the corresponding dose escalation/de-escalation decision. For the safety run-in part of the 
study, mTPI2 rules (see Table 5) will be applied as follows, unless decided otherwise by the SB: 
• If the dose recommendation from mTPI2 is “E” (Escalate to the next higher dose) or “S” 
(Stay at the same dose), all cohorts treated at the current regimen will continue with the 
SAR444245 24 µg/kg dose;  
• If the dose recommendation from mTPI2 is to de-escalate to a lower dose (either “D” 
[De-escalate to the previous lower dose] or “DU” [De-escalate to the previous lower dose 
and the current dose will never be used again in the trial]), a dose lower than 24 µg/kg will 
be tested and assessed with the same methodology. 
Table 5 - Dose escalation rule of the modified toxicity probability interval-2 method  
 
 
Number of DLT-evaluable participants 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of dose limiting toxicities 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
2 
 
DU 
D 
D 
D 
S 
S 
S 
E 
E 
3 
 
 
DU 
DU 
D 
D 
D 
D 
S 
S 
4 
 
 
 
DU 
DU 
DU 
D 
D 
D 
D 
5 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
D 
6 
 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
7 
 
 
 
 
 
 
DU 
DU 
DU 
DU 
8 
 
 
 
 
 
 
 
DU 
DU 
DU 
9 
 
 
 
 
 
 
 
 
DU 
DU 
 
10 
 
 
 
 
 
 
 
 
 
DU 
E: Escalate to the next higher dose, S: Stay at the current dose, D: De-escalate to the next lower dose, DU: De-escalate to the next lower 
dose and the current dose will never be used again because unacceptable high toxicity.. 
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Dose limiting toxicity: The following events occurring during the DLT observation period 
(21 days of first cycle) are considered as DLT unless due to disease progression or to a cause 
obviously unrelated to SAR444245. Based on the occurrence of DLT and overall assessment of 
safety data supplemented with data from other SAR444245 studies, the SB will determine if the 
dose of SAR444245 needs to be reduced to 
 or another lower dose level, in 
agreement with the Sponsor. 
Hematologic abnormalities:  
• Grade 4 neutropenia for ≥7 consecutive days. 
• Grade 3 or 4 neutropenia complicated by fever (temperature of >38.3°C [101°F] or a 
sustained temperature of ≥38.0°C [100.4°F] for more than 1 hour) or microbiologically or 
radiographically documented infection. 
• Grade 3 or 4 thrombocytopenia associated with clinically significant bleeding requiring 
clinical intervention. 
Non-hematologic abnormalities:  
• Grade 3 or above alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in 
combination with a bilirubin >2 times upper limit of normal (ULN) with no evidence of 
cholestasis or another cause such as viral infection or other drugs. 
• Grade 3 or above Vascular Leak Syndrome (VLS).  
• Grade 3 or above hypotension. 
• Grade 3 or above cytokine release syndrome. 
• Other Grade 3 or above AE except: 
- 
Grade 3 fatigue that resolves within 1 week.  
- 
Grade 3 nausea, vomiting, or diarrhea that resolves within 72 hours with antiemetics 
and standard supportive care measures.  
• Any Grade 3 non-hematologic laboratory value  
Exceptions:  
- 
Grade 3 electrolyte abnormalities that are not clinically complicated and resolve within 
72 hours with conventional medical interventions.   
- 
Grade 3 amylase or lipase that is not associated with symptoms or clinical 
manifestations of pancreatitis. 
• Any Grade 4 non-hematologic laboratory value. 
Other abnormalities: 
• Any death not clearly due to the underlying disease or extraneous causes. 
• Any toxicity requiring permanent discontinuation of the study drug(s). 
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Study Board 
The study Investigators (or designee) participating in the safety run-in of applicable cohorts and 
the Sponsor clinical team members will constitute the Study Board (SB). The SB will review 
clinical data on a regular basis in order to decide dose confirmation or dose reduction on the basis 
of their knowledge of the safety data. Minutes of each meeting will be written by the Sponsor and 
distributed to all sites participating in the safety run-in. Decisions regarding final dose selection 
will be made during one of the SB meetings and documented in the meeting minutes. After safety 
run-in dose confirmation, occurrence of any treatment related G3 or higher AE (excluding 
lymphocyte count decrease) not resolving within 72 hours in >25% of participants per regimen 
will trigger SB to rapidly convene to assess safety, or need to pause enrollment to allow for a 
safety review. The SB (during safety run-in), IDMC (during core phase and expansion) and 
Sponsor can decide to stop any cohort in the event excessive toxicity (for example but not limited 
to excessive irAE or excessive number of G4/5 events) is observed. 
Safety run-in and core phase enrollment sequence 
SAR444245 and pembrolizumab - Cohorts A1, A2, B1 and C1 
As safety run-in of this regimen is opened first, Cohorts A1, A2, B1 and C1 will be the initial 
cohorts to enroll. 
A safety run-in will also be performed for Cohorts A3 and B2 in the sequence described below.  
SAR444245, pembrolizumab, pemetrexed, and carboplatin/cisplatin - Cohort A3  
Once enrollment is completed for Cohort A2, the safety run-in of Cohort A3 can be conducted 
with up to 10 participants enrolled to receive SAR444245, pembrolizumab, pemetrexed, and 
carboplatin/cisplatin prior to an enrollment pause. If Cohort A1 is still enrolling when Cohort A3 
is opened, a participant who is eligible for both Cohorts A1 and A3 should be enrolled in Cohort 
A1 until Cohort A1 enrollment is completed. 
Participants who are enrolled into Cohort A3 and the safety run-in of Cohort A3 and treated at the 
confirmed safe dose will be included in the total number of participants for Cohort A3. 
SAR444245, pembrolizumab, and nab-paclitaxel - Cohort B2  
Once enrollment is completed for Cohort B1, the safety run-in of Cohort B2 can be conducted 
with up to 10 participants enrolled to receive SAR444245, pembrolizumab, and nab-paclitaxel 
prior to an enrollment pause. Participants who are enrolled into Cohort B2 in the safety run-in and 
treated at the confirmed safe dose will be included in the total number of participants for 
Cohort B2.  
Additional cohorts with different regimens or indications may be added to this protocol. 
Interactive Response Technology will be used to control recruitment, assignment per site and 
facilitate drug supply.  
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The duration of the study for a participant will include: 
• Screening period: up to 28 days. 
• Treatment Period: enrolled participants will receive continuous treatment until PD, 
unacceptable AE, other full permanent discontinuation criteria as described in Section 7, 
or completion of Cycle 35 (for Cohorts A1, A2, B1, B2 and C1).  
• End of Treatment and Follow-up. End of Treatment Visit will occur 30 days ±7 days 
from last IMP administration or prior to initiation of further therapy. Participants will then 
enter the Observation period and will be followed differently depending on the reason 
leading to EOT: 
1. Participants who discontinue study treatment without radiological or clinical PD or 
who complete 35 cycles of treatment without PD (per RECIST 1.1 or mRECIST), 
will be followed every 3 months ±7 days from last IMP administration, for safety 
(as per Section 1.3) 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 radiological or clinical PD (per 
RECIST 1.1 or mRECIST) or 
 will be followed in the Follow-Up 
Visit 1 occurring 3 months ±7 days from last IMP administration before moving to the 
Survival Phone Call Follow-Up Period. 
Participants who move into the Survival Phone Call Follow-Up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Information on the first 
subsequent anticancer treatment, and best reported response, and date of progression will also be 
collected. Survival Phone Call Follow up will continue until death, participant request to 
discontinue from follow-up, or final cohort cut-off, or upon cancellation of Survival Follow up at 
the discretion of the Sponsor at any prior timepoint. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The proposed study aims to establish proof-of-concept that combining the ICI pembrolizumab 
with the non-alpha IL-2 SAR444245 with or without chemotherapy will result in a significant 
increase in the population experiencing an objective response rate.  
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, chemo-immune combination, or available chemotherapy as a benchmark to 
show outstanding objective response rate. The ORR will be assessed using RECIST 1.1 for 
participants with NSCLC, and modified RECIST for participants with mesothelioma. The 
objective response will be assessed per Investigator in first intention. Central imaging reading 
may be done retrospectively if significant activity is observed.  
A safety run-in on the first 6-10 participants being enrolled to each regimen has been embedded in 
the study to confirm the absence of safety issue before launching enrollment of the remaining 
participants. Some NSCLC cohorts may be expanded to enroll more participants to accumulate 
evidence of clinical activity. 
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4.2.1 Participant input into design  
There was no participant input into the design of the trial. 
4.3 
JUSTIFICATION FOR DOSE  
4.3.1 SAR444245 dose  
Dose escalation for SAR444245 monotherapy and in combination with pembrolizumab or 
cetuximab is ongoing in the first-in-human HAMMER study. Data from a total of 68 patients who 
have received SAR444245 Q2W or Q3W in monotherapy, in a Q3W regimen in combination with 
pembrolizumab 200 mg Q3W, or with cetuximab 400/250 mg/m² QW is available as of 18 June 
2021. 
The dose levels tested to date for SAR444245 monotherapy administered using a Q3W schedule 
are 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=11), 32 µg/kg (n=6), and 40 µg/kg (n=2). In 
combination with pembrolizumab, SAR444245 has been administered Q3W at the doses of 
8 µg/kg (n=4), 16 µg/kg (n=9), 24 µg/kg (n=6), 32 µg/kg (n=1). In combination with cetuximab, 
SAR444245 has been administered Q3W at 16 µg/kg (n=5) and 24 µg/kg (n=5). 
For monotherapy cohort, the only DLT observed to date is a Grade 3 infusion-related reaction 
(occurred on C2D1 and resolved on the same day with supportive care) reported in a patient on 
32 µg/kg Q3W. 
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 in the cohort of patients receiving SAR444245 24 µg/kg Q3W in 
combination with cetuximab. 
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 AE in the 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) and gamma-glutamyl 
transferase (GGT) increased (2 participants each for AST and ALT increased, 33.3%; 
1 participant for GGT increased, 16.7%), Grade 3 blood phosphorus decreased and 
hypophosphatemia (1 participant each, 16.7%), and Grade 3 dyspnea (1 participant, 16.7%).  
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Grade 3/4 TEAEs reported by participants who received SAR444245 24 µg/kg in combination 
with cetuximab (n=5) were Grade 3 chills (1 participant, 20.0%) and Grade 3 abdominal pain, 
vomiting and pyrexia (each in 1 participant, 20.0%). 
Within the HAMMER study, a total of 13 patients experienced a CRS event of any grade (per 
CTCAE version 5) as of 18 June 2021. 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%) was reported among 
participants who received SAR444245 monotherapy (n=38). Among participants who received 
SAR444245 in combination with pembrolizumab (n=20), grade 3 CRS (with 16 µg/kg Q3W) was 
observed in 1 participant (5.0%) with Grade 3 hypotension and Grade 2 fever. 
According to literature, prophylactic hydration on the dosing days could mitigate incidence and 
severity of hypotension as part of CRS. As HAMMER study was not mandating prophylactic 
hydration before January 2021, the patients who experienced CRS in the HAMMER Phase 1 
study did not always receive peri-infusion hydration.  Based on this learning, hydration and CRS 
management guidelines are included in this study. 
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. 
Unlike 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 has less impact on 
immunosuppressive Treg cells. Therefore, the PDy change of CD8+ T, NK and Treg cells is 
closely monitored in HAMMER study as supportive information for RP2D 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 postdose was 1.75-fold. For dose levels 16 µg/kg and 24 µg/kg, the 
peripheral blood CD8+ T cell expansion was 2.47- and 4.47-fold at the day 8 postdose peak of 
expansion. The day 8 sample timepoint was added after the first 3 participants in the 8 µg/kg 
cohort were dosed.  
In addition, the average increase in peripheral blood NK cells was 4.22-fold at 72 hours for 
8 µg/kg. The 16 µg/kg and 24 µg/kg dose levels resulted in 5.9- and 7.67-fold NK expansion, 
compared to baseline at the Day 8 peak expansion.  
Among the dose levels tested to date for SAR444245 in combination with pembrolizumab 
administered using Q3W schedule, PDy data are available 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 Day 8 peak expansion. Moreover, the comparison 
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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). This study showed that SAR444245-induced 
cytokine release in human whole blood was not affected in the presence of pembrolizumab at 
Q3W schedule (please refer to the SAR444245 IB for details). 
This study proposes to evaluate the clinical benefit of SAR444245 24 µg/kg combined with 
pembrolizumab 200 mg (see Section 4.3.2), using a Q3W schedule of administration, with initial 
dose confirmation in a cohort of approximately 6-10 patients considering that: 
• SAR444245 monotherapy up to 32 µg/kg Q3W, pembrolizumab combination up to 
32 µg/kg Q3W and cetuximab combination 24 µg/kg Q3W were all cleared in the 
HAMMER study; 
• sustained relevant PDy effect in blood, higher at higher doses, was documented in 
participants; 
• observed safety data from the Hammer study suggests the combination of SAR444245 
combined with anti-PD1 (eg, pembrolizumab) may not lead to significant overlapping 
toxicities. 
4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W). 
• 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 
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10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
penetration and PD1 expression. This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight-based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. Supported by 
these PK characteristics and given that fixed-dose has advantages of reduced dosing complexity 
and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for evaluation 
across all pembrolizumab protocols. 
4.4 
END OF STUDY DEFINITION  
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. For participants enrolled in France and Japan 
please refer to Section 10.7. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply for a 
given cohort: 
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. Cancer diagnosis at study entry: 
- 
For participants in Cohorts A1, A2, B1 and B2 - Histologically or cytologically 
confirmed diagnosis of Stage IV (per American Joint Committee on Cancer [AJCC] 
8th edition [112]) NSCLC, 
- 
For participants in Cohort A3 - Histologically or cytologically confirmed diagnosis of 
Stage IV (per AJCC 8th edition) non-squamous NSCLC,  
- 
For participants in Cohort C1 - Histologically confirmed unresectable MPM. 
I 03. PD-L1 expression TPS as determined (with an absolute value provided to Sponsor) at local 
laboratory (for details on PD-L1 assay, please refer to lab manual). 
- 
For participants in Cohort A1 - PD-L1 expression TPS ≥50%, 
- 
For participants in Cohort A2 - PD-L1 expression TPS 1%-49%.  
I 04.  Provision of tumor tissue: 
- 
Mandatory baseline biopsy for participants to Cohorts A1 and A2 in Core Phase 
(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) AND all cohorts 
for Expansion Phase (minimum 10 slides with 4-5 micron thickness). Archival 
tumor tissue samples should be obtained from biopsies done within 6 months, and 
there should be no systemic anti-cancer therapy between collection of biopsy and 
enrollment. Slide specifications are detailed in Lab Manual. 
- 
The Sponsor may approve the written request to enroll, on a case-by-case basis, 
participants with: 
- 
Location of the tumor not amenable to biopsy due to significant risk, OR, 
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- 
Less than required number of slides or archival tumor tissue sample collected more 
than 6 months prior to first IMP administration. 
- 
Optional per Investigator’s discretion and evaluation for participants to 
Cohorts A3, B1, B2 and C1 in Core Phase. 
I 05. Measurable disease: 
- 
For participants in Cohorts A1, A2, A3, B1 and B2 - 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.  
- 
For participants in Cohort C1 - At least 1 measurable lesion per modified RECIST 
criteria for mesothelioma (either a pleural lesion with tumor thickness perpendicular to 
the chest wall or mediastinum measurable on transverse cuts of CT scan, or 
non-pleural lesion >1 cm - for details, see Section 10.10) (2). Target lesions may be 
located in a previously irradiated field if there is documented radiographic disease 
progression in that site. 
I 06. Prior anticancer therapy 
- 
For participants in Cohorts A1, A2 and A3 - Have not received prior systemic therapy 
for advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant 
therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 
6 months prior to the development of metastatic disease. 
- 
For participants in Cohorts B1 and B2:  
- 
Patients with metastatic NSCLC should have progressed after having received 
prior benefit from an anti-PD1/PD-L1* containing regimen (SD, partial response 
[PR], or CR).  Patients must have received prior anti-PD1/PD-L1 containing 
regimen given concurrently or sequentially with a platinum-based chemotherapy.  
Patients who received concurrent anti-PD1/PD-L1 chemotherapy combination are 
allowed to receive one additional chemotherapy. Platinum ineligible patients can 
enroll after anti-PD1/PD-L1 monotherapy, or anti-PD1/PD-L1 monotherapy 
followed by a non-platinum form of chemotherapy.  
*If anti-PD1/PD-L1 was used beyond initial radiological progression while continuing to use the 
same anti-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. 
- 
For participants in Cohort C1 - At least 1 but no more than 2 prior systemic treatments 
for advanced mesothelioma that included a pemetrexed-based regimen in combination 
with platinum agent. For participants in whom pemetrexed was contraindicated or not 
tolerated, prior therapy with a first-line platinum-based regimen is required. 
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I 07. For participants in Cohorts B1 and B2 - Based on the Investigator’s judgment, at this time, 
either docetaxel or pemetrexed is not the best treatment option for this specific participant. 
The eligibility of participant to take part in the study will be validated at the 
multidisciplinary collegial meeting in countries listed in Section 10.7 of the protocol. 
See wording specific to Japan in Section 10.7 
Sex 
I 08. All (male and female) 
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
A) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 330 days (for Cohort A3) or 210 days (for Cohorts A1, 
A2, B1, B2 and C1), [corresponding to time needed to eliminate study intervention(s) plus 
an additional 90 days (a spermatogenesis cycle)] after the last dose of study intervention: 
- 
Refrain from donating or cryopreserving sperm. 
PLUS either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR 
- 
Must agree to use contraception/barrier as detailed below 
- 
A male condom with female partner use of an additional highly effective 
contraceptive method with a failure rate of <1% per year as described in 
Appendix 4 (Section 10.4) of the protocol when having sexual intercourse with a 
woman of childbearing potential (WOCBP) who is not currently pregnant, or 
during homosexual intercourse. 
B) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding 
(see wording specific to Japan in Section 10.7), 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 Appendix 4 
(Section 10.4) during the intervention period (to be effective before starting the 
intervention) and for at least 420 days (for Cohort A3) or 150 days (for Cohorts A1, 
A2, B1, B2 and C1), [corresponding to the time needed to eliminate any study 
intervention(s) plus 30 days (a menstrual cycle)] after the last dose of study 
intervention. 
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- 
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 and agrees not 
to donate or cryopreserve eggs (ova, oocytes) for the purpose of reproduction during 
this period. 
- 
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 4 (Section 10.4). 
- 
The Investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy. 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol 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: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. 
E 02. Predicted life expectancy ≤3 months. 
E 03. Active brain metastases or leptomeningeal metastases.  
- 
Patients with previously treated brain metastases are eligible provided they are 
clinically stable for at least 4 weeks with no evidence of new or enlarging brain 
metastases and have not received corticosteroids at least 2 weeks prior to first IMP 
administration (Note: participants with brain involvement due to direct extension of 
invading tumor, rather than metastasis, may be allowed to enroll if they do not require 
greater than 10 mg prednisone daily, after discussion and approval from the Sponsor). 
- 
 Patients with asymptomatic brain metastases (ie, no neurological symptoms, no 
requirements for corticosteroids, and no lesion >1.5 cm) are eligible but will require 
regular imaging of the brain as a site of disease. 
E 04. History of allogenic tissue/solid organ transplant (participants with prior corneal transplant 
may be allowed to enroll after discussion with and approval from Sponsor). 
E 05. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD1/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. 
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E 06. Last administration of prior antitumor therapy (chemotherapy, targeted agents, and 
immunotherapy) or any investigational treatment within 28 days or less than 5 times the 
half-life, whichever is shorter; major surgery or local intervention within 28 days.  
E 07. For participants in Cohort A3 - Uncontrolled pleural/peritoneal effusion, pericardial 
effusion or ascites requiring recurrent drainage procedures (twice monthly or more 
frequently). 
E 08. 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 09. 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 16), or other infection that is not controlled or requires IV or oral antibiotics. 
E 10. 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 11. 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. 
E 12. 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 13. Current pneumonitis or interstitial lung disease, or history of interstitial lung disease or 
pneumonitis that required oral or IV glucocorticoids to assist with management.  
E 14. 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 15. Receipt of a live or live-attenuated virus vaccination within 28 days of planned treatment 
start. Seasonal flu vaccines that do not contain live virus are permitted. 
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E 16. 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. 
E 17. Known uncontrolled hepatitis B infection, known untreated current hepatitis C infection, 
active tuberculosis, or severe infection requiring parenteral antibiotic treatment. 
- 
To control HBV infection, participants with positive HBsAg should have started 
anti-HBV therapy before initiation of IMP. Antiviral therapy for HBV must be given 
for at least 4 weeks and HBV viral load must be less than 100 IU/mL prior to first dose 
of study drug. Participants on active HBV therapy with viral loads under 100 IU/mL 
should stay on the same therapy throughout study treatment.   
- 
Participants who are positive for anti-hepatitis B core antibody HBc, negative for 
hepatitis B surface antigen (HBsAg), and negative or positive for anti-hepatitis B 
surface antibody (HBs), and who have an HBV viral load under 100 IU/mL, do not 
require HBV anti-viral prophylaxis. 
- 
Participants with past or ongoing hepatitis C virus (HCV) infection will be eligible for 
the study. The treated participants must have completed their treatment at least 1 
month prior to starting study intervention. Participants with positive HCV antibody 
and undetectable HCV RNA without anti-HCV therapy are eligible. 
E 18. Known second malignancy either progressing or requiring active treatment within the last 
3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded. 
E 19. For participants in Cohort A3. Participants with predominantly squamous cell histology 
NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell 
elements are present, the participant is ineligible. 
E 20. For participants in Cohorts A1, A2, A3, B1, and B2 - Known driver alternations which 
include epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), 
Proto-oncogene tyrosine-protein kinase (ROS)1, or BRAF mutation for participants with 
non-squamous NSCLC. 
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E 21. Known hypersensitivity to or contraindication for the use of any study intervention or 
components thereof, including premedication to be administered in this study, as well as 
PEG or any pegylated drug and E. coli-derived protein. 
E 22. Participants with baseline SpO2 ≤92% (without oxygen therapy). 
Prior/concomitant therapy 
E 23. Has received prior IL-2-based anticancer treatment. 
E 24. Is unable or unwilling to take premedication. 
E 25. Deleted by protocol amendment 03 
E 26. Participants treated under anti-hypertensive treatment who cannot temporarily (for at least 
36 hours) withhold antihypertensive medications prior to each IMP dosing 
E 27. For participants in Cohorts A1, A2, A3, C1 - Prior treatment with an agent (approved or 
investigational) that blocks the PD1/PD-L1 pathway (participants who joined a study with 
an anti-PD1/PD-L1 but have written confirmation they were on control arm are allowed). 
E 28. For participants in Cohort A3 - Is unable to interrupt aspirin or other nonsteroidal 
anti-inflammatory drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day 
period (8-day period for long-acting agents, such as piroxicam). 
Prior/concurrent clinical study experience 
E 29. Current enrollment or past participation in a study of an investigational treatment or has 
used an investigational device within 28 days prior to the first dose of study treatment.  
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 28 days after the last dose of the previous investigational 
treatment. 
Organ and bone marrow function 
E 30. Absolute neutrophil count <1500 /μL (1.5 × 109/L) (after at least one week off G-CSF). 
E 31. Platelets <100 × 103 μ/L (after at least 3 days without platelet transfusion). 
E 32. 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 33. Total bilirubin >1.5 × 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 34. Aspartate aminotransferase and/or alanine aminotransferase >2.5 × ULN (or >5 × ULN for 
participants with liver metastases). 
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E 35. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m2 (Modification of Diet in 
Renal Disease [MDRD] Formula). 
E 36. 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 37. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 38. Any country-related specific regulation that would prevent the participant from entering 
the study - see Section 10.7. 
E 39. 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 40. 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 41. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 42. History or current evidence of any condition, therapy that might confound the results of the 
trial, interfere with the subject's participation for the full duration of the trial, or is not in 
the best interest of the subject to participate, in the opinion of the treating Investigator.   
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No food or drink restrictions are required. Guidelines on fluid intake are presented in 
Section 6.1.3. 
5.3.2 Caffeine, alcohol, and tobacco  
No restrictions are required. 
5.3.3 Activity  
Participants are advised to abstain from strenuous exercise and avoid long hot showers and saunas 
on Days 1 to 4 of every treatment cycle. 
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5.3.4 Hydration  
Since SAR444245 may induce episodes of hypotension, participants should be informed of the 
importance of being well hydrated and provided hydration instructions. Guidelines pertaining to 
fluid intake on the day of SAR444245 dosing and for the 3 days after administration are detailed 
in Section 6.1.3. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) and for 
whom resolution of the screen failure reason may not be expected within a reasonable time frame, 
will be recorded as screen failures. In case the participant is a temporary screen failure 
(ie, prolonged screening), there is no need to have participant re-consent (ie, new ICF signed) if 
the participant finally participates in the trial. However, if the reason for temporary screen failure 
is a reason that might have altered the initial given agreement of the participant to participate, the 
Investigator should ensure the willingness of the participant to continue or redo some screening 
procedures and his/her participation to the trial. This oral agreement should be documented in the 
participant’s chart. All the tests out of protocol window should be repeated and entered to the 
additional pages.  
A participant who screen failed may be rescreened; in this situation, the rescreened participant 
should sign a new ICF. A participant may be rescreened only once.  
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
SCREENING/ENROLLMENT/ADMINISTRATION OF STUDY INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol-mandated procedures, contingency measures are proposed 
in Section 10.11. 
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6 
STUDY INTERVENTION AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTIONS ADMINISTERED  
Participants will receive study treatment until confirmed PD, unacceptable toxicity, other 
permanent discontinuation criteria as described in Section 7, or completion of Cycle 35. 
6.1.1 Investigational medicinal product  
Investigation medicinal product is defined as SAR444245, pembrolizumab, and chemotherapy 
administered in combination as described in Section 4.1. Details of each IMP component to be 
administered are shown in Table 6.  
Preparation and administration of IMP are detailed in the pharmacy manual. 
Hydration is required for SAR444245 and cisplatin infusions. Details are provided 
in Section 6.1.3. 
Table 6 - Overview of IMP administered  
Intervention 
name 
SAR444245 Pembrolizumab Pemetrexed Carboplatin 
Cisplatin 
Nab-
paclitaxel 
Type  
Biologic 
Biologic 
Drug 
Drug 
Drug 
Drug 
Dose 
formulation 
Concentrate 
for solution for 
infusion 
Solution for 
infusion 
Concentrate 
for solution for 
infusion (or 
any other 
formulation 
approved 
locally) 
Concentrate 
for solution for 
infusion (or 
any other 
formulation 
approved 
locally) 
Concentrate 
for solution for 
infusion (or 
any other 
formulation 
approved 
locally) 
Powder for 
suspension 
for infusion 
(or any other 
formulation 
approved 
locally) 
Unit dose 
strength(s) 
2.0 mg/mL 
25 mg/mL 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
Dosage 
level(s)a 
24 μg/kg Q3W 
(or reduced to 
 
or another 
lower dose 
level 
recommended 
by SB) 
200 mg Q3W 
500 mg/m2 
Q3W 
AUC of 
5 Q3W for 
4 cycles 
75 mg/m2 
Q3W for 
4 cycles 
100 mg/m2, 
on Days 1 
and 8 of  
each cycle for 
6 cycles 
Route of 
administration 
IV infusion 
IV infusion 
IV infusion  
IV infusion  
IV infusion  
IV infusion  
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Intervention 
name 
SAR444245 Pembrolizumab Pemetrexed Carboplatin 
Cisplatin 
Nab-
paclitaxel 
Use 
Experimental 
Treatment of 
cancer 
(combination) 
Treatment of 
cancer 
(combination) 
Treatment of 
cancer 
(combination) 
Treatment of 
cancer 
(combination) 
Experimental 
IMP or NIMP 
IMP  
IMP  
IMP 
IMP 
IMP 
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. 
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/mark
eted where 
possible. 
Central 
sourcing (EU 
sourced and 
clinically 
labeled only 
for the 
countries 
where local 
sourcing is not 
possible) 
To be locally 
sourced as 
locally 
available/mark
eted where 
possible. 
Central 
sourcing (EU 
sourced and 
clinically 
labeled only 
for the 
countries 
where local 
sourcing is not 
possible) 
To be locally 
sourced as 
locally 
available/mark
eted where 
possible. 
Central 
sourcing (EU 
sourced and 
clinically 
labeled only 
for the 
countries 
where local 
sourcing is not 
possible) 
To be locally 
sourced as 
locally 
available/mar
keted 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) 
NA 
Keytruda 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
As per locally 
approved 
formulation 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to 
the infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent 
weight assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the 
eCRF. 
6.1.2 Non-investigational medicinal products  
Non-investigational medicinal products (NIMP) include the premedication administered for 
SAR444245, pemetrexed, and cisplatin. 
6.1.2.1 Premedication for SAR444245  
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, preferably 30 to 60 minutes prior to 
SAR444245 infusion (ideally no longer than 60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or PO, 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 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 the next cycle. If no IRR is observed for the next cycle without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during the next cycle without premedication the participant 
experiences an IRR (any grade), premedication must be restarted for all subsequent cycles. 
• In case of permanent SAR444245 discontinuation and continuation of pembrolizumab 
treatment as part of AE management, premedication no longer needs to be administered 
6.1.2.2 Premedication for pemetrexed  
All participants in Cohort A3 should receive the appropriate supplementation of vitamin B12 and 
folic acid and corticosteroid prophylaxis as listed below:  
• Folic acid 350-1000 μg oral: At least 5 daily doses of folic acid must be taken during the 7 
days preceding the first dose of pemetrexed, and folic acid dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed. 
• Vitamin B12 1000 μg intramuscular injection in the week preceding the first dose of 
pemetrexed and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be 
given the same day as pemetrexed administration. 
• Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during Cycles 1-4 but not to exceed doses in MASCC 
(Multinational Association for Supportive Care in Cancer) guidelines (5). 
6.1.2.3 Premedication for cisplatin  
All participants in Cohort A3 should receive premedication for cisplatin as per local practice and 
locally approved label. 
6.1.3 Hydration guidelines for SAR444245 administration  
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6.1.4 Readiness for treatment of severe cytokine release syndrome  
Doses of tocilizumab should be available at site at all times in the event that a participant requires 
rapid intervention for the treatment of severe CRS. Please refer to Section 6.6.5.3 for detailed 
guidelines for the management of CRS. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site staff. 
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3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
Treatment preparation and administration (including compatible materials) will be further detailed 
in the pharmacy manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Participants must be dosed at the site and will receive IMP directly from the Investigator or 
designee, under medical supervision. The person responsible for drug dispensing is required to 
maintain adequate records of the IMP administration. These records include the date the IMP 
components are received from the Sponsor, dispensed to the participant and destroyed or returned 
to the Sponsor. The packaging batch number and the treatment number on the vial must be 
recorded on the drug accountability form. The date and time of each dose administered in the 
clinic will be recorded in the source documents and recorded in the electronic case report form 
(eCRF). The dose of study intervention and study participant identification will be confirmed at 
the time of dosing by a member of the study site staff other than the person administering the 
study intervention. 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter [OTC] or prescription medicines, 
vitamins, and/or herbal supplements) or other specific categories of interest) that the participant is 
receiving at the time of enrollment or receives during the study must be recorded along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior therapy. 
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Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from trial therapy may be required. The Investigator 
should discuss any questions regarding this with the Sponsor. The final decision on any 
supportive therapy or vaccination rests with the Investigator and/or the participant's primary 
physician. However, the decision to continue the participant on trial therapy schedule requires the 
mutual agreement of the Investigator, the Sponsor and the participant. 
6.5.1 Acceptable concomitant medications  
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form 
(e-CRF) including all prescription, OTC, herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of route, and date will also be included on 
the e-CRF. 
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms. Surgery or radiotherapy for tumor control is not 
permitted during the study; however, radiotherapy or procedures for symptom management is 
allowed after discussion with and approval by the Sponsor. 
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Follow-up Visit should be recorded. 
Colony-Stimulating Factors 
Routine use of colony-stimulating factors (CSFs) is not permitted. American Society of Clinical 
Oncology guidelines for use of CSFs should be followed (113). See requirements specific to 
Japan in Section 10.7. 
Nonsteroidal Anti-Inflammatory Drugs 
For Cohort A3, participants taking NSAIDs or salicylates will not take the NSAID or salicylate 
(other than an aspirin dose ≤1.3 g per day) for 2 days before, the day of, and 2 days after receiving 
pemetrexed. Participants taking NSAIDs or salicylates with a long half-life (for example, 
naproxen, piroxicam, diflunisal, or nabumetone) will not take the NSAIDs or salicylates for 
5 days before, the day of, and 2 days after pemetrexed. 
6.5.2 Prohibited concomitant medications  
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol. 
• Immunotherapy not specified in this protocol. 
• Investigational agents other than specified in this protocol. 
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• Radiotherapy for tumor control (please refer to Section 6.5.1 for allowed radiotherapy). 
• Live or live attenuated virus vaccines within 28 days prior to the first dose of trial 
treatment and while participating in the trial. Examples of live-virus vaccines include, but 
are not limited to, the following: measles, mumps, rubella, chickenpox, yellow fever, 
seasonal flu (seasonal flu vaccines that do not contain live virus are permitted), nasal 
H1N1 flu, rabies, Bacillus Calmette-Guérin (BCG), and typhoid. 
• Systemic glucocorticoids and other immunosuppressive therapies such as anti-TNF, 
anti-IL6, etc, except for: 
- 
Treatment of immune-mediated AEs when indicated (IRR, CRS, irAE, and ICANS 
see Table 12, Table 13, Table 14 and Table 16),  
- 
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). 
• Phenytoin during therapy with cisplatin/carboplatin. 
Participants who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Participants 
may receive other medications that the Investigator deems to be medically necessary. 
The exclusion criteria describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Observation and Survival Follow-up Periods. 
For withholding antihypertensive medications as part of hydration guidelines, please refer 
to Section 6.1.3. 
6.6 
DOSE MODIFICATION  
6.6.1 General rules  
Dose modifications for SAR444245 and chemotherapy (reduction) 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, delay of IMP) or dose omission (ie, omission of any component of the IMP 
within a cycle) are permitted in case of TEAE. Dose modification will be made according to the 
worst grade of toxicity observed within a cycle. If a participant experiences several toxicities and 
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there are conflicting recommendations, the most conservative recommended dose adjustment 
should be followed. Once a dose has been decreased, intra-patient re-escalation back to the 
previous dose level is not permitted. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
For cohorts B1 and B2, if a toxicity leads to SAR444245 discontinuation, pembrolizumab must be 
discontinued unless the TEAE leading to permanent IMP discontinuation is clearly attributable 
only to SAR444245, and patients have clinical benefit as determined by the treating physician. 
Participants who continue pembrolizumab in this scenario are informed as part of the initial 
consent process that pembrolizumab monotherapy is not a standard of care. For other cohorts, if 
any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 are met. In this 
case it is partial permanent discontinuation and the end of treatment (EOT) assessment will be 
30 days after the date of the last administration of the remaining IMP. When 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). 
6.6.2 Cycle delay and dose omission  
The treatment window is ±3 days for each of the Q3W administrations, and ±1 day for each 
nab-paclitaxel administration on Day 8 of the first 6 cycles. Within a cycle, a dose is deemed to 
have been delayed if the treatment is ≥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 6.6.3, Section 6.6.4, and Section 6.6.5. After treatment is withheld/cycle 
delayed, such participants may be considered for treatment resumption once the toxicity resolves 
or improves to Grade 1 or baseline. 
Participants may have cycle delay or dose omission if toxicity occurs and the participant does not 
recover according to following rules: 
• For nab-paclitaxel Day 1 and Day 8 administration in the first 6 cycles: 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. 
• For Q3W IMP administration: If toxicity occurs and the participant does not recover on 
the day of planned administration or within the following 14 days, dose of a Q3W 
administered IMP may be omitted. Dose omitted for toxicity should not be replaced: 
restart of study IMPs could occur only on the initiation of the subsequent cycle. 
• 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. 
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- 
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. 
• IMP may be interrupted for situations other than TEAEs such as medical/surgical events 
or logistical reasons not related to study therapy. Participants should be placed back on 
study therapy within 21 days of the scheduled interruption, unless otherwise discussed 
with the Sponsor (for example for national or regional emergencies). The reason for 
interruption should be documented in the participant’s study record. 
6.6.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 treatment-related adverse events (TRAEs) at any time of 
the study (including clinically significant grade 3 laboratory abnormalities as defined 
in Section 10.3.1) will be required to temporarily withhold the IMP, unless specified otherwise in 
the protocol, and with the exception of the TRAEs resolving within 5 days. After treatment 
withhold, such participants may be considered for treatment resumption once the TRAE resolves 
or improves to Grade 1 or baseline. Treatment resumption is at the discretion of the Investigator 
and Sponsor, if thought to be in the best interest of the participant, except when specified 
otherwise in this protocol, or if the event has required the IMP temporary interruption for more 
than 84 days from the last scheduled dose.  
The withholding of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No withholding of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 24 µg/kg to 
 µg/kg (or another lower dose recommended 
by SB) may be decided when specified in the protocol or following discussions with the Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
VLS and IRR are presented in Section 6.6.5. 
6.6.4 Dose modification for chemotherapy  
Participants can have a maximum of 2 dose modifications (if applicable) to each of the 
components of chemotherapy throughout the course of the study for toxicities. Participants who 
require a third dose modification of any particular component will have that agent discontinued. 
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion of 
the Investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of the 
Investigator, the toxicity is related to the combination of multiple agents, all agents should be 
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reduced (if applicable), interrupted or discontinued according to the recommended dose 
modifications. Participants may have chemotherapy discontinued and continue on 
SAR444245/pembrolizumab. Similarly, participants may discontinue 
SAR444245/pembrolizumab and continue on chemotherapy alone if appropriate. 
6.6.4.1 Dose modification for cisplatin, carboplatin and pemetrexed  
Recommended dose modifications for key chemotherapy toxicities are outlined in Table 7, 
Table 8, and Table 9. These serve as a guide and do not replace investigator judgment and 
applicable local label recommendations if more stringent. 
Table 7 - Dose modification for chemotherapy agents  
 
Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Cisplatin 
75 mg/m² 
56 mg/m² 
38 mg/m² 
Discontinue 
Carboplatin 
AUC 5 
Maximum dose 750 mg 
AUC 3.75 
 Maximum dose 562.5 mg 
AUC 2.5 
Maximum dose 375 mg 
Discontinue 
Pemetrexed 
500 mg/m² 
375 mg/m² 
250 mg/m² 
Discontinue 
 
Table 8 - Recommended dose modifications for chemotherapy hematological toxicity  
 
 
Pemetrexed 
Cisplatin/Carboplatin 
Platelets 
ANC 
Dose level (DL) from Table 7  
≥50 × 103 /uL AND 
≥500 /uL 
DL 0 
DL 0 
≥50 × 103 /uL AND 
< 500 /uL 
DL -1 
DL -1 
<50 × 103 /uL without bleeding AND 
ANY 
DL -1 
DL -1 
<50 × 103 /uL with Grade ≥2 bleeding AND 
ANY 
DL -2 
DL -2 
ANY AND 
<1000/mm3 + fever ≥38.5°C 
DL -1 
DL -1 
 
Table 9 - Recommended dose modifications for chemotherapy non-hematological toxicity  
 
 
Pemetrexed 
Cisplatin 
Carboplatin 
Event 
CTC Grade 
Dose level (DL) from Table 7  
Nausea or vomiting 
Grade 3 or 4 
DL 0 
DL 0 
DL 0 
Diarrhea 
Grade 3 or 4 
DL -1 
DL -1 
DL 0 
Mucositis 
Grade 3 or 4 
DL -2 
DL 0 
DL 0 
Neurotoxicity 
Grade 2 
DL 0 
DL -2 
DL 0 
Grade 3 or 4 
DL -1 
Discontinue 
DL -1 
Transaminase elevation 
Grade 3 
DL -1 
DL -1 
DL -1 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological toxicity 
Grade 3 or 4 
DL -1 
DL -1 
DL -1 
 
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6.6.4.2 Dose modification for nab-paclitaxel  
Do not administer nab-paclitaxel on Day 1 of a cycle until ANC is at least 1500 /uL and platelet 
count is at least 100 × 103 /uL. In participants who develop severe neutropenia or 
thrombocytopenia withhold treatment until counts recover to an ANC of at least 1500 /uL and 
platelet count of at least 100 × 103 /uL on Day 1 or to an ANC of at least 500 /uL and platelet 
count of at least 50 × 103 /uL on Day 8 of the cycle. Upon resumption of dosing, permanently 
reduce nab-paclitaxel dose as outlined in Table 10. 
Withhold nab-paclitaxel for Grade 3-4 peripheral neuropathy. Resume nab-paclitaxel at reduced 
doses (see Table 10) when peripheral neuropathy improves to Grade 1 or completely resolves. 
Table 10 - Recommended dose modifications for chemotherapy hematological and neurological 
toxicity  
Event 
Occurrence 
Weekly nab-paclitaxel dose 
(mg/m²) 
Neutropenic Fever (ANC <500 /uL with fever >38.5°C) 
OR 
Delay of next cycle by more than 7 days for ANC 
<1500 /uL  
OR 
ANC <500 /uL for more than 7 days 
First 
75 
Second 
50 
Third 
Discontinue nab-paclitaxel treatment 
Platelet count less than 50 000/mm3 
First 
75 
Second 
Discontinue nab-paclitaxel treatment 
Severe sensory neuropathy - Grade 3 or 4 
First 
75 
Second 
50 
Third 
Discontinue nab-paclitaxel treatment 
 
Table 11 - Recommended dose modifications for chemotherapy non-hematological toxicity  
Non-hematologic toxicity 
Occurrence 
Weekly dose of nab-paclitaxel (mg/m²) 
Grade 2 or 3 cutaneous toxicity 
Grade 3 diarrhea 
Grade 3 mucositis 
≥ Grade 3 peripheral neuropathy 
Any other Grade 3 or 4 non-hematologic toxicity  
First 
75 
Second 
50 
Third 
Discontinue nab-paclitaxel treatment 
Grade 4 cutaneous toxicity, diarrhea or mucositis 
First  
Discontinue nab-paclitaxel treatment 
 
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6.6.5 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as AESIs, depending on grading 
according to NCI-CTCAE V5.0 (see Section 8.3.8). In case a specific adverse event meets the 
AESI definition it must be documented in the electronic case report form (e-CRF). 
6.6.5.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1, prior to 
SAR444245 administration, to prevent or reduce the incidence or severity of IRRs. 
An IRR in this study is defined as any signs or symptoms which develop during the infusion or up 
to 24 hours after the completion of the infusion. The term IRR indicates only a specific temporal 
relationship with the infusion and does not specify a particular mechanism underlying the signs or 
symptoms.  
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after drug 
infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 12. 
Guidelines for the management of SAR444245 IRR events are provided in Table 13. 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. 
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Table 12 - Pembrolizumab infusion reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
• 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the investigator. 
None 
Grade 2 
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 Infusiona. 
• 
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.  
a After an infusion-related reaction due to pembrolizumab infusion, the SAR444245 infusion will be delayed and can be administered after 
resolution of symptoms. The Investigator should discuss with the Sponsor’s Medical Monitor if the SAR444245 infusion needs to be 
delayed more than 1 day 
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Table 13 - SAR444245 Infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
If IRR happens during infusion, continuation of SAR444245a infusion is per 
Investigator’s judgment following close direct monitoring of the participant’s 
clinical status. 
SAR444245 infusion may be interrupted at any time if deemed necessary.  
If interrupted, IRR will be classified as Grade 2 as per NCI-CTCAE definition. 
If IRR happens after completion of infusion, increase monitoring of vital signs 
as medically indicated until the participant is deemed medically stable in the 
opinion of the investigator. 
Grade 2 
Requires therapy or infusion interruption but 
responds promptly to symptomatic treatment 
(eg, antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications indicated 
for ≤24 hrs. 
Interrupt SAR444245 infusion.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion 
may be restarted at 50% of the original infusion rate. Otherwise dosing will be 
held until symptoms resolve and the participant should be premedicated for 
the next scheduled dose according to Section 6.1.2.1. 
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  
 
Permanently discontinue SAR444245. The participant can continue treatment 
with pembrolizumab. 
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 
 
Permanently discontinue SAR444245. The participant can continue treatment 
with pembrolizumab. 
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. 
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6.6.5.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and pembrolizumab and any chemotherapy being 
administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines 
in 114, 115, 116). 
6.6.5.3 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 ASTCT criteria integrated with central 
laboratory cytokine results, and managed per guidelines in Table 14. 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 for 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 14. 
ASTCT CRS consensus grading scale is provided in Section 10.13. 
Table 14 - Guidelines for the management of suspected cytokine release syndrome (CRS)  
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended IMP  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245/pembrolizumaba. 
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 both SAR444245 and pembrolizumab, 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. 
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Event severity (ASTCT CRS 
Consensus Grading) 
Recommended IMP  
dose modification and supportive care guidelines 
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.  
IMP may be resumed when clinical symptoms have resolved or improved to 
Grade 1 and corticosteroid taper. No dose modification is required but 
decreasing to half the infusion rate can be considered. 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a 
vasopressor with or without 
vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi 
mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding 
vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, 
intubation and mechanical 
ventilation) 
If CRS grade 3, both SAR444245 and pembrolizumab should be temporarily 
withheld, 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. The participant can continue treatment with 
pembrolizumab without dose modification. 
If CRS Grade 4, SAR444245 should be permanently discontinued and 
pembrolizumab temporarily withheld or permanently discontinued. If 
temporarily interrupted, pembrolizumab can be resumed without dose 
modification only when symptoms have resolved or improved to Grade 1.  
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 and pembrolizumab are 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. 
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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. 
6.6.5.4 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 administer 
corticosteroids. 
SAR444245 may increase the incidence and severity of these events.  
Dose modification and toxicity management guidelines for irAEs are provided in Table 15. Of 
note, if the AE is considered immune-related, both drugs in the combination should be held 
according to recommended dose modifications.  If a participant experiences several irAEs, the 
most conservative recommendation should be followed. 
The CTCAE V5.0 must be used to grade the severity of AEs.  
When SAR444245 or pembrolizumab can be restarted, they should be administered at the initial 
planned dose and schedule as no modification is allowed: 
• If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study drugs.  
• If the toxicities do resolve and conditions are aligned with what is defined in Table 15, 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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Chemotherapy should be modified similarly as that for SAR444245 in case of irAE, ie withheld or 
permanently discontinued. 
Table 15 - 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 resume 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 
Withhold  
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 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
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 
discontinue 
AST or ALT 
elevation or 
Increased 
Bilirubin/hepatitis 
Grade 2a 
Withhold 
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 returned to baseline or is 
stable). 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and 
SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Grade 3b or 4c 
Permanently 
discontinue 
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 
Withholdd 
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 
Withhold 
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 
Withhold or 
permanently 
discontinued 
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 
Withhold or 
permanently 
discontinued 
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 
Withhold 
Administer 
corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
 
 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinue 
Based on severity of AE 
administer 
corticosteroids. 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes. 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and 
SAR444245 
Corticosteroid 
and/or other 
therapies 
Monitoring and follow-up 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
Based on severity of AE 
administer 
corticosteroids 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 
Withhold 
Based on severity of AE 
administer 
corticosteroids. 
Ensure adequate evaluation to 
confirm etiology or exclude other 
causes. 
Grade 3 
Withhold or 
discontinue based 
on the evente  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for 
Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune 
related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper 
limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a 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. 
b 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. 
c 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. 
d 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. 
e Events that require discontinuation include but are not limited to: encephalitis, and other clinically important irAEs (eg, vasculitis and 
sclerosing cholangitis). 
6.6.5.5 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 10.13). 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 16. The proposed management should be considered only as 
recommendations and in light of recommendations from site specialist. 
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Table 16 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended IMP  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245a and pembrolizumabashould be withheld. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 and/or pembrolizumab may be resumed only after participant 
recovery or improvement to Grade 1 after corticosteroid taper. No modification 
in pembrolizumab dose is recommended, and consideration for reduction of 
SAR444245 dose to 
 µg/kg as per Investigator with Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 1-2. 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 (>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 and pembrolizumab should be withheld. 
When symptoms have resolved or improved to Grade 1 after corticosteroid 
taper, SAR444245 can be either restarted at 
 µg/kg or permanently 
discontinued, as clinically indicated, and upon discussions between the 
Investigator and Sponsor.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab and should be handled as described in Table 14. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days 
If Grade 4 ICANS, 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 14. 
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 and pembrolizumab are provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.6.5.6 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 
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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 17. 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 (117).  
Table 17 - 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 
IMP should be withheld. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
 µg/kg, 
and pembrolizumaba can be resumed without dose reduction. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent 
intervention indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued. The participant can continue treatment with pembrolizumab 
upon resolution of the event or improvement to Grade 1.   
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 and pembrolizumab are provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
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6.7 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There will be no intervention beyond the end of the study. 
6.8 
TREATMENT OF OVERDOSE  
There is no specific antidote for overdose with SAR444245, pembrolizumab, or other anticancer 
therapies.  
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. 
Procedures for treating symptoms and complications of irAEs are provided in Section 6.6.5.4. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 90 days). 
3. Obtain a plasma sample for PK analysis right after the overdose event is identified (only if 
an overdose is identified within 5 days from start of overdose infusion). 
4. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Permanent discontinuation  
Study intervention should be permanently discontinued in any of the following cases: 
• At the participant’s request, at any time and irrespective of the reason (consent’s 
withdrawal), or at the request of their legally authorized representative. “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 patient to the 
patient’s participation in the procedure(s) involved in the research.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s wellbeing, such as:  
- 
Unacceptable AE. 
- 
Documented disease progression (including both radiological PD and clinical PD). 
- 
- 
If a participant has PD per mRECIST and is clinically stable, it is at the discretion 
of the Investigator to continue treating the subject with the assigned treatment per 
protocol until pseudo-progression is ruled out. Radiological re-assessment should 
be done at least 4 weeks, but no longer than 8 weeks  from the date of the scan 
suggesting progression of disease (Section 10.10.4). Clinical Stability is defined 
as: 1) Absence of symptoms and signs indicating clinically significant progression 
of disease (including worsening of laboratory values) indicating disease 
progression. 2) No decline in ECOG performance status. 3) Absence of rapid 
progression of disease or progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention. 
- 
Poor compliance to the study protocol. 
- 
Other, such as concurrent illness, that prevents further administration of study 
intervention, or that in the Investigator’s opinion, in the best interest of the participant. 
• In case of pregnancy occurrence. 
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for serial tumor assessment if permanent discontinuation is not due to PD, for safety 
assessment as per SoA (Section 1.3) and until resolution or stabilization of AE, and any other 
assessment as per SoA. Data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed are reported in the SoA. 
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7.1.1.1 Unacceptable adverse events leading to permanent intervention discontinuation  
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Table 15, or if the 
Investigator believes that it is in best interest of the participant.  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
Any potentially clinically significant abnormal laboratory value or ECG parameter will be 
immediately rechecked for confirmation and repeated after 24 hours to document evolution before 
making a decision of permanent intervention discontinuation for the concerned participant. 
Decision criteria for discontinuation following immune-mediated AEs are described in  
Section 6.6.5 (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 10.11; Appendix 11: Contingency Measures for a regional or 
national emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of 
the e-CRF.  
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7.1.3 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned event was unlikely 
and if the selection criteria for the study are still met. 
Recommendations for rechallenge in the context of an epidemic/pandemic (eg, COVID-19) are 
included in Appendix 11 Contingency Measures for a regional or national emergency 
(Section 10.11) that is declared by a governmental agency. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• At the time of discontinuing from the treatment, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of 
the e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
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Participants who have been withdrawn from the study treatment cannot be re-included in the 
study. Their inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures are summarized in this section and their timing is presented in the SoA 
(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. 
• Regular blood samples will be collected from each participant throughout the duration of 
the study. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. Details on blood sampling, including the estimated volume 
collected for each analysis are provided in the laboratory manual. 
•  For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Section 10.11. 
8.1 
EFFICACY ASSESSMENTS  
The assessment of anti-tumor activity documented by objective response to the IMP is the primary 
endpoint for this study and is conducted as per schedule provided in the SoA. All participants 
treated must have at least one measurable lesion for inclusion.    
Decision to pursue treatment will be based on the response evaluation made by the Investigator, 
however, measures of lesions will be collected in the e-CRF for a determination of response by 
the Sponsor. A partial or complete response must be confirmed on a second examination done at 
least 4 weeks apart, in order to be documented as a confirmed response to therapy. For NSCLC, 
confirmation of PD using 
 may be done at the discretion of the Investigator when 
clinically indicated. For mesothelioma, pseudo-progression may need to be ruled out. Please refer 
to Section 7.1.1 for details. 
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. 
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Assessment of tumor response will be conducted using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 (for NSCLC) or mRECIST (for mesothelioma) (see Section 10.8 
and Section 10.10) according to the nature of the measurable lesions, as described below. 
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s)  
For participants with disease that is measured radiologically according to RECIST 1.1 criteria 
(Section 10.8), 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. Participants 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. 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 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 and 
 
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).  
 
mRECIST 
Tumor evaluation will be assessed by the investigator using mRECIST criteria for mesothelioma 
(Section 10.10).  
To account for the possibility of unconventional immune responses, participants may continue 
treatment beyond progression if pseudo-progression is ruled out after discussion and approval 
from the Sponsor.   
Any participant who experiences best response (PR or CR) after initial progression in the context 
of continued treatment (according to principles of pseudo-progression and after Sponsor approval) 
will not have that best response (partial or complete) counted towards the primary endpoint of this 
study.   
8.2 
SAFETY ASSESSMENTS  
The main anticipated adverse effect for the combination of SAR444245 with other anticancer 
therapies includes manifestations of cytokine release that can range from fever to hypoxia to 
hypotension, with or without manifestations that may include any of the organ systems. These 
mild events occur between around 12 to 18 hours after the first administration and a more 
intensive monitoring of vital signs is planned during that period. Targeted physical exams and 
standard laboratory tests will be conducted to monitor potential changes in the main body 
functions. Measurement of cytokines in plasma are planned at relevant timepoints. White blood 
cell differential count will be measured to monitor for transient lymphopenia which is commonly 
observed in the first few days following SAR444245 infusion. Eosinophilia that is surrogate to 
VLS will also be monitored. IL-5, which is also a marker of VLS, will be included in the PDy 
cytokine panel. Combining SAR444245 with other anticancer therapies may increase the 
frequency and severity of irAEs related to other anticancer therapies. Immune-mediated 
endocrinopathies involving the thyroid being the most frequent, T3, T4, TSH, and cortisol level 
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will be monitored.  When clinically indicated, on-treatment ECG and LVEF will be assessed and 
compared to baseline. More details on the safety assessment are provided below. Planned time 
points for all safety assessments are provided in the SoA.  
8.2.1 Physical examinations  
• A full physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, neurological and skin systems. Height and weight will also be 
measured and recorded. 
• A directed physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Investigators should also pay attention to clinical signs suggestive of VLS, such 
as peripheral edema, pericardial effusion and pleural effusion, as well as clinical signs 
suggestive of irAEs, such as pneumonitis, colitis, endocrinopathies, to name a few. 
Complementary assessments should be performed to establish the diagnosis when 
clinically indicated.  Early signs of cytokine release syndrome should also prompt a 
thorough clinical assessment to identify the involvement of a specific organ system, 
including neurological system. 
8.2.2 Vital signs  
• Vital signs including temperature, pulse rate, respiratory rate and blood pressure will be 
measured after 5 minutes rest. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• At Cycle 1 Day 1, vital signs after infusion initiation will be collected more intensively;  
- 
For the safety run-in participants vital signs will be measured at Pre-dose, 
0.5 (±0.25), 1 (±0.25), 2 (±0.5), 4 (±0.5), 8 (±0.5), 12 (±1), 16 (±1), 20 (±1),  
24 (±1) hours after start of SAR444245 dose in an in-patient setting. 
- 
For other participants, vital signs will be measured at Pre-dose, 0.5 (±0.25),  
1 (±0.25), 2 (±0.5), 4 (±0.5) hours after start of SAR444245 dose. At Investigator’s 
discretion, participants (not in the safety run-in) may have intensive vital sign 
monitoring.  
• From Cycle 2 and beyond, study therapy will be administered for all patients in out-patient 
clinic with vital signs taken at baseline, at least 4 to 6 hours after the start of SAR444245 
dosing, or for longer periods of time if clinically indicated. 
8.2.3 Electrocardiograms and LVEF  
• Includes single 12-lead ECG and LVEF that will be performed at screening and then, as 
clinically indicated. 
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• Triplicate 12-lead ECG will be obtained when indicated, for instance to further document 
a QTc prolongation, using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTcF intervals.  
• Each time a triplicate ECG is required, 3 individual ECG tracings should be obtained as 
closely as possible in succession, but no more than 2 minutes apart. The full set of 
triplicates should be completed in less than 4 minutes. 
• LVEF evaluation will be done by echocardiography or multigated acquisition (MUGA), 
and any repeated assessment should be done with the same technology used at screening. 
• Additional evaluations such as unscheduled ECG, LVEF, Holter monitoring, cardiac 
enzymes and consultation with a cardiologist should be done when clinically indicated. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
the SoA (Section 1.3) for the timing and frequency.  
• The clinical safety laboratory assessments will be done in the local laboratory.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study. The laboratory reports must be filed 
with the source documents. Abnormal laboratory findings associated with the underlying 
disease are not considered clinically significant, unless judged by the Investigator to be 
more severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within Follow-Up Visit 1 should be repeated until the values 
return to normal or baseline or are no longer considered clinically significant by the 
Investigator or Sponsor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified, and the Sponsor 
notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded.  
8.2.5 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria I 08 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 
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• 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 150 days (for Cohorts A1, A2, B1, B2 and C1) or 420 days (for Cohort A3) after the 
last dose of study treatment. If urine pregnancy results cannot be confirmed as negative, a 
serum pregnancy test will be required. Pregnancy tests (serum and/or urine tests) should be 
repeated if required by local guidelines.  
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Appendix 3 (Section 10.3). The definition of AESI is provided in Section 8.3.8. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7).  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs, including adverse events of new onset, as well as worsening of baseline signs and 
symptoms will be collected throughout study period, from the signing of the informed consent 
form (ICF) until 30 days following cessation of study treatment.  
All SAEs and AESIs will be collected throughout the study period, from the signing of the 
informed consent form (ICF) until 90 days following last administration of study treatment. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
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. 
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8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, and AESIs 
(as defined in Section 8.3.8), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Stabilization is 
defined as an AE ongoing without any change for at least 3 months. Participants with an AE of 
Grade >1 will be further followed until the resolution of the AE to Grade 0-1 or starting of a new 
antineoplastic therapy, whichever occurs first. 
Further information on follow-up procedures is provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information (IB for SAR444245 and country-approved product labeling for 
pembrolizumab). 
- 
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 150 days (for Cohorts A1, 
A2, B1, B2 and C1) or 420 days (for Cohort A3), following cessation of study treatment, 
or 30 days following cessation of study treatment if the participant initiates another 
anticancer therapy.  
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• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant/pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
8.3.6 Cardiovascular and death events  
Cardiovascular events that meet AESI criteria should be reported as such (see Section 8.3.8 for 
details). 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable.  
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An adverse event of special interest is an AE (serious or nonserious) of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
The following events need to be reported as AESIs: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Section 10.3). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
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- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Section 10.4). 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP (excluding 
pembrolizumab)  
- 
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.  
• Symptomatic or asymptomatic overdose with pembrolizumab: 
- 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or ≥5 times the 
indicated dose.  
• An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing*. 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be made available. It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including AST, ALT, bilirubin, and alkaline phosphatase that do not meet 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 
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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. 
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. 
Non-compartmental analysis of SAR444245 plasma concentrations will be conducted where 
applicable. Plasma concentrations of SAR444245 will be analyzed in a popPK modelling 
framework and reported separately. In this context, further exposure-response analysis may be 
conducted. 
8.5 
PHARMACODYNAMICS  
Refer to Section 8.7 for details of pharmacodynamics biomarker.  
8.6 
GENETICS AND/OR PHARMACOGENOMICS  
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8.7 
BIOMARKERS  
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8.8 
IMMUNOGENICITY ASSESSMENTS  
The sampling time points for ADAs may be reduced or increased during the course of the study 
based on the updated knowledge of drug behavior and its immunogenicity, upon notification from 
the Sponsor. 
Samples for the immunogenicity assessment of SAR444245 will be collected according to the PK 
flowcharts. Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. Sample analysis will be performed at a laboratory designated by the Sponsor. 
Samples will be screened and then confirmed for anti-drug antibodies and the titer of confirmed 
positive samples will be reported. Additional analyses may be performed to further characterize 
the immunogenicity of SAR444245. 
Anti-drug antibody samples remaining after determination of immunogenicity may be kept for 
possible exploratory analysis of biomarkers. The exploratory data will not be included in the study 
report but will be kept on file. 
8.9 
  HEALTH ECONOMICS   
No health economics data will be collected. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
All 6 cohorts of the study are designed to obtain antitumor activity, safety, PK, and 
pharmacodynamic (PDy) data on SAR444245 administered in combination with pembrolizumab 
with or without different anticancer agents.  
The study is designed to assess clinical benefit of SAR444245 when combined with 
pembrolizumab in participants with lung cancer or pleural mesothelioma. As this study is not 
intended to explicitly test a hypothesis, calculations of power and Type I error were not 
considered in the study design. No formal testing procedure is going to be considered. 
9.2 
SAMPLE SIZE DETERMINATION 
The study will start with a safety run-in to confirm the dose of SAR444245 when combined with 
other anticancer therapies in a sample of at least 6 participants in each study intervention. 
Overall in the core phase (all cohorts), the plan is to treat approximately 40 participants at the 
confirmed safe dose per cohort. 
In the expansion phase (Cohort B only), approximately 57 participants are planned to be treated at 
the confirmed safe dose per cohort. 
Core Phase 
Table 18 lists estimated ORR and the corresponding 90% exact CIs by number of responders in 
each cohort.  
Table 18 - Estimated objective response rate (ORR) and 90% CI for core phase 
Number of responders 
(N=40) 
ORR 
90% CI for ORR 
(Clopper-Pearson) 
6 
15.0% 
(6.7%, 27.5%) 
7 
17.5% 
(8.5%, 30.4%) 
8 
20.0% 
(10.4%, 33.2%) 
9 
22.5% 
(12.3%, 36.0%) 
10 
25.0% 
(14.2%, 38.7%) 
11 
27.5% 
(16.3%, 41.4%) 
13 
32.5% 
(20.4%, 46.6%) 
15 
37.5% 
(24.7%, 51.7%) 
17 
42.5% 
(29.2%, 56.7%) 
19 
47.5% 
(33.8%, 61.5%) 
24 
60.0% 
(45.8%, 73.1%) 
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Expansion Phase (Only for Cohort B1 and/or Cohort B2) 
At the end of the core phase of Cohorts B1 and B2, the overall efficacy and safety profile will be 
assessed. The Sponsor may decide to open a 57-participant expansion phase based on the totality 
of data from the core phase if the posterior probability that the true ORR is greater than 23%, 
which is considered minimal efficacious signal of interest, is greater than 80% with durable 
response. Based on a conjugate non-informative prior of beta (0.5, 0.5) at the time of the design of 
the study, at least 12 responders out of 40 exposed participants at the confirmed safe dose 
(ORR=30%) need to be observed in the core phase. However, emerging data generated from 
outside of the study may warrant a different prior to be considered before the formal IA. Analyses 
based on the total 97 participants at the confirmed safe dose by combining the core phase and 
expansion phase will be performed for each cohort. Table 19 lists estimated ORR and the 
corresponding 95% exact CIs by number of responders from a sample size of 97 participants 
evaluable for activity in each cohort.  
Table 19 - Estimated objective response rate (ORR) and 95% CI for Cohorts B1 and B2 (combining 
core and expansion phases)  
Number of responders 
(N=97) 
ORR 
95% CI for ORR 
(Clopper-Pearson) 
10 
10.3% 
(5.1%, 18.1%) 
15 
15.5% 
(8.9%, 24.2%) 
20 
20.6% 
(13.1%, 30%) 
25 
25.8% 
(17.4%, 35.7%) 
28 
28.9% 
(20.1%, 39%) 
30 
30.9% 
(21.9%, 41.1%) 
With a sample size of 40 study participants at the confirmed safe dose in the core phase, the 
probability of observing 1 or more instances of a specific AE with a true incidence rate of 1%, 
2%, or 5% is 33.1%, 55.4%, or 87.1%, respectively. With a sample size of 97 study participants in 
total, the probability of observing 1 or more instances of a specific AE with a true incidence rate 
of 1%, 2%, or 5% is 62.3%, 85.9%, or >99%, respectively. This provides reasonable assurance 
that events occurring at ≥5% frequency can be identified in this study. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 20): 
Table 20 - 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). 
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Population 
Description 
Efficacy 
Efficacy population will include all participants from the exposed population with at least one evaluable 
post-baseline tumor assessment or who permanently discontinued study treatment. 
DLT-evaluable 
DLT-evaluable population will include all exposed participants in the safety run-in who have been 
observed for at least 21 days. Any participant who experienced a DLT during DLT observation period 
will also be DLT-evaluable 
PK 
The PK population will include all participants from the exposed population with at least 1 PK 
concentration available after the first dose of study intervention. 
PDy 
The PDy population will include all participants from the exposed population with at least 1 PDy 
parameter assessed after the first dose of study intervention. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan SAP will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary, key secondary endpoints and 
exploratory endpoints. 
9.4.1 General considerations  
This study is not intended to explicitly test a hypothesis, and 90% confidence interval (CI) will be 
provided for primary and secondary efficacy endpoints for descriptive purpose only.  
All efficacy analyses will be performed on the efficacy population and analyzed by cohort and by 
dose (as applicable). Some cross-cohort summaries will be presented too. For Cohorts B1 and B2, 
results will be presented by core phase and overall phase (combining core phase and expansion 
phase). Objective response rate, as well as PFS, DoR, and CBR will be derived using the local 
radiologist’s/Investigator’s assessment for all cohorts. Central imaging may be done 
retrospectively if significant activity is observed. The assessments for Cohort C1 are based on 
mRECIST and all other 5 cohorts will use RECIST 1.1. 
All safety analyses will be performed on the exposed population by cohort, by dose (if applicable) 
and overall (if applicable). Baseline values will be defined as the latest value or measurement 
taken up to the first administration of the IMP.  
The analysis period will be divided into 3 segments: 
• The pre-treatment period is defined as the time from when the participants give informed 
consent to the first administration of the IMP. 
• The on-treatment period (ie, treatment-emergent period) is defined as the time from the 
first administration of IMP up to 30 days after the last administration of IMP. 
• The post-treatment period is defined as the time from the 31 days after the last 
administration of IMP. 
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9.4.2 Primary endpoint(s)  
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 anticancer therapy, whichever 
occurs first. The BOR will be summarized with descriptive statistics. The Objective Response 
Rate (ORR) is defined as the percentage of participants from the analysis population with BOR is 
either CR or PR assessed per investigators. The ORR will be summarized with descriptive 
statistics and the corresponding two-sided 90% CIs calculated from Clopper-Pearson exact 
method will be also presented. All objective responses need to be confirmed by a subsequent 
assessment performed at least 4 weeks apart from the initial response observation.  
9.4.3 Secondary endpoint(s)  
The secondary endpoints include efficacy (DoR, CBR, PFS, TTR), safety, immunogenicity, and PK. 
9.4.3.1 Time to response  
Time to response will be defined as the time from the first administration of IMP to the first tumor 
assessment at which the overall response was recorded as PR or CR that is subsequently 
confirmed.  
Time to response will be descriptively summarized on the subgroup of participants who have 
achieved confirmed objective response. 
9.4.3.2 Duration of response  
The DoR will only be analyzed on the subgroup of participants who have achieved confirmed 
objective response. The DoR will be defined as the time from the date of first tumor assessment at 
which the overall response was recorded as PR or CR that is subsequently confirmed to the date 
of first documentation of objective PD before the initiation of any post-treatment anticancer 
therapy or death due to any cause, whichever occurs first.  
Duration of response will be summarized with descriptive statistics using Kaplan-Meier methods. 
The median DoR and associated 90% CI will be provided. 
9.4.3.3 Clinical benefit rate  
The CBR will be defined as the proportion of participants with clinical benefit (confirmed CR or 
PR as BOR, or 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).  
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9.4.3.4 Progression-free survival  
Progression-free survival is defined as the time from the date of first IMP to the date of the 
first documentation of objective progressive disease, 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). 
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 and classified by SOC and Preferred 
Term (PT) according to the latest available version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Immune cell-associated neurotoxicity syndrome and CRS events will be 
graded using ASTCT Consensus Grading and will be summarized separately. 
• Pre-treatment AEs are defined as any AEs occurring during the pre-treatment period. 
• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the 
Investigator’s opinion), or become serious during the on-treatment period.  
• Post-treatment AEs are defined as AEs that are reported during the post-treatment period.  
For participants with multiple occurrences of the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
Treatment-emergent adverse events: 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• TEAEs. 
• TEAEs of Grade ≥3. 
• Grade 5 TEAE (any TEAE with a fatal outcome during the on-treatment period). 
• Serious TEAEs. 
• Serious treatment-related TEAEs (for each individual drug). 
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• TEAE leading to partial intervention discontinuation. 
• TEAE leading to full intervention discontinuation. 
• Treatment-related TEAEs (for each individual drug). 
• Treatment-related TEAEs of Grade ≥3 (for each individual drug). 
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE V5.0 grade (all grades and Grade ≥3). Missing grades, if any, will 
be included in the “all grades” category. Similar summaries will be prepared for treatment-related 
TEAEs related to each individual drug, TEAEs leading to partial intervention discontinuation, 
TEAEs leading to full intervention discontinuation, TEAEs leading to dose modification, serious 
TEAEs, TEAEs with fatal outcome, AESIs, and AEs/SAEs occurring during the post-treatment 
period. In addition, the number (%) of participants with any Grade 5 AE (TEAE and post-
treatment) will be summarized.  
The following deaths summaries will be generated: 
• Number and percentage of participants who died by study period (treatment, post-
treatment) and reasons for death (disease progression, AE, or other reason). 
• All TEAEs leading to death by primary SOC and PT showing number and percentage (%) 
of participants. 
9.4.3.6 Clinical laboratory evaluations  
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
When relevant, for laboratory variables, descriptive statistics for results and changes from 
baseline will be provided for the last value and the worst value (minimum and/or maximum value 
depending on the parameter) during the on-treatment period.  
Hematology and clinical chemistry results will be graded according to the NCI-CTCAE V5.0, when 
applicable. Number and percentage of participants with laboratory abnormalities (all grades and by 
grade) using the worst grade during the on-treatment period will be provided for the exposed 
population.  
When the NCI-CTCAE V5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
For laboratory variables graded by NCI-CTCAE: 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade.   
• The number (%) of participants with abnormal laboratory tests during the 
treatment-emergent period will be summarized by grade.  When appropriate, the 
number (%) of participants with abnormality of any grade and with Grade 3-4 
abnormalities will be provided. 
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9.4.3.7 Other secondary endpoints  
Immunogenicity analyses will be described in the SAP finalized before database lock. The PK 
analysis and pharmacodynamic analyses will be presented separately from the main clinical study 
report (CSR).  
Plasma concentrations of SAR444245 will be summarized with descriptive statistics by each cohort. 
9.4.4 Tertiary/exploratory endpoint(s)  
9.4.4.1 Exploratory antitumor indicators  
9.4.4.2 Biomarker endpoints  
9.4.5 Other safety analyse(s)  
All safety analyses will be made on the exposed population. When relevant, the summary 
statistics (including mean, median, standard error, minimum and maximum) of all vital signs (raw 
data and changes from baseline) will be calculated for baseline, last on-treatment value and/or 
worst value.  
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9.4.6 Other analyse(s)  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.11. 
9.5 
INTERIM ANALYSES  
During the core phase, no formal interim analyses are planned. However, the following analyses 
will be performed: 
• At the end of the safety run-in of each regimen, the occurrence of DLT and other safety 
data will be reviewed by SB to decide about continuation of the dose of SAR444245 of 
24 µg/kg or reduction to 
 or another lower dose level. 
• After the dose is confirmed by the SB, the cumulative safety data for each study 
intervention across cohorts will be reviewed periodically by the Independent Data 
Monitoring Committee (IDMC). The enrollment will not be paused or stopped during the 
safety monitoring unless severe safety concern arises. IDMC will review safety data 
periodically. Ad hoc IDMC meetings may also be held if a significant safety issue or an 
issue deemed important for discussion arises on this or other SAR444245 studies. The 
IDMC procedures will be detailed in the IDMC charter and approved by the IDMC 
members.  
In addition, in order to support project strategic planning and design of future studies, informal 
interim analysis(es) may be conducted during the study, eg, in each cohort, after 20 participants at 
the confirmed safe dose have undergone two post-baseline tumor assessments (approximately 
18 weeks from the 20 participants are first treated) or have discontinued study treatment, 
whichever is earlier.  
At the end of the core phase, cohorts B1 and B2 will have one formal interim analysis when all 
participants in the core phase have at least 2 post-baseline tumor assessments or discontinued 
study treatment (whichever occurs first). The Sponsor will decide if the expansion will be initiated 
based on totality of the data observed.  
Therefore, for Cohort A1, Cohort A2, Cohort A3 and Cohort C1, the cohort cut-off for the 
primary ORR endpoint analyses is estimated to be approximately 9 months from the date of the 
last participant’s first infusion in the core phase (to document that last participant response is 
maintained for 6 months in the core phase). For Cohort B1 and Cohort B2, the cohort cut-offs for 
the analyses are as follows: 
• IA cut-off: the date on which all participants in the core phase have at least 2 post-baseline 
tumor assessments or discontinue study treatment (whichever occurs first).  
• Primary analysis cut-off: the date on which the last participant response is maintained for 
6 months in the expansion phase (approximately 9 months from the last participant’s first 
infusion in the expansion phase). 
For each cohort, the cut-off date for the final analysis will be 3 years from the date of cohort last- 
patient-in, or when all patients within the cohort have completed the study.   
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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, and answer all questions regarding 
the study, including what happens to the participant when his/her participation ends 
(post-trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and 
Data Protection requirements including those of the Global Data Protection Regulation 
(GDPR) and of the French law, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
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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, where applicable.  
 Participants who are rescreened are required to sign a new ICF. 
The ICF contains a separate section that addresses the use for research of participants’ data and/or 
leftover biological samples. This future research is described in Core Study Informed Consent 
Form (CSICF) Part 2. The option to participate in future research 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 why data and samples are important for future 
research. Participants will be told that they are free to refuse to participate and may withdraw their 
consent at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 11: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency (Section 10.11). 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on African-American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation. 
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• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study, 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
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- 
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 phamaceutical 
company members of the Transcelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the Transcelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
Independent Data Monitoring Committee 
Independent from the Sponsor and Investigators, the IDMC 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. 
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. 
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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, 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
- 
Total number of participants included earlier than expected. 
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If the study or cohort is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. He/she should also stop all 
screening activities pertaining to the study or the relevant cohort(s). Should the Sponsor decide to 
pause recruitment in a cohort to allow decision making, the Investigator should pause all 
screening activities until further notice. 
If the study is early terminated the patients who are receiving and benefitting from study treatment 
as per Investigator judgment may continue study treatment until protocol defined treatment 
discontinuation criteria are met.  The patients who continue study treatment after early study 
termination should be followed for safety (ie, study treatment administrations, ongoing 
SAE/related AE, new related AE, AESI or SAE and their associated concomitant medications and 
lab if any) and end of treatment reason during this time period. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 21 will be performed by local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.  
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Table 21 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematologya 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
Urea or blood urea nitrogen (BUN) 
 
Creatinine and eGFR (MDRD formulab) 
 
Glucose  
 
Potassium 
 
Sodium 
 
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 
Endocrine function testsd 
Thyroid-stimulating hormone (TSH) 
 
Tri-iodothyronine (T3) 
 
Free thyroxine (FT4) 
 
Cortisol (preferably in the morning) 
Coagulation  
International normalized ratio (INR) or Prothrombin Time (PT) (or Activated Partial 
Thromboplastin Time [aPTT]) 
Routine urinalysis 
• 
Specific gravity, pH, glucose, protein, blood, ketones, and leukocytes by 
dipstick. 
• 
Microscopic examination (if blood or protein is abnormal). 
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Laboratory assessments 
Parameters 
Other screening tests 
• 
Follicle-stimulating hormone and estradiol may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)e. 
• 
Serology (hepatitis B surface antigen [HBsAg], hepatitis C virus antibody), 
Hepatitis B viral load, HCV RNA level, CD4 counts & HIV viral Loadf. 
• 
The results of each test must be entered into the e-CRF. 
• 
See additional requirement specific to Japan in Section 10.7 
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, D2, D8 and D15 during Cycle 1, then on Day 1 of every cycle up to Cycle 12, then every other cycle 
during Treatment Phase. For participants in the safety run-in, it will be also performed at D3. During the Observation Period, it will be 
performed at Follow-Up Visit 1. It can also be performed as clinically indicated. In case of Grade ≥3 liver function abnormal tests, additional 
tests will be repeated every 2-3 days until recovery to baseline value. 
b Modification of Diet in Renal Disease (MDRD) equation: Glomerular filtration rate (mL/min/1.73 m2) = 175 × (Serum Creatinine)-1.154 × (Age)-0.203 
× (0.742 if Female) × (1.212 if African American) 
c Bicarbonate or carbon dioxide (venous) (if bicarbonate or carbon dioxide are assessed only on arterial blood at site level, to be done only if 
clinically indicated) 
d 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. 
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 150 days (for Cohorts A1, A2, B1, B2 and C1) or 420 days (for Cohort A3) 
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 serology at screening will be tested in any countries where 
mandatory as per local requirements. See requirements specific to Japan in Section 10.7. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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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: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)*. 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
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An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the 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 a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any 
post-mortem findings including histopathology. 
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• 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’s representative via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• 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’s representative via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator study file. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). A postmenopausal state is 
defined as the period of time after a woman has experienced no menses for 12 consecutive months 
without an alternative medical cause. 
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• 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 
criterion  I 08. 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
• 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
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). 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
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• 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  
Use/Analysis of DNA/RNA 
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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  
France  
In France, the eligibility of patients to take part in the study is to be validated at the 
Multidisciplinary Collegial Meeting.  
Section 5 Study population 
For Cohort A1: French patients with potential risk of rapidly progressing disease (eg, high tumor 
burden, tumor with risk of mediastinal or spinal cord compression, or rapidly growing tumor) will 
be excluded.  
For Cohort A2: French patients will be excluded.  
For Cohort A3: French patients will not be considered for safety run-in. ANSM approval will be 
required before opening this cohort. 
Japan 
Section 1.3 Schedule of Activities (see Section 1.3) 
All Japanese patients must be hospitalized until Cycle 1 Day 8, and participants can be discharged 
if physician-in-charge judges no significant safety concerns for discharge based on the available 
safety data until the day of discharge (eg, vital signs, physical examination/signs, symptoms, 
blood hematology, and blood chemistry). 
Section 1.5 Pharmacokinetic Flowchart (see Section 1.5) 
All Japanese patients are subject to the intensive PK sampling as shown in Table 22. 
 
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Table 22 - Japanese participants enrolled in either Cohorts B1 or C1  
Cohort 
 Japanese participants of EITHER B1 OR C1 (SAR444245 + pembrolizumab) 
Cycle 
Treatment Cycle 1 
Treatment 
Cycle 2 
Treatment Cycle 4 
Treatment 
Cycle 7, 
10 + every 5th 
cycle 
EOT 
visit 
Day 
D1 
D2 D3 
D4 
D8 
D1 
D1 
D1 
30 (±7) 
days 
after 
last 
IMP 
admin 
  
Time after start of 
SAR444245 dosing 
[h] 
SOI EOI 
1 
2 
4 
8 
24 
48 72 
any 
time 
SOI 
EOI 
SOI 
EOI 
1 
2 
4 
8 
SOI 
EOI 
SAR444245 PK sample 
ID 
P00a P01b P02 P03 P04 
P05 P06 P07 
P08 
 
P00a 
P01b 
P00a 
P01b P02 
P03 
P04 
P05 
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 
  
  
  
SAR444245 ADA 
sample ID 
AB00a 
  
  
  
  
  
  
  
- 
AB01 AB00a 
  
AB00a 
  
  
  
  
  
AB00a 
  
ABF00 
a Samples collected strictly before start of infusion (SOI). 
b P01 samples = End of infusion (EOI) sample. Must be taken at end of infusion precisely. 
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 1 h, 2 h, 
4 h, 8 h, (24 h, 48 h and 72 h for Cycle 1) 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 for Cycle 1) after end of resumed infusion (as per protocol). 
ADA = Anti-drug antibodies; D: day; EOT: end of treatment; PK = Pharmacokinetic. 
 
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Section 5.1 Inclusion Criteria (see Section 5.1) 
The following underlined wording is added to the inclusion criteria: 
I 07. 
For participants in Cohorts B1 and B2 - Based on the Investigator’s judgment, at this time, 
either docetaxel or pemetrexed, or other local standard of care is not the best treatment option for 
this specific participant. The eligibility of participant to take part in the study will be validated at 
the multidisciplinary collegial meeting in countries listed in Section 10.7 of the protocol. 
I 08. 
B) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding (including 
breastfeeding woman who will stop breastfeeding), and at least one of the following conditions 
applies: 
Section 6.5.1 Acceptable Concomitant Medications (see Section 6.5.1) 
The following local regulatory requirement should be noted. 
Colony-Stimulating Factors 
• Granulocyte macrophage colony-stimulating factor, and macrophage colony-stimulating 
factor are not indicated for neutropenia caused by cancer chemotherapy. 
Section 10.2 Appendix 2 Clinical Laboratory tests, Table 21 (see Table 21)   
The following local regulatory requirements should be noted. 
Other screening tests  
To identify interstitial lung disease during screening period, and for early detection of interstitial 
lung disease after IMP initiation when clinically indicated, tests such as chest X-ray and sialylated 
carbohydrate antigen KL-6 may be performed (in addition to scheduled CT scan, vital sign, and 
blood test). 
footnote f  
• Screening and monitoring for hepatitis B virus are performed based on the Guidelines for 
Prevention of Hepatitis B Induced by Immunosuppression and Chemotherapy in the JSH 
Guidelines for the Management of Hepatitis B Virus Infection (120). 
10.8 
APPENDIX 8: RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 1.1  
Response and progression will be evaluated in this study using the international criteria proposed 
by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline Version 1.1 (1). 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria. 
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Confirmatory scans should be obtained at least 4 weeks following initial documentation of 
objective response. 
Selection of Lesions 
• Measurable disease: Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest X-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. All 
tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
• Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in 
follow-up, only the short axis will be measured and followed. 
• Non-measurable disease: All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm 
[≥1 to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT 
or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for 
radiographically defined simple cysts should not be considered as malignant lesions 
(neither measurable nor non-measurable) since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
• Target lesions: All measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
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 (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: 
  
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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.” 
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.  
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MRI is also acceptable in certain situations (eg, for body scans). Other specialized imaging or 
other techniques may also be appropriate for individual case (1). For example, while PET scans 
are not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is not 
advised.  However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is advised to differentiate between response or SD and PD.  
10.10 APPENDIX 10: MODIFIED RECIST CRITERIA FOR MESOTHELIOMA  
Tumor response will be assessed by the investigator using modified RECIST Criteria for 
Mesothelioma (2, 121). 
10.10.1 Target lesion measurements  
Uni-dimensional measurement for tumor lesion around the pleural surface 
Unidimensional measurements of tumor thickness perpendicular to the chest wall or to the 
mediastinum should be performed in 2 sites (on the same slice interval) at 3 separate levels on CT 
scan. At least one of these unidimensional measurements must have a thickness of at least 10 mm. 
In order to allow reproducible assessment at different time-points, CT scan cuts should be chosen 
at least 1 cm apart and related to anatomical landmarks in the thorax (preferably above the level 
of division of the main bronchi). At re-assessment, pleural thickness must be measured at the 
same position and level. Whether possible, subsequent tumor reassessment should be performed 
by the same observer. 
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The sum of these 6 measurements = one pleural uni-dimensional measure.  
Uni-dimensional measurement for other tumor lesions 
Nodal, subcutaneous and other bi-dimensionally measurable lesions are measured 
uni-dimensionally as per RECIST 1.1. 
Total tumor measurement  
Uni-dimensional measures of nodal lesions are added to the pleural uni-dimensional measure to 
obtain the total tumor measurement. 
10.10.2 Non-target lesion measurements  
Non-target lesions are defined as per RECIST 1.1 (eg, pleural effusion). Re-appearance or 
increase of pleural effusion will require further investigations (including pleuroscopy to affirm 
progression if judged necessary by investigator). 
10.10.3 Definitions of response  
• The overall tumor response is defined per RECIST 1.1. 
10.10.4 Pseudo-progression  
Pseudo-progression is defined as radiological tumor growth, followed by disease stability or 
tumor shrinkage. An unconventional pattern of response should meet the following criteria 
(4, 93). Re-assessment to rule out pseudo-progression should be done at least 4 weeks, but no 
more than 8 weeks from the initial radiological evidence suggesting progression. 
Patients who had not experienced a best overall response of partial or complete response prior to 
initial RECIST 1.1-defined progression, and met at least one of the following: 
• Appearance of a new lesion followed by decrease from baseline of at least 10% in sum of 
target lesions. Or 
• Initial increase from nadir ≥20% in sum of target lesions followed by reduction from 
baseline of at least 30%. Or 
• Initial increase from nadir ≥20% in sum of target lesions followed by at least 2 tumor 
assessments showing no further progression defined as 10% additional increase in sum of 
target lesions and new lesions. 
10.11 APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
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Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening and enrollment of participants and administration of study intervention may 
be temporarily delayed (see also Section 7.1.2). 
10.11.1 Informed consent  
The participant or their legally authorized representative should be verbally informed prior to 
initiating any changes that are to be implemented for the duration of the emergency (eg, study 
visit delays/treatment extension, use of local labs). 
10.11.2 Study procedures  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  If onsite visits are possible and there is a need to reduce the time spent on site 
to a minimum, the focus should be on IMP infusion/administration, collection of safety 
information (vital signs, adverse events) and safety blood collection (mainly biochemistry, 
hematology and ADA, if planned for the visit). However, all efforts should be made to perform 
the measurements of key parameters for efficacy endpoints, namely CT/MRI scan and tumor 
tissue collection for this study. 
If onsite visits are not possible due to a temporary disruption caused by an emergency, focus 
should be given to assessments necessary to ensure the safety of participants and those important 
to preserving the main scientific value of the study.   
• Remote visits (eg, with home nurses, home health vendor, etc) may be planned for the 
collection of possible safety and/or efficacy data. 
• Visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely.   
• Use of local clinic or laboratory locations may be allowed. 
10.11.3 Statistical analysis  
The impact of any regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
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10.11.4 Temporary discontinuation  
Study intervention must be administered intravenously and at study site under the responsibility of 
the Investigator. Consequently, for participants who have started treatment but are unable to come 
to the site, administration of study intervention must be paused until regular study visits can be 
safely resumed at the study site.   
In the event of disruption of the clinical trial due to an epidemic/pandemic (eg, COVID-19), 
reinitiation of IMP can only occur once the Investigator has determined, according to his/her best 
judgement, that the contribution of the IMP(s) to the occurrence of the epidemic event 
(eg, COVID-19) was unlikely. 
Contingencies implemented due to emergency will be documented. 
10.12 APPENDIX 12: RISK ASSESSMENT  
The information shown in Table 23 reflects the clinical safety data currently available in the 
SAR444245 IB. For pembrolizumab, the information below is per currently available USPI and 
EU SmPC. Please always refer to the latest version of the SAR444245 IB and pembrolizumab 
local label for the most up-to-date safety data. 
Table 23 - 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 have reported such AE as 
detailed in the SAR444245 IB. 
Pembrolizumab 
Common, but infusion-related reactions in labeling 
include drug hypersensitivity, anaphylactic reaction, 
anaphylactoid reaction, hypersensitivity and cytokine 
release syndrome. 
SAR444245 
Standard pre-medication 
Dose modification and treatment 
guidelines for SAR444245 
infusion-related reactions are 
provided in Table 13. 
Pembrolizumab 
Dose modification and treatment 
guidelines for pembrolizumab 
infusion-related reactions are 
provided in Table 12. 
Hypersensitivity, including 
anaphylaxis 
SAR444245 
Not observed in non-clinical toxicology studies. 
No reports of anaphylaxis in the HAMMER study to 
date. 
Pembrolizumab 
Not specifically reported, but included among 
infusion-related reactions in label. 
Exclusion of participants with known 
hypersensitivity to or contraindication 
for any components of SAR444245, 
PEG, pegylated drugs or 
pembrolizumab.  
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
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. 
Pembrolizumab 
Common: pneumonia. 
Routine mitigation:  
Participants must have appropriate 
ANC and other organ/bone marrow 
function to be included. 
During treatment, regular hematology 
and biochemistry is examined. 
Signs and symptoms of infection are 
monitored as part of TEAE. 
Cytokine release syndrome 
SAR444245 
No major increases in cytokines have been reported 
in non-clinical toxicology studies. 
A minority of patients in the HAMMER study have 
reported such AE as detailed in the SAR444245 IB. 
Pembrolizumab 
Not specifically reported. 
Study to be conducted at sites 
experienced with CRS management, 
with bed available in ICU. 
Premedication with paracetamol, 
diphenhydramine (or equivalent 
medications). 
Hydration guidelines, including 
management of anti-hypertensive 
treatment around the time of infusion, 
are provided. 
Extensive post-dosing monitoring will 
be performed. 
Dose modification and treatment 
guidelines are provided in Table 14. 
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 Table 17. 
Hematological/bone marrow 
toxicity 
SAR444245 
In 28-day repeat-dose study of IV SAR444245 in 
non-human primates, SAR444245-related changes in 
clinical pathology parameters were observed at all 
doses and were generally most prominent 3 days 
following each dose. Changes in hematology 
parameters included decreased or attenuated 
reticulocytes followed by decreases in red blood cell 
(RBC) mass at 
 mg/kg/dose, and increased 
WBCs (lymphocytes and monocytes) and transiently 
mildly decreased platelets at 
 mg/kg/dose. The 
increases in lymphocytes were attributed to the 
expected pharmacology of SAR444245 and 
correlated with the gross and microscopic findings of 
splenic and lymph node enlargement and increased 
lymphoid cellularity; there were no microscopic or 
clinical correlates for the decreases in platelets. 
Adverse events of bone marrow toxicity have been 
reported in the HAMMER study and are presented in 
the SAR444245 IB. 
Routine mitigation:  
Participants must have appropriate 
ANC and other organ/bone marrow 
function to be included. 
During treatment, regular hematology 
and biochemistry is examined. 
Dose modification/discontinuation of 
IMP for Grade 3/4 anemia, 
thrombocytopenia and/or neutropenia 
as per general guidelines for the 
management of TRAEs 
(see Section 6.6.3). 
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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 IB. 
Pembrolizumab 
Pembrolizumab can cause immune-mediated 
hepatitis. Immune-mediated hepatitis occurred in 
0.7% (19/2799) of patients receiving pembrolizumab, 
including Grade 4 (<0.1%), Grade 3 (0.4%), and 
Grade 2 (0.1%) adverse reactions. Systemic 
corticosteroids were required in 68% (13/19) of 
patients with hepatitis. Eleven percent of these 
patients required additional immunosuppressant 
therapy. Hepatitis led to permanent discontinuation of 
pembrolizumab in 0.2% of patients and withholding of 
pembrolizumab in 0.3% of patients. All patients who 
were withheld reinitiated pembrolizumab after 
symptom improvement; of these, none had 
recurrence of hepatitis. Hepatitis resolved in 79% of 
the 19 patients.  
Patients with significant impaired liver 
functions are excluded. 
Monitor clinical signs and symptoms 
of hepatic impairment as part of 
TEAE. 
Monitor liver function parameters 
(AST, ALT, bilirubin & ALP) regularly 
from screening and throughout the 
study. 
Dose modification and treatment 
guidelines for liver enzyme increase 
are provide under immune-related 
reactions in Table 15.  
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. 
Pembrolizumab 
Common: nephritis, acute kidney injury. 
Participants must have appropriate 
eGFR to be included. 
Monitor renal function parameters 
(BUN/urea & creatinine) regularly 
from screening and throughout the 
study. 
Dose modification and treatment 
guidelines for nephrotoxicity are 
provide under immune-related 
reactions in Table 15.  
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 μg/kg 
monotherapy) associated with neurological 
manifestations [hypertension, chills/rigors, flushing, 
fever (maximum temperature: 102.8°F), as well as 
Exclusion of participants with active 
brain metastases or leptomeningeal 
metastases. See E 03 for details. 
Guidelines for the management of 
ICANS are provided in Table 16 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
neurological symptomatology (loss of ability to follow 
commands, confusion, aphasia, and involuntary fist 
clinching)] was reported in the HAMMER study. The 
event resolved completely within 30 to 60 mins after 
treatment with tocilizumab and steroid. This patient 
later discontinued the study. 
 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy (common) for 
pembrolizumab in combination with chemotherapy.  
Uncommon: epilepsy. 
 
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 IB. 
Pembrolizumab 
Combination with chemotherapy, common: hypertension, 
cardiac arrhythmia (including atrial fibrillation). 
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 10 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. 
Pembrolizumab 
Immune-mediated adverse events are designated as 
important identified risk for pembrolizumab. 
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). 
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Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Close monitoring for endocrine 
abnormalities and other potentially 
autoimmune phenomena will be 
performed.  
Dose modification and treatment 
guidelines for immune-related 
reactions are provided in Table 15. 
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. 
Pembrolizumab 
Pembrolizumab should not be used during pregnancy 
unless the clinical condition of the woman requires 
treatment with pembrolizumab. 
Exclusion of participants who are 
pregnant or breastfeeding, or 
expecting to conceive or father 
children within the projected duration 
of the trial as per inclusion criterion 
I 08. 
Guidance on highly effective 
contraceptive methods is provided in 
the protocol. Pregnancy tests are to 
be performed regularly as described 
in Section 8.2.5. 
Use in children 
The safety and efficacy of the study interventions in 
children below 18 years of age have not yet been 
established. 
Exclusion of participants under 
18 years of age. 
Participants over 75 years of 
age 
SAR444245 
At this stage of development, no safety data are 
available for this population. 
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%) (122, 123, 124). 
Strict adherence to the protocol. 
Adequate and verified training of staff 
at investigational sites. 
Overdose and its treatment 
 There is no specific antidote for overdose with 
SAR444245. 
No specific information is available on the treatment 
of overdose of pembrolizumab. 
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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10.13 APPENDIX 13: ASTCT ASSESSMENT FOR ICANS AND CRS  
Table 24 - Encephalopathy assessment ICE tool for ICANS Grading  
Immune Effector Cell-Associated Encephalopathy (ICE) Assessment 
Number of points 
Orientation: Orientation to year, month, city, hospital 
4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button) 
3 points 
Ability to follow simple commands: (eg, “Show me 2 fingers” or “Close your eyes and stick 
out your tongue”) 
1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is the bald eagle”) 
1 point 
Attention: ability to count backwards from 100 by 10  
1 point 
Source: (3). 
Table 25 - 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: (5). 
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Table 26 - 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: (3) 
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10.14 APPENDIX 14: ABBREVIATIONS  
 
1L: 
first-line 
2/3L: 
second- or third-line 
ADA: 
anti-drug antibody 
ADL: 
activities of daily living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ART: 
anti-retroviral therapy 
ASCO: 
American Society of Clinical Oncology 
AST: 
aspartate aminotransferase 
ASTCT: 
American Society for Transplantation and Cellular Therapy  
BOR: 
best overall response 
CBR: 
clinical benefit rate 
CI: 
confidence interval 
CLS: 
capillary leak syndrome 
CR: 
complete response 
CRF: 
case report form 
CRS: 
cytokine release syndrome 
CSFs: 
colony-stimulating factors 
CT: 
computed tomography 
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
 
DLT: 
dose-limiting toxicity 
DoR: 
duration of response  
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
EGFR: 
epidermal growth factor receptor 
EOT: 
end of treatment 
ESMO: 
European Society for Medical Oncology 
FU: 
Follow-up visit 
HCV: 
hepatitis C virus 
IB: 
Investigator’s Brochure 
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICI: 
immune checkpoint inhibitor 
IDMC: 
Independent Data Monitoring Committee 
IHC: 
immunohistochemistry 
IL: 
interleukin 
IMP: 
investigational medicinal product 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
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MPM: 
malignant pleural mesothelioma 
mRECIST: 
 Modified response evaluation criteria in solid tumors  
MRI: 
magnetic resonance imaging 
MTD: 
 Maximum Tolerated Dose  
mTPI2: 
 modified toxicity probability interval 2  
NCI CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP: 
non-human primate  
NIMP: 
 non-investigational medicinal product 
NK: 
natural killer 
NSAIDs: 
nonsteroidal anti-inflammatory drugs 
NSCLC: 
non-small cell lung cancer 
ORR: 
objective response rate 
 
OTC: 
over-the-counter 
PD: 
progressive disease 
PD1: 
programmed cell death protein 1 
PD-L1: 
programmed cell death-ligand 1 
PDy: 
pharmacodynamic 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PO: 
oral route 
PR: 
partial response 
PT: 
preferred term 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
RCC: 
renal cell carcinoma 
RECIST: 
response evaluation criteria in solid tumors 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SB: 
Study Board 
SD: 
stable disease 
SmPC: 
Summary of Product Characteristics 
SOC: 
standard of care 
SpO2: 
oxygen saturation 
TCR: 
T cell receptor 
TEAEs: 
treatment-emergent adverse events 
TIL: 
tumor infiltrating lymphocytes 
TLS: 
tumor lysis syndrome 
TME: 
tumor microenvironment 
TPS: 
tumor proportion score 
T-regs: 
regulatory T-cells 
ULN: 
upper limit of normal 
UPM: 
 unit probability mass  
VLS: 
vascular leak syndrome 
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WOCBP: 
woman of childbearing potential 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amended protocol 01 (19 March 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 rationale for the amendment is to clarify criteria for cytokine release syndrome reporting and 
simplify the Independent Data Monitoring Committee set-up. 
Protocol amendment summary of changes table 
Section # 
and Name 
Description of Change 
Brief Rationale 
1.3 Schedule 
of activities  
Footnote n has been updated to add that CRS 
will be graded using ASTCT criteria integrated 
with central laboratory cytokine results 
To clarify CRS grading criteria for reporting 
1.4 Biomarker 
flowchart 
Clarified that every effort should be made to 
obtain a cytokine sample for an event of CRS of 
any grade 
To facilitate comprehensive CRS reporting 
6.6.5.3 Fever, 
flu-like 
symptoms 
and cytokine-
release 
syndrome 
(CRS)  
Clarified that central laboratory cytokine results 
will be integrated into the grading of CRS events 
and the guidelines provided are for any 
suspected CRS event 
To facilitate comprehensive CRS reporting 
9.5 Interim 
analyses 
The frequency of Independent Data Monitoring 
Committee review was revised 
To simplify the Independent Data Monitoring Committee 
set-up 
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Amended protocol 02 (05 May 2021) 
This amended protocol for Review (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 primary reason for the amendment is to respond to Health Authority requests for correction 
and clarification. Other changes have been made for clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
and Section 4.1 
Overall Design 
The wording concerning the number of participants in the 
safety run-in has been clarified. 
Regulatory Authority (FDA) request 
and to improve clarity 
Section 1.1 Synopsis: 
Overall design, 
Section 4.1 Overall 
Design, and Section 
9.3 Populations for 
Analyses (Table 19) 
The following text has been deleted: “and have received at 
least 80% of the intended Cycle 1 dose”. 
Regulatory Authority (FDA) request 
and for clarification 
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design, and Section 
5.1 Inclusion criteria 
For Cohorts B1 and B2, the following text “Participants 
must have clinically benefitted but later experienced 
disease progression on an anti PD1/PD-L1-based regimen 
and no more than 1 chemotherapy regimen (detailed in 
Section 5.1 Inclusion Criteria I 06) to treat their NSCLC to 
be eligible)” has been removed for clarity. 
Eligibility criterion I06 for Cohorts B1 and B2 was changed 
to include participants for enrollment who experienced 
disease progression on or after one platinum-based 
chemotherapy which is either given as part of the anti-
PD1/PD-L1 containing regimen, or as a separate regimen. 
Regulatory Authority (FDA) request 
Section 1.1 Synopsis 
and Section 6.1.2.2 
Premedication for 
pemetrexed 
In the instructions regarding premedication for 
pemetrexed, text was revised to clarify that folic acid 
dosing should be daily. 
Change made for clarification 
1.3 Schedule of 
activities (SoA) 
(footnote q) and 
8.1.1 Assessment of 
objective response 
using the most 
appropriate modality 
according to the 
nature of the 
measurable lesion(s) 
The text “If lesions are identified, the lesions must be 
treated, regardless of symptoms” has been deleted and 
replaced with “Participants 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. In all other cases, the lesions must be 
treated”. 
Change made to be consistent with 
exclusion criterion E03 
 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 4.1 Overall 
Design: Dose limiting 
toxicity 
The following DLT criteria have been added as follows:  
• 
Any Grade 3 non-hematologic laboratory value  
Exceptions:  
- 
Grade 3 electrolyte abnormalities that are not 
clinically complicated and resolve within 72 hours 
with conventional medical interventions.   
- 
Grade 3 amylase or lipase that is not associated 
with symptoms or clinical manifestations of 
pancreatitis. 
• 
Any Grade 4 non-hematologic laboratory value 
• 
Other Abnormalities: 
- 
Any death not clearly due to the underlying 
disease or extraneous causes 
- 
Any toxicity requiring permanent discontinuation of 
the study drug(s). 
The following DLT criteria has been changed from: 
• 
Grade 3 or above AE that does not resolve to grade 
≤2 within 7 days of starting accepted standard of 
care medical management 
To 
• 
Other Grade 3 or above AE except:  
- 
Grade 3 fatigue that resolves within 1 week.  
- 
Grade 3 nausea, vomiting, or diarrhea that 
resolves within 72 hours with antiemetics 
and standard supportive care measures.  
The following DLT criteria have been removed: 
“The following non-hematologic AEs are exceptions: 
Grade 3 or 4 laboratory abnormalities that are not clinically 
significant per recruiting Investigator and Sponsor”. 
Regulatory Authority (FDA) request 
and to clarify DLT criteria 
Section 4.1 Overall 
Design: Study 
Committee 
The following text has been added: “After safety run-in 
dose confirmation, occurrence of any treatment related G3 
or higher AE (excluding lymphocyte count decrease) not 
resolving within 72 hours in >25% of participants per 
regimen will trigger SC to rapidly convene to assess safety 
or need to pause enrollment to allow for a safety review. 
SC (during safety run-in), IDMC (during core phase and 
expansion) and Sponsor can decide to stop any cohort in 
case of excessive toxicity (for example but not limited to 
excessive irAE or excessive number of G4/5 events) is 
observed”.  
Regulatory Authority (FDA) request, 
and to clearly define study stopping 
rules and provide a rate of adverse 
events (AEs) resulting in a pause in 
study enrollment, and to allow the 
Study Committee (SC) to review the 
safety data before study enrollment 
may resume. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 Exclusion 
criteria and Section 6.5.2 
Prohibited Concomitant 
Medications 
E15 and text in Section 6.5.2 were updated to include live-
attenuated virus vaccines 
Changes made for clarification 
Section 6.6.1 General 
rules 
The following text has been added: “For cohorts B1 and 
B2, if a toxicity leads to SAR444245 discontinuation, 
pembrolizumab must be discontinued unless the TEAE 
leading to permanent IMP discontinuation is clearly 
attributable only to SAR444245, and patients have clinical 
benefit as determined by the treating physician. 
Participants who continue pembrolizumab in this scenario 
are informed as part of the initial consent process that 
pembrolizumab monotherapy is not a standard of care”. 
Regulatory Authority (FDA) request 
and to clarify that participants enrolled 
in B1 or B2 cohorts are adequately 
informed that continuation of 
pembrolizumab monotherapy after 
SAR444245 discontinuation is not a 
standard of care. 
 
The sentence “When both IMP components are 
permanently discontinued it is full permanent 
discontinuation” was revised to “When all IMP components 
are permanently discontinued it is full permanent 
discontinuation.  
Change made for accuracy 
Table 8 and Section 
6.6.4.2 Dose 
modification for nab-
paclitaxel 
Units for platelet count were corrected 
Change made for correction 
Section 6.6.5.1 
Infusion-related 
reactions (IRR) 
The following text has been highlighted in bold in Table 11: 
“Participant is permanently discontinued from further study 
drug treatment”. 
In Table 11, “interrupt” has been changed to “stop”. 
Regulatory Authority (FDA) request, for 
clarification, and to align with current 
pembrolizumab standard text. 
Section 6.6.5.4 
Immune-related 
adverse events 
Table 14 has been updated to add instructions regarding 
immune-related adverse events of Neurological Toxicities 
and Exfoliative Dermatologic Conditions. An abbreviations 
list and a note stating “Non-irAE will be managed as 
appropriate, following clinical practice recommendations” 
have been added to the footnote. In footnote e, the events 
of “Guillain-Barre Syndrome, Stevens-Johnson Syndrome 
and toxic epidermal necrolysis” were removed and 
replaced by “and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis)” 
To align with current pembrolizumab 
standard text.  
Section 8.2.2 Vital 
signs 
Collection of vital signs including timing and in/out-patient 
settings has been clarified for participants in the safety 
run-in and other cohorts at Cycle 1 and beyond.  
Regulatory Authority (FDA) request 
 
The requirement to measure vital signs in a semi-supine 
position has been removed 
To simplify instructions 
Section 8.3.1 Time 
period and frequency 
for collecting AE and 
SAE information 
The following text has been added to specify the collection 
of all immune-related adverse events (irAEs) until 90 days:  
“This does not include irAEs, which will be collected until 
90 days following last administration of study treatment 
regardless of whether or not another anticancer therapy is 
initiated.” 
Regulatory Authority (FDA) request 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.4 
Pharmacokinetics 
Added clarification on pharmacokinetics (PK) analysis 
plan. 
Regulatory Authorities (FDA) request 
Section 9.2 Sample 
size determination: 
Expansion Phase 
(Only for Cohort B1 
and/or Cohort B2) 
“The posterior probability that the true ORR is greater” has 
been changed from 20% to 23% to align with the ORR 
from the combination therapy of docetaxel and 
ramucirumab. The minimum number of responders has 
been amended from 11 to 12. The ORR has been 
changed from 27.5% to 30%. 
Regulatory Authority (FDA) request 
Section 9.4.3.4 
Progression-free 
survival 
The following text was revised: Progression-free survival is 
defined as the time from the date of first IMP to the date of 
the first documentation of objective progressive disease 
when relevant, or death due to any cause, whichever 
occurs first. 
Change made for clarification 
10.1.9 Study and site 
start and closure 
The following information was added: If the study is early 
terminated the patients who are receiving and benefitting 
from study treatment as per Investigator judgment may 
continue study treatment until protocol defined treatment 
discontinuation criteria are met.  The patients who 
continue study treatment after early study termination 
should be followed for safety (i.e. 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. 
Change made for clarification 
10.7 Appendix 7 
Country-specific 
requirements 
Instructions specific to participants from Japan have been 
added. Reference to Appendix 7 for country-specific 
requirements in Japan was provided wherever applicable. 
Regulatory Authority (PMDA) request 
10.14 Appendix 14 
Abbreviations 
The abbreviations list has been updated 
Changes made for clarification 
Throughout the 
document 
Minor editorial corrections and document formatting 
revisions were made. 
Changes made for consistency and 
clarity, and to comply with company 
standards. 
 
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11 
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