Phase 2 Non-randomized, Open-label, Multi-cohort, Multicenter Study Assessing the Clinical Benefit of SAR444245 (THOR-707) With or Without Other Anticancer Therapies for the Treatment of Adults and Adolescents With Relapsed or Refractory B Cell Lymphoma
Phase: PHASE2
Conditions: Classic Hodgkin Lymphoma, Diffuse Large B-cell Lymphoma
Sponsor: Sanofi

 
 
 
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disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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According to Template: Sanofi OneDocument Version 5.0, dated 28-JAN-2021 
Page 1 
 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 01 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, multi-
center study assessing the clinical benefit of SAR444245 
(THOR-707) with or without other anticancer therapies for the 
treatment of adults and adolescents with relapsed or 
refractory B cell lymphoma  
Protocol number: 
ACT16941 Master 
Amendment number: 
01 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable)  
Brief title: 
A study of SAR444245 with or without other anticancer 
therapies for the treatment of adults and adolescents with 
relapsed or refractory B cell lymphoma (Master Protocol) 
   
Acronym 
Pegathor Lymphoma 205 
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: 
156112  
EudraCT: 
2021-002150-91 
NCT: 
NCT05179603 
WHO: 
U1111-1251-5834 
 
Date: 
28-Apr-2022 
Total number of pages: 124 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Master Protocol 01  
All 
28 April 2022, version 1 
(electronic 1.0) 
Clinical Trial Master Protocol 
16 July 2021, version 1 
(electronic 1.0) 
Amended protocol 01 (28 April 2022) 
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 main rationale for this amendment is to change from an every 3 weeks (Q3W) to an every 2 
weeks (Q2W) investigational medicinal product (IMP) dosing schedule in one of the cohorts, and 
in response to requests from Health Authorities after initial review. Other changes have been 
made for clarification, accuracy, and correction.  
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover page and 1.1 
Synopsis 
The following study name: “Pegasus Lymphoma 
205” has been removed from the protocol title and 
the new study acronym “Pegathor Lymphoma 
205” has been added on the cover page.  
For consistency across the program. 
Cover page 
The NCT number has been added. 
This study has been registered on 
clinicaltrials.gov, the NCT number is 
applicable. 
1.1 Synopsis- Figure 1, 
4.1 Overall Design 6.1.1 
Investigational 
medicinal product-Table 
3, and 9.5 Interim 
analyses 
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. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 4.1 
Overall Design 
 
The following sentence “Information on the first 
subsequent anticancer treatment, best reported 
response, and date of progression will also be 
collected.” has been deleted. 
Reduction in protocol complexity and 
patient/site burden. 
1.1 Synopsis, 4.1 
Overall design 
The following sentence has been removed “delay 
of >14 days between end of Cycle 1 and start of 
Cycle 2 because of toxicity will be considered a 
DLT”. 
To align with the dosing schedule changes for 
one of the cohorts.  
1.1 Synopsis, 4.1 
Overall design 
The following sentence has been deleted “or until 
start of another anticancer therapy or final cohort 
cut-off, whichever comes first” for the reason 
leading to EOT for the participants who 
discontinue study treatment with PD. 
For consistency and clarification. 
1.1 Synopsis, 
6.1.2.1 Premedication 
for SAR444245, Table 7 
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. 
1.2 Schema 
“FDG-PET must be performed for the 9-week and 
18-week on-treatment assessment” has been 
added for Figure 2 and Figure 3.  
For Figure 3, the previous “Cycle 2-8” of the 
treatment period has been changed to “Cycle 2-
16”, and previous “Cycle 8 and subsequent” has 
been changed to “Cycle 17 and subsequent”. 
For clarity. 
 
 
To align with the dosing schedule changes for 
one of the cohorts. 
1.4 Biomarker 
flowcharts 
 
5.1 Inclusion criteria, 
8.2.5 Pregnancy 
testing, 
8.3.5 Pregnancy, 10.2 
Appendix 2 Clinical 
laboratory tests -Table 5 
footnote e 
In I04, the requirement for contraception for male 
participants has been changed from “at least 210 
days [corresponding to time needed to eliminate 
study intervention(s) plus an additional 90 days (a 
spermatogenesis cycle)] after the last dose of 
study intervention” to “at least 3 days 
[corresponding to time needed to eliminate 
SAR444245] after the last dose of SAR444245”.  
 
 
 
The recommended duration for continuing 
contraception after last dose of study intervention 
has been changed for female participants from 
180 days to 120 days (or refer to the individual 
To change measures for male participants as 
per Clinical Trials Facilitation and Coordination 
Group (CTFG) guideline on “recommendations 
related to contraception and pregnancy testing 
in clinical trials version 1.1” of 21 Sept 2020. 
As SAR444245 is not genotoxic, there is no 
need to extend the requirement for 
contraception to 90 days (3 months) for male 
participants, but to take into account the 5 half-
lives of the study intervention before its 
elimination. 
None of the products in combination is 
genotoxic in this study, there is no need to 
extend the requirement for contraception to 30 
days (1 month) corresponding to a menstrual 
cycle for female participants. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
substudy protocol), and the requirement of 
extension extra 30 days (1 month) has been 
removed. 
Regulatory Authority (Italy) request. 
5.1 Inclusion criteria 
In I04, the requirement for the use of a male 
condom has been updated.  
For consistency between recommended male 
and female contraception. 
5.2 Exclusion criteria 
In E 01, the Lansky Scale has been changed from 
“< 50%” to “≤ 60%”. 
To align with the ECOG performance status as 
per Regulatory Authority (ANSM) request. 
5.2 Exclusion criteria 
In E 11, a note has been newly added to refer to 
substudy protocol. 
Cohort specific requirement has been added 
for one of the substudies. 
5.2 Exclusion criteria 
E 19 has been changed from “Known severe 
hypersensitivity (≥ Grade 3) to or contraindication 
for the use of any study intervention, including 
premedication to be administered in this study, as 
well as PEG or any pegylated drug” to “Known 
severe hypersensitivity (≥ Grade 3) to or 
contraindication for the use of any study 
intervention or components thereof, including 
premedication to be administered in this study, as 
well as PEG or any pegylated drug and E. coli-
derived protein”. 
To clarify that patients with known 
hypersensitivity to any excipient of the study 
interventions or to E. coli-derived protein must 
be excluded. 
5.2 Exclusion criteria 
E 23 “Participants treated under anti-hypertensive 
treatment who cannot temporarily (at least 36 
hours) withhold antihypertensive medications prior 
to each SAR444245 dosing” has been deleted. 
Temporary withholding of anti-hypertensive 
drugs is based on the physician’s decision 
based on individual patients.  
5.2 Exclusion criteria 
E24 “Has undergone prior allogeneic 
hematopoietic stem cell transplantation within the 
last 5 years.  (Participants who have had a 
transplant greater than 5 years ago are eligible as 
long as there are no symptoms of graft-versus-
host disease [GVHD]).” has been removed from 
master protocol and added to relevant substudy. 
For clarification. 
5.2 Exclusion criteria 
E 25 has been changed from: Participation in a 
concurrent clinical study in the treatment period 
To  
Current enrollment or past participation in a study 
of an investigational treatment or has used an 
investigational device within 28 days prior to the 
first dose of study treatment.  
Note:  Participants who have entered the follow-up 
phase of an investigational study may participate 
as long as it has been 28 days after the last dose 
of the previous investigational treatment. 
For clarification. 
5.2 Exclusion Criteria, 
10.2 Appendix 2: 
Clinical laboratory tests, 
Requirement for human immunodeficiency virus 
(HIV) has been added at screening for participants 
in France and specified in exclusion criteria E16, 
Regulatory Authority (ANSM) request. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
and 10.7 Appendix 7: 
Country-Specific 
Requirements 
Clinical laboratory tests and Country-specific 
requirements sections.  
5.4 Screen failures 
The following text has been added “A participant 
may be rescreened only once”. 
For clarity. 
6.1.3 Hydration 
guidelines for 
SAR444245 
administration 
 
6.1.4 Readiness for 
treatment of severe 
cytokine release 
syndrome 
The following statement “alternative therapies per 
site practice in CRS management” has been 
added to “tocilizumab”. 
For flexibility following tocilizumab availability. 
6.2 Preparation/handlin
g/ storage/accountability 
The following text regarding DTP shipment of IMP 
has been 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.  
6.8.2 Prohibited 
concomitant 
medications, 10.10 
Appendix 10 Risk 
assessment Table 7 
The following sentence in Section 6.8.2 has been 
deleted: “Participants requiring medication(s) that 
are metabolized by the liver and have narrow 
therapeutic index require close monitoring (drug 
blood levels or other surrogate of drug exposure) 
when on study treatment. If a participant cannot 
be closely monitored, he/she should be removed 
from the trial.” 
In Table 7, the row for drug-drug interactions has 
been deleted. 
Based on new de-risking in-vitro data. 
8 Study Assessments 
and Procedures 
 
 
 
 
 
8.2 Safety assessment, 
8.2.3 
Electrocardiograms and 
LVEF,  
 
 
 
 
The assessment of troponin level has been 
added. 
The following text has been added: 
“A comprehensive medical history will be 
assessed for any cardiovascular signs or 
symptoms prior to treatment, along with a baseline 
ECG, echocardiogram and troponin level”. 
Troponin has been added as an example of 
cardiac enzymes within additional evaluation to 
carry out when clinically indicated. 
The following text has also been added for 
evaluations during treatment and post treatment 
follow-up: 
“During treatment, or post treatment follow-up: 
Troponin will be performed at Cycle 4 Day 1. In 
To allow assessment of any potential 
cardiotoxicity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
 
 
 
 
 
and 10.2 Appendix 2 
Clinical laboratory tests-
Table 5 
case of a suspicion of a drug related cardiac event 
(eg, including signs/symptoms of cardiac disease, 
ECG and/or echo changes, troponin elevation, 
etc.), Investigators are encouraged to do ECG, 
echocardiography and/or cardiac biomarker tests, 
as medically indicated, including cardiology 
consultation”. 
Troponin has been added to “other screening 
tests”. 
8.1 Efficacy 
assessments 
Table 7 for imaging or disease assessment 
collection plan has been added. 
For clarity. 
8.2.2 Vital signs 
“In an in-patient setting” has been added for Cycle 
1 Day 1 vital sign collection for the safety run-in 
participants. 
For clarity. 
8.3.1 Time period and 
frequency for collecting 
AE and SAE information 
The instruction to stop collecting AE and SAE 
information should the participant initiate another 
anticancer therapy has been removed. All AEs 
and SAEs are to be collected until 30 days and 
90 days, respectively, following cessation of study 
treatment. 
For consistency with Sanofi standards. 
8.3.8 Adverse event of 
special interest 
SARS-CoV-2 infection/COVID-19 disease has 
been removed from AESIs. 
COVID19 infection is removed from AESI 
considering progress of the vaccination and 
change in severity of the symptoms associated 
with new variants. 
8.6 Biomarkers 
The following sentence has been added for 
i
 “This method will only 
apply to samples from clinical sites not exhibiting 
feasibility constrains on handling/shipment”. 
To improve flexibility in case local constrains 
exist. 
8.6 Biomarkers 
Concerning collection of samples, the following 
text “will be stored for a period of up to 15 years 
after the last participant’s last visit for potential re-
analyses” has been changed to “may be used for 
further research if consent is provided 
(see Section 8.9)”. 
Harmonization per Sanofi standard 
terminology. 
8.9 Use of biological 
samples and data for 
future research and 
10.5 Appendix 5: 
Genetics 
The text has been revised to state that the 
duration of storage for biological samples and 
relating data is up to 25 years. The duration of 
biological sample storage was previously given as 
a maximum of 15 years. 
For consistency with the latest Sanofi 
standards. 
9.3 Populations for 
Analyses 
The efficacy population definition has been 
revised to "All participants from the exposed 
population with at least one evaluable post-
baseline tumor assessment or who permanently 
discontinued study treatment”. 
To characterize the efficacy excluding 
participants newly enrolled. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
9.5 Interim analysis 
The following sentence has been added 
“Occurrence of any treatment related Grade 3 or 
higher AE (excluding lymphocyte count decrease) 
not resolving within 72 hours in >25% of 
participants will trigger ad hoc DMC.” 
For clarity. 
10.1.6 Dissemination of 
clinical study data 
The text has been revised as follows: “Sanofi 
shares information about clinical trials and results 
on publicly accessible websites for each 
completed sub study and final study results”. 
Per CTFG guidance 2019: Recommendation 
Paper on the Initiation and Conduct of 
Complex Clinical Trials. 
10.1.9 Study and site 
start and closure 
The wording has been revised to specify “provided 
by the Sponsor” after “study treatment”. 
For clarification 
10.4.2 Contraception 
guidance 
The duration for study intervention may affect ova 
or sperm have been updated from “ova up to 180 
days and sperm up to 210 days” to “ova and 
sperm for up to the number of days specified 
respectively for each cohort in the inclusion 
criteria”. 
To align with the updates of I04. 
10.7 Appendix 7 
Country-Specific 
Requirements  
Country-specific requirements for France has 
been added.  
Regulatory Authority request. 
10.14 Appendix 14 
Definition of line of 
therapy 
Section newly added to clarify the definition of line 
of therapy. The subsequent section has been re- 
numbered accordingly. 
For clarity. 
Throughout the 
document 
Minor editorial updates. 
For clarity and consistency. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL MASTER PROTOCOL 01 .............................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 8 
LIST OF TABLES ......................................................................................................................................... 13 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 22 
1.2.1 
Study design for Cohort testing Q3W regimen .............................................................................. 22 
1.2.2 
Study design for Cohort testing Q2W regimen .............................................................................. 23 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 24 
1.4 
BIOMARKER FLOWCHARTS ....................................................................................................... 24 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 24 
2 
INTRODUCTION ............................................................................................................................ 25 
2.1 
STUDY RATIONALE...................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.2.1 
Rationale for B cell lymphoma and selected participant population .............................................. 26 
2.2.2 
Current standard of care in B cell lymphoma ................................................................................. 27 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 28 
2.3.1 
Risk assessment ............................................................................................................................ 28 
2.3.1.1 
Aldesleukin experience .................................................................................................................. 28 
2.3.1.2 
SAR444245 .................................................................................................................................... 29 
2.3.1.3 
NKTR-214 (bempegaldesleukin) clinical data ................................................................................ 30 
2.3.2 
Benefit assessment ........................................................................................................................ 31 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 31 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 32 
2.3.4.1 
Risks in the context of COVID-19 .................................................................................................. 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 34 
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3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 40 
4.2.1 
Participant input into design ........................................................................................................... 40 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 41 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 43 
5 
STUDY POPULATION .................................................................................................................. 44 
5.1 
INCLUSION CRITERIA .................................................................................................................. 44 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 46 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 50 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 50 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 50 
5.3.3 
Activity ............................................................................................................................................ 50 
5.3.4 
Hydration ........................................................................................................................................ 51 
5.4 
SCREEN FAILURES...................................................................................................................... 51 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 51 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 52 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 52 
6.1.1 
Investigational medicinal product ................................................................................................... 52 
6.1.2 
Non-investigational medicinal products ......................................................................................... 53 
6.1.2.1 
Premedication for SAR444245 ...................................................................................................... 53 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 53 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 54 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 54 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 55 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 55 
6.5 
DOSE MODIFICATION .................................................................................................................. 55 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 55 
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6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 55 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 56 
6.8.1 
Acceptable concomitant medications ............................................................................................. 56 
6.8.2 
Prohibited concomitant medications .............................................................................................. 57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 59 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 59 
7.1.1 
Permanent discontinuation ............................................................................................................ 59 
7.1.1.1 
Unacceptable adverse events leading to permanent intervention discontinuation ........................ 59 
7.1.2 
Temporary discontinuation ............................................................................................................. 60 
7.1.3 
Rechallenge ................................................................................................................................... 60 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 61 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 61 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 63 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 63 
8.1.1 
Assessment of objective response using the most appropriate modality according to the 
nature of the measurable lesion(s) ................................................................................................ 64 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 66 
8.2.1 
Physical examinations ................................................................................................................... 66 
8.2.2 
Vital signs ....................................................................................................................................... 66 
8.2.3 
Electrocardiograms and LVEF ....................................................................................................... 67 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 67 
8.2.5 
Pregnancy testing .......................................................................................................................... 68 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 68 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 69 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 69 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 69 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 69 
8.3.5 
Pregnancy ...................................................................................................................................... 70 
8.3.6 
Cardiovascular and death events .................................................................................................. 70 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 71 
8.3.8 
Adverse event of special interest ................................................................................................... 71 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 72 
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8.4 
PHARMACOKINETICS .................................................................................................................. 72 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 72 
8.6 
BIOMARKERS ............................................................................................................................... 73 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 74 
8.8 
HEALTH ECONOMICS .................................................................................................................. 74 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 74 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 76 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 76 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 76 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 76 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 77 
9.4.1 
General considerations .................................................................................................................. 77 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 77 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 77 
9.4.3.1 
Time to Response (TTR) ............................................................................................................... 77 
9.4.3.2 
Duration of response (DoR) ........................................................................................................... 78 
9.4.3.3 
Clinical benefit rate (CBR) ............................................................................................................. 78 
9.4.3.4 
Progression-free survival (PFS) ..................................................................................................... 78 
9.4.3.5 
Adverse events .............................................................................................................................. 78 
9.4.3.6 
Clinical Laboratory evaluations ...................................................................................................... 79 
9.4.3.7 
Other Secondary endpoints ........................................................................................................... 80 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 80 
9.4.4.1 
Biomarker endpoints ...................................................................................................................... 80 
9.4.5 
Other safety analysis...................................................................................................................... 80 
9.4.6 
Other analysis ................................................................................................................................ 81 
9.5 
INTERIM ANALYSES .................................................................................................................... 81 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 82 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 82 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 82 
10.1.2 
Financial disclosure........................................................................................................................ 83 
10.1.3 
Informed consent process .............................................................................................................. 83 
10.1.4 
Data protection ............................................................................................................................... 84 
10.1.5 
Committees structure ..................................................................................................................... 86 
10.1.6 
Dissemination of clinical study data ............................................................................................... 86 
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10.1.7 
Data quality assurance .................................................................................................................. 87 
10.1.8 
Source documents ......................................................................................................................... 88 
10.1.9 
Study and site start and closure ..................................................................................................... 88 
10.1.10 Publication policy ........................................................................................................................... 89 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 89 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 91 
10.3.1 
Definition of AE .............................................................................................................................. 91 
10.3.2 
Definition of SAE ............................................................................................................................ 92 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 94 
10.3.4 
Reporting of SAEs.......................................................................................................................... 96 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 96 
10.4.1 
Definitions ...................................................................................................................................... 96 
10.4.2 
Contraception guidance ................................................................................................................. 97 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 100 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 100 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 100 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT...................................................... 101 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 103 
10.9.1 
Informed consent ......................................................................................................................... 103 
10.9.2 
Study procedures ......................................................................................................................... 103 
10.9.3 
Statistical analysis ........................................................................................................................ 104 
10.9.4 
Temporary discontinuation ........................................................................................................... 104 
10.10 
APPENDIX 10: RISK ASSESSMENT .......................................................................................... 104 
10.11 
APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS ................................................ 109 
10.12 
APPENDIX 12 GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS SYNDROME 
(TLS) ............................................................................................................................................ 112 
10.13 
APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE ................................ 117 
10.14 
APPENDIX 14: DEFINITION OF LINE OF THERAPY ................................................................ 118 
10.15 
APPENDIX 15: ABBREVIATIONS ............................................................................................... 118 
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10.16 
APPENDIX 16: PROTOCOL AMENDMENT HISTORY .............................................................. 120 
11 
REFERENCES ............................................................................................................................. 121 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 34 
Table 2 - Dose escalation rule of the modified toxicity probability interval-2 method ................................... 38 
Table 3 - Overview of IMP administered ....................................................................................................... 52 
Table 4 - Imaging or disease assessment collection plan ............................................................................. 65 
Table 5 - Populations for analyses ................................................................................................................ 76 
Table 6 - Protocol-required laboratory assessments .................................................................................... 90 
Table 7 - Criteria for Response Assessment............................................................................................... 101 
Table 8 - Risk assessment .......................................................................................................................... 105 
Table 9 - Encephalopathy assessment ICE tool for ICANS Grading .......................................................... 109 
Table 10 - ASTCT ICANS consensus grading for adults ............................................................................ 110 
Table 11 - ASTCT ICANS consensus grading for children ......................................................................... 110 
Table 12 - ASTCT CRS consensus grading ............................................................................................... 111 
Table 13 - Tumor lysis syndrome definitions ............................................................................................... 113 
Table 14 - Specific recommendations for treatment of TLS ........................................................................ 115 
Table 15 - Recommendations on the use of hypouricemic agents ............................................................. 116 
Table 16 - Recommendations on selection of hypouricemic agents ........................................................... 116 
Table 17 - ECOG PERFORMANCE STATUS ............................................................................................ 117 
Table 18 - Lansky Play/Performance Status ............................................................................................... 117 
 
LIST OF FIGURES 
Figure 1 - Overall study schema ................................................................................................................... 17 
Figure 2 - Graphical study design-Cohort testing Q3W regimen .................................................................. 22 
Figure 3 - Graphical study design-Cohort testing Q2W regimen .................................................................. 23 
 
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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) with or without other anticancer therapies for the treatment 
of adults and adolescents with relapsed or refractory B cell lymphoma  
Brief title: 
A study of SAR444245 with or without other anticancer therapies for the treatment 
of adults and adolescents with relapsed or refractory B cell lymphoma (Master Protocol) 
Rationale: 
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the interleukin (IL)-2 α receptor, while retaining stimulatory activity for cells expressing the 
moderate affinity IL-2 βγ receptor. The first in human clinical study with SAR444245 
(TCD16843/HAMMER, hereafter referred to as HAMMER) demonstrated that treatment with 
SAR444245 leads to expansion of CD8+ T cells and natural killer (NK) cells (with higher IL-2 βγ 
receptor expression) with negligible IL-2Rα induced effect on immunosuppressive Treg cells 
expansion, vascular leak syndrome related eosinophils expansion and IL-5 release. 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with other anticancer therapies or as a monotherapy, in trial participants with relapsed or 
refractory B cell lymphoma.  
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with or without other anticancer therapies in specific cohort of relapsed or refractory 
B cell lymphoma. Common protocol elements are contained in this document (“Master Protocol”) 
and cohort-specific protocol elements are contained in separate substudy protocols. This design 
has the flexibility to open new treatment cohorts as new treatment become available and close 
existing treatment cohorts that demonstrate minimal clinical activity or unacceptable toxicity. 
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
 
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Objectives and endpoints  
  
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245 
with or without other anticancer therapies. 
• 
Refer to individual substudy. 
Secondary 
 
• 
To confirm the dose and to assess the safety profile 
of SAR444245 when combined with or without other 
anticancer therapies. 
• 
Incidence of treatment emergent adverse events 
(TEAEs), dose-limiting toxicities (DLTs), serious 
adverse events (SAEs), laboratory abnormalities 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) V5.0 and American Society for 
Transplantation and Cellular Therapy (ASTCT) 
consensus gradings (1). 
• 
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 documented evidence of 
partial response (PR) or complete response (CR) 
determined by Investigator per Lugano response 
criteria 2014 (2). 
• 
Duration of response (DoR) defined as the time 
from first documented evidence of PR or CR until 
progressive disease (PD) determined by 
Investigator per Lugano response criteria 2014 (2), 
or death from any cause, whichever occurs first. 
• 
Clinical benefit rate (CBR) including CR or PR at 
any time or stable disease (SD) of at least 6 months 
(determined by Investigator per Lugano response 
criteria 2014) (2). 
• 
Progression free survival (PFS) defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by Investigator per Lugano response 
criteria 2014 (2) or death due to any cause, 
whichever occurs first. 
• 
To assess the plasma concentrations of 
SAR444245 when given with or without other 
anticancer therapies. 
• 
Plasma concentrations of SAR444245. 
• 
To assess the immunogenicity of SAR444245. 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245. 
 
 
 
 
 
 
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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 with or without other anticancer 
therapies in adults and adolescents with relapsed or refractory B cell lymphoma.  
Brief summary:  
A graphical presentation of the study schema is shown in Figure 1. 
A safety run-in will confirm the dose of SAR444245 in each substudy. Participants who fulfill 
the eligibility criteria of any cohort may be enrolled to the safety run-in of that cohort. After a 
maximum of 10 participants have been enrolled into a specific cohort, enrollment will be paused 
for that cohort. 
Once a total of at least 6 participants are evaluable for DLT in a specific cohort, safety data for 
these participants will be reviewed by the Study Board (SB). The Study Board will comprise the 
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 part who have been observed for the DLT observation period (defined in the 
individual substudy). Any participant who experienced a DLT at any time during the DLT 
observation period will also be DLT-evaluable. 
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 for that specific cohort (for example, if 10 
Cohort A participants are enrolled in the safety run-in, and treated at the confirmed safe dose, 
approximately 15 additional participants will be enrolled into Cohort A to have the total number 
of 25 participants). 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an intravenous (IV) infusion 
over 30 minutes during each cycle (see Section 1.1 Study interventions for details). Overall safety 
monitoring will be performed throughout the study.  If recommended by the Study Board, 
SAR444245 dose may be reduced to
μg/kg or another lower dose level which will be explored 
following the same process described in the safety run-in for 24 μg/kg dose level. 
The dose confirmation will follow modified toxicity probability interval 2 (mTPI2) design. 
Dose limiting toxicity: Selected events occurring during the DLT observation period (defined in 
the individual substudy) 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 Study Board will determine if the dose of SAR444245 needs to be 
reduced to 
 μg/kg or another lower dose level, in agreement with the Sponsor.  
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Figure 1 - Overall study schema  
 
 
a The DLT observation period is defined in the individual substudy.  
b Including participants enrolled in the safety run-in at the confirmed safe dose. 
Abbreviations: DLT: dose limiting toxicity; N: number. 
 
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Special considerations pertaining to methodology  
Interactive Response Technology will be used to control recruitment, assignment per site and 
facilitate the handling, management, and accountability of drug supply. 
Number of participants: 
Please refer to the individual substudy for the numbers of participants to be enrolled and treated at 
the confirmed safe dose. 
Note: Enrolled participants are all participants from screened participants who have been allocated 
to an intervention regardless of whether the intervention was received or not. 
Intervention groups and duration: 
The duration of the study for a participant will include: 
• Screening period: Up to 28 days. 
• Treatment Period: Enrolled participants will receive continuous treatment until PD, 
unacceptable adverse event (AE), or other full permanent discontinuation criteria as 
described in Section 7, or complete the maximum cycles allowed in the individual 
substudy. However, treatment beyond PD may be allowed for up to 9 weeks if the 
participant appears to be benefiting clinically after discussion with the Sponsor. 
• End of Treatment and Follow-up: End of Treatment Visit will occur 30 days ±7 days 
from last IMP administration or prior to initiation of further therapy. Participants will then 
enter the Observation period and will be followed differently depending on the reason 
leading to End of Treatment (EOT): 
1. Participants who discontinue study treatment without PD or who complete the 
maximum cycles allowed in the individual substudy without PD (per Lugano 
response criteria 2014[2]), will be followed every 3 months ±7 days from last IMP 
administration, for safety (as per Schedule of Activities [SoA] in the individual 
substudy) and tumor imaging assessments, until PD, start of another anticancer 
therapy, final cohort cut-off, whichever comes first, before moving to the Survival 
Phone Call Follow-Up Period. 
2. Participants who discontinue study treatment with PD (per Lugano response criteria 
2014[2]) will be followed for safety in the Follow-Up Visit 1 occurring 3 months ±7 
days from last IMP administration, before moving to the Survival Phone Call Follow-
Up Period. 
Participants who move into the Survival Phone Call Follow-up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status Updated survival status may be 
requested by the Sponsor at any time during the study. Survival Phone Call Follow up will 
continue until death, participant request to discontinue from follow-up, or cut-off date for final 
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analysis has been reached, or upon cancellation of Survival follow-up at the discretion of the 
Sponsor at any prior timepoint. 
After the cohort cut-off date for the primary 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 in the 
individual substudy. 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of primary objective) will be 3 years from cohort last participant in (LPI).   
Study interventions 
Investigational medicinal product(s) 
SAR444245 
• Formulation: SAR444245 is provided as a 2 mg/mL concentrate for solution for infusion 
in a single-dose vial with an extractable volume of 1 mL. 
• Route of administration: intravenous (IV) infusion.  
• Dose regimen: refer to individual substudy. 
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window of -5 
minutes and +10 minutes is permitted. 
See substudy protocols for other IMPs. 
Non-investigational medicinal products 
Premedication for SAR444245 
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, 30 to 60 minutes prior to SAR444245 
infusion (no longer than 60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg IV or oral route (PO) (or equivalent), and 
then optionally thereafter as needed. 
• Diphenhydramine 25 to 50 mg IV or PO (or equivalent eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter as needed. 
SAR444245 premedication may be optional after 4 cycles: 
• For a participant who has no IRR during the first 4 cycles: Premedication for the 
subsequent infusions is optional at the Investigator’s discretion. However, if during the 
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subsequent infusions without premedication the participant experiences an IRR (any 
grade), premedication must be restarted for all subsequent infusions.  
• If a participant develops an IRR Grade <2 during their first cycle only and then 
experiences no further IRRs during their next 3 cycles: The Investigator may consider 
omitting premedication for Cycle 5. If no IRR is observed during Cycle 5 without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during Cycle 5 without premedication the participant experiences 
an IRR (any grade), premedication must be restarted for all subsequent cycles. 
Statistical considerations: 
• Analysis of primary endpoint:  
Refer to individual substudy. 
• Analysis of secondary efficacy endpoints: 
- 
Time to response (TRR) will be assessed on the subgroup of participants who have 
achieved objective response in the efficacy population. 
- 
Duration of response (DoR) will only be summarized on the subgroup of participants 
who have achieved objective response in the efficacy population.  
- 
Clinical benefit rate (CBR) will be estimated by dividing the number of participants 
with clinical benefit by the number of participants in the efficacy population. 
- 
Progression free survival (PFS) will be summarized on the efficacy population using 
Kaplan-Meier methods. The median PFS times and associated 90% confidence interval 
(CI) will be provided. 
• Analysis of secondary safety endpoints: 
- 
Number and percentage of participants experiencing treatment-emergent adverse 
events (TEAEs) by primary System Organ Class (SOC) and Preferred Term (PT) will 
be summarized by National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE V5.0) grade (all grades and Grade ≥3) for the exposed 
population. Similar summaries will be prepared for treatment-related TEAEs, TEAEs 
leading to full intervention discontinuation, TEAEs leading to partial intervention 
discontinuation (if applicable), TEAEs leading to dose modification, serious TEAEs, 
TEAEs with fatal outcome, adverse events of special interest (AESIs), and AEs/SAEs 
occurring during the post-treatment period. In addition, the number (%) of participants 
with any Grade 5 AE (TEAE and post-treatment) and participants who died by study 
period (treatment-emergent period, post-treatment period) and reasons for death will 
be summarized. Immune Cell-Associated Neurotoxicity Syndrome (ICANS) and 
cytokine release syndrome (CRS) events will be graded using American Society for 
Transplantation and Cellular Therapy (ASTCT)  Consensus Grading and will be 
summarized separately. 
- 
Hematology and clinical chemistry results will be graded according to the 
NCI-CTCAE V5.0, when applicable. Number and percentage of participants with 
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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. 
Data Monitoring/Other Committee: Yes (see Section 10.1.5 for details). 
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1.2 
SCHEMA 
1.2.1 Study design for Cohort testing Q3W regimen 
Figure 2 - Graphical study design-Cohort testing Q3W regimen 
 
C=Study cycle (1 cycle = 21 days); D=Study day; EOT=end of treatment; FDG-PET=fluorodeoxyglucose-positron emission tomography; IMP=Investigational medicinal product; Q3W= every 3 weeks; Q9W= every 9 
weeks; Q12W= every 12 weeks. 
  
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1.2.2 Study design for Cohort testing Q2W regimen 
Figure 3 - Graphical study design-Cohort testing Q2W regimen 
 
C=Study cycle (1 cycle=14 days); D=Study day; EOT=end of treatment; FDG-PET=fluorodeoxyglucose-positron emission tomography; IMP=Investigational medicinal product, Q3W= every 3 weeks; Q9W= every 9 
weeks; Q12W= every 12 weeks. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Please refer to individual substudy. 
 
1.4 
BIOMARKER FLOWCHARTS  
Please refer to substudies for the individual biomarker flowcharts. 
1.5 
PHARMACOKINETIC FLOWCHARTS 
The sampling time-points for pharmacokinetic (PK) and anti-drug antibodies (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. 
Please refer to substudies for the individual pharmacokinetic flowchart. 
 
 
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2 
INTRODUCTION 
The purpose of this study is to evaluate the potential impact of SAR444245 with or without other 
anti-cancer therapies to improve outcome in adults and adolescents with B cell lymphoma, 
including classic Hodgkin lymphoma (cHL), primary mediastinal large B cell lymphoma 
(PMBCL), and diffuse large B cell lymphoma (DLBCL). Preclinical data, as described below, 
support the clinical study design. SAR444245 is a recombinant human interleukin 2 (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 and keep comparable binding to IL-2Rβ, while 
maintaining CD8+ T cell and natural killer (NK) cells anti-tumor activity and resulting in an 
improved safety profile relative to aldesleukin. Aldesleukin is approved in the United States (US) 
for the following indications: the treatment of metastatic renal cell carcinoma (RCC) and 
metastatic melanoma, with the same or limited approval status in other countries. Its use has 
resulted in durable complete response (CR) in some patients with anti-tumor effects via elevations 
in CD8+ T cells (naïve, effector, and memory T cells). However, widespread use of aldesleukin is 
limited by its low response rate, short half-life (t1/2), and severe toxicities, including primarily 
vascular leak syndrome (VLS), and cytokine release syndrome (CRS). 
In contrast to native IL-2 and aldesleukin, SAR444245 does not have high potency at the IL 
2Rα/β/γ receptor expressed on Treg cells because the site-specific pegylation blocks IL-2Rα 
engagement. Due to this re-programmed receptor bias, SAR444245 induces proliferation of 
peripheral CD8+ T and NK cells in vivo as observed in mice and non-human primates (NHP) with 
negligible effect on the expansion of immunosuppressive Treg cells. Furthermore, SAR444245 
does not bind IL-2Rα, and does not activate cells that express low levels of the high affinity IL 
2Rα, such as Type 2 innate lymphoid cells (ILC-2s), eosinophils, and endothelial cells.  Thus, it is 
expected to have a greatly reduced risk of VLS, and therefore a wider therapeutic window as 
compared to aldesleukin. In preclinical NHP studies, no signs of VLS were observed at a dose of 
SAR444245 that was 
 higher than the dose eliciting maximal expansion of peripheral 
CD8+ T cells. Therefore, in the clinic, SAR444245 is expected to have a wider therapeutic 
window as compared to aldesleukin due to a greatly reduced risk of VLS. 
Furthermore, the site-specific pegylation extends the plasma t1/2 of IL-2 in SAR444245 in mice 
and NHP to 9-13 hours versus 85 minutes 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. SAR444245 is hypothesized to have a synergistic effect 
with immunotherapies. Refer to individual substudies for specific background and rationales. The 
first in human clinical study with SAR444245 (TCD16843/HAMMER, hereafter referred to as 
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HAMMER) demonstrated that treatment with SAR444245 leads to expansion of CD8+ T cells 
and natural killer (NK) cells (with higher IL-2 βγ receptor expression) with negligible IL-2Rα 
induced effect on immunosuppressive Treg cells expansion, vascular leak syndrome related 
eosinophils expansion and IL-5 release. 
2.2 
BACKGROUND 
2.2.1 Rationale for B cell lymphoma and selected participant population  
Lymphomas are an important cause of cancer death world-wide. There are many different sub-
types of lymphoma. Immunotherapy has demonstrated efficacy in most types of B cell lymphoma, 
although the approach varies according to the subtype. There is still considerable unmet need for 
patients with B cell lymphoma, including cHL, PMBCL, and DLBCL, thus this study focuses on 
these indications. Non-Hodgkin lymphoma (NHL) is the most common type of lymphoma, while 
DLBCL is the most common type of aggressive NHL. In 2019, the annual incidence (US) for 
NHL was 80,000.  Hodgkin lymphoma (HL) is a relative rare malignancy, but one of the most 
common hematologic malignancies in young adults. Primary mediastinal B cell lymphoma 
(PMBCL) is a rarer hematologic malignancy that is typically seen in young adult women and 
adolescents.  In 2021, the US annual incidence for NHL and HL is expected 81,560 and 8,830 
respectively (3).  Hodgkin lymphoma (HL) and PMBCL are of special interest because they are 
the first hematologic malignancies in which checkpoint blockade with anti-PD1 therapy has been 
shown to be effective.  Pembrolizumab monotherapy is approved in both indications in the 
relapsed or refractory setting, while nivolumab monotherapy is approved in relapsed or refractory 
HL only. 
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There is still a considerable area of unmet need for patients with relapsed or refractory NHL or 
HL. At diagnosis NHL and HL exhibit 5-year overall survival rates of 73.2% and 88.3%, 
respectively (3), however patients who develop relapsed or refractory disease exhibit a PFS of 
14.7 months or 4-12 months for HL or NHL, respectively, if their disease persists despite 
intensive salvage therapy or if they are ineligible for intensive therapy (4, 5, 6, 7). Anti-PD1 
monotherapy for patients with relapsed or refractory HL who have received 2 or more prior lines 
of systemic therapy has yielded ORR’s of 65-87%, however CRR is 16-17% and PFS is 46% at 1 
year (8, 9).  Similarly for patients with relapsed or refractory PMBCL who have received a 
median of 3 prior lines of sytemic therapy, pembrolizumab monotherapy yields an ORR of 45-
48%, however CRR is 13-33% and PFS is 38-47% at 1 year.  These data highlight the need for 
more effective treatment combinations that synergize with checkpoint inhibitor therapy in HL and 
PMBCL (10).   
For patients with relapsed or refractory DLBCL who are ineligible for intensive therapy, there are 
several treatment options; however, none of these regimens are considered curative and PFS is 
generally 1 year or less.  The rituximab-based combination, rituximab+gemcitabine+oxaliplatin 
(RGemOx), is a well-tolerated form of chemoimmunotherapy that has been shown to be effective 
in relapsed or refractory DLBCL patients (ORR 43-61%) (5, 11). Recently published data 
supporting accelerated approvals of tafasitamab+lenalidomide and polatuzumab vedotin 
+bendamustine+rituximab demonstrate ORR of 43% and 70%, respectively, and PFS of 9-12 
months (6, 7) in patients with relapsed or refractory DLBCL who were previously treated with 
rituximab or other anti-CD20 agents.   
For patients who are eligible for intensive therapy for relapsed or refractory DLBCL, approved 
CD19-directed chimeric antigen receptor T-cell immunotherapy (CAR-T) achieves remarkable 
durations of response (median 9 months-not estimated) for patients who reach a CR, however 
about 50% of patients do not achieve a CR and thus will not receive a sustained benefit.  Patients 
achieving a partial response (PR) exhibit a median duration of response of 2-3 months (12, 13). 
There have been trials using IL-2 in lymphoma, below is the information from the trials.  
In multiple Phase 1 or Phase 2 studies, aldesleukin has demonstrated preliminary effacicy and in 
generally tolerable as a combination with rituximab (375 mg/m2 Q2W or QW for 4 infusions) in 
patients with NHL (14, 15, 16, 17, 18, 19).  The response rate was approximately 10% (for 
rituximab-refractory) to 50%.  Multiple CR cases were reported.  
Phase 1/2 study of a modified non-alpha IL-2 (nemvaleukin alfa, ALKS 4230) in combination 
with pembrolizumab showed 1 PR from a PD1-naïve HL patient (20). 
2.2.2 Current standard of care in B cell lymphoma 
Standard of care in B cell lymphoma is provided in the individual substudy. 
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2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of SAR444245 may be found in the Investigator’s brochure (IB). 
2.3.1 Risk assessment 
Safety data from clinical studies conducted with SAR444245 in humans is currently limited to 
available data from the Phase 1/2 first-in-human study (TCD16843[HAMMER], hereafter 
referred to as HAMMER). Consequently, the assessment of the risks associated to SAR444245 is 
based on existing preclinical data and takes into consideration the known safety profile of the 
structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Table 8 summarizes potential risks for SAR444245 identified from preclinical experience and 
from the Phase 1/2 first-in-human (HAMMER) study.  
2.3.1.1 Aldesleukin experience  
There is currently one marketed IL-2 product, Proleukin (aldesleukin). It is an IL-2 therapeutic 
that is currently licensed in the US for the treatment of metastatic RCC and metastatic melanoma, 
and in several European countries for the treatment of metastatic RCC. 
Aldesleukin is a human recombinant interleukin-2 which has been shown to possess the biological 
activities of human native IL-2 mediated through its binding with the high-affinity IL-2Rαβγ and 
intermediate-affinity IL-2Rβγ receptors. The widespread use of aldesleukin has been limited by its 
low response rate, a short t1/2 that requires dosing three times per day, and toxicities (21), which 
include life-threatening and sometimes fatal VLS. Vascular leak syndrome is characterized by a 
loss of vascular tone and extravasation of plasma proteins and fluid into the extravascular space. It 
results in hypotension and reduced organ perfusion which, if severe, can result in death. It may be 
associated with cardiac arrhythmias (supraventricular and ventricular), angina, myocardial 
infarction, respiratory insufficiency requiring intubation, gastrointestinal bleeding or infarction, 
renal insufficiency, edema, and mental status changes. 
Aldesleukin has been associated with exacerbation of pre-existing or initial presentation of auto 
immune disease and inflammatory disorders. Exacerbation of Crohn’s disease, scleroderma, 
thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic 
IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome and bullous 
pemphigoid, have been reported following treatment with IL-2. 
It was recognized early in clinical studies that eosinophilia appeared to mark the onset of VLS, 
with several reports of fast, dose-dependent elevation in eosinophils. Additional publications 
suggested a causal connection between the increase in peripheral IL-5 levels and identified ILC-2 
as the source of this powerful chemoattractant and activator of eosinophils (22). Aldesleukin 
mediates activation of ILC-2s via interaction with the high affinity IL-2R⍺ chain that exists at low 
levels on ILC-2s. 
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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 (22). As SAR444245 also exercises IL-2 activity, the Investigator should monitor 
clinical effects of narrow therapeutic index drugs that are hepatically metabolized.  
2.3.1.2 SAR444245 
2.3.1.2.1  Preclinical data  
Among the potential risks, preclinical data for SAR444245 are lacking for infusion-related 
reactions (IRRs), immunogenicity (anti-drug antibodies), hypersensitivity, and immune-mediated 
adverse events. Those are, however, typical effects associated with the use of biologic drugs in 
oncology and should be considered for SAR444245. 
Further, preclinical data for SAR444245 do not indicate the potential for nephrotoxicity, 
neurotoxicity, or pulmonary toxicity, which are known adverse effects for aldesleukin. However, 
mitigation strategies for nephrotoxicity and neurotoxicity are also proposed in the protocol. 
Preclinical data for SAR444245 do not indicate higher risk for infections. However, infections are 
typically associated with the use of aldesleukin and are to be expected. 
There are no preclinical data for tumor lysis syndrome (TLS) associated with the use of 
SAR444245, but it is known to occur when aldesleukin is combined with cisplatinum, vinblastine 
and dacarbazine (refer to Proleukin US label). 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 
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monocyte chemoattractant protein-1 (MCP-1), IL-2, and IL-1RA were observed in NHP, 
indicating that SAR444245 administration may be associated with CRS. 
No manifestations of VLS have been reported in pre-clinical toxicity studies with SAR444245. 
Although there is a theoretical risk of VLS occurring in an immunotherapy setting, it has not been 
observed for IL-2 variants with ‘non-alpha’ profiles. Being a “non-alpha” IL-2, SAR444245 is not 
anticipated to cause VLS. 
No data pertaining to pregnancy and lactation exposure and outcomes are available for 
SAR444245. Due to the missing information for this important risk, detailed mitigation measures 
will be introduced. Conditions for eligibility of women of reproductive potential and male 
subjects with female partners of childbearing potential are detailed in Section 5.1. Also, since it is 
not known whether SAR444245 is excreted in human breast milk, nursing mothers cannot 
participate in this study. 
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 or cetuximab. 
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, 
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IL-2Rβγ-biased IL2 could be safely administered as outpatient basis, and there was no report of 
capillary leak syndrome (CLS) or VLS (23). 
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: Grade 3 hypotension [n=1] & Grade 4 hyperglycemia + 
metabolic acidosis [n=1]) when combined with 360 mg of nivolumab. All 38 patients had TEAEs 
that were considered related to the study combination. The MTD of the combination was defined 
as NKTR 214 0.006 mg/kg + nivolumab 360 mg Q3W and this dose was selected as the 
recommended Phase 2 dose (RP2D). The most common TRAEs (≥30%) at the RP2D were flu-
like symptoms (80%), rash (80%), fatigue (76%), pruritis (48%), arthralgia (44%), headache and 
diarrhea (40%), nausea (40%), decreased appetite (36%) and peripheral edema (36%), myalgia 
(32%), and nasal congestion (32%). Grade ≥3 TRAEs occurred in 16% of patients at the RP2D 
(hyperglycemia, lipase increase, rash, cerebrovascular accident, hyponatremia, infectious pleural 
effusion, syncope). Immune-mediated AEs were observed in 31.6% overall: hypothyroidism (11), 
hyperthyroidism (2), hyperglycemia (2). Cytokine-related symptoms were observed primarily in 
Cycles 1 & 2 and significantly reduced thereafter. There were no treatment related deaths and 
generally, Grade ≥3 TRAEs were manageable using standard guidelines. Tumor responses were 
observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating 
lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for 
response to PD-1/PD-L1 blockade. These data demonstrated that NKTR-214 can be safely 
combined with a checkpoint inhibitor as dual immunotherapy for the treatment of a range of 
advanced solid tumors (24). 
2.3.2 Benefit assessment 
The ability of IL-2 to expand T cells with maintenance of functional activity has been translated 
into the first reproducible effective human cancer immunotherapies. The first-generation IL-2 
(aldesleukin) was the first immunotherapy effective for human cancer. Aldesleukin is approved in 
metastatic RCC and metastatic melanoma and its use has resulted in durable, complete responses 
in some patients with anti-tumor effects via elevations in CD8+ T cells (naïve, effector, and 
memory T cells). However, clinical benefit of aldesleukin requires high dose as the enhancement 
of the CD8+ T-cell population is mediated through the intermediate-affinity by IL-2Rβγ, the 
suppressor CD4+ Treg cells are preferentially enhanced at lower dose through the high-affinity 
IL-2Rαβγ which is probably responsible for the limited proportion of responding patients (ORR 
16% in metastatic melanoma patients - US Label), and at the price of significant toxicities. 
SAR444245, as a “non-alpha” new generation IL-2 is expected to result in greater anti-tumor 
activity than aldesleukin that has already demonstrated clinical benefit. 
2.3.3 Overall benefit: risk conclusion 
SAR444245, with its site-specific pegylation, was designed to substantially reduce association 
with the IL-2 α receptor, while retaining stimulatory activity for cells expressing the moderate 
affinity IL-2 βγ receptor. These design features are anticipated to minimize safety liability 
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associated with Proleukin® by avoiding expansion of immunosuppressive immune cell 
populations (regulatory T cells) and off-target complications such as VLS, while still promoting 
expansion of immune populations that can support anti-tumor immune responses. 
Taking into account the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with this new generation IL-2 SAR444245 with or without other 
anticancer therapies are justified by the anticipated benefits that may be afforded to participants 
with relapsed or refractory B cell lymphoma. 
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
2.3.4.1 Risks in the context of COVID-19 
2.3.4.1.1 Risks related to the patient population 
Patients potentially eligible for this study have relapsed or refractory B cell lymphoma.  In 
general, patients with hematologic malignancies are at increased risk for bacterial, fungal, or viral 
infection, however data on the incidence of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection (Corona Virus Disease 2019 [COVID-19]) in patients with lymphoma 
are limited. The first cohort study of the incidence of COVID-19 in patients with hematologic 
malignancies, hospitalized in Wuhan, China during the COVID-19 pandemic, indicate that the 
case rate was not significantly higher than for that of health care providers in Wuhan (10% vs 7%, 
p=0.322), however the case fatality rates were significantly higher for patients with hematologic 
cancers than for health care providers (62% vs 32%, p=0.002) (25).  A recent study indicates that 
reduced therapy intensity during the COVID-19 pandemic is associated with increased anxiety 
levels and impaired health-related quality of life for patients with lymphoma (26).  Furthermore, 
guidelines have been developed to limit the spread of SARS-CoV-2 infection to lymphoma 
patients, even while these patients continue to receive treatment and participate in clinical trials, 
given the potentially serious consequences that may result from delaying treatment and the high 
degree of unmet need for effective therapies for patients with relapsed or refractory disease (27, 
28, 29). To that end, trial participation will proceed during the COVID-19 pandemic, however 
measures will be taken to mitigate the potential risk of SARS-CoV-2 infection to trial participants.   
Testing for SARS-CoV-2 infection during the screening phase should be at Investigator’s 
discretion and should also follow local/international guidelines (eg, asymptomatic but high risk of 
infection patients, patients with symptoms that could be associated with SARS-CoV-2 infection). 
To be eligible for trial participation, participants with a history of SARS-CoV-2 infection must 
have completed clinical recovery from SARS-CoV-2 infection at least 1 month prior to 
enrollment and no longer have a positive polymerase chain reaction (PCR) test for SARS-CoV-2 
at the time of enrollment (E 17).     
During the study, if a participant is diagnosed with SARS-CoV-2 infection, dose modification of 
study intervention should be based on the recommendations provided in Section 6.5. In addition, 
all Investigators are instructed to consult official COVID-19 clinical research guidance from their 
local hospital/institution along with other relevant resources, such as: 
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• American society of clinical oncology (ASCO) (30). 
• European Society for Medical Oncology (ESMO) (31). 
2.3.4.1.2 Risks related to study treatment 
SAR444245 has the potential to induce CRS which could exacerbate the manifestations of 
COVID-19 infection. It is, however, worth noting that pegylated IL-2 bempegaldesleukin is 
currently being evaluated for the treatment of patients with mild COVID-19 in a Phase 1b study 
(NCT04646044). 
2.3.4.1.3 Risks related to study related activity 
It is important to minimize the risk of exposure of patients to COVID-19. In addition to the 
contingency measures described in Section 10.9, the following prevention and mitigation plans 
could be implemented at clinical sites: 
• All participating sites should have implemented measures according to regional/local 
Health Authorities, European Medicines Agency (EMA), ESMO, ASCO guidelines 
including but not limited to restrictions of access to the hospitals for visitors, physical 
distancing and personal protective equipment (PPE).  
• Study participants should be treated in a dedicated area that is separated from patients with 
COVID-19 infection. 
2.3.4.1.4 Conclusion on the benefit-risk assessment pertaining to COVID-19 
Overall, the benefit-risk ratio is deemed acceptable in patients with relapsed or refractory B cell 
lymphoma during COVID-19 pandemic. The Sponsor will continue to evaluate the benefit-risk 
ratio during the study period. 
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3 
OBJECTIVES AND ENDPOINTS 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245 
with or without other anticancer therapies. 
• 
Refer to individual substudy. 
Secondary 
 
• 
To confirm the dose and to assess the safety profile 
of SAR444245 when combined with or without other 
anticancer therapies. 
• 
Incidence of treatment emergent adverse events 
(TEAEs), dose-limiting toxicities (DLTs), serious 
adverse events (SAEs), laboratory abnormalities 
according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI 
CTCAE) V5.0 and American Society for 
Transplantation and Cellular Therapy (ASTCT) 
consensus gradings (1). 
• 
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 documented evidence of 
PR or CR determined by Investigator per Lugano 
response criteria 2014 (2). 
• 
Duration of response (DoR) defined as the time 
from first documented evidence of PR or CR until 
progressive disease (PD) determined by 
Investigator per Lugano response criteria 2014 (2), 
or death from any cause, whichever occurs first. 
• 
Clinical benefit rate (CBR) including CR or PR at 
any time or stable disease (SD) of at least 6 months 
(determined by Investigator per Lugano response 
criteria 2014) (2). 
• 
Progression free survival (PFS) defined as the time 
from the date of first IMP administration to the date 
of the first documented disease progression 
determined by Investigator per Lugano response 
criteria 2014 (2) or death due to any cause, 
whichever occurs first. 
• 
To assess the plasma concentrations of 
SAR444245 when given with or without other 
anticancer therapies. 
• 
Plasma concentrations of SAR444245. 
• 
To assess the immunogenicity of SAR444245. 
• 
Incidence of anti-drug antibodies (ADAs) against 
SAR444245. 
Exploratory 
 
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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 with or without other anticancer 
therapies in adults and adolescents with relapsed or refractory B cell lymphoma. 
This study is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with or without other anticancer therapies by identifying early signals. This design is 
with the flexibility to open new treatment cohorts as new treatment become available and close 
existing treatment cohorts that demonstrate minimal clinical activity or unacceptable toxicity. 
The information that is introductory and common to all cohorts is included in the present 
document (“Master Protocol”), and cohort-specific elements are included in separate substudies. 
This study is designed with the flexibility to open new treatment arms or add new indications as 
permitted by scientific rationale. 
A graphical presentation of the study schema is shown in Figure 1. 
A safety run-in will confirm the dose of SAR444245 in each substudy. Participants who fulfill 
the eligibility criteria of any cohort may be enrolled to the safety run-in of that cohort. After a 
maximum of 10 participants have been enrolled into a specific cohort, enrollment will be paused 
for that cohort.  
Once a total of at least 6 participants are evaluable for DLT in a specific cohort, safety data for 
these participants will be reviewed by the Study Board. DLT-evaluable participants include all 
treated participants in the safety run-in part who have been observed for the DLT observation 
period (defined in the individual substudy). Any participant who experienced a DLT at any time 
during the DLT observation period will also be DLT-evaluable. 
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 for that specific cohort (for example, if 10 
Cohort A participants are enrolled in the safety run-in, and treated at the confirmed safe dose, 
approximately 15 additional participants will be enrolled into Cohort A to have the total number 
of 25 participants). 
The SAR444245 dose to be confirmed is 24 μg/kg, administered as an IV infusion over 30 
minutes during each cycle (see Section 1.1 Study interventions for details). Overall safety 
monitoring will be performed throughout the study.  If recommended by the Study Board, 
SAR444245 dose may be reduced to 
 μg/kg or another lower dose level which will be explored 
following the same process described in the safety run-in for 24 μg/kg dose level.  
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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 Study Board and will be guided by the decision rules from the mTPI2 design. The mTPI2 
decision rules are based on calculating the unit probability mass (UPM) of intervals as following: 
(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 
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 2) will be applied as follows, unless decided otherwise by the Study 
Board: 
• If the dose recommendation from mTPI2 is “E” (Escalate to the next higher dose) or “S” 
(Stay at the same dose), 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. 
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Table 2 - Dose escalation rule of the modified toxicity probability interval-2 method  
 
 
Number of DLT-evaluable participants 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Number of dose limiting toxicities 
0 
E 
E 
E 
E 
E 
E 
E 
E 
E 
E 
1 
D 
D 
S 
S 
E 
E 
E 
E 
E 
E 
2 
 
DU 
D 
D 
D 
S 
S 
S 
E 
E 
3 
 
 
DU 
DU 
D 
D 
D 
D 
S 
S 
4 
 
 
 
DU 
DU 
DU 
D 
D 
D 
D 
5 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
D 
6 
 
 
 
 
 
DU 
DU 
DU 
DU 
DU 
7 
 
 
 
 
 
 
DU 
DU 
DU 
DU 
8 
 
 
 
 
 
 
 
DU 
DU 
DU 
9 
 
 
 
 
 
 
 
 
DU 
DU 
 
10 
 
 
 
 
 
 
 
 
 
DU 
E: Escalate to the next higher dose, S: Stay at the current dose, D: De-escalate to the previous lower dose, DU: De-escalate to the 
previous lower dose and the current dose will never be used again because of unacceptable high toxicity. 
Note: a total of at least 6 participants are evaluable for DLT in a specific cohort, safety data for these participants will be reviewed by 
the Study Board to determine if the dose needs to be reduced. 
 
 
Dose limiting toxicity: Selected events occurring during the DLT observation period (defined in 
the individual substudy) 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 as below. Based on the 
occurrence of DLT and overall assessment of safety data supplemented with data from other 
SAR444245 studies, the Study Board will determine if the dose of SAR444245 needs to be 
reduced to 
μg/kg or another lower dose level, in agreement with the Sponsor.  
Hematologic abnormalities:  
• Grade 4 neutropenic fever (temperature ≥38.5°C on more than 1 occasion). 
• Grade 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 × 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 
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• Grade 3 or above cytokine release syndrome 
• Grade 3 or above AE that does not resolve to grade ≤ 2 within 7 days of starting accepted 
standard of care medical management.  
• The following non-hematologic AEs are exceptions that are not considered DLTs: 
- 
Grade 3 or 4 laboratory abnormalities that are not clinically significant per recruiting 
Investigator and Sponsor will not be considered a DLT. 
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 an ad hoc Data Monitoring Committee (DMC) to rapidly convene to assess 
safety or need to pause enrollment to allow for a safety review. The SB (during safety run-in), 
independent DMC (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. 
Special considerations pertaining to methodology 
Interactive Response Technology will be used to control recruitment, assignment per site and 
facilitate the handling, management, and accountability of drug supply. 
The duration of the study for a participant will include: 
• Screening period: Up to 28 days. 
• Treatment Period: Enrolled participants will receive continuous treatment until PD, 
unacceptable adverse event (AE), or other full permanent discontinuation criteria as 
described in Section 7, or completion of  the maximum cycles allowed in the substudies. 
However, treatment beyond PD may be allowed for up to 9 weeks if the participant 
appears to be benefiting clinically after discussion with the Sponsor. 
• End of Treatment and Follow-up: End of Treatment Visit will occur 30 days ±7 days 
from last IMP administration or prior to initiation of further therapy. Participants will then 
enter the Observation period and will be followed differently depending on the reason 
leading to End of Treatment (EOT): 
1. Participants who discontinue study treatment without PD or who complete  the 
maximum cycles allowed in the substudies without PD (per Lugano response criteria 
2014[2]), will be followed every 3 months ±7 days from last IMP administration, for 
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safety (as per Schedule of Activities [SoA] in the individual substudy) and tumor 
imaging assessments, until PD, start of another anticancer therapy, final cohort cut-off, 
whichever comes first, before moving to the Survival Phone Call Follow-Up Period. 
2. Participants who discontinue study treatment with PD (per Lugano response criteria 
2014[2]) will be followed for safety in the Follow-Up Visit 1 occurring 3 months ±7 
days from last IMP administration, before moving to the Survival Phone Call Follow-
Up Period. 
Participants who move into the Survival Phone Call Follow-up Period will be contacted by 
telephone every 3 months ±14 days to assess for survival status. Updated survival status may be 
requested by the Sponsor at any time during the study. Survival Phone Call Follow up will 
continue until death, participant request to discontinue from follow-up, or cut-off date for final 
analysis has been reached, or upon cancellation of Survival follow-up at the discretion of the 
Sponsor at any prior timepoint. 
After the cohort cut-off date for the primary 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 in the 
individual substudy. 
For each cohort, the cut-off date for the final analysis (ie, analysis of secondary objectives and 
update of the primary objective) will be 3 years from cohort last participant in (LPI).  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with other anticancer therapies, or as monotherapy, in trial participants with relapsed or refractory 
B cell lymphoma. 
The design of the study is a non-randomized study where the experimental combination or 
monotherapy will be assessed in a single cohort for each indication, using historical data for single 
agent as a benchmark to show outstanding objective response rate. The primary endpoint will be 
assessed using Lugano response criteria 2014 for participants with relapsed or refractory B cell 
lymphoma. It will be assessed per Investigator. Central imaging reading may be done 
retrospectively if significant activity is observed. 
A safety run-in on the first 6-10 participants being enrolled in the individual substudy has been 
embedded in the study to confirm the absence of safety issues before launching enrollment of the 
remaining participants in a specific cohort. 
4.2.1 Participant input into design 
Teenagers with a history of lymphoma and their parents participated in an advisory panel, 
reviewed the study design, and provided input. 
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4.3 
JUSTIFICATION FOR DOSE 
Dose escalation for SAR444245 monotherapy and in combination with pembrolizumab or 
cetuximab is ongoing in the first-in-human HAMMER study. Data from a total of 68 patients who 
have received SAR444245 Q2W or Q3W in monotherapy, in a Q3W regimen in combination with 
pembrolizumab 200 mg Q3W, or with cetuximab 400/250 mg/m² QW is available as of 18 June 
2021. HAMMER Safety Review Committee have cleared SAR444245 24 µg/kg Q3W 
pembrolizumab combination dose level based on this data cut-off. 
The dose levels tested to date for SAR444245 monotherapy administered using a Q3W schedule 
are 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=11), 32 µg/kg (n=6) and 40 µg/kg (n=2). 
In combination with pembrolizumab, SAR444245 has been administered Q3W at the doses of 8 
µg/kg (n=4), 16 µg/kg (n=9), 24 µg/kg (n=6), 32 µg/kg (n=1). In combination with cetuximab, 
SAR444245 has been administered Q3W at 16 µg/kg (n=5) or 24 µg/kg (n=5). 
For monotherapy cohort, the only DLT observed to date is a Grade 3 infusion reaction (occurred 
on C2D1 which resolved on the same day with supportive care) reported in a patient on 32 µg/kg 
Q3W monotherapy.  
For SAR444245 in combination with pembrolizumab 200 mg Q3W, 1 DLT (Grade 3 liver 
enzyme elevation with Grade 2 bilirubin elevation meeting drug-induced liver injury [DILI] 
criteria occurred on C1D1 which resolved after 7 days with steroids) was observed in a participant 
with SAR444245 24 µg/kg Q3W with pembrolizumab. 
No DLTs were reported by SAR444245 cetuximab combination cohort (SAR444245 24 µg/kg 
Q3W). 
Grade 3/4 TEAEs commonly reported by participants who received SAR444245 24 µg/kg 
monotherapy (n=11) include in particular Grade 4 lymphocyte count decreased/lymphopenia 
(7 participants, 63.6%) and 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 is reported as an adverse event (AE) in 
HAMMER study. 
Grade 3/4 TEAEs reported by participants who received SAR444245 24 µg/kg in combination 
with pembrolizumab (n=6) include Grade 4 lymphocyte count decreased (3 participants, 50.0%), 
Grade 3 aspartate aminotransferase (AST), alanine aminotransferase (ALT) & gamma-glutamyl 
transferase (GGT) increased (2 participants each for AST & ALT increased, 33.3%; 1 participant 
for GGT increased, 16.7%), Grade 3 blood phosphorus decreased & hypophosphatemia 
(1 participant each, 16.7%) and Grade 3 dyspnea (1 participant, 16.7%). 
Grade 3/4 TEAEs reported by participants who received SAR444245 24 µg/kg in combination 
with cetuximab (n=5) include Grade 3 chills (1 participant, 20.0%) and Grade 3 abdominal pain 
and vomiting (1 participant for each, 20.0%). 
Only 1 high grade CRS with Grade 3 hypertension, Grade 2 fever, and Grade 2/3 neurological 
symptoms (with 24 µg/kg Q3W, 2.6%) is reported among participants who received SAR444245 
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monotherapy (n=38). From participants who received SAR444245 pembrolizumab combination 
(n=20), Grade 3 CRS (with 16 µg/kg Q3W) is observed in 1 participant (5.0%) with Grade 3 
hypotension and Grade 2 fever. 
According to literature, prophylactic hydration on the dosing days could mitigate incidence and 
severity of hypotension as part of CRS. As HAMMER study was not mandating prophylactic 
hydration before January 2021, the participants who experienced CRS in HAMMER study did not 
receive peri-infusion hydration. Based on this learning, hydration and CRS management 
guidelines have been included in the Phase 2 study protocols. 
With respect to PK, SAR444245 exposure increased in an approximately dose-proportional 
manner in the monotherapy cohorts, and no impact of anti-drug antibody (ADA) on SAR444245 
PK could be identified. Also, in the combination cohort, there was no apparent impact of 
pembrolizumab on the PK of SAR444245. 
Differently from native IL-2 and aldesleukin, SAR444245 does not have high potency at the 
IL-2Rα/β/γ receptor subunit expressed on T regulatory (Treg) cells because the site-specific 
pegylation blocks IL-2Rα engagement and demonstrates high potency at the IL2Rβ/γ receptor 
subunit expressed on CD8+ T and natural killer cells (NK). Due to this re-programmed receptor 
bias, SAR444245 induces proliferation of peripheral CD8+ T and NK cells and less impact on 
immunosuppressive Treg cells. Therefore, we closely monitored the PD change of CD8+ T, NK 
and Treg cells in HAMMER study as supportive information for R2PD selection. 
In the SAR444245 monotherapy dose levels (8 µg/kg, 16 µg/kg, 24 µg/kg, and 32 µg/kg Q3W), 
the PD data suggest that a trend for dose-dependent expansion of CD8+ T cells and NK cells has 
been achieved. In the 8 µg/kg dose levels, the average increase in peripheral blood CD8+ T cells 
over baseline at 72 hours post-dose was 1.75-fold. For dose levels 16 µg/kg and 24 µg/kg, the 
peripheral blood CD8+ T cell expansion was 2.47 and 4.47-fold at the day 8 post-dose peak of 
expansion. The day 8 sample timepoint was added after the first 3 participants in the 8 µg/kg 
cohort were dosed. 
In addition, the average increase in peripheral blood NK cells was 4.22-fold at 72 hours for 
8 µg/kg. The 16 µg/kg and 24 µg/kg dose levels resulted in 5.9 and 7.67-fold NK expansion, 
compared to baseline at the day 8 peak expansion. Among the dose levels tested to date for 
SAR444245 in combination with pembrolizumab administered using Q3W schedule, we have 
collected available PD data for the 8 µg/kg (n=4) and 16 µg/kg cohort (n=6), in which the average 
increase in CD8+ T cells, compared to baseline, is 2.06-fold and 3.71-fold, respectively; and the 
average increase in NK cells, compared to baseline, is 6.73-fold and 13.43-fold, respectively at 
the peak expansion day 8. In addition, the comparison of T and NK cell expansion between 
 µg/kg and 
µg/kg cohorts indicated that the anticipated maximum CD8+ T and NK cells 
expansion PD effect may have been achieved at 
 µg/kg cohort. Based on these data, additional 
quantitative systems pharmacology (QSP) and popPK/PD 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 
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pembrolizumab. This study used SAR444245 concentration ranges that went significantly higher 
than current clinical dosages (0.2-4.5 µg/mL) and showed that SAR444245-induced cytokine 
release in human whole blood was not affected in the presence of pembrolizumab at Q3W 
schedule. 
Considering below, Sponsor proposes to evaluate the clinical benefit of SAR444245 24 µg/kg in 
this Phase 2 study. 
1. SAR444245 monotherapy up to 32 µg/kg Q3W, pembrolizumab combination up to 
24 µg/kg Q3W and cetuximab combination 16 µg/kg Q3W are all cleared in 
HAMMER study. 
2. Sustained relevant PD effect in blood, higher at higher dose, was documented in 
participants; and 
3. Overlapping toxicities not expected for SAR444245 in combination with 
pembrolizumab or cetuximab, as suggested by safety data observed. 
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 in individual substudies for the last 
participant in the trial globally. 
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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
The inclusion criteria listed in the master protocol are only those applicable to all the participants 
common to all substudies. For additional substudy specific criteria, refer to the particular 
substudy. 
Participants are eligible to be included in the study only if all of the following criteria apply for a 
given cohort: 
Age 
I 01. Participant must be ≥12 years of age, at the time of signing the informed consent. 
See requirement specific to France in Appendix 7 (Section 10.7). 
Type of participant and disease characteristics 
I 02. Provision of tumor tissue: 
- 
Disease location amenable to mandatory tumor biopsy (optional for participants ≥ 12 
and <18 years of age) at baseline unless clinically unfeasible (minimum 10 slides with 
4-5 micron thickness for the participants who have signed ICF [excluding screen 
failure participants]) and possibly at Cycle 2 Day 1. Fine needle aspirates are not 
acceptable. Availability of a tissue specimen from core needle or excisional biopsies, 
or resected tissue are required. Provision of archival tumor tissue sample obtained 
within 6 months (there should be no systemic anti-cancer therapy between collection 
of biopsy and enrollment) is allowed to replace mandatory baseline biopsy.  
Note: Clinically unfeasible biopsy should be documented by a written communication 
from the Investigator to the Sponsor that performing a biopsy will put the wellbeing of 
the subject at an excessive risk. 
- 
The Sponsor may approve the written request to enroll, on a case-by-case basis, 
participants with: 
- 
Location of the tumor not amenable to biopsy due to significant risk, OR 
- 
Less than required number of slides or archival tumor tissue sample collected more 
than 6 months prior to screening. 
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I 03. Measurable disease: 
The participant must have relapsed or refractory disease. Measurable disease defined as at 
least one measurable node that must have an LDi (longest diameter) >1.5 cm and/or 
measurable extranodal lesion that must have a LDi >1 cm according to Lugano response 
criteria 2014. Tumor sites that are considered measurable must not have received prior 
radiotherapy, unless among them at least one is FDG-avid. 
Weight (not applicable) 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 04. All (male and female) 
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 3 days [corresponding to time needed to eliminate 
SAR444245] after the last dose of SAR444245: 
- 
Refrain from donating or cryopreserving sperm. 
PLUS either: 
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
OR 
- 
Must agree to use contraception/barrier as detailed below 
- 
A male condom when having sexual intercourse with a woman of childbearing 
potential (WOCBP) who is not currently pregnant, or during homosexual 
intercourse. The participant should also be advised of the benefit for a female 
partner to use a highly effective method of contraception (as described in Appendix 
4 Contraceptive and barrier requirements [Section 10.4]) as a condom may break or 
leak when having sexual intercourse with a woman of childbearing potential 
(WOCBP) who is not currently pregnant. 
b) Female participants 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP). 
OR 
- Is a WOCBP and agrees to use a contraceptive method that is highly effective (with 
a failure rate of <1% per year), with low user dependency, as described in Appendix 
4 (Section 10.4) during the intervention period (to be effective before starting the 
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intervention) and for at least 120 days (or refer to the individual substudy protocol) 
[corresponding to the time needed to eliminate any study intervention(s) ] after the 
last dose of study intervention and agrees not to donate or cryopreserve eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
- A WOCBP must have a negative highly sensitive pregnancy test (as required by 
local regulations) within 72 hours before the first dose of study intervention. 
- Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 4 (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 05. Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. For participant below legal age to provide ICF, a specific ICF 
must be signed by the participant’s legally authorized representative. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply. For additional 
individual substudy specific criteria, refer to the particular substudy. 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2 (≥ 16 years old). 
Lansky Scale (< 16 years old) ≤ 60%. 
E 02. Lymphomatous involvement of the central nervous system. 
E 03. Predicted life expectancy ≤3 months. 
E 04. History of solid organ transplant. 
E 05. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents and anti-cytotoxic T 
lymphocyte associated protein 4 monoclonal antibodies) that caused permanent 
discontinuation of the agent, or that were Grade 4 in severity. 
E 06. Prior IV or subcutaneous anticancer therapy, investigational agent, major surgery within 21 
days prior to initiation of IMP; oral anticancer therapy within 5 half-lives or completed 
palliative radiotherapy within 21 days prior to initiation of IMP. 
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E 07. Uncontrolled pleural/peritoneal effusion, pericardial effusion or ascites requiring recurrent 
drainage procedures (once monthly or more frequently). 
E 08. Comorbidity requiring corticosteroid therapy (>10 mg prednisone/day or equivalent) 
within 14 days 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 or as premedication for erythrocyte or platelet transfusions) are not 
excluded. 
E 09. Antibiotic use (excluding topical antibiotics) ≤14 days prior to the 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. Participants who require prophylactic 
antibiotics because of chronic immunodeficiency will be allowed. 
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 anticancer therapy ≥Grade 2 (NCI-CTCAE Version 
5.0). Participants with Grade 2 peripheral neuropathy, or Grade 2 alopecia are permitted. 
Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone 
replacement may be eligible.  
Note: If the participant had major surgery, the participant must have recovered adequately 
from the procedure and/or any complications from the surgery prior to starting study 
intervention. 
Note: please refer to the individual substudy protocol for cohort specific requirement. 
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. History of (non-infectious) pneumonitis / interstitial lung disease that required steroids or 
has current pneumonitis / interstitial lung disease. 
E 14. History of thoracic radiation therapy of >30 Gy within 6 months of the first dose of trial 
treatment. 
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E 15. Receipt of a live or live attenuated virus vaccine within 28 days of planned treatment start. 
Seasonal flu vaccines or SARS-CoV-2 vaccines that do not contain live virus are 
permitted. 
E 16. Human immunodeficiency virus (HIV)-infected participants with a history of Kaposi 
sarcoma and/or Multicentric Castleman Disease or known uncontrolled infection with 
HIV. HIV-infected participants must be on anti-retroviral therapy (ART) and have a well-
controlled HIV infection/disease defined as: 
- 
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of 
screening. 
- 
Participants on ART must have achieved and maintained virologic suppression defined 
as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification 
(below the limit of detection) using the locally available assay at the time of screening 
and for at least 12 weeks prior to screening. 
- 
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1). 
- 
Combination ART regimen must not contain any antiretroviral medications other than: 
abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or tenofovir. 
HIV serology will be tested at screening for participants in France (see details and specific 
instructions in Section 10.2 and Section 10.7). 
E 17. Known uncontrolled hepatitis B infection, known untreated current hepatitis C infection, 
active tuberculosis, SARS-CoV-2 infection, 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. 
- 
Participants with a history of SARS-CoV-2 infection must have completed clinical 
recovery at least 1 month prior to enrollment and no longer have a positive PCR test 
for SARS-CoV-2 at the time of enrollment.  
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 
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skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded. 
E 19. Known severe hypersensitivity (≥ Grade 3) to or contraindication for the use of any study 
intervention or components thereof, including premedication to be administered in this 
study, as well as PEG or any pegylated drug and E. coli-derived protein.  
E 20. Participants with baseline oxygen saturation (SpO2) ≤92% (without oxygen therapy). 
Prior/concomitant therapy 
E 21. Has received prior IL2-based anticancer treatment. 
E 22. Is unable or unwilling to take premedication. 
E 23. Deleted by protocol amendment 01. 
E 24. Deleted by protocol amendment 01.  
Prior/concurrent clinical study experience 
E 25. 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 26. Absolute neutrophil count <1000/uL (1 × 109/L) (after at least one week off G-CSF). 
E 27. Platelets <50 × 10³ /uL (after at least 3 days without platelet transfusion).  
E 28. Hemoglobin <9 g/dL or <5.6 mmol/L (after at least 1 week without packed red blood cell 
[pRBC] transfusion. Participants can be on stable dose of erythropoietin (≥ approximately 
3 months)). 
E 29. 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 30. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 × ULN (or 
>5 × ULN for participants with lymphoma involving the liver). 
E 31. Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73 m² (Modification of Diet in 
Renal Disease [MDRD] Formula, see Section 10.2 Appendix 2). 
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E 32. 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 33. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 34. Any country-related specific regulation that would prevent the participant from entering 
the study – see Section 10.7 Appendix 7 (country-specific requirements). 
E 35. 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 36. 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 37. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 38. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the trial, interfere with the subject's participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating Investigator. 
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 (or the participant’s legally authorized 
representative) 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 (or 
the participant’s legally authorized representative) should sign a new ICF. A participant may be 
rescreened only once. Rescreened participants should be assigned a different participant number 
as for the initial screening. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION 
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 10.9. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Study intervention is defined as any investigational intervention(s), marketed product(s), intended 
to be administered to a study participant according to the study protocol.  
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Participants will receive study treatment until PD, unacceptable toxicity, other permanent 
discontinuation criteria as described in Section 7, or completion of  the maximum cycles allowed 
in the substudies. However, treatment beyond PD may be allowed for up to 9 weeks if the 
participant appears to be benefiting clinically after discussion with the Sponsor. 
6.1.1 Investigational medicinal product 
Details of SAR444245 are shown in Table 3.  
Preparation and administration of investigational medicinal product (IMP) are detailed in the 
pharmacy manual. 
Hydration is required for SAR444245 infusions. Details are provided in Section 6.1.3. 
Table 3 - Overview of IMP administered 
Intervention name 
SAR444245 
Type 
Biologic 
Dose formulation 
Concentrate for solution for infusion 
Unit dose strength(s) 
2.0 mg/mL 
Dosage level(s)a 
24 μg/kg (or reduced to 
 μg/kg or another lower dose level recommended by Study Board) 
Route of 
administration 
IV infusion 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and 
labeling 
Supplied in a single-dose vial in a treatment box. Each vial contains 2 mg/mL with an extractable 
volume of 1 mL. Each vial and treatment box will be labeled as required per country requirement. 
Current/Former 
name(s) or alias(es) 
NA 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the e-CRF. Study 
sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted. 
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6.1.2 Non-investigational medicinal products 
Non-investigational medicinal products (NIMP) include the premedication administered for 
SAR444245. 
6.1.2.1 Premedication for SAR444245  
All participants will receive the following premedication to prevent or reduce the acute effect of 
infusion-related reactions (IRR) or flu-like symptoms, 30 to 60 minutes prior to SAR444245 
infusion (no longer than 60 minutes) for the first 4 cycles: 
• Acetaminophen (paracetamol) 650 to 1000 mg (IV or PO) (or equivalent), and then 
optionally thereafter as needed. 
• Diphenhydramine 25 to 50 mg IV or PO (or equivalent eg, cetirizine, promethazine, 
dexchlorpheniramine, according to local approval and availability), and then optionally 
thereafter as needed. 
SAR444245 premedication may be optional after 4 cycles: 
• For a participant who has no IRR for the first 4 cycles, premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the participant experiences an IRR (any grade), 
premedication must be restarted for all subsequent infusions.  
• If a participant develops an IRR Grade <2 during their first cycle only and then 
experiences no further IRRs during their next 3 cycles the Investigator may consider 
omitting premedication for Cycle 5. If no IRR is observed during Cycle 5 without 
premedication, premedication is optional for the subsequent cycles at the Investigator’s 
discretion. However, if during Cycle 5 without premedication the participant experiences 
an IRR (any grade), premedication must be restarted for all subsequent cycles. 
6.1.3 Hydration guidelines for SAR444245 administration  
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6.1.4 Readiness for treatment of severe cytokine release syndrome  
Doses of tocilizumab or alternative therapies per site practice in CRS management should be 
available at site at all times in the event that a participant requires rapid intervention for the 
treatment of severe CRS. Please refer to the individual substudies for detailed guidelines for the 
management of CRS. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
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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 e-CRF. The dose of study 
intervention and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study intervention. 
6.5 
DOSE MODIFICATION 
Refer to individual substudy for details. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
There will be no intervention beyond the end of the study. 
6.7 
TREATMENT OF OVERDOSE 
There is no specific antidote for overdose with SAR444245.  
If overdose occurs (see Section 8.3.8 for definitions), symptomatic management is indicated.  
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Treatment of overdose should consist of general supportive care with aggressive fluid 
management, if clinically indicated. 
Procedures for treating symptoms and complications of immune-related adverse events (irAEs) 
are provided in the individual substudies. 
In the event of an overdose, the Investigator should: 
1. Contact the Sponsor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically (at least 3 months). 
3. Obtain a plasma sample for PK analysis right after the overdose event is identified (only if 
an overdose is identified within 5 days from start of overdose infusion). 
4. Document appropriately in the e-CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant. 
6.8 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements, or other specific categories of interest) that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial. If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from study intervention may be required. The 
Investigator is to discuss prohibited medication/vaccination with the Sponsor. The final decision 
on any supportive therapy or vaccination rests with the Investigator and/or the participant's 
primary physician. However, the decision to continue the participant on trial therapy schedule 
requires the mutual agreement of the Investigator, the Sponsor, and the participant. 
6.8.1 Acceptable concomitant medications 
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form (e-
CRF) including all prescription, OTC, herbal supplements, and IV medications and fluids. If 
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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 28 days before the first dose of trial treatment 
through the Follow-up Visit should be recorded. 
Colony-Stimulating Factors 
Routine use of colony-stimulating factors (CSFs) is not permitted. American Society of Clinical 
Oncology guidelines for use of CSFs should be followed (32).   
6.8.2 Prohibited concomitant medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Period of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol. 
• Immunotherapy not specified in this protocol. 
• Investigational agents other than specified in this protocol. 
• Radiotherapy for tumor control (please refer to Section 6.8.1 for allowed radiotherapy). 
• Live or live attenuated virus vaccines within 28 days prior to the first dose of trial 
treatment and while participating in the trial. Examples of live-virus vaccines include, but 
are not limited to, the following: measles, mumps, rubella, chickenpox, yellow fever, 
seasonal flu (seasonal flu vaccines that do not contain live virus are permitted), nasal 
H1N1 flu, rabies, Bacillus Calmette–Guérin (BCG), and typhoid. 
• Systemic glucocorticoids and other immunosuppressive therapies such as anti-TNF, anti-
IL6, etc, except for: 
- 
Use in premedication defined in the study protocol, 
- 
Treatment of immune-mediated AEs when indicated (irAE, CRS, ICANS, IRR, see 
details in the substudies),  
- 
Treatment of any life-threatening emergency, 
- 
Physiologic replacement as long as they are not being administered for 
immunosuppressive intent, and 
- 
A brief course (≤7 days) of systemic corticosteroid for prophylaxis (eg, contrast dye 
allergy) or for the treatment of non-autoimmune conditions (eg, delayed-type 
hypersensitivity reactions caused by contact allergen). 
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Participants who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. Participants 
may receive other medications that the Investigator deems to be medically necessary. 
The exclusion criteria describe other medications which are prohibited in this trial. 
There are no prohibited therapies during the Observation and Survival Follow-up Period. 
For withholding antihypertensive medications as part of hydration guidelines, please refer to 
Section 6.1.3. 
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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 participant to the 
patient’s participation in the procedure(s) involved in the research.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s wellbeing, such as:  
- 
Unacceptable AE. 
- 
Documented disease progression 
- 
 
- 
Poor compliance to the study protocol. 
- 
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 in the individual substudy and until resolution or stabilization of AE, and 
any other assessment as per SoA. Data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed are reported 
in the SoA. 
7.1.1.1 Unacceptable adverse events leading to permanent intervention discontinuation  
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in the dose modification and 
toxicity management guidelines (see individual substudy protocols), or if the Investigator believes 
that it is in best interest of the participant.  
If a clinically significant finding is identified after enrollment, the Investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the electrocardiogram (ECG) printed at the time 
of collection must be documented. Any new clinically relevant finding should be reported as an 
AE. 
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Any potentially clinically significant abnormal laboratory value or ECG parameter will be 
immediately rechecked for confirmation and repeated after 24 hours to document evolution before 
making a decision of permanent intervention discontinuation for the concerned participant. 
Decision criteria for discontinuation following immune-mediated AEs are described in the 
individual substudy (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 in the individual substudy for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent intervention discontinuation, the participants will be assessed 
using the procedure normally planned for the last dosing day with the IMP including a 
pharmacokinetics sample, if appropriate. Tumor assessment should be repeated if not done at the 
last cycle. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 10.9). For all temporary intervention discontinuations, 
duration should be recorded by the Investigator in the appropriate pages of the e-CRF.  
7.1.3 Rechallenge 
Re-initiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned adverse event was 
unlikely and if the selection criteria for the study are still met. 
Recommendations for rechallenge in the context of an epidemic/pandemic (eg, COVID-19) are 
included in Appendix 9 Contingency Measures for a regional or national emergency  
(Section 10.9) that is declared by a governmental agency.  
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
• A participant may withdraw from the study at any time at his/her own request (or at their 
legally authorized representative’s request), or may be withdrawn at any time at the 
discretion of the Investigator for safety, behavioral or compliance reasons. This is 
expected to be uncommon. 
• At the time of discontinuing from the study. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, or their legally authorized representative(s) no 
longer wish the participant to take it, 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 (or their legally authorized representative) may withdraw his/her consent 
to stop participating in the study. Withdrawal of consent for intervention should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-
participant contact follow-up, eg, medical record checks. The site should document any case of 
withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-included in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
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The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9). 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (refer to individual 
substudy). Protocol waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• During the screening period, demography, medical/surgical, and disease history will be 
evaluated. Demography includes age, gender, race, and ethnicity. Medical/surgical history 
includes relevant history of previous pathologies and smoking status. Disease history 
includes stage at diagnosis and at study entry, and previous anti-tumor therapy (type, 
duration, reason for discontinuation and response to the therapy). In addition, results of 
driver gene mutation are also to be collected. 
• A comprehensive medical history will be assessed for any cardiovascular signs or 
symptoms prior to treatment, along with a baseline ECG, echocardiography and troponin 
level. 
• Regular blood samples will be collected from each participant throughout the duration of 
the study. Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples. Details on blood sampling, including the estimated volume 
collected for each analysis are provided in the laboratory manual. 
•  For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Section 10.9. 
8.1 
EFFICACY ASSESSMENTS  
The assessment of anti-tumor activity documented by objective response or complete response to 
the IMP is the primary endpoint for this study and is conducted as per schedule provided in the 
SoA (refer to individual substudy). All participants treated must have relapsed or refractory 
disease.    
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. Tumor assessment using Lugano response criteria 2014 may be done at the 
discretion of the Investigator when clinically indicated. Please refer to Section 7.1.1 for details. 
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Investigators will obtain copies of the images and will provide them to repository facility 
identified by the Sponsor for potential central review. Study sites must retain tumor assessment 
images, as Sponsor may decide to collect these images for possible Independent Central Review 
in the future. 
Assessment of tumor response will be conducted using Lugano response criteria 2014 (see 
Section 10.8) according to the nature of the measurable lesions, as described below. 
8.1.1 Assessment of objective response using the most appropriate modality according 
to the nature of the measurable lesion(s) 
For participants with disease that is measured radiologically according to Lugano response criteria 
2014 (2) (Section 10.8), a PET-CT-based or CT-based criteria for tumor assessment will be 
performed as detailed in the individual substudy SOA.  
Baseline imaging should include all known target lesions. Baseline and follow-up 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 tumor imaging FDG-PET CT and/or MRI 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. FDG-PET must be performed for the 9-week and 18-week on-
treatment assessments. 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) until progressive disease (PD). Brain CT/MRI will be performed if clinically 
indicated. 
PET imaging is always required to confirm the first documented complete response (CR). If the 
first documented radiological CR is seen on CT scan only, a confirmatory PET scan (either FDG 
PET or PET-CT) should be obtained within 14 days to confirm that timepoint’s response of CR. If 
the PET scan is not obtained within 14 days, the timepoint must be assessed as a PR, and the next 
scan should be done by one of the 3 methods above as soon as possible to confirm the CR. Once 
CR has been established by PET imaging, subsequent CR and/or PD may be followed by CT 
imaging only. The CT component of the PET-CT may be used in lieu of a standalone CT/MRI, 
only if the CT component is of similar diagnostic quality as a contrast enhanced CT performed 
without PET. If contrast enhanced PET-CT with diagnostic CT is not available, a standard FDG-
PET must be performed, and a standalone diagnostic CT/MRI should be performed in addition to 
the FDG-PET scan. If independent CT and PET scanners are used, and the participant is receiving 
both scans on the same day, the PET must be performed prior to the CT with IV contrast so as to 
not compromise PET results. The PET-CT acquisition methodology (eg, administration of 
intravenous contrast) should remain consistent at all imaging visits for any given patient. 
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Bone marrow sample is mandated to confirm CR if bone marrow was involved by lymphoma or 
involvement is unknown prior to study treatment and as “clinically indicated” and “If bone 
marrow biopsy is not negative, a radiographic timepoint response (TPR) of CR at that time point 
would be downgraded to an overall PR”. 
Progressive disease (PD) by CT scan, with complete metabolic response (CMR) or partial 
metabolic response (PMR) by PET, should be reported as PD. Although the results of PET/CT are 
generally prioritized over CT, CT evidence of progressive disease cannot be discounted in the 
overall response assessment. Additionally, the Lugano PET/CT criteria for CMR and PMR 
require absence of new lesions. CT may, for example, reveal progressive disease in non-
measurable or non-FDG avid sites (eg, ascites, bony lesions, effusions, bowel lesions). Such cases 
should be reported as PD. Likewise, a CT finding of progressive disease, in the context of no 
metabolic response on PET, is to be considered overall disease progression, rather than stable 
disease. 
The findings of clinical (non-radiographic) progressive disease (PD) per Investigator should be 
considered PD: 
• Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
• If skin lesions are identified as a result of a physical exam, these are to be documented via 
the Lugano classification 2014 assessment as a physical exam, skin lesion. 
Skin lesions must be histologically confirmed for lymphoma involvement and photographed 
including a ruler (color photography using digital camera). Response assessment of skin lesions 
should be performed at baseline and at the time of each radiological assessment. 
Table 4 - Imaging or disease assessment collection plan 
Procedure 
Screening 
Post-administration assessment 
Bone marrow biopsy 
- 
As clinically indicated during the treatment period, EOT, and 
Follow-visit 1a 
Spleen measurement by PET-CT 
Mandated 
As clinically indicated during the treatment period, at EOT visit 
and Follow-up visit 1 
CT/MRI (chest, abdomen, pelvis 
and any other locations with 
suspicion or evidence of disease 
involvement) 
Mandated 
Every 9 weeks and if clinically indicated until Week 45, and 
every 12 weeks from Week 45 until progressive disease 
Brain imaging 
If clinically indicated 
- 
FDG-PET 
Mandated 
As clinically indicated during the treatment period, at EOT visit 
and Follow-up visit 1, and must be performed for the 9-week 
and 18-week on-treatment assessments. 
a A reported response of CR by CT, or CMR by FDG-PET, must be confirmed by a bone marrow assessment performed within 14 days of the 
assessment. 
 
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Response assessment is detailed in Table 7. 
8.2 
SAFETY ASSESSMENTS  
The main anticipated adverse effect for the monotherapy of SAR444245 or combination of 
SAR444245 with other anticancer therapies includes manifestations of cytokine release that can 
range from fever to hypoxia to hypotension, with or without manifestations that may include any 
of the organ systems. These mild events occur between around 12 to 18 hours after the first 
administration and a more intensive monitoring of vital signs is planned during that period. 
Targeted physical exams and standard laboratory tests will be conducted to monitor potential 
changes in the main body functions. Measurement of cytokines in plasma are planned at relevant 
timepoints. White blood cell differential count will be measured to monitor for transient 
lymphopenia which is commonly observed in the first few days following SAR444245 infusion. 
Eosinophilia that is surrogate to VLS will also be monitored. IL-5, which is also a marker of VLS, 
will be included in the PDy cytokine panel. Combining SAR444245 with other anticancer 
therapies may increase the frequency and severity of immune-related adverse events related to 
other anticancer therapies. Immune-mediated endocrinopathies involving the thyroid being the 
most frequent, T3, T4, TSH, and cortisol level will be monitored.  When clinically indicated, on-
treatment ECG, LVEF, and troponin will be assessed and compared to baseline. More details on 
the safety assessment are provided below. Planned time points for all safety assessments are 
provided in the individual substudy SoA.  
8.2.1 Physical examinations 
• A full physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, neurological, and skin systems. Height and weight will also 
be measured and recorded. 
• A directed physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Investigators should also pay attention to clinical signs suggestive of VLS, such 
as peripheral edema, pericardial effusion, and pleural effusion, as well as clinical signs 
suggestive of immune-related adverse events, such as pneumonitis, colitis, 
endocrinopathies, to name a few. Complementary assessments should be performed to 
establish the diagnosis when clinically indicated.  Early signs of cytokine release 
syndrome should also prompt a thorough clinical assessment to identify the involvement 
of a specific organ system, including neurological system. 
8.2.2 Vital signs 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• Vital signs including temperature, pulse rate, respiratory rate, and blood pressure will be 
measured after 5 minutes rest. 
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• 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 (to be measured at Pre-dose, 0.5 [±0.25], 1 [±0.25], 2 [±0.5], 4 [±0.5], 
8 [±0.5], 12 [±1], 16 [±1], 20 [±1], 24 [±1] hours after start of SAR444245 dose in an 
in-patient setting). 
8.2.3 Electrocardiograms and LVEF 
• Includes single 12-lead ECG, LVEF, and troponin that will be performed at screening and 
troponin at Cycle 4 Day 1, then, as clinically indicated. 
• 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 (such as troponin) and consultation with a cardiologist should be done when 
clinically indicated. 
• During treatment, or post treatment follow-up:  Troponin will be performed at Cycle 4 
Day 1. In case of a suspicion of a drug related cardiac event (eg, including signs/symptoms 
of cardiac disease, ECG and/or echo changes, troponin elevation, etc.), Investigators are 
encouraged to do ECG, echocardiography and/or cardiac biomarker tests, as medically 
indicated, including cardiology consultation. 
8.2.4 Clinical safety laboratory assessments 
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (refer to individual substudy) 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. 
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- 
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 individual substudy 
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 05 for pregnancy testing criteria; the Investigator is 
responsible for review of medical history, menstrual history, and recent sexual activity to 
decrease the risk for inclusion of a woman with an early undetected pregnancy 
• Women of childbearing potential must have a negative urine pregnancy test result within 
72 hours prior to first IMP administration of each cycle, at EOT and every 30 (±7) days 
until 120 days (or refer to the individual substudy protocol) 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 adverse event of special interest (AESI) is provided 
in Section 8.3.8 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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8.3.1 Time period and frequency for collecting AE and SAE information 
All AEs, including adverse events of new onset, as well as worsening of baseline signs and 
symptoms will be collected throughout study period, from the signing of the informed consent 
form (ICF) until 30 days following cessation of study treatment. 
All SAEs and AESIs will be collected throughout the study period, from the signing of the 
informed consent form (ICF) until 3 months following last administration of study treatment. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  At the pre-specified study end-date, all SAEs, and 
AESIs (as defined in Section 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 
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relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events (SAEs) that are considered expected will be specified in the 
reference safety information (IB for SAR444245).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, should be expedited to regulatory 
authorities. 
8.3.5 Pregnancy 
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until 120 days (or refer to the 
individual substudy protocol) following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates another anticancer therapy 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant /pregnant 
female partner and the neonate, and the information will be forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants /pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
8.3.6 Cardiovascular and death events 
Cardiovascular events that meet AESI criteria should be reported as such (see Section 8.3.8 for 
details). 
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8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment. The following events need to be reported as 
AESIs: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose of IMP is defined as: increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half 
the recommended duration of administration. 
- 
An overdose (accidental or intentional) with the NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug. 
• An elevated AST or ALT lab value that is greater than or equal to 3X the ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2X the ULN and, at the 
same time, an alkaline phosphatase lab value that is less than 2X the ULN, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory testing*. 
*Note:  These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be made available. It may also be appropriate to conduct additional 
evaluation for an underlying etiology in the setting of abnormalities of liver blood tests 
including AST, ALT, bilirubin, and alkaline phosphatase that do not meet the criteria noted 
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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 
- 
Any immune-related AE Grade ≥3 
- 
Arrhythmia Grade ≥3 
8.3.9 Guidelines for reporting product complaints 
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS 
The sampling time-points for PK and ADA for/against SAR444245 and/or other IMPs may be 
updated during the course of the study based on the updated knowledge of drug behavior upon 
notification from the Sponsor. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
in the laboratory manual. The actual date and time (24-hour clock time) of each sample will be 
recorded while for samples to be collected at time of biomarker sampling, no specific time on the 
given day is necessary. 
Instructions on the collection, processing, storage, and shipment of samples will be provided in 
the laboratory manual. Sample analysis will be performed at a laboratory designated by the 
Sponsor. 
Samples collected for analyses of SAR444245 concentration may also be used to evaluate safety 
or efficacy aspects related to concerns arising during or after the study and any remaining 
plasma/serum volume may also be used for further exploratory analysis if deemed relevant. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS 
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8.6 
BIOMARKERS 
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8.7 
IMMUNOGENICITY ASSESSMENTS 
The sampling time points for ADAs may be reduced or increased during the course of the study 
based on the updated knowledge of drug behavior and its immunogenicity, upon notification from 
the Sponsor. 
Samples for the immunogenicity assessment of SAR444245 will be collected according to the PK 
flowcharts in the individual substudy. Instructions for the collection and handling of biological 
samples will be provided by the Sponsor. Sample analysis will be performed at a laboratory 
designated by the Sponsor. 
Samples will be screened and then confirmed for anti-drug antibodies and the titer of confirmed 
positive samples will be reported. Additional analyses may be performed to further characterize 
the immunogenicity of SAR444245. 
Anti-drug antibody (ADA) samples remaining after determination of immunogenicity may be 
kept for possible exploratory analysis of biomarkers. The exploratory data will not be included in 
the study report but will be kept on file. 
8.8 
HEALTH ECONOMICS 
No health economics data will be collected. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
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9 
STATISTICAL CONSIDERATIONS 
Please refer to the individual substudy protocols for additional statistical considerations. 
9.1 
 STATISTICAL HYPOTHESES  
All cohorts of the study are designed to obtain antitumor activity, safety, PK, pharmacodynamic 
(PDy), and immunogenicity data on SAR444245 administered either in monotherapy or in 
combination.  
The study is designed to assess clinical benefit of SAR444245 with or without other anticancer 
therapies in adults and adolescents with relapsed or refractory B cell lymphoma. 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 with 6-10 participants from each cohort. 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 from their given cohort. 
Sample size: 
Number of participants to be enrolled in each cohort is described in the substudies.  
9.3 
POPULATIONS FOR ANALYSES 
The following populations for analyses are defined:  
Table 5 - Populations for analyses 
Population 
Description 
Exposed 
Exposed population will include all participants who have given their informed consent and received at least 
one dose (even incomplete) of IMP (SAR444245 or other anticancer therapies). 
Efficacy 
Efficacy population will include all participants from the exposed population with at least one evaluable post-
baseline tumor assessment or who permanently discontinued study treatment. 
DLT-evaluable 
DLT-evaluable population will include all participants in safety run-in part who have been treated and 
observed for DLT observation period (defined in the individual substudy). Any participants who have 
experienced a DLT during DLT observation period will also be DLT-evaluable. 
Pharmacokinetic (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 (biomarker) 
parameter assessed after the first dose of study intervention. 
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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 and key secondary 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. 
Objective response rate (ORR), CRR as well as all other efficacy variables will be derived using 
local radiologist’s/Investigator’s assessment for all cohorts according to Lugano response criteria 
2014. 
All safety analyses will be performed on the exposed population by cohort, by dose (if applicable) 
and overall (if applicable). A baseline value will be defined as the latest value or measurement 
taken up to the first administration of the IMP. 
The analysis period will be divided into 3 segments: 
• The pre-treatment period is defined as the time from when the participants give 
informed consent to the first administration of the IMP. 
• The on-treatment period (ie, treatment-emergent period) is defined as the time from the 
first administration of IMP up to 30 days after the last administration of IMP. 
• The post-treatment period is defined as the time from the 31 days after the last 
administration of IMP. 
9.4.2 Primary endpoint(s) 
Refer to individual substudy for details. 
9.4.3 Secondary endpoint(s) 
The secondary endpoints include efficacy (TTR, DoR, CBR, PFS), safety, immunogenicity, and PK. 
9.4.3.1 Time to Response (TTR) 
The TTR will be assessed on the subgroup of participants who have achieved objective response. 
Time to Response will be defined as the time from the first administration of IMP to the first 
documented evidence of PR or CR determined by Investigator per Lugano response criteria 2014. 
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9.4.3.2 Duration of response (DoR) 
The DoR will only be analyzed on the subgroup of participants who have achieved objective 
response. The DoR will be defined as the time from the date of first initial occurrence of the PR or 
CR 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 (CBR) 
The CBR is defined as the proportion of participants with clinical benefit (CR or PR as BOR, or 
SD lasting at least 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) determined by Investigator per Lugano 
response criteria 2014. 
9.4.3.4 Progression-free survival (PFS) 
For all cohorts, 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 cohort cut-off date for final analysis and 
prior to the initiation of a further anticancer therapy, then PFS will be censored at the date 
of the last valid tumor assessment performed before the cohort cut-off date for final 
analysis 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.  
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For participants with multiple occurrences of the same PT, the maximum grade will be used. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately. 
Treatment-emergent adverse events: 
An overall summary of TEAEs will be provided. The number and percentage of participants 
experiencing any of the following will be provided: 
• TEAEs. 
• TEAEs of Grade ≥3. 
• Grade 5 TEAE (any TEAE with a fatal outcome during the treatment-emergent period). 
• Serious TEAEs. 
• Serious treatment-related TEAEs. 
• TEAE leading to full intervention discontinuation. 
• TEAE leading to partial intervention discontinuation (for each individual drug, if 
applicable). 
• Treatment-related TEAEs. 
• Treatment-related TEAEs of Grade ≥3. 
Number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE v 5.0 grade (all grades and Grade ≥3). Missing grades, if any, will 
be included in "all grades" category. Similar summaries will be prepared for TEAEs related to 
SAR444245 and those related to each individual drug (if applicable), TEAEs leading to partial 
intervention discontinuation (if applicable), TEAEs leading to full intervention discontinuation, 
TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, AESIs, and 
AEs/SAEs occurring during the post-treatment period. In addition, the number (%) of participants 
with any Grade 5 AE (TEAE and post-treatment) will be summarized. 
The following deaths summaries will be generated: 
• Number and percentage of participants who died by study period (treatment-emergent 
period, post-treatment period) and reasons for death (disease progression, AE, or other 
reason). 
• All TEAEs leading to death by primary SOC and PT showing number and percentage (%) 
of participants. 
9.4.3.6 Clinical Laboratory evaluations 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
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Hematology and clinical chemistry results will be graded according to the NCI-CTCAE v 5.0, 
when applicable. Number and percentage of participants with laboratory abnormalities (all grades 
and by grade) using the worst grade during the treatment period will be provided for the exposed 
population. 
When the NCI-CTCAE v 5.0 grading scale is not applicable, the number of participants with 
laboratory abnormality out-of-normal laboratory range value will be displayed. 
For laboratory variables graded by NCI-CTCAE: 
• The number (%) of participants with abnormal laboratory tests at baseline will be 
presented by grade. 
• The number (%) of participants with abnormal laboratory tests during the treatment 
emergent period will be summarized by grade. When appropriate, the number (%) of 
participants with abnormality of any grade and with Grade 3-4 abnormalities will be 
provided. 
9.4.3.7 Other Secondary endpoints 
Immunogenicity analyses will be described in the SAP finalized before database lock. The PK 
analysis and pharmacodynamic analyses will be presented separately from the main clinical study 
report (CSR). 
Plasma concentrations of SAR444245 will be summarized with descriptive statistics. 
9.4.4 Tertiary/exploratory endpoint(s)  
9.4.4.1 Biomarker endpoints  
9.4.5 Other safety analysis 
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 analysis 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 . 
9.5 
INTERIM ANALYSES  
No formal interim analyses are planned. However, at the end of the safety run-in of each cohort, 
the occurrence of DLTs and other safety data will be reviewed by the Study Board to decide about 
continuation of the dose of SAR444245 24 µg/kg or reduced to 
 μg/kg or another lower dose 
level.   
For each cohort, in order to support project strategic planning and design of future studies, 
informal interim analysis(es) may be conducted during the study (eg, after half of the planned 
number of participants have undergone two post-baseline tumor assessment or have discontinued 
study treatment, whichever is earlier). 
In addition, the cumulative safety data for each study intervention across cohorts will be reviewed 
periodically by the independent DMC. The enrollment will not be paused or stopped during the 
safety monitoring unless severe safety concern arises. DMC will review safety data periodically. 
An ad hoc DMC meeting may also be held if a significant safety issue or an issue deemed 
important for discussion arises on this or other SAR444245 studies. Occurrence of any treatment 
related Grade 3 or higher AE (excluding lymphocyte count decrease) not resolving within 72 
hours in >25% of participants will trigger an ad hoc DMC. The DMC procedures will be detailed 
in the DMC charter and approved by the DMC members. 
The cohort cut-off for the primary endpoint analysis is in the individual substudy. 
After the cohort cut-off date for the primary 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 in the 
individual substudy. 
For each cohort, the cut-off date for the final analysis will be 3 years from cohort LPI. 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1.1 Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, 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 
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- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical 
validity.  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other 
individuals, eg, the finding relates to a communicable disease, Investigators 
should seek independent ethical advice before determining next steps. 
- 
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.  
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• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s).Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc.). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable.  
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9 (Appendix 9: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
10.1.4 Data protection 
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
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Participant race and ethnicity will be collected in this study because they are required by 
regulatory agencies (eg, on African American population for the FDA or on Japanese population 
for the Pharmaceuticals and Medical Devices Agency in Japan). They will not be collected in the 
countries where this is prohibited by local regulation.  
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure 
Data Monitoring Committee 
Independent from the Sponsor and Investigators, the DMC role will be to monitor the safety of the 
participants enrolled in the study (ie, exposed to study treatment and/or to study procedures) and 
to provide the Sponsor with appropriate recommendations in due time to ensure the safety of the 
participants. 
10.1.6 Dissemination of clinical study data 
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites for each 
completed substudy and final study results. This is based on company commitments, international 
and local legal and regulatory requirements, and other clinical trial disclosure commitments 
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established by pharmaceutical industry associations.  These websites include clinicaltrials.gov, 
EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
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 electronic CRF (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 case report form (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 
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report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents 
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the e-CRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 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 
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• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study or cohort is prematurely terminated or suspended, the Sponsor shall promptly inform 
the Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. He/she should also stop all 
screening activities pertaining to the study or the relevant cohort(s).  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 provided by the Sponsor until protocol 
defined treatment discontinuation criteria are met.  The patients who continue study treatment 
after early study termination should be followed for safety (ie, study treatment administrations, 
ongoing SAE/related AE, new related AE, AESI or SAE and their associated concomitant 
medications and lab if any) and end of treatment reason during this time period. 
10.1.10 
Publication policy 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
• The tests detailed in Table 6 will be performed by the local laboratory.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
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Table 6 - Protocol-required laboratory assessments 
 
Laboratory tests 
Parameters 
Hematologya 
Platelet count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
 
Clinical chemistrya 
Urea or blood urea nitrogen (BUN) 
 
Creatinine and eGFR (MDRD formulab) 
 
Glucose 
 
Potassium 
 
Sodium 
 
Corrected Calcium 
 
Phosphate 
 
Chloride 
 
Magnesium 
 
Bicarbonatec 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase  
 
Total and direct bilirubin 
 
Total protein 
 
Lactate dehydrogenase (LDH) 
 
Albumin 
 
Amylase  
 
Lipase 
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) 
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 
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B viral load, HCV RNA level, CD4 counts & HIV viral Loadf  
• 
Troponin 
• 
The results of each test must be entered into the e-CRF 
NOTES: 
a Blood Chemistry/hematology should be done with an overnight fasting if possible (should not interfere with hydration requirements). It will be 
performed weekly on D1 pre-dose, D8 and D15 (D15 for participants who receive Q3W only) during Cycle 1, then on Day 1 of every cycle up 
to Cycle 12, then every other cycle during Treatment Phase. Visits and assessments on C1D2-D3 will be performed for participants in the 
safety run-in or participants who are hospitalized because of high tumor burden or at Investigator’s discretion. 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. 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 120 days (or refer to the individual substudy protocol) 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 Section 10.7). 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
10.3.1 Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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  
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- 
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. 
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. 
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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) 
- 
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   
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The purpose of the seriousness criteria listed above is to guide regulatory reporting 
obligations by the Sponsor. The Sponsor is required to expedite serious unexpected 
adverse reactions to regulatory health authorities and Investigators. 
10.3.3 Recording and follow-up of AE and/or SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the e-CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE e-CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories as per NCI CTCAE V5.0 definitions (except 
for ICANS and CRS that will be graded using ASTCT criteria): 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)*. 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
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Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, if available the Investigator will provide the Sponsor’s representative with a copy 
of any post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
 
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10.3.4 Reporting of SAEs 
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator study file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator study file. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
10.4.1 Definitions 
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). A postmenopausal state is 
defined as the period of time after a woman has experienced no menses for 12 consecutive months 
without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
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their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 Contraception guidance  
Participants should be given advice about donation and cryopreservation of germ cells prior to the 
start of the study intervention, in line with the fact that study intervention may affect ova and 
sperm for up to the number of days specified respectively for each cohort in the inclusion criteria 
(see inclusion criteria I 04). 
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CONTRACEPTION GUIDANCE: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when used consistently and 
correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Intravaginal 
• 
Transdermal 
• 
Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Oral 
• 
Injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently 
and correctly. 
c If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited 
to those which inhibit ovulation as the primary mode of action. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Male condom and female condom should not be 
used together (due to risk of failure with friction). 
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COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant’s pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 
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10.5 
APPENDIX 5: GENETICS 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
France 
Section 5.1 Inclusion Criteria (Section 5.1): 
I 01. Participants must be ≥18 years of age, at the time of signing the informed consent. 
Section 5.2 Exclusion Criteria (Section 5.2) and Section 10.2 Clinical Laboratory tests 
(Section 10.2):  
In France, serology for HIV will be tested at screening. 
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10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Table 7 - Criteria for Response Assessment 
Response and Site 
PET-CT–Based Response 
CT-Based Response 
Complete 
 
 
Lymph nodes and 
extralymphatic sites 
 
 
 
 
 
 
 
 
 
 
 
Nonmeasured lesion 
 
Organ enlargement 
 
New lesions  
 
Bone marrow  
Complete metabolic response 
 
 
Score 1, 2, or 3 with or without a residual mass 
on 5PS† 
It is recognized that in Waldeyer’s ring or 
extranodal sites with high physiologic uptake or 
with activation within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater 
than surrounding normal tissue even if the tissue 
has high physiologic uptake 
 
Not applicable  
 
Not applicable  
 
None  
 
No evidence of FDG-avid disease in marrow 
Complete radiologic response (all of the 
following) 
 
Target nodes/nodal masses must regress 
to≤1.5 cm in LDi 
No extralymphatic sites of disease 
 
 
 
 
 
 
 
 
 
 
Absent  
 
Regress to normal  
 
None  
 
Normal by morphology; if indeterminate, IHC 
negative 
Partial  
Lymph nodes and 
extralymphatic sites 
 
 
 
 
 
 
 
 
Nonmeasured lesions  
 
Organ enlargement  
 
 
New lesions  
 
Bone marrow  
 
 
 
Partial metabolic response 
Score 4 or 5† with reduced uptake compared with 
baseline and residual mass(es) of any size 
At interim, these findings suggest responding 
disease 
 
At end of treatment, these findings indicate 
residual disease  
 
 
 
Not applicable  
 
Not applicable  
 
 
None 
 
Residual uptake higher than uptake in normal 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive changes 
from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the 
context of a nodal response, consideration 
Partial remission (all of the following) 
≥50% decrease in SPD of up to 6 target 
measurable nodes and extranodal sites 
When a lesion is too small to measure on 
CT, assign 5 mm X 5 mm as the default 
value 
When no longer visible, 0 X 0 mm 
For a node >5 mm X 5 mm, but smaller than 
normal, use actual measurement for 
calculation  
 
Absent/normal, regressed, but no increase  
 
Spleen must have regressed by>50% in 
length beyond normal  
 
None 
 
Not applicable 
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Response and Site 
PET-CT–Based Response 
CT-Based Response 
should be given to further evaluation with MRI or 
biopsy or an interval scan 
No response or stable 
disease  
 
Target nodes/nodal 
masses, extranodal 
lesions 
 
 
Nonmeasured lesions  
 
Organ enlargement  
 
New lesions 
 
Bone marrow  
No metabolic response  
 
 
Score 4 or 5 with no significant change in FDG 
uptake from baseline at interim or end of 
treatment 
 
 
Not applicable  
 
Not applicable  
 
None  
 
No change from baseline 
Stable disease 
 
 
<50% decrease from baseline in SPD of up 
to 6 dominant, measurable nodes and 
extranodal sites; no criteria for progressive 
disease are met 
 
No increase consistent with progression 
 
No increase consistent with progression 
 
None  
 
Not applicable 
Progressive disease  
 
 
Individual target 
nodes/nodal masses 
 
Extranodal lesions  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nonmeasured lesions  
 
 
New lesions  
 
 
 
 
 
 
 
 
Bone marrow  
Progressive metabolic disease 
 
 
Score 4 or 5 with an increase in intensity of 
uptake from baseline and/or  
 
New FDG-avid foci consistent with lymphoma at 
interim or end-of-treatment assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
None  
 
 
New FDG-avid foci consistent with lymphoma 
rather than another etiology (eg, infection, 
inflammation). If uncertain regarding etiology of 
new lesions, biopsy or interval scan may be 
considered  
 
 
 
 
New or recurrent FDG-avid foci 
Progressive disease requires at least 1 of the 
following 
 
PPD progression:  
 
 
An individual node/lesion must be abnormal 
with: 
LDi >1.5 cm and  
Increase by≥50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions≤2 cm  
1.0 cm for lesions>2 cm 
In the setting of splenomegaly, the splenic 
length must increase by>50% of the extent 
of its prior increase beyond baseline (eg, a 
15-cm spleen must increase to>16 cm). If no 
prior splenomegaly, must increase by at 
least 2 cm from baseline 
New or recurrent splenomegaly  
 
New or clear progression of preexisting 
nonmeasured lesions 
 
Regrowth of previously resolved lesions  
A new node >1.5 cm in any axis 
A new extranodal site>1.0 cm in any axis; 
if<1.0 cm in any axis, its presence must be 
unequivocal and must be attributable to 
lymphoma  
Assessable disease of any size 
unequivocally attributable to lymphoma 
 
New or recurrent involvement 
Abbreviations: 5PS, 5-point scale; CT, computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry; LDi, longest transverse 
diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography; PPD, cross product of the LDi and 
perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for multiple 
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Response and Site 
PET-CT–Based Response 
CT-Based Response 
lesions.  
*A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim scan. However, in 
trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as inadequate response (to avoid 
undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal masses, and extranodal lesions selected to be 
clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, 
cutaneous lesions, or those noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as truly assessable 
disease, which is any site of suspected disease that would be difficult to follow quantitatively with measurement, including pleural effusions, 
ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot be confirmed and followed by imaging. In 
Waldeyer’s ring or in extranodal sites (eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete 
metabolic response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors). 
†PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake>mediastinum but ≤ liver; 4, uptake moderately liver; 5, 
uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma. 
Source: Lugano Classification (2). 
 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below for an emergency that prevents access to the study 
site, to ensure the safety of the participants, to consider continuity of the clinical study conduct, 
protect trial integrity, and assist in maintaining compliance with Good Clinical Practice in 
Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, screening and enrollment of participants and administration of study intervention may 
be temporarily delayed (see also Section 7.1.2). 
10.9.1 Informed consent  
The participant or their legally authorized representative should be verbally informed prior to 
initiating any changes that are to be implemented for the duration of the emergency (eg. study 
visit delays/treatment extension, use of local labs). 
10.9.2 Study procedures  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  If onsite visits are possible and there is a need to reduce the time spent on site 
to a minimum, the focus should be on IMP infusion/administration, collection of safety 
information (vital signs, adverse events) and safety blood collection (mainly biochemistry, 
hematology and ADA, if planned for the visit). However, all efforts should be made to perform 
the measurements of key parameters for efficacy endpoints, namely CT/MRI scan and tumor 
tissue collection for this study. 
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If onsite visits are not possible due to a temporary disruption caused by an emergency, focus 
should be given to assessments necessary to ensure the safety of participants and those important 
to preserving the main scientific value of the study.   
• Remote visits (eg, with home nurses, home health vendor, etc.) may be planned for the 
collection of possible safety and/or efficacy data. 
• Visit windows may be extended for assessment of safety and/or efficacy data that cannot 
be obtained remotely.   
• Use of local clinic or laboratory locations may be allowed. 
10.9.3 Statistical analysis  
The impact of any regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
10.9.4 Temporary discontinuation  
Study intervention must be administered intravenously and at study site under the responsibility of 
the Investigator. Consequently, for participants who have started treatment but are unable to come 
to the site, administration of study intervention must be paused until regular study visits can be 
safely resumed at the study site.   
In the event of disruption of the clinical trial due to an epidemic/pandemic (eg COVID-19), 
reinitiation of IMP can only occur once the Investigator has determined, according to his/her best 
judgement, that the contribution of the IMP(s) to the occurrence of the epidemic event (eg. 
COVID-19) was unlikely. 
Contingencies implemented due to emergency will be documented. 
 
10.10 APPENDIX 10: RISK ASSESSMENT 
The information shown in Table 8 reflects the clinical safety data available at the time of 
Edition 4 of the SAR444245 IB. Please always refer to the latest version of the IB for the most up-
to-date safety data. 
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Table 8 - 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 IB.  
SAR444245 
Standard pre-medication 
Dose modification and treatment 
guidelines for SAR444245 
infusion-related reactions are provided in 
the individual substudy. 
Hypersensitivity, including 
anaphylaxis 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
No reports of anaphylaxis in the HAMMER 
study to date. 
Exclusion of participants with known 
hypersensitivity to or contraindication any 
components of SAR444245, PEG, or 
pegylated drugs.  
 
Infections 
SAR444245 
Nonclinical data do not indicate higher risk for 
infections. 
Adverse events of infections have been 
reported in the HAMMER study and are 
presented in the SAR444245 IB. 
 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function to 
be included. 
During treatment, regular hematology 
and biochemistry is examined. 
Signs and symptoms of infection are 
monitored as part of TEAE. 
Cytokine release syndrome 
SAR444245 
No major increases in cytokines have been 
reported in non-clinical toxicology studies. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
 
 
Study to be conducted at sites 
experienced with CRS management, with 
bed available in ICU. 
Premedication with paracetamol, 
diphenhydramine (or equivalent 
medications). 
Hydration guidelines, including 
management of anti-hypertensive 
treatment around the time of infusion, are 
provided. 
Extensive post-dosing monitoring will be 
performed. 
Dose modification and treatment 
guidelines are provided in the individual 
substudy. 
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 the individual 
substudy. 
Hematological/bone marrow toxicity 
SAR444245 
In 28-day repeat-dose study of 
IV SAR444245 in non-human primates, 
SAR444245-related changes in clinical 
Routine mitigation:  
Participants must have appropriate ANC 
and other organ/bone marrow function to 
be included. 
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pathology parameters were observed at all 
doses and were generally most prominent 
3 days following each dose. Changes in 
hematology parameters included decreased 
or attenuated reticulocytes followed by 
decreases in red blood cell (RBC) mass at 
 mg/kg/dose, and increased WBCs 
(lymphocytes and monocytes) and transiently 
mildly decreased platelets at 
 
mg/kg/dose. The increases in lymphocytes 
were attributed to the expected pharmacology 
of SAR444245 and correlated with the gross 
and microscopic findings of splenic and lymph 
node enlargement and increased lymphoid 
cellularity; there were no microscopic or 
clinical correlates for the decreases in 
platelets. 
Adverse events of bone marrow toxicity have 
been reported in the HAMMER study and are 
presented in the SAR444245 IB. Transient 
lymphopenia has also been observed. 
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 6.5.3 in the individual 
substudy). 
Hepatotoxicity 
SAR444245  
In 28-day repeat-dose study of IV 
SAR444245 in mice, males at  mg/kg/dose 
and females at  and  mg/kg/dose also had 
mild increases in AST and ALT activity that 
corresponded to a spectrum of microscopic 
findings in the liver including mononuclear cell 
infiltration, apoptosis, necrosis, mixed 
leukocyte inflammation, oval cell hyperplasia, 
and Kupffer cell hypertrophy. 
No such data are reported in 28-day 
Repeat-Dose Study of IV SAR444245 in non-
human primates. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB.  
Patients with significant impaired liver 
functions are excluded. 
Monitor clinical signs and symptoms of 
hepatic impairment as part of TEAE. 
Monitor liver function parameters (AST, 
ALT, bilirubin & ALP) regularly from 
screening and throughout the study. 
Dose modification and treatment 
guidelines for liver enzyme increase are 
provide under immune-related reactions 
in the individual substudy.  
 
Nephrotoxicity 
SAR444245 
There are no non-clinical data indicating a 
potential for nephrotoxicity. 
One relevant serious adverse event (SAE) 
considered related to SAR444245 (Acute 
Kidney Injury) has been reported in the 
HAMMER study within a monotherapy cohort. 
Participants must have appropriate 
eGFR to be included. 
Monitor renal function parameters 
(BUN/urea & creatinine) regularly from 
screening and throughout the study. 
Dose modification and treatment 
guidelines for nephrotoxicity are provide 
under immune-related reactions in the 
individual substudy.  
 
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. 
 
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Neurological AEs, including ICANS 
SAR444245 
Not observed in non-clinical toxicology 
studies. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
One SAE of CRS (Grade 4 with 24 ug/kg 
monotherapy) associated with neurological 
manifestations [hypertension, chills/rigors, 
flushing, fever (maximum 
temperature: 102.8°F), as well as 
neurological symptomatology (loss of ability 
to follow commands, confusion, aphasia, and 
involuntary fist clinching)] was reported in the 
HAMMER study. The event resolved 
completely within 30 to 60 minutes after 
treatment with tocilizumab and steroid. This 
patient later discontinued the study. 
Exclusion of participants with 
lymphomatous involvement of the central 
nervous system.  
Guidelines for the management of 
ICANS are provided in individual 
substudies. 
Cardiovascular effects, including QT 
interval prolongation 
SAR444245 
In 28-day repeat-dose study of 
IV SAR444245 in non-human primates, there 
were no SAR444245-related changes to the 
PR or QRS intervals or the heart rate (HR) 
corrected QTca interval. There was a 
SAR444245-related, dose dependent, 
non-adverse higher HR at doses of 
≥
 mg/kg/dose beginning on Day 1 
compared to the control dose group and 
persisting through each respective dose 
following applicable telemetry recording 
sessions, with recovery. There was also an 
expected physiologic inverse relationship in 
the respiration rate (RR) intervals as well as 
the raw QT intervals, which correlated to the 
changes in HR, and were also considered to 
be non-adverse. There were increases in 
individual females of troponin I minimal post 
first dose. There were marked decreases in 
females and males.  
These changes correlated with findings of 
mononuclear cell infiltrates and/or myocardial 
degeneration. All changes however, 
recovered by the end of a 28 day or 42/44 
day treatment free period. 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB.  
Routine mitigation:  
Selection of qualified investigative 
centers with availability of intensive 
critical care/equipment. 
Exclusion of patients with severe or 
unstable cardiac condition within 
6 months prior to starting study 
treatment, see E10 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 hospitalization in safety 
run-in. For subsequent cycles, monitoring 
will depend on site assessment of 
participant’s symptoms. 
Immune-mediated Adverse Events 
SAR444245 
A minority of patients in the HAMMER study 
have reported such AE as detailed in the IB. 
 
Exclusion of participants with: 
Active, known, or suspected autoimmune 
disease that has required systemic 
treatment in the past 2 years (ie, with use 
of disease modifying agents, 
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corticosteroids or immunosuppressive 
drugs), except controlled by replacement 
therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement 
therapy for adrenal or pituitary 
insufficiency, etc). 
Close monitoring for endocrine 
abnormalities and other potentially 
autoimmune phenomena will be 
performed.  
Dose modification and treatment 
guidelines for under immune-related 
reactions are provided in the individual 
substudy. 
Risks related to special 
populations 
 
 
Pregnancy and lactation exposure 
and outcomes 
SAR444245 
No studies have been conducted with 
SAR444245 on fertility or general 
reproductive performance. 
 
Exclusion of participants who are 
pregnant or breastfeeding or expecting to 
conceive or father children within the 
projected duration of the trial as per 
inclusion criterion I05. 
Guidance on highly effective 
contraceptive methods is provided in the 
protocol. Pregnancy tests are to be 
performed regularly as described 
in Section 8.2.5. 
Use in children 
The safety and efficacy of the study 
interventions in children below 18 years of 
age have not yet been established. 
 
Participants over 75 years of age 
SAR444245 
At this stage of development, no safety data 
are available for this population. 
No specific mitigation strategy for this 
population. 
Clinically significant medication 
errors 
With the increased complexity of the design 
of oncology clinical trials, medication errors 
need to be considered. Although their 
occurrence is estimated to be low (eg, 
chemotherapy errors occur at a rate of about 
one to four per 1000 orders), their impact may 
be high. According to the report on 
medication safety in cancer clinical trials, the 
processes in which the errors originated were 
prescribing (47%), administering (10%), 
dispensing (6%), and monitoring (5%). 
Prescribing errors typically arise from not 
following an institutional procedure or the 
protocol (39%, most likely due to the protocol 
procedures differing from existing standards 
of care), followed by the written order (30%), 
and poor communication involving both the 
healthcare team and the patient (26%) 
Strict adherence to the protocol. 
Adequate and verified training of staff at 
investigational sites. 
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(33,34,35). 
Overdose and its treatment 
There is no specific antidote for overdose with 
SAR444245. 
 
Strict adherence to the protocol; 
Adequate and verified training of staff at 
investigational sites. 
See Section 6.7 
Study procedures 
Biopsies of tumor tissue are 
expected during the trial. 
 
Strict adherence to the guidance in the 
protocol 
 
10.11 APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS  
Table 9 - Encephalopathy assessment ICE tool for ICANS Grading  
Immune Effector Cell-Associated Encephalopathy 
(ICE) Assessment 
Number of points 
Orientation: Orientation to year, month, city, hospital 
4 points 
Naming: ability to name 3 objects (eg, point to clock, pen, button) 
3 points 
Following commands: ability to follow simple commands (eg, “Show 
me 2 fingers” or “Close your eyes and stick out your tongue”) 
1 point 
Writing: ability to write a standard sentence (eg, “Our national bird is 
the bald eagle”) 
1 point 
Attention: ability to count backwards from 100 by 10  
1 point 
Source: (1). 
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Table 10 - ASTCT ICANS consensus grading for adults  
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE scorea 
7-9 
3-6 
0-2 
0 (participant is unrousable and unable 
to perform ICE). 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to tactile 
stimulus 
Participant is unarousable or requires 
vigorous or repetitive tactile stimuli to 
arouse. Stupor or coma. 
Seizure 
N/A  
N/A  
Any clinical seizure 
focal or generalized that 
resolves rapidly or 
nonconvulsive seizures 
on EEG that resolve 
with intervention. 
Life-threatening prolonged seizure (>5 
min); or Repetitive clinical or electrical 
seizures without return to baseline in 
between. 
Motor findingsc 
N/A  
N/A  
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis. 
Elevated ICP cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimagingd 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or 
Cranial nerve VI palsy; or Papilledema; or 
Cushing’s triad. 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised ICP/cerebral edema) 
not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. 
a A patient with an ICE score of 0 may be classified as Grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may 
be classified as Grade 4 ICANS if unrousable. 
b Depressed level of consciousness should be attributable to no other cause (eg, no sedating medications). 
c Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE V5.0, but they do not influence 
ICANS grading. 
d Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It 
may be graded according to CTCAE V5.0.  
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; CTCAE = Common Terminology Criteria for Adverse Events; 
EEG = Electroencephalogram; ICANS = Immune effector cell-associated neurotoxicity syndrome; ICE = Immune Effector Cell-Associated 
Encephalopathy; ICP = Intracranial pressure;  
N/A = Not applicable. 
Source: (1). 
Table 11 - ASTCT ICANS consensus grading for children  
Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score for children 
age > 12 yearsa 
7-9 
3-6 
0-2 
0 (participant is unrousable and unable 
to perform ICE). 
CAPD score for 
children age < 12 
years 
1-8 
1-8 
≥9 
Unable to perform CAPD 
Depressed level of 
consciousnessb 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to tactile 
stimulus 
Unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. 
Stupor or coma. 
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Neurotoxicity 
domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Seizure (any age) 
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 weakness (any 
age)c 
N/A  
N/A  
N/A 
Deep focal motor weakness such as 
hemiparesis or paraparesis. 
Elevated ICP/ cerebral 
edema (any age) 
N/A 
N/A 
Focal/local edema on 
neuroimagingd 
Decerebrate or decorticate posturing, 
cranial nerve VI palsy, papilledema, 
Cushing's triad, or signs of diffuse 
cerebral edema on neuroimaging 
ICANS grade is determined by the most severe event (ICE or CAPD score, level of consciousness, seizure, motor findings, raised ICP/cerebral 
edema) not attributable to any other cause. Baseline CAPD score should be considered before attributing to 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: (1). 
Table 12 - 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: (1) 
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10.12 APPENDIX 12 GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS SYNDROME 
(TLS) 
TLS is a metabolic derangement that is the result of rapid destruction of tumor cells. TLS is 
common in hematological malignancies and can cause several side effects; some of them may 
become life-threatening. Early recognition of TLS and initiation of therapy is essential.  
Intravenous hydration is recommended for all participants prior to start of SAR444245 infusions 
and is left to Investigator judgment for further cycles.  
The participants at greatest risk of TLS are those with a high tumor burden prior to treatment. 
These patients should be monitored closely, and appropriate precautions should be taken (such as 
use of prophylactic uric acid lowering agents (eg, allopurinol or rasburicase) and regular 
measurement of electrolytes.  
This appendix provides parameters to be checked in case of TLS suspicion and recommendations 
for TLS management. Abnormalities listed in this appendix do not exclusively support TLS 
diagnosis and any differential diagnosis also needs to be assessed, if appropriate.  
TLS may present with laboratory parameters changes, clinical manifestations, or both as indicated 
in Table 13. 
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Table 13 - Tumor lysis syndrome definitions   
 
 
For participants in the safety run-in or participants who are hospitalized because of high tumor 
burden or at Investigator’s discretion, tumor lysis laboratory tests (corrected calcium, magnesium, 
phosphate, uric acid, and lactate dehydrogenase [LDH] levels) will be obtained per details 
provided in the individual substudy).  
Cardiac monitoring and admission to the ICU is required if TLS is established, as well as 
continuing laboratory monitoring every 4-6 hours. Additional measures to treat metabolic 
derangements associated with TLS may be required, as shown in Table 14. 
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Prophylaxis against TLS may be required depending on the patient’s risk for TLS, as described 
below.  
Low-risk is defined as: 
- 
Patients with low tumor burden (WBC ≤ 50 x 109/l and normal LDH level) 
- 
Patients receiving low intensity cytoreductive therapy 
- 
Normal pre-existing uric acid 
- 
Adequate hydration 
- 
No tumor infiltration in the kidney 
High-risk is defined as: 
- 
Hematological malignancies with high proliferative rate 
- 
High tumor burden (WBC ≥ 50 x 109/l and high LDH level) 
- 
Elevated uric acid level 
- 
Patients receiving intensive cytoreductive therapy 
- 
Poor hydration 
- 
Leukemia infiltration of the kidney 
Recommendations for intravenous hydration during SAR444245 treatment in patients at high 
risk for TLS, include the following: 
-
 
For high risk patients, prophylactic treatment with allopurinol should begin 2 to 3 days before the 
start of antineoplastic therapy and continue for 10 to 14 days, as described in Table 15. 
Rasburicase is indicated for patients with the following features: 
- 
High-risk of TLS development 
- 
Urgent need to initiate therapy in a patient with a high bulk of malignant disease 
- 
In a situation where adequate hydration may be difficult or impossible 
- 
Acute renal failure 
The dose for rasburicase is indicated in Table 15. Redosing must be individualized.  
Recommendations regarding the selection of allopurinol and/or rasburicase are summarized in 
Table 16. 
 
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Table 14 - Specific recommendations for treatment of TLS  
 
 
Hyperphosphatemia: ≥ 2.1 mmol/L 
Removing phosphates from i.v. solutions 
Oral phosphate binders: e.g. aluminum hydroxide orally at 50-
150 mg/kg/24 h q6h 
Peritoneal dialysis, hemodialysis or continuous venovenous 
hemofiltration may be required in a case of severe 
hyperphosphatemia. 
Calcium infusion is prohibited! 
Hypocalcemia: ≤ 1.75 mmol/L (serum) or ionized calcium is ≤ 
of ionized local limit 
Treatment not required if asymptomatic. 
Symptomatic hypocalcemia (muscle cramps and spasms, 
paresthesias, arrhythmias, heart block, hypotension, confusion, 
delirium, hallucination, seizures) requires treatment: 
Calcium gluconate 50 – 100 mg/kg/dose i.v. 
Hyperkalemia 
Moderate and asymptomatic (≥ 6.0 mmol/L): 
Avoid i.v. and oral potassium 
ECG and cardiac rhythm monitoring 
Sodium polystyrene sulphonate 1 g/kg with 50 % 
sorbitol po or per rectum 
Severe (>7.0 mmol/L) and/or symptomatic 
Same as above, plus 
      Calcium gluconate (100–200 mg/kg) i.v. and/or 
              Regular insulin (0.1 unit/kg i.v.) + D25 (2 mL/kg) i.v. 
Dialysis 
Renal dysfunction (uremia)  
 
Fluid and electrolyte management 
Uric acid and phosphate management 
Adjust renally excreted drug doses 
Dialysis (hemo- or peritoneal) 
Hemofiltration (CAVH, CVVH, CAVHD or CVVHD) 
 
Hyperuricemia:  
uric acid ≥ 476 mcmol/L 
See Table 15 and Table 16 regarding selection and dose of 
hypouricemic agents: 
Allopurinol 
Rasburicase (recombinant urate oxidase). 
 
 
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Table 15 - Recommendations on the use of hypouricemic agents 
Allopurinol 
100 mg/m2/dose q8 h (10 mg/kg/d divided q8 h) p.o. 
(maximum 800 mg/d) or 200–400 mg/m2/d in 1–3 divided doses i.v. (maximum 600 mg/d) 
Reduce dose by 50% or more in renal failure  
Reduce 6-mercaptopurine and/or azathioprine doses by 65–75% with concomitant allopurinol 
Adjust doses of drugs metabolized by P450 hepatic microsomal enzymes with concomitant allopurinol 
Rasburicase 
Avoid in glucose-6-phosphate dehydrogenase deficient patients. 
Immediate and permanent stop of treatment if methemoglobinemia is result.  
0.05–0.20 mg/kg i.v. over 30 min 
To measure uric acid levels place blood sample immediately on ice to avoid continual pharmacological ex vivo enzymatic 
degradation. 
10% incidence of antibody formation. 
 
Table 16 - Recommendations on selection of hypouricemic agents  
 
Allopurinol 
Rasburicase 
Uric acid level 
Normal 
Elevated 
Tumor type 
Non-hematological 
Hodgkin’s lymphoma, 
CML 
Burkitt’s lymphoma, 
lymphoblastic 
lymphoma, ALL, AML 
Tumor burden 
WBC count 
≤50 · 109/L 
>50 · 109/L 
LDH 
≤ 2· normal 
>2 · normal 
Cytoreductive 
intensity 
Mild 
Aggressive 
Kidney tumor 
infiltration 
Absent 
Present 
 
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10.13 APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE 
Table 17 - ECOG PERFORMANCE STATUS 
 Grade  
ECOG  
0  
Fully active, able to carry on all pre-disease performance 
without restriction  
1  
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
house work, office work  
2  
Ambulatory and capable of all selfcare but unable to carry out 
any work activities. Up and about more than 50% of waking 
hours  
3  
Capable of only limited selfcare, confined to bed or chair more 
than 50% of waking hours  
4  
Completely disabled. Cannot carry on any selfcare. Totally 
confined to bed or chair  
5  
Dead  
Source: (36). 
 
Table 18 - Lansky Play/Performance Status 
A. Normal range of play 
Able to carry on usual play activities both active and quiet; child initiates play; no special adult assistance or direction 
needed; participation in interactive play 
 
• 
100 Fully active 
• 
90   Minor restrictions in physically strenuous play 
• 
80   Restricted in physically strenuous play (eg. chasing games); may tire more easily, otherwise active 
B. Mild to moderate restriction of play 
Able to engage in some active play, but spends greater than usual time in quiet play; requires varying degree of 
assistance in setting up and completing play; restricted in interactive play 
 
• 
70   Both greater restriction of, and less time spent in, active play 
• 
60   Ambulatory 50% of time; limited active play with adult assistance, supervision 
• 
50   Considerable adult assistance required for any active play; fully able to engage in quiet play (set up games, turn     
on TV, etc.) 
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A. Normal range of play 
Able to carry on usual play activities both active and quiet; child initiates play; no special adult assistance or direction 
needed; participation in interactive play 
 
• 
100 Fully active 
• 
90   Minor restrictions in physically strenuous play 
• 
80   Restricted in physically strenuous play (eg. chasing games); may tire more easily, otherwise active 
C. Moderate to severe restriction of play 
No active play; play limited to quiet activities; requires varying degree of assistance for quiet play 
 
• 
40   Able to initiate most quiet activities 
• 
30   Needs considerable assistance even for quiet activities 
• 
20   Play entirely limited to very passive activities initiated by other (eg. TV) 
• 
10   Completely disabled, no play  
• 
0     Unresponsive 
Source: (37). 
For participants < 16 years old. 
10.14 APPENDIX 14: DEFINITION OF LINE OF THERAPY 
One line of therapeutic regimen is defined as a composite of one or several treatment modalities 
(may include transplantation, radiotherapy and/or drug[s]) instituted based on the results of a 
restaging exam. 
If a regimen is composed of several drugs and one of the drugs is stopped for any reason, the 
regimen must be considered as ongoing until the entire regimen is stopped due to any reason. 
If a new line of therapy is instituted based on the results of a restaging exam, it is usually 
considered a distinct line of therapy (38). 
10.15 APPENDIX 15: ABBREVIATIONS 
 
ADA: 
anti-drug antibody 
ADL: 
activities of daily living 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
aPTT: 
activated Partial Thromboplastin Time 
AST: 
aspartate aminotranferase 
ASTCT: 
American Society for Transplantation and Cellular Therapy 
CBR: 
clinical benefit rate 
cHL: 
classic Hodgkin lymphoma 
CI: 
confidence interval 
CLS: 
capillary leak syndrome 
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COVID-19: 
Corona Virus Disease 2019 
CR: 
complete response 
CRS: 
cytokine release syndrome 
DLBCL: 
diffuse large B cell lymphoma 
DLT: 
dose-limiting toxicity 
DMC: 
Data Monitoring Committee 
DoR: 
duration of response 
ECOG: 
Eastern Cooperative Oncology Group 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end of treatment 
IB: 
Investigator’s brochure 
ICANS: 
immune cell-associated neurotoxicity syndrome 
ICF: 
informed consent form 
IHC: 
immunohistochemistry 
IL-2: 
interleukin 2 
IMP: 
investigational medicinal product 
INR: 
International Normalized Ratio 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
IV: 
intravenous 
MCP-1: 
monocyte chemoattractant protein-1 
MTD: 
maximum tolerated dose 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHP: 
non-human primate 
NIMP: 
non-investigational medicinal product 
NK: 
natural killer 
NSCLC: 
non-small cell lung cancer 
PD: 
progressive disease 
PD-L1: 
programmed death-ligand 1 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PMBCL: 
primary mediastinal large B cell lymphoma 
PO: 
oral route 
PR: 
partial response 
pRBC: 
packed red blood cell 
Q2W: 
every 2 weeks 
Q3W: 
every 3 weeks 
RCC: 
renal cell carcinoma 
RP2D: 
recommended Phase 2 dose 
SAE: 
serious adverse event 
SARS-CoV-2: 
severe acute respiratory syndrome coronavirus 2 
SB: 
Study Board 
SUSAR: 
suspected unexpected serious adverse reaction 
TLS: 
tumor lysis syndrome 
TRAE: 
treatment-related adverse event 
TRR: 
time to response 
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ULN: 
upper limit of normal 
VLS: 
vascular leak syndrome 
WOCBP: 
woman of childbearing potential 
 
10.16 APPENDIX 16: PROTOCOL AMENDMENT HISTORY 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
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11. Lopez A, Gutierrez A, Palacios A, Blancas I, Navarrete M, Morey M, et al. GEMOX-R 
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18. Gluck WL, Hurst D, Yuen A, Levine AM, Dayton MA, Gockerman JP, et al. Phase I Studies 
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19. Khan KD, Emmanouilides C, Benson DM Jr, Hurst D, Garcia P, Michelson G, et al. A Phase 
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20. Boni V, Winer IS, Gilbert L, Vaishampayan UN, Rosen SD, Muzaffar J, et al. ARTISTRY-1: 
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Inc.; 2011. [revised 2012 Jul; cited 2020 Oct 07]. Available from: 
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22. Van Gool F, Molofsky AB, Morar MM, Rosenzwajg M, Liang HE, Klatzmann D, et al. 
Interleukin-5-producing group 2 innate lymphoid cells control eosinophilia induced by 
interleukin-2 therapy. Blood. 2014;124(24):3572-6. 
23. Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, et al. A 
First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rßγ-Biased 
Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discov. 
2019;9(6):711-21. 
24. Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, et al. 
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: 
Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). 
Cancer Discov. 2020;10(8):1158-73. 
25. Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. American society 
of clinical oncology 2007 clinical practice guideline update on the role of bisphosphonates in 
multiple myeloma. J Clin Oncol. 2007;25(17):2464-72. 
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SARS-CoV-2 pandemic in persons with lymphoma. J Cancer Res Clin Oncol. 2021;147(5): 
1469-1479. 
27. Bachanova V, Bishop MR, Dahi P, Dholaria B, Grupp SA, Hayes-Lattin B, et al. Chimeric 
Antigen Receptor T Cell Therapy During the COVID-19 Pandemic. Biol Blood Marrow 
Transplant. 2020;26(7):1239-46. 
28. Di Ciaccio P, McCaughan G, Trotman J, Ho PJ, Cheah CY, Gangatharan S, et al. Australian 
and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic 
leukaemia and myeloma during the COVID-19 pandemic. Intern Med J. 2020;50(6):667-79. 
29. Weinkove R, McQuilten ZK, Adler J, Agar MR, Blyth E, Cheng AC, et al. Managing 
haematology and oncology patients during the COVID-19 pandemic: interim consensus 
guidance. Med J Aust. 2020;212(10):481-9. 
30. ASCO. COVID-19 Patient Care Information. [Online]. [cited 2020 Dec 11]. Available from: 
URL:https://www.asco.org/asco-coronavirus-information/care-individuals-cancer-during-
covid-19. 
31. ESMO. COVID-19 AND CANCER. [Online]. [cited 2020 Dec 11]. Available from: 
URL:https://www.esmo.org/covid-19-and-cancer 
32. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations 
for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice 
Guideline Update. J Clin Oncol. 2015;33(28):3199-212. 
33. Moon JY, Lee Y, Han JM, Lee MH, Yee J, Song KM, et al. Effects of pharmacist 
interventions on reducing prescribing errors of investigational drugs in oncology clinical trials. 
J Oncol Pharm Pract. 2020;26(1):29-35. 
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34. Weingart SN, Zhang L, Sweeney M, Hassett M. Chemotherapy medication errors. Lancet 
Oncol. 2018;19(4):e191-9. 
35. Kyle RA, Yee GC, Somerfield MR, Flynn PJ, Halabi S, Jagannath S, et al. American society 
of clinical oncology 2007 clinical practice guideline update on the role of bisphosphonates in 
multiple myeloma. J Clin Oncol. 2007;25(17):2464-72.  
36. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
37. Lansky LL, List MA, Lansky SB, Cohen ME, Sinks LF. Toward the Development of a Play 
Performance Scale for Children (PPSC). Cancer. 1985;56(7 Suppl):1837-40. 
38. CIBMTR Forms Manual: Appendix T Pre-HCT Treatment for Hodgkin’s / Non-Hodgkin’s 
Lymphoma.  A00565 version 1. [Cited 09 Mar 2022]. 
https://www.cibmtr.org/DATAMANAGEMENT/TRAININGREFERENCE/MANUALS/DA
TAMANAGEMENT/DOCUMENTS/APPENDIX%20T_PRE-
HCT%20TREATMENT%20FOR%20LYMPHOMA.PDF) 
  
 
 
 
 
 
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According to Template: Sanofi OneDocument Version 5.0, dated 28-JAN-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 01)  
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) combined with pembrolizumab 
for the treatment of adults and adolescents with 
relapsed or refractory classic Hodgkin lymphoma 
Protocol number: 
ACT16941-S01 
Amendment number: 
01 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable)  
Brief title: 
A study of SAR444245 combined with pembrolizumab for the 
treatment of adults and adolescents with cHL 
   
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: 
156112 
EudraCT: 
2021-002150-91 
NCT: 
NCT05179603 
WHO: 
U1111-1251-5834 
 
Date: 
28-Apr-2022 
Total number of pages: 67 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 01 
(Substudy 01) 
All 
28 April 2022, version 1 
(electronic 1.0) 
Clinical Trial Protocol (Substudy 01) 
16 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 01 (28 April 2022) 
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 
In response to the requests from the French Health Authority (National Agency for the Safety of 
Medicines and Health Products [ANSM]) after initial review. Other changes have been made for 
clarification, accuracy, and correction. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover page 
The NCT number has been added. 
This study has been registered on 
clinicaltrials.gov, the NCT number is 
applicable. 
1.2 Schema 
The Graphical study design for Cohort A has been 
updated with the instruction for FDG-PET. 
For clarity and consistency. 
1.3 Schedule of 
activities (SOA) 
The assessment of troponin level has been 
added. 
For footnote “d”, the following sentence 
“Information on the first subsequent anticancer 
treatment, best reported response, and date of 
progression will also be collected.” has been 
deleted. 
To allow assessment of any potential 
cardiotoxicity. 
Reduction in protocol complexity and 
patient/site burden. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Footnote “e” has been newly added for 
clarification on C1D2, D3 visits. The subsequent 
footnotes are re-numbered accordingly. 
Footnote “f” for blood draws and/or tumor biopsy 
for biomarker assessment has been removed and 
changed to “Study Board may decide to cancel 
safety assessment on C1D15, upon agreement 
with Sponsor, if safety data justifies it.” The 
reference to the footnote “f” has been deleted at 
C1D8 in the SOA. 
For footnote “i” (previous footnote h), tumor lysis 
laboratory tests on C1D1 have been changed 
from “for all participants” to “for safety run-in 
participants or participants who are hospitalized”. 
For clarity. 
                  
To make operational procedures easier. 
 
 
 
For clarity. 
1.3 Schedule of 
Activities (SOA), 
10.7 Appendix 7: 
Country-Specific 
Requirements 
Requirement of human immunodeficiency virus 
(HIV) has been added at screening for participants 
in France and specified in SOA newly added 
footnote “m” and country-specific requirements 
sections. 
Regulatory Authority (ANSM) request. 
1.4 Biomarker 
flowcharts 
1.5 Pharmacokinetic 
flowcharts 
PK sample collection on Cycle 1 D15 has been 
changed to “D8”. 
To align with participants’ visit. 
5.1 Exclusion criteria 
E02 “Has undergone prior allogeneic 
hematopoietic stem cell transplantation within the 
last 5 years.  (Participants who have had a 
transplant greater than 5 years ago are eligible as 
long as there are no symptoms of graft-versus-
host disease [GVHD]).” has been added from the 
master protocol (E24). 
For clarity. 
6.5.4.3 Fever, flu-like 
symptoms and 
cytokine-release 
syndrome (CRS); 
6.5.4.5 Immune cell-
associated neurotoxicity 
syndrome (ICANS) 
The following statement “alternative therapies per 
site practice in CRS management” has been 
added to “tocilizumab”. 
For flexibility following tocilizumab availability. 
 
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome 
(CRS) 
In Table 5, the following sentence has been 
deleted 
i
.” 
For consistency with instructions given in 
Section 6.5.1 General rules. 
Regulatory Authority (ANSM) request. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
6.5.4.7 Tumor Lysis 
Syndrome (TLS) 
Tumor lysis laboratory tests on C1D1 have been 
changed from “for all participants” to “for safety 
run-in participants or participants who are 
hospitalized”. 
For clarity and consistency. 
10.1.6 Dissemination of 
clinical study data 
The following texts has been added “Study 
participants results summaries will be provided in 
any one of the clinical trial portals after completion 
of the substudy, until the end of study”.   
Per CTFG guidance 2019: Recommendation 
Paper on the Initiation and Conduct of 
Complex Clinical Trials. 
Throughout 
“Study Committee” has been changed to “Study 
Board”.  
Harmonization per Sanofi standard 
terminology. 
Throughout 
Minor editorial updates. 
For clarity and consistency. 
 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 01) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.2.1 
Study design for Cohort A .............................................................................................................. 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
1.4 
BIOMARKER FLOWCHARTS ....................................................................................................... 25 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 26 
2 
INTRODUCTION ............................................................................................................................ 27 
2.1 
STUDY RATIONALE...................................................................................................................... 27 
2.2 
BACKGROUND ............................................................................................................................. 27 
2.2.1 
Pembrolizumab .............................................................................................................................. 27 
2.2.1.1 
Pharmaceutical and therapeutic background ................................................................................ 27 
2.2.1.2 
Pre-clinical trials ............................................................................................................................. 28 
2.2.2 
Rationale for B cell lymphoma and selected participant population .............................................. 29 
2.2.3 
Current standard of care in classic Hodgkin lymphoma ................................................................ 29 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Risk assessment ............................................................................................................................ 29 
2.3.1.1 
Pembrolizumab .............................................................................................................................. 29 
2.3.1.2 
SAR444245 combined with pembrolizumab .................................................................................. 30 
2.3.2 
Benefit assessment ........................................................................................................................ 31 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 31 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 32 
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3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 32 
4 
STUDY DESIGN ............................................................................................................................ 33 
4.1 
OVERALL DESIGN ........................................................................................................................ 33 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 33 
4.2.1 
Participant input into design ........................................................................................................... 33 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 34 
4.3.1 
SAR444245 dose ........................................................................................................................... 34 
4.3.2 
Pembrolizumab dose ..................................................................................................................... 34 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 35 
5 
STUDY POPULATION .................................................................................................................. 36 
5.1 
INCLUSION CRITERIA .................................................................................................................. 36 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 36 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 37 
5.4 
SCREEN FAILURES...................................................................................................................... 37 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 37 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 38 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 38 
6.1.1 
Investigational medicinal product ................................................................................................... 38 
6.1.2 
Non-investigational medicinal products ......................................................................................... 39 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 39 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 39 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 39 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 39 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 39 
6.5 
DOSE MODIFICATION .................................................................................................................. 39 
6.5.1 
General rules .................................................................................................................................. 39 
6.5.2 
Cycle delay ..................................................................................................................................... 40 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 41 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 41 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 41 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 44 
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6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 44 
6.5.4.4 
Immune-related adverse events .................................................................................................... 46 
6.5.4.5 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 50 
6.5.4.6 
Vascular Leak Syndrome (VLS) ..................................................................................................... 51 
6.5.4.7 
Tumor Lysis Syndrome (TLS) ........................................................................................................ 52 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 52 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 52 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 52 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 53 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 53 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 53 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 53 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 54 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 54 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 54 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 54 
8.3.1 
Time period and frequency for collecting AE and SAE information. .............................................. 54 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 54 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 54 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 54 
8.3.5 
Pregnancy ...................................................................................................................................... 54 
8.3.6 
Cardiovascular and death events .................................................................................................. 55 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 55 
8.3.8 
Adverse event of special interest ................................................................................................... 55 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 55 
8.4 
PHARMACOKINETICS .................................................................................................................. 55 
8.5 
PHARMACODYNAMICS ............................................................................................................... 55 
8.6 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 55 
8.7 
BIOMARKERS ............................................................................................................................... 55 
8.8 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 55 
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8.9 
HEALTH ECONOMICS .................................................................................................................. 55 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 56 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 57 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 57 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 58 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 58 
9.4.1 
General considerations .................................................................................................................. 58 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 58 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 58 
9.4.3.1 
Objective response rate ................................................................................................................. 58 
9.5 
INTERIM ANALYSES .................................................................................................................... 58 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 59 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 59 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 59 
10.1.2 
Financial disclosure........................................................................................................................ 59 
10.1.3 
Informed consent process .............................................................................................................. 59 
10.1.4 
Data protection ............................................................................................................................... 59 
10.1.5 
Committees structure ..................................................................................................................... 59 
10.1.6 
Dissemination of clinical study data ............................................................................................... 59 
10.1.7 
Data quality assurance .................................................................................................................. 59 
10.1.8 
Source documents ......................................................................................................................... 59 
10.1.9 
Study and site start and closure ..................................................................................................... 60 
10.1.10 Publication policy ........................................................................................................................... 60 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 60 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 60 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 60 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 60 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 60 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 60 
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10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 60 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 61 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 61 
10.11 
APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 63 
10.12 
APPENDIX 12: GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS SYNDROME 
(TLS) .............................................................................................................................................. 63 
10.13 
APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE .................................. 63 
10.14 
APPENDIX 14: ABBREVIATIONS ................................................................................................. 63 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY ................................................................ 64 
11 
REFERENCES ............................................................................................................................... 65 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 32 
Table 2 - Overview of IMP administered ....................................................................................................... 38 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines ................. 42 
Table 4 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 43 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 45 
Table 6 - Dose modification and toxicity management guidelines for immune-related AEs associated with 
pembrolizumab and SAR444245 .................................................................................................................. 47 
Table 7 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) ... 50 
Table 8 - Guidelines for the management of Vascular Leak Syndrome (VLS) ............................................. 51 
Table 9 - Cohort A: Estimated complete response rate (CRR) depending on number of responders ......... 57 
Table 10 - Risk assessment .......................................................................................................................... 62 
 
LIST OF FIGURES 
Figure 1 - Overall study schema ................................................................................................................... 12 
Figure 2 - Graphical study design-Cohort A .................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Substudy 
specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) combined with pembrolizumab for the treatment of adults 
and adolescents with relapsed or refractory classic Hodgkin lymphoma 
Brief title: 
A study of SAR444245 combined with pembrolizumab for the treatment of adults 
and adolescents with cHL 
Rationale: 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and non-human primate (NHP) models while anti programmed cell death-
1 (anti-PD1) antibody prevents T cell suppression through the programmed cell death-
1/programmed cell death-ligand 1 (PD1/PD-L1) pathway. The combination of anti-PD1 treatment 
with SAR444245 was tested in the syngeneic murine colon cancer CT-26 model and induced 
enhanced anti-tumor activity as demonstrated by an increased number of complete responses (CR) 
and tumor-free surviving animals compared to each agent in monotherapy. These data support 
evaluation of SAR444245 in combination with an anti-PD1 antibody. 
The proposed study aims to establish proof-of-concept that non-alpha interleukin 2 (IL-2) 
SAR444245 combined with the anti-PD1 antibody, pembrolizumab in trial participants with 
classic Hodgkin lymphoma (cHL) who are anti-PD-(L)1-naïve and have received at least 2 or 3 
lines of systemic therapy  .  
Objectives and endpoints  
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below. 
 
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Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245 
with or without other anticancer therapies. 
• 
Complete response rate (CRR) defined as the 
proportion of participants who have a complete 
response (CR) determined by Investigator per 
Lugano response criteria 2014 (1). 
Secondary 
 
• 
To assess other indicators of antitumor activity. 
• 
Objective response rate (ORR) defined as the 
proportion of participants who have CR or partial 
response (PR) determined by Investigator per 
Lugano response criteria 2014 (1). 
 
 
 
 
 
Overall design: 
Please refer to the master protocol. 
Brief summary:  
Cohort A:  This substudy will include approximately 25 participants with cHL who have received 
at least 2 or 3 lines of systemic therapy and will assess SAR444245 combined with 
pembrolizumab as at least 3rd or 4th line of therapy.   
A graphical presentation of the substudy schema is shown in Figure 1. 
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Figure 1 - Overall study schema  
 
 
a The DLT observation period is 21 days for Cohort A. 
b Including participants enrolled in the safety run-in at the confirmed safe dose. 
Abbreviations: 3L/4L: third-line or fourth-line; auto-SCT: autologous stem-cell transplantation; cHL: classic Hodgkin lymphoma; DLT: dose limiting toxicity; N: number; PD1: programmed cell death 1.   
 
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Number of participants: 
Overall, approximately 25 participants will be treated in Cohort A 
Intervention groups and duration: 
Please refer to the master protocol for common description of the study duration. For Cohort A, 
the maximum cycles allowed are 35 cycles. 
Study interventions 
Cohort A: cHL participants, SAR444245 + pembrolizumab as at least 3L/4L therapy 
Dosing sequence: 
Investigational medicinal product(s) 
Pembrolizumab 
• Formulation: Keytruda® (pembrolizumab) as 100 mg/4 mL (25 mg/mL) solution in single-
dose vials. 
• Route of administration: intravenous (IV) infusion. 
• Dose regimen: Pembrolizumab will be administered at a dose of 200 mg (for pediatric 
participants: 2 mg/kg, up to maximum 200 mg) using a 30-minute IV infusion on Day 1 of 
each 3-week treatment cycle for up to 35 cycles.   
Study sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window between -5 
minutes and +10 minutes is permitted (ie, infusion time is 30 minutes -5 min/+10 min). 
SAR444245 
SAR444245 formulation and route of administration as described in the master protocol. 
• Dose regimen: 24 μg/kg (or reduced to 
 μg/kg or another lower dose level recommended 
by Study Board) 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. 
Non-investigational medicinal products 
Please refer to the master protocol. 
After 4 cycles, in case of permanent SAR444245 discontinuation and continuation of 
pembrolizumab treatment as part of AE management, premedication for SAR444245 no longer 
needs to be administered. 
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Statistical considerations: 
Please refer to the master protocol for description of common statistical considerations. Substudy-
specific analyses are summarized below. 
• Analysis of primary endpoint:  
- 
The complete response rate (CRR) will be summarized for the efficacy population with 
descriptive statistics. In addition, two-sided 90% CIs for CRR will be computed using 
the Clopper-Pearson method. 
• Analysis of secondary efficacy endpoints: 
- 
The objective response rate (ORR) 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.  
Data Monitoring/Other Committee: Yes 
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1.2 
SCHEMA 
1.2.1 Study design for Cohort A 
Figure 2 - Graphical study design-Cohort A 
 
 
C=Study cycle (1 cycle = 21 days); D=Study day; EOT=end of treatment; IMP=Investigational medicinal product; FDG-PET=fluorodeoxyglucose-positron emission tomography. 
 
 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgical 
and disease 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 
8 in the 
master 
protocol 
Performance 
status (ECOG or 
Lansky Scale) 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
See 
Appendix 
13 in the 
master 
protocol 
Body 
weight/Heightg 
X 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
Full physical 
examination  
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Directed physical 
examination 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
See Section 
8.2.1 in the 
master 
protocol  
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See Section 
8.2.2 in the 
master 
protocol 
SpO2h 
X 
As clinically indicated 
 
 
 
 
 
 
Bone marrow 
biopsy 
  
As clinically indicated to confirm complete response 
 
 
 
See 
Section 8.1 
in the 
master 
protocol 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
Spleen 
measurement 
X 
As clinically indicated to evaluate response 
 
 
 
See Section 
8.1 in the 
master 
protocol 
12-Lead ECG   
X 
As clinically indicated 
 
 
 
See Section 
8.2.3 in the 
master 
protocol 
LVEF 
X 
As clinically indicated 
 
 
 
See Section 
8.2.3 in the 
master 
protocol 
Troponin 
X 
As clinically indicated 
X (Cycle 4 
Day 1) 
As clinically indicated 
 
 
 
See Section 
8.2.3 and 
Section 
10.2 in the 
master 
protocol 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
Pregnancy test 
X 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
 
 
See Section 
8.2.5 and 
Section 
10.2 in the 
master 
protocol 
Blood chemistryh 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
See Section 
10.2 in the 
master 
protocol 
Tumor Lysis 
Laboratory Testsi 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
T3, FT4, TSH and 
cortisolj 
X 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
See Section 
10.2 in the 
master 
protocol 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
Coagulationk 
X 
As clinically indicated 
X 
 
 
 
See Section 
10.2 in the 
master 
protocol 
Urinalysisl  
X 
On C1D1 and C2D1, then as clinically indicated 
X 
 
 
 
See Section 
10.2 in the 
master 
protocol 
Hepatitis serology, 
CD4+ counts and 
viral load 
Xm 
As clinically indicated 
 
 
 
See Section 
10.2 in the 
master 
protocol 
IMP 
 
X 
 
 
 
 
X 
 
X 
 
 
 
 
 
 
Hospitalizationo  
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
AE/SAE 
assessmentp 
X 
Continuous throughout treatment period 
X 
 
 
 
See Section 
8.3 in the 
master 
protocol 
Prior/Concomitant 
Meds 
Xn 
Continuous throughout treatment period 
 
 
 
 
See Section 
6.8 in the 
master 
protocol 
First subsequent 
anti-cancer 
therapy 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PD) / Immunogenicity assessments 
 
PK 
See PK Flow-Charts in Section 1.5 
 
ADA 
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Evaluationa 
Screening  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Survival 
phone 
call 
follow-up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-8 
Cycle  
9 – 35 
EOT visit 
Follow-up 
visit 1 
Follow-up 
visit 2 
Follow-up 
visit 3 and 
beyond 
Phone call 
Follow-up 
Cycle day  
D-28 to D-1 
D1 
D2e 
D3e 
D8 
D14/ 
D15f 
D1(±3 
days) 
D8 
D1(±3 
days) 
30 (±7) days 
after last IMP 
admin or prior 
to initiation of 
further 
therapy 
3 months 
(±7 days) 
after last 
IMP admin 
6 months 
(±7 days) 
after last 
IMP admin 
Every 3 
months ±7 
days 
Every 3 
months ±
14 days  
 
PDy - Blood and 
tumor tissue 
collectionr 
See Biomarker Flow-Chart in Section 1.4 
 
Tumor assessment  
 
CT/MRIq 
X 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
See Section 
8.1.1 in the 
master 
protocol  
Brain imagings 
If clinically 
indicated 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 
8.1.1 in the 
master 
protocol  
FDG-PETq 
X 
As clinically indicated, and must be performed for the 9-week and 18-week on-treatment 
assessments 
 
 
 
See Section 
8.1.1 in the 
master 
protocol  
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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 study treatment discontinuation. See Section 4.1 of the master 
protocol. For participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and should be 
contacted by telephone approximately every 3 months ±14 days to assess for survival status. Updated survival status may be requested by the Sponsor at any time during the study. 
e Visits on C1D2, D3 are for safety-run in participants only. 
f 
Study Board may decide to cancel safety assessment on C1D15, upon agreement with Sponsor, if safety data justify it. 
g Weight/Height: Height is required at baseline only for patients > or =18 years old. For trial participants <18 years old, height should be assessed on day 1+/-1 of each cycle. Weight is required at Screening and 
prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a reasonable time frame according to 
Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible considering the variability of local process from site to site. If the infusion is prepared 
with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each cycle. 
h Blood chemistry/ hematology will be performed weekly on D1 pre-dose, D8 and D15 during Cycle 1, then on Day 1 of every cycle up to Cycle 12, then every other cycle during Treatment Phase. Visits and 
assessments on C1D2-D3 are only for participants in the safety run-in or participants who are hospitalized because of high tumor burden or at investigator’s discretion.  For these participants, vital signs, SpO2 and 
complete blood counts (CBC) and differentials, chemistries (blood urea nitrogen (BUN), creatinine (Cr), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (Alk Phos), total bilirubin 
(TBil) will be obtained daily. 
i 
Tumor lysis laboratory tests (corrected calcium, magnesium, phosphate, uric acid, and lactate dehydrogenase [LDH] levels) will be obtained every 8 hours on C1D1 for safety run-in participants or participants who 
are hospitalized, and C1D2-D3 for safety run in or participants who are hospitalized because of high tumor burden or at investigator’s discretion.  
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated. 
k Coagulation includes international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
l 
Urinalysis will be performed on C1D1 and C2D1, then as clinically indicated during the treatment period, and will be performed at Follow-Up Visit 1. 
m For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in France (see details and specific instructions in Section 10.2 
and Section 10.7 in the master protocol, and Section 10.7 in this substudy 01). 
n Prior medications that are received within 30 days before the first dose of IMP. 
o Hospitalization for 48 h for safety run-in participants or for participants with a high tumor burden or at investigator’s discretion. 
p AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5. ICANS and CRS will be graded using ASTCT criteria integrated with central laboratory cytokine results (2).   
q The initial tumor imaging FDG-PET CT and/or MRI 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. FDG-PET 
must be performed for the 9-week and 18-week on-treatment assessments. 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 and follow-up assessments.  
r 
If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. Tumor biopsy should be considered for new lesions if their pathologic etiology is 
ambiguous. 
s Brain CT/MRI: To be performed if clinically indicated.   
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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; FDG-PET = fluorodeoxyglucose-positron emission tomography; 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; PD = Progressive disease; PDy = 
Pharmacodynamic; PK = Pharmacokinetic; Q3W = Every 3 weeks; SAE = Serious adverse event; TSH = Thyroid stimulating hormone. 
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1.4 
BIOMARKER FLOWCHARTS 
 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
 
Cycle 
Treatment Cycle 1 
Treatment Cycle 2, 4, 7, 
10 + every 5th cycle 
EOT visit 
Day 
D1 
D2 
D3 
D8 
D1 
30 (±7) days after last 
IMP administration 
Time after start of 
SAR444245 dosing [h] 
SOI 
EOI  
4h post 
EOI  
At any time 
At any time 
At any time 
SOI 
EOI 
At any time 
SAR444245 PK 
sample  
 
P00b  
P01 
P02c 
P03c 
 
 
P00b  
 
SAR444245 ADA 
sample  
AB00a  
 
 
 
AB01 
AB00a  
 
ABF00 
a Samples collected strictly before start of infusion (SOI). ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
b PK sample must be taken at the end of infusion (EOI) after flush.  
c P02 and P03 to be collected during safety run-in and when participants are hospitalized. 
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 4 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end resumed infusion and subsequent sample should be drawn at 0.5 h after 
end of resumed infusion. PK sampling may be discontinued by the Sponsor once sufficient data have been collected. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOT: end of treatment; PK: pharmacokinetic. 
 
 
 
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2 
INTRODUCTION 
Study ACT16941 is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with or without various anticancer therapies by identifying early signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to Cohort A (participants with cHL who are anti-PD-(L)1-naïve and have 
received at least 2 or 3 lines of systemic therapy) for the combination therapy with 
pembrolizumab. 
Please refer to the master protocol for an introduction for ACT16941.    
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.  
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 programmed cell death protein 1 (PD1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (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 many advanced malignancies. 
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications, including as monotherapy for relapsed or refractory cHL or PMBCL. For more details 
on specific indications refer to the pembrolizumab Investigator’s Brochure (IB). 
Refer to the approved local labeling for detailed background information on pembrolizumab. 
2.2.1.1 Pharmaceutical and therapeutic background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decade (3). 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 
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survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma (RCC). Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses 
in cancers such as melanoma (4, 5). 
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)  
(6, 7). 
The structure of murine PD1 has been resolved (8). PD1 and its family members are Type I 
transmembrane glycoproteins containing an Ig-variable type (IgV type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. The 
cytoplasmic tail of PD1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif. Following T-cell 
stimulation, PD1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3  
T-cell signaling cascade (7, 9, 10, 11). 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 (12, 13). As a consequence, the PD 1/PD-L1 pathway is an 
attractive target for therapeutic intervention in cHL. 
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 (14, 
15, 16, 17, 18, 19, 20). 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 (8, 17, 19, 20, 21). 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 (19). 
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 Investigator’s brochure [IB]). 
A summary of clinical trial data and the justification of the choice of pembrolizumab dose is 
provided in Section 4.3.2. 
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2.2.2 Rationale for B cell lymphoma and selected participant population  
Please refer to Section 2.2.1 of the master protocol. 
2.2.3 Current standard of care in classic Hodgkin lymphoma 
At diagnosis, patients usually receive multiagent chemotherapy (eg, adriamycin, bleomycin, 
vinblastine, and dacarbazine [ABVD]; adriamycin, vinblastine, and dacarbazine [AVD]; 
bleomycin, etoposide, adriamycin, cytoxan, vincristine, procarbazine, and prednisone 
[BEACOPP]) with or without brentuximab and/or radiotherapy.  For refractory disease, or at first 
relapse, transplant-eligible patients are referred for autologous stem cell transplant with or without 
radiotherapy and/or brentuximab or allogeneic stem cell transplant (in select patients).  
Transplant-ineligible patients may be treated with brentuximab monotherapy or in combination 
with nivolumab (off-label).  At second relapse and beyond, patients are offered currently 
approved therapy, such as pembrolizumab or nivolumab, or enrollment in a clinical trial (22). 
Pembrolizumab is approved to treat adults and children with relapsed/refractory cHL (USPI). The 
KN204 study compared pembrolizumab to brentuximab vedotin (BV) in patients who were 
ineligible for or relapsed following an autologous stem cell transplant (ASCT). With the KN204 
approval, pembrolizumab is now a treatment option as 2nd line therapy in the US. 
2.3 
BENEFIT/RISK ASSESSMENT 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of SAR444245 and other combinations may be found in the 
Investigator’s Brochure. 
2.3.1 Risk assessment 
Please refer to the master protocol for risk assessment for SAR444245, the known safety profile 
of the structurally similar product aldesleukin (Proleukin®) and current knowledge of the new-
generation, investigational IL-2 analog NKTR-214 (bempegaldesleukin). 
Risk assessment of SAR444245 combined with pembrolizumab results from anticipated risks for 
SAR444245 and from the label information for pembrolizumab, taking into account potential 
overlapping risks. The available safety data for pembrolizumab, along with proposed mitigation 
strategies are summarized below and also provided in Table 10. 
2.3.1.1 Pembrolizumab  
Pembrolizumab potentiates T-cell responses, including antitumor responses, through blockade of 
PD1 binding to PD-L1 and PD-L2, which are expressed in antigen presenting cells and may be 
expressed by tumors or other cells in the tumor microenvironment. 
The use of pembrolizumab may cause infusion-related reactions (IRRs) (drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, and hypersensitivity). Pembrolizumab use may be 
associated with infections (pneumonia), bone marrow suppression (anemia, thrombocytopenia, 
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leukopenia), increase in the level of hepatic enzymes (alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase), kidney damage (nephritis, acute kidney injury), as well 
as adverse effects on the functioning of nervous system (dizziness, headache, peripheral 
neuropathy, dysgeusia (very common) and lethargy). In combination therapy with other 
chemotherapeutic drugs, pembrolizumab administration is commonly associated with 
hypertension and cardiac arrhythmia (including atrial fibrillation). 
Immune-mediated adverse events are designated as important identified risks for pembrolizumab 
(23). 
Immune-related adverse reactions, including severe and fatal cases, have occurred in patients 
receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment 
with pembrolizumab were reversible and managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or supportive care. Immune-related adverse reactions have 
also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting 
more than one body system can occur simultaneously. 
Among the immune-related adverse events (irAEs) associated with pembrolizumab are: immune-
related pneumonitis, immune related colitis, immune-related hepatitis, immune-related nephritis, 
immune-related endocrinopathies, immune-related skin adverse reactions and other additional 
clinically significant, immune-related adverse reactions (reported in clinical studies or in post 
marketing experience): uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré 
syndrome, myasthenic syndrome, hemolytic anemia, sarcoidosis, encephalitis, and myelitis. 
Efficacy and safety data for pembrolizumab from patients ≥75 years are limited. In this 
population, pembrolizumab combination therapy should be used with caution after careful 
consideration of the potential benefit/risk on an individual basis. 
Please refer to pembrolizumab country-approved product labeling (eg, United States Package 
Insert [USPI], Summary of Product Characteristics [SmPC]) for more detailed information. 
2.3.1.2 SAR444245 combined with pembrolizumab  
Due to synergistic action of SAR444245 and pembrolizumab, combining these two substances 
may lead to an increased frequency and/or severity of adverse events (AEs) related to immune 
activation for each substance individually or may cause occurrences of qualitatively different 
AEs. Serious adverse drug reactions reported with agents known to increase immune activation 
include pneumonitis, hepatitis, nephritis, colitis, and hormonal dysfunction (see Section 2.3.1.1). 
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. 
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2.3.2 Benefit assessment 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol, and the combination of SAR444245 and pembrolizumab are provided below. 
In a syngeneic mouse model CT-26, relatively resistant to immune checkpoint treatment, 
SAR444245 potentiated the activity of an anti-PD1 antibody. Combination treatment in animals, 
when compared to respective monotherapies, increased the number of complete responses and 
prolonged survival which was durable as demonstrated by the failure of the tumor to grow upon 
re-engraftment on the tumor free animals, indicating the establishment of a durable memory T-cell 
population in response to the initial treatment (see SAR444245 IB).  
The regimen proposed to be evaluated in this substudy is anticipated to bring benefit to patients 
with cHL. 
2.3.3 Overall benefit: risk conclusion 
More detailed information about the expected benefits of SAR444245 may be found in the master 
protocol. Overall, the potential risks identified in association with this new generation IL-2 
SAR444245 combined with the anti-PD1 inhibitor pembrolizumab are justified by the anticipated 
benefits that may be afforded to participants with cHL. 
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
Please refer to the master protocol for more details about risks related to the patient population, 
SAR444245 treatment, and study related activity.  
In addition, the impact of PD-1 blockade therapy on Coronavirus Disease 2019 (COVID-19) 
severity was explored by 2 groups who did not find a clinically meaningful signal (24, 25). 
 
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for description of common objectives and endpoints. Substudy-
specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245 
with or without other anticancer therapies. 
• 
Complete response rate (CRR) defined as the 
proportion of participants who have a complete 
response (CR) determined by Investigator per 
Lugano response criteria 2014 (1). 
Secondary 
 
• 
To assess other indicators of antitumor activity. 
• 
Objective response rate (ORR) defined as the 
proportion of participants who have CR or partial 
response (PR) determined by Investigator per 
Lugano response criteria 2014 (1). 
 
 
 
 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This substudy will include approximately 25 participants with classic Hodgkin lymphoma (cHL) 
who have received at least 2 or 3 lines of systemic therapy and will assess SAR444245 combined 
with pembrolizumab as at least 3rd or 4th line of therapy. 
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts.   
A graphical presentation of the study schema is shown in Figure 1. 
The dose-limiting toxicity (DLT) observation period is 21 days for Cohort A.  
Please refer to the master protocol for the full list of common events and below for substudy 
specific events occurring during the DLT observation period (21 days) which are considered as 
DLT unless due to disease progression or to a cause obviously unrelated to SAR444245.  
Hematologic abnormalities:  
• Grade 3 neutropenic fever (ANC<1000/mm3 with single temperature >38.3°C [101°F] or 
sustained temperature >38°C [100.4°F] for more than 1 hour) for Cohort A. 
The maximum cycles allowed in this substudy for Cohort A are 35 cycles. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 combined 
with the anti-PD1 antibody, pembrolizumab, in trial participants with cHL. 
The design of the study is a non-randomized study where the experimental combination will be 
assessed in a single cohort, using historical data for single agent immune-checkpoint as a 
benchmark to show outstanding complete response rate. The CRR will be assessed using Lugano 
response criteria 2014 for participants with cHL.  
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
Please refer to the master protocol. 
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4.3 
JUSTIFICATION FOR DOSE 
4.3.1 SAR444245 dose  
Please refer to the master protocol.   
4.3.2 Pembrolizumab dose  
The planned dose of pembrolizumab for this study is 200 mg (for pediatric participants: 2 mg/kg, 
up to maximum 200 mg), every 3 weeks (Q3W). Based on the totality of data generated in the 
Keytruda development program, 200 mg Q3W is an appropriate dose of pembrolizumab for adults 
across all indications. As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies in melanoma and non-small cell lung cancer 
(NSCLC) indications demonstrating flat dose- and exposure-efficacy relationships from 2 
mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W) representing an approximate 5 to 7.5 fold 
exposure range (refer to the pembrolizumab IB)  
• Population pharmacokinetic (PK) analysis showing that both fixed dosing and weight-
based dosing provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W 
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications. And 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK [PBPK] analysis) at 
200 mg Q3W. 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and NSCLC, covering different disease settings (treatment naïve, previously treated, 
PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and in 
combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and KN006). All of 
these studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5- fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-exposure-response relationships were also observed in other tumor types including head and 
neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are consistent 
with the mechanism of action of pembrolizumab, which acts by interaction with immune cells, 
and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD1 saturation over a wide range of tumor 
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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. 
To date, pembrolizumab (2 mg/kg Q3W) has been evaluated in 161 pediatric participants (aged 1 
to 18 years) with advanced melanoma, PD-L1 positive advanced, relapsed, or refractory solid 
tumors, or lymphoma. The exposures in pediatric participants following the 2 mg/kg Q3W 
regimen were found to be similar to that observed in adult participants. Pediatric data has also 
been incorporated in an integrated population PK analysis, which confirmed that a 
pembrolizumab dose of 2 mg/kg Q3W (up to a maximum of 200 mg Q3W) in pediatric 
participants renders exposures similar to adults. Based on these results, the pediatric dose for 
evaluation in this trial is 2 mg/kg Q3W (up to a maximum of 200 mg Q3W). 
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort A specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Cancer diagnosis at study entry:  
Histologically or cytologically confirmed diagnosis of classic Hodgkin lymphoma (cHL), 
according to the WHO 2016 classification. 
I 02. Prior anticancer therapy: 
- 
Must have received at least two prior lines of systemic therapy for cHL, including at 
least one containing an anthracycline or brentuximab. 
- 
Must have failed or declined autologous stem cell transplantation (ASCT), or not be a 
candidate for ASCT.   
- 
May have received a prior autologous stem cell transplant but must be at least ≥100 
days post-auto-transplant, and all transplant- related adverse events must have 
resolved to grade 1 or less and meet all other eligibility criteria. 
5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply (in addition to the 
criteria listed in the master protocol): 
Prior/concomitant therapy 
E 01. Prior treatment with an agent (approved or investigational) that blocks the PD-1/PD-L1 
pathway (participants who joined a study with an anti-PD-1/PD-L1 but have written 
confirmation they were on control arm [must not contain anti-PD1/PD-L1] are allowed).   
E 02. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 
years.  (Participants who have had a transplant greater than 5 years ago are eligible as long 
as there are no symptoms of graft-versus-host disease [GVHD]). 
 
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5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION 
Please refer to the master protocol. 
 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
The maximum cycles allowed in this substudy for Cohort A are 35 cycles.  
Dosing sequence: 
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245, and pembrolizumab 
administered as described in Section 4.1. Details of each IMP component to be administered are 
shown in Table 2.  
Preparation and administration of IMP are detailed in the pharmacy manual. Hydration is required 
for SAR444245 infusions. Details are provided in Section 6.1.3 of the master protocol. 
Table 2 - Overview of IMP administered 
Intervention name 
SAR444245 
Pembrolizumab 
Type 
See master protocol 
Biologic 
Dose formulation 
See master protocol 
Solution for infusion 
Unit dose strength(s) 
See master protocol 
100 mg/vial 
Dosage level(s)a 
24 μg/kg Q3W (or reduced to 
 μg/kg 
 
or another lower dose level recommended by 
Study Board) 
200 mg Q3W (for pediatric participants: 2 mg/kg, 
up to maximum 200 mg) 
Route of 
administration 
See master protocol 
IV infusion 
Use 
See master protocol 
Treatment of cancer (combination) 
IMP or NIMP 
IMP 
IMP 
Packaging and 
labeling 
See master protocol 
Supplied in single-dose vials containing 
100 mg/4 mL pembrolizumab labelled with a 
multilingual booklet. 1 vial per treatment box. 
Current/Former 
name(s) or alias(es) 
NA 
Keytruda 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the electronic 
case report form (e-CRF). Study sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window between -5 minutes and +10 minutes is permitted (ie, infusion time is 30 
minutes -5 min/+10 min). 
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6.1.2 Non-investigational medicinal products 
Please refer to the master protocol. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modification for SAR444245 is permitted according to the guidelines described in this 
section. Pembrolizumab dose reductions are not permitted. Pembrolizumab treatment may be 
withheld or discontinued due to toxicity. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for all IMPs) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed. 
Once a dose has been decreased, intra-patient re-escalation back to the previous dose level is not 
permitted. 
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Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other TEAE that, in the opinion of the Investigator, 
warrants discontinuation. 
If any of the IMP components is permanently discontinued, the other IMP component can be 
continued until disease progression or other criteria as detailed in Section 7.1.1 of the master 
protocol are met. In this case it is partial permanent discontinuation and the end of treatment 
(EOT) assessment will be 30 days after the date of the last administration of the remaining IMP. 
When all IMP components are permanently discontinued it is full permanent discontinuation. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Cycle delay   
The treatment window is ±3 days for each of the Q3W administrations. A cycle is deemed to have 
been delayed if the treatment is administrated ≥4 days beyond the theoretical day of Q3W IMP 
administration. The participant may receive the next dose after recovery from the toxicity as 
described in Section 6.5.3, and Section 6.5.4. After cycle is delayed, such participants may be 
considered for treatment resumption once the toxicity resolves or improves to Grade 1 or baseline 
or is stable and manageable through supportive/medical therapy. 
Participants may have cycle delay, if toxicity occurs and the participant does not recover 
according to following rules: 
• For Q3W IMP administration:  If toxicity occurs and the participant does not recover on 
the day of planned administration, the cycle will be delayed: restart of study IMPs could 
occur only on the initiation of the subsequent cycle. 
• In case of cycle delay for the recovery of toxicity, the following rules should be followed 
for restart or discontinuation of the treatment: 
- 
In case of a cycle delay up to 14 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After a cycle delay of >14 days and ≤84 days, it is per Investigator’s decision to 
restart the study treatment, if a clear benefit from treatment is observed and after 
consultation with the Sponsor. 
- 
The study treatment must be permanently discontinued if the cycle delay is longer 
than 84 days. 
• Cycle may be delayed for situations other than TEAEs such as medical / surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study 
therapy within 21 days of the scheduled delay, unless otherwise discussed with the 
Sponsor (for example for national or regional emergencies). The reason for this delay 
should be documented in the participant’s study record. 
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6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 treatment-related adverse events (TRAEs) at any time of 
the study (including clinically significant grade 3 laboratory abnormalities as defined in Section 
10.3.1 of the master protocol) will be required to cycle delay the IMP, unless specified otherwise 
in the protocol, and with the exception of the TRAEs resolving within 5 days. After cycle delay, 
such participants may be considered for treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline or is stable and manageable through supportive/medical therapy. 
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 withheld for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
µg/kg to 
 µg/kg (or another lower dose recommended 
by Study Board) may be decided when specified in the protocol or following discussions with the 
Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
vascular leak syndrome (VLS) and IRR are presented in Section 6.5.4. 
6.5.4  Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interests (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
electronic case report form (e-CRF). 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol, prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An infusion-related reaction (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 
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infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion reaction 
are provided in Table 3. 
After an IRR due to pembrolizumab infusion (Grade 3 or Grade 4), the SAR444245 infusion will 
be delayed and can be administered after resolution of symptoms. The Investigator should discuss 
with the Sponsor’s Medical Monitor if the SAR444245 infusion needs to be delayed more than 1 
day. 
Guidelines for the management of SAR444245 IRR events are provided in Table 4. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol. 
Table 3 - Pembrolizumab infusion-related reaction dose modification and treatment guidelines  
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
Grade 1 
Mild 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 
• 
Stop Infusion. 
• 
Additional appropriate medical therapy may 
include but is not limited to: 
- 
Epinephrine*, 
- 
IV fluids, 
- 
Antihistamines, 
- 
NSAIDs, 
No subsequent dosing 
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NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilator support indicated 
- 
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. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.  
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov.  
  
Table 4 - 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. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise, dosing will be held 
until symptoms resolve and the participant should be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics.  
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
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Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be prematurely 
permanently discontinued. The participant can continue treatment with the other 
anti-cancer therapy in combination. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; pressor or ventilator support 
indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be prematurely 
permanently discontinued. The participant can continue treatment with the other 
anti-cancer therapy in combination. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
 
6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of both SAR444245 and pembrolizumab being administered.  
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines)  
(26, 27, 28). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS) 
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cytokine-release syndrome should be graded as per American Society for Transplantation and 
Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 5. If any grade of CRS is suspected, sites should make every 
effort to draw an additional blood sample for cytokines levels (by central laboratory), prior to the 
administration of tocilizumab, as well as for C-reactive protein (CRP) and ferritin (by local 
laboratory).  
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Sites should have at least 2 full doses of tocilizumab available, or alternative therapies per site 
practice in CRS management, and access to an intensive care unit (ICU), in case participants 
develop CRS. 
Guidelines for management of CRS according to severity grading are provided in Table 5. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 5 - Guidelines for the management of suspected cytokine release syndrome (CRS)  
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a. 
Appropriate symptomatic treatment may include but is not limited to IV 
fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less 
frequently as the participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interrupt of SAR444245, if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as 
medically indicated should be increased until the participant recovers. 
Transfer to ICU may be required. 
For participants with comorbidities, older age, or with oxygen requirement, 
hypotension, or participants in whom symptoms (eg, high grade fever) that 
do not respond to antipyretics within 72 hours treatment with 
corticosteroids and/or tocilizumab or alternative therapies per site practice 
in CRS management should be considered, as per guidance for Grade 3 
events.  
SAR444245 may be resumed when clinical symptoms have resolved or 
improved to Grade 1 and corticosteroid taper. No dose modification is 
required but decreasing to half the infusion rate can be considered. 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a vasopressor 
with or without vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding vasopressin) 
If CRS grade 3, SAR444245 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. 
 
If CRS Grade 4, SAR444245 should be permanently discontinued, as 
clinically indicated.  
If CRS Grade 3 or Grade 4, IV corticosteroids should be initiated (outside 
of the context of CAR-T cells, corticosteroids alone maybe initiated in first 
intention) and tocilizumab or alternative therapies per site practice in CRS 
management should be 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 
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Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
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), or alternative therapies per 
site practice in CRS management, should be administered, and steroids 
should be administered concurrently. If still no improvement in 
oxygenation, hypotension, fever and other manifestations is observed 
after the first dose of tocilizumab, or alternative therapies per site practice 
in CRS management, it may be repeated after an interval of at least 8 
hours and should not exceed 4 doses in total. 
For participants with severe CRS who fail to improve after repetitive 
treatment with both tocilizumab or alternative therapies per site practice in 
CRS management and steroids, alternative options should be discussed 
with clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or alternative therapies per site practice in CRS management or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
6.5.4.4 Immune-related adverse events  
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
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. 
Immune-related AEs are thought to be caused by unrestrained cellular immune responses directed 
at the normal host tissues. Therefore, early recognition and initiation of treatment is critical to 
reduce complications. Based on existing pembrolizumab clinical study data, most irAEs were 
reversible and could be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care.  
Investigators must be extremely vigilant and be ready to intervene early in the management of 
irAEs because the onset of symptoms of irAEs (eg, pneumonitis) may be subtle. For suspected 
irAEs, adequate evaluation should be performed to confirm etiology or exclude neoplastic, 
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infectious, metabolic, toxin, or other etiologic causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based on the 
severity of irAEs, withhold or permanently discontinue pembrolizumab and/or SAR444245 and 
administer corticosteroids. 
SAR444245 may increase the incidence and severity of these events.   
Dose modification and toxicity management guidelines for irAEs are provided in Table 6. Of 
note, when study interventions are administered in combination, if the AE is considered immune-
related, both drugs in the combination should be held according to recommended dose 
modifications.  If a participant experiences several irAEs, the most conservative recommendation 
should be followed.  
The CTCAE V5.0 must be used to grade the severity of AEs. 
When 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 6,  the 
combination of SAR444245 and pembrolizumab may be restarted at the discretion of the 
Investigator. In these cases where the toxicity is attributed to the combination or to 
SAR444245 alone, re-initiation of pembrolizumab as a monotherapy may be considered 
after communication with the Sponsor. 
Table 6 - Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab and SAR444245 
General instructions: 
1. 
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids.  
2. 
Pembrolizumab and SAR444245 must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last pembrolizumab treatment. 
3. 
The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks. 
4. 
If pembrolizumab and SAR444245 have been withheld, pembrolizumab and SAR444245 may be resumed after the irAE 
decreased to ≤ Grade 1 after corticosteroid taper. 
irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Pneumonitis  
Grade 2 
Withholda  
Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Add prophylactic 
antibiotics for 
opportunistic infections. 
Monitor participants for signs 
and symptoms of 
pneumonitis. 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid 
treatment. 
Recurrent Grade 2, 
Grade 3 or 4  
Permanently 
discontinueb 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Diarrhea/Colitis  
Grade 2 or 3 
Withholda 
Administer corticosteroids 
(initial dose of 1 - 2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with 
or without fever) and of bowel 
perforation (ie, peritoneal 
signs and ileus). 
Participants with ≥Grade 2 
diarrhea suspecting colitis 
should consider GI 
consultation and performing 
endoscopy to rule out colitis. 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is 
not feasible, fluid and 
electrolytes should be 
substituted via IV infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinueb 
AST or ALT 
elevation or 
Increased Bilirubin 
Grade 2c 
Withholda 
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper. 
Monitor with liver function 
tests (consider weekly or 
more frequently until liver 
enzyme value returned to 
baseline or is stable). 
Grade 3d or 4e 
Permanently 
discontinueb 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper. 
Type 1 Diabetes 
Mellitus (T1DM) or 
Hyperglycemia 
New onset T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholdaf 
Initiate insulin 
replacement therapy for 
participants with T1DM. 
Administer 
anti-hyperglycemic in 
participants with 
hyperglycemia. 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withholda 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated. 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency). 
Grade 3 or 4 
Withholda or 
permanently 
discontinuebf 
Hyperthyroidism  
Grade 2 
Continue 
Treat with non-selective 
beta-blockers 
(eg, propranolol) or 
thionamides as 
appropriate. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withholda or 
permanently 
discontinuebf 
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irAEs 
Toxicity grade 
(CTCAE V5.0) 
Action with 
pembrolizumab 
and SAR444245  
Corticosteroid 
and/or other 
therapies 
Monitoring and 
follow-up 
Hypothyroidism 
Grade 2, 3, or 4 
Continue 
Initiate thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyronine) per standard 
of care. 
Monitor for signs and 
symptoms of thyroid 
disorders. 
Nephritis: 
grading according 
to increased 
creatinine or acute 
kidney injury 
Grade 2 
Withholda 
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper. 
Monitor changes of renal 
function. 
Grade 3 or 4 
Permanently 
discontinueb 
Neurological 
Toxicities 
Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinueb 
Myocarditis 
Grade 2, 3 or 4 
Permanently 
discontinueb 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes. 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withholda 
Based on severity of AE 
administer corticosteroids 
Ensure adequate evaluation 
to confirm etiology and/or 
exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinueb 
All Other irAEs 
Persistent Grade 2 
Withholda 
Based on severity of AE 
administer corticosteroids. 
Ensure adequate evaluation 
to confirm etiology or exclude 
other causes. 
Grade 3 
Withholda or 
discontinue based 
on the eventg  
Recurrent Grade 3 
or Grade 4  
Permanently 
discontinueb 
a SAR444245 to be withheld plus pembrolizumab to be withheld corresponds to “cycle delay”. 
b Permanently discontinuation of full study treatment. 
c AST/ALT: >3.0 - 5.0 x ULN if baseline normal; >3.0 - 5.0 x baseline, if baseline abnormal; bilirubin:>1.5 - 3.0 x ULN if baseline normal;  
>1.5 - 3.0 x baseline if baseline abnormal. 
d AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 - 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 - 10.0 x ULN if baseline normal; 
>3.0 - 10.0 x baseline if baseline abnormal. 
e AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; bilirubin: >10.0 x ULN if baseline normal; 
>10.0 x baseline if baseline abnormal. 
f 
The decision to withhold or permanently discontinue pembrolizumab and SAR444245 is at the discretion of the Investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab and SAR444245 may be resumed. 
g Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg. vasculitis and 
sclerosing cholangitis). 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse 
Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 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. 
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6.5.4.5 Immune Cell-Associated Neurotoxicity Syndrome (ICANS) 
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment 
of cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.11 
of the master protocol). Recommendations for ICANS management mainly include the use of 
steroids, whereas tocilizumab, or alternative therapies per site practice in CRS management, 
should only be used in the context of CRS, as outlined in Table 7. The proposed management 
should be considered only as recommendations and in light of recommendations from site 
specialist. 
Table 7 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245 a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or 
improvement to Grade 1 after corticosteroid taper. Consideration for 
reduction of SAR444245 dose to 
µg/kg as per Investigator with 
Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
EEG that resolve with intervention. 
Grade 4  
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or 
coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after 
corticosteroid taper, SAR444245 can be either restarted at 
 µg/kg or 
permanently discontinued, as clinically indicated, and upon discussions 
between the Investigator and Sponsor.  
If Grade 4 ICANS, SAR444245 should be permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
may require tocilizumab, or alternative therapies per site practice in CRS 
management, and should be handled as described in Table 5. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab, or alternative therapies per site practice in CRS 
management, 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. 
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a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.5.4.6 Vascular Leak Syndrome (VLS) 
Vascular leak syndrome (VLS) is a disorder characterized by leakage of intravascular fluids into 
the extravascular space and can lead to generalized edema and multiple organ failure. This 
syndrome is observed in patients who demonstrate a state of generalized leaky capillaries 
following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, 
medications, or poisoning. In various human diseases, an increase in capillary permeability to 
proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space 
manifested by any of the following clinical presentations: diffuse pitting edema, exudative 
serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, 
hypovolemic shock with multiple-organ failure. Fluid management is the cornerstone of VLS 
management; it is a balance between maintaining the intravascular volume to ensure organ 
perfusion to prevent organ failure, while avoiding volume overload. The management of VLS 
according to severity grading is described in Table 8. These guidelines are not comprehensive and 
the Investigator should exercise clinical judgment based on the symptoms and condition of the 
individual participant and refer to current guidelines to the topic (29).  
 
Table 8 - Guidelines for the management of Vascular Leak Syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of 
µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued. 
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
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Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
6.5.4.7 Tumor Lysis Syndrome (TLS) 
Tumor lysis laboratory tests (corrected calcium, magnesium, phosphate, uric acid, and lactate 
dehydrogenase [LDH] levels) will be obtained every 8 hours on C1D1 for safety run-in  
participants and participants who are hospitalized, and C1D2-D3 for safety run in or participants 
who are hospitalized because of high tumor burden or at investigator’s discretion (refer to  
Section 1.3 SOA for details).  If it occurs, appropriate treatment will be initiated that will include 
correction of serum calcium, potassium, or phosphorus abnormalities, and treatment of 
hyperuricemia with allopurinol and/or rasburicase, as indicated in Appendix 12 of the master 
protocol (30). 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater. There is no 
specific antidote for overdose with pembrolizumab. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol. 
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol. 
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.3.1 Time period and frequency for collecting AE and SAE information. 
Please refer to the master protocol for AEs and SAEs collection. For participants in Cohort A, 
irAEs will be collected until 3 months following last administration of study treatment regardless 
of whether or not another anticancer therapy is initiated. 
8.3.2 Method of detecting AEs and SAEs 
Please refer to the master protocol. 
8.3.3 Follow-up of AEs and SAEs 
Please refer to the master protocol. 
8.3.4 Regulatory reporting requirements for SAEs 
Please refer to the master protocol.  
For pembrolizumab, serious adverse events (SAEs) that are considered expected will be specified 
in the reference safety information (country-approved product labeling for pembrolizumab). 
8.3.5 Pregnancy 
Please refer to the master protocol. 
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8.3.6 Cardiovascular and death events 
Please refer to the master protocol. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs 
Not applicable. 
8.3.8 Adverse event of special interest 
Please refer to the master protocol. 
In addition, symptomatic or asymptomatic overdose with pembrolizumab are described as below: 
• An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater.  
8.3.9 Guidelines for reporting product complaints 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol. 
8.5 
PHARMACODYNAMICS  
Please refer to the master protocol. 
8.6 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.7 
BIOMARKERS 
Please refer to the master protocol.  
8.8 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.9 
HEALTH ECONOMICS 
Please refer to the master protocol. 
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8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
 STATISTICAL HYPOTHESES  
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION 
The study will start with a safety run-in with 6-10 participants from Cohort A. 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 Cohort A. 
Sample size: 
The plan is to treat a total of 25 participants at the confirmed safe dose in Cohort A. 
Table 9 lists estimated CRR and the corresponding 90% exact confidence interval (CI) by number 
of responders from a sample size of 25 participants in Cohort A. 
Table 9 - Cohort A: Estimated complete response rate (CRR) depending on number of responders 
 
Number of Responders 
(N=25) 
Complete Response Rate in % 
(90% Clopper-Pearson CI) 
1 
4 % (0.2% - 17.6%) 
3 
12 % (3.4% - 28.2%) 
4 
16 % (5.7% - 33%) 
5 
20 % (8.2% - 37.5%) 
6 
24 % (11% - 42%) 
8 
32 % (17% - 50.4%) 
9 
36 % (20.2% - 54.4%) 
 
With a sample size of 25 participants in Cohorts A, the probability of observing 1 or more 
instances of a specific AE with a true incidence rate of 1%, 2% or 5% is 22.2%, 39.7% or 72.3% 
respectively. 
This provides reasonable assurance that events occurring at ≥ 5% frequency can be identified in 
this substudy. 
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9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
For Cohort A, the complete response rate (CRR) is defined as the proportion of participants who 
have a CR per Investigator assessment (Lugano response criteria 2014). 
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 CRR and the BOR will be summarized with descriptive statistics. In addition, two-sided 90% 
CIs will be computed for CRR from Clopper-Pearson exact method.  
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol for descriptions of common secondary endpoints. Substudy-
specific analysis for secondary endpoints is summarized below. 
9.4.3.1 Objective response rate 
The ORR is defined as the proportion of participants who have a CR or partial response (PR) per 
Investigator assessment (Lugano response criteria 2014). 
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. 
9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
The cohort cut-off for the primary endpoint analysis is estimated to be approximately 8 months 
from the date of the last participant’s first infusion. This would allow the possibility to observe the 
response of the last participant for 6 months, assuming there is a response at first treatment 
assessment. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1.1 Regulatory and ethical considerations 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol.  
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study.  
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
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10.1.9 Study and site start and closure 
Please refer to the master protocol. 
10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Please refer to the master protocol. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Please refer to the master protocol. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol, and in addition to the requirements listed in the master 
protocol: 
France 
Section 1.3 Schedule of Activities (SoA) (Section 1.3)  
In France, serology for HIV will be tested at screening. 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
Please refer to the master protocol. 
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10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol for detailed information about SAR444245, available 
information about pembrolizumab is shown in Table 10. 
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Table 10 - Risk assessment 
Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Infusion-related reactions 
Pembrolizumab 
Common, but infusion-related reactions in 
labeling include drug hypersensitivity, 
anaphylactic reaction, anaphylactoid reaction, 
hypersensitivity and cytokine release 
syndrome.  
Pembrolizumab 
Dose modification and treatment 
guidelines for pembrolizumab 
infusion-related reactions are provided in 
Table 3. 
Hypersensitivity, including 
anaphylaxis 
Pembrolizumab 
Not specifically reported, but included among 
infusion-related reactions in label. 
Exclusion of participants with known 
hypersensitivity to any components of 
pembrolizumab.  
Infections 
Pembrolizumab 
Common: pneumonia. 
See routine mitigation in the master 
protocol. 
Hepatotoxicity 
Pembrolizumab 
Hepatitis occurred in 1.0% of patients, 
including Grade 2, 3 or 4 cases in 0.1%, 0.7% 
and 0.1% patients, respectively, receiving 
pembrolizumab. The median time to onset of 
hepatitis was 3.8 months (range 8 days to 
26.3 months). The median duration was 1.1 
months (range 1 day to 20.9+ months). 
Hepatitis led to discontinuation of 
pembrolizumab in 0.4% patients. Hepatitis 
resolved in 46 patients. 
Dose modification and treatment 
guidelines for liver enzyme increase are 
provided under immune-related reactions 
in Table 6.  
  
Nephrotoxicity 
Pembrolizumab 
Common: nephritis, acute kidney injury. 
Dose modification and treatment 
guidelines for nephrotoxicity are provided 
under immune-related reactions 
in Table 6.  
Neurological AEs 
Pembrolizumab 
Dizziness, headache, neuropathy peripheral, 
dysgeusia (very common) and lethargy 
(common) for pembrolizumab in combination 
with chemotherapy.  
Uncommon: epilepsy. 
Dose modification and treatment 
guidelines for neurological AEs are 
provided under immune-related reactions 
in Table 6. 
Immune-mediated Adverse Events 
Pembrolizumab 
Immune-mediated adverse events are 
designated as important identified risk for 
pembrolizumab. 
Dose modification and treatment 
guidelines for immune-related reactions 
are provided in Table 6. 
Risks related to special 
populations 
 
 
Pregnancy and lactation exposure 
and outcomes 
Pembrolizumab 
Pembrolizumab should not be used during 
pregnancy unless the clinical condition of the 
woman requires treatment with 
pembrolizumab. 
See master protocol for exclusion of 
participants, guidance on highly effective 
contraceptive methods, and pregnancy 
tests to be performed regularly. 
Drug-drug interactions 
No data available. 
 
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Potential risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Overdose and its treatment 
No specific information is available on the 
treatment of overdose of pembrolizumab. 
See Section 6.7 
 
10.11 APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol. 
10.12 APPENDIX 12: GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS 
SYNDROME (TLS) 
Please refer to the master protocol. 
10.13 APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE 
Please refer to the master protocol. 
10.14 APPENDIX 14: ABBREVIATIONS 
 
AE: 
adverse event 
ASCT: 
autologous stem cell transplantation 
BOR: 
best overall response 
cHL: 
classic Hodgkin lymphoma 
COVID-19: 
Corona Virus Disease 2019 
CR: 
complete response 
CRF: 
case report form 
CRS: 
cytokine-release syndrome  
CTLA-4: 
cytotoxic T-lymphocyte-associated protein 4 
DLT: 
dose-limiting toxicity 
ICANS: 
immune cell-associated neurotoxicity syndrome 
IL-2: 
interleukin 2 
IMP: 
investigational medicinal product 
irAE: 
immune-related adverse event 
IRR: 
infusion-related reaction 
IV: 
intravenous 
NHP: 
non-human primate 
ORR: 
objective response rate 
PD1: 
programmed cell death protein 1 
PD-L1: 
programmed cell death-ligand 1 
PR: 
partial response 
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Q3W: 
every 3 weeks 
TIL: 
tumor-infiltrating lymphocyte 
TRAE: 
 treatment-related adverse event 
VLS: 
vascular leak syndrome 
 
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). 
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11 
REFERENCES 
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3. Disis ML. Immune Regulation of Cancer. J Clin Oncol. 2010;28(29):4531-8. 
4. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive 
Cell Transfer Therapy Following Non-Myeloablative but Lymphodepleting Chemotherapy for 
the Treatment of Patients With Refractory Metastatic Melanoma. J Clin Oncol. 
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5. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 
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6. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 Family Revisited. Annu Rev Immunol. 
2005;23:515-48. 
7. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA. 2001;98(24):13866-71. 
8. Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Lorenz M, et al. Structural and Functional 
Analysis of the Costimulatory Receptor Programmed Death-1. Immunity. 2004;20(3):337-47. 
9. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 Associate with 
Immunoreceptor Tyrosine-Based Switch Motif of Programmed Death 1 upon Primary Human 
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10. Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooter, J, et al. PD-1 inhibits T-cell 
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11. Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009;229(1):114-25. 
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CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol. 
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13. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42. 
14. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 
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effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer 
Res. 2004;64(3):1140-5. 
16. Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010:37(5):430-9. 
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augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res. 
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18. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of 
tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored 
IL-2 production and proliferation of CD8(+) T cells directly within the tumor 
microenvironment. J Immunother Cancer. 2014;2:3. 
19. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA. 2010;107(9):4275-80. 
20. Pilon-Thomas S, Mackay A, Vohra N, Mulé JJ. Blockade of programmed death ligand 1 
enhances the therapeutic efficacy of combination immunotherapy against melanoma. J 
Immunol. 2010;184(7):3442-9. 
21. Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in 
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Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr 
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Coronavirus Disease 2019 Infection in a Patient Population with Lung Cancer: Incidence, 
Presentation, and Alternative Diagnostic Considerations. JTO Clin Res Rep. 
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25. Luo J, Rizvi H, Egger JV, Preeshagul IR, Wolchok JD, Hellmann MD. Impact of PD-1 
blockade on severity of COVID-19 in patients with lung cancers. Cancer Discov. 
2020;10(8):1121-8. 
26. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
27. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18. 
28. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
29. Siddall E, Khatri M , Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, 
and management. Kidney Int. 2017 Jul;92(1):37-46. 
30. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11. 
 
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disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 03) 
Protocol title: 
A Phase 2 non-randomized, open-label, multi-cohort, 
multi-center study assessing the clinical benefit of 
SAR444245 (THOR-707) as monotherapy for the 
treatment of adults and adolescents with relapsed or 
refractory diffuse large B-cell lymphoma 
Protocol number: 
ACT16941-S03 
Amendment number: 
01 
Compound number 
(INN/Trademark): 
SAR444245 
(Not applicable) 
Brief title: 
A study of SAR444245 monotherapy for the treatment of 
adults and adolescents with DLBCL 
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: 
156112 
EudraCT: 
2021-002150-91 
NCT: 
NCT05179603 
WHO: 
U1111-1251-5834 
Date: 
28-Apr-2022 
Total number of pages: 58 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 01 
(Substudy 03) 
All 
28 April 2022, version 1 
(electronic 1.0) 
Clinical Trial Protocol (Substudy 03) 
16 July 2021, version 1 
(electronic 1.0) 
 
Amended protocol 01 (28 April 2022) 
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 main rationale for this amendment is to: (1) change the SAR444245 dosing schedule (from 
one injection every 21 days [21 days a cycle] to one injection every 14 days [14 days a cycle]) in 
order to
; and (2) in response to requests from the French Health 
Authority (National Agency for the Safety of Medicines and Health Products [ANSM]) after 
initial review. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover page 
The NCT number has been added. 
This study has been registered on 
clinicaltrials.gov, the NCT number is 
applicable. 
1.1 Synopsis-Rationale, 
Brief summary; 2 
Introduction; 4.1 Overall 
design 
Trial participants in this study have been updated 
from “must have received at least 2 lines of 
systemic therapy and are post-CAR-T treatment” 
to “must have received at least 2 lines of systemic 
therapy and have either stable or progressive 
disease 1-3 months after receiving a Health 
For clarity and consistency. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Authority approved CAR-T therapy”. 
1.1 Synopsis- 
Objectives and 
endpoints, Statistical 
considerations; 3 
Objectives and 
endpoints; 9.4.3 
Secondary endpoint (s) 
For the secondary endpoints “
 has been changed to 
and
has been 
removed. 
Program level alignment. 
1.1 Synopsis-Brief 
summary; 4.1 Overall 
design 
The DLT observation period for Cohort C1 has 
been changed from “21 days” to “28 days”. 
To align with the Cohort C1 Q2W dosing. 
1.1 Synopsis-Study 
interventions 
SAR444245 dosing schedule has been changed 
from “every 3 weeks on Day 1” to “every 2 weeks 
on Day 1”. 
1.2 Schema 
The Graphical study design for Cohort C1 has 
been updated with the instruction for FDG-PET. 
For clarity. 
1.2 Schema, 1.3 
Schedule of activities 
(SOA) 
For the treatment period, the previous “Cycle 2-8” 
has been changed to “Cycle 2-16”, and previous 
“Cycle 9-52” has been changed to “Cycle 17-52”. 
To align with the Cohort C1 Q2W dosing. 
1.3 Schedule of 
activities (SOA) 
D14/D15 visit has been removed for Cycle 1. The 
time window for D1 from Cycle 2 has been 
changed from 3 days to 2 days. 
For the treatment period, the previous “Cycle 2-8” 
has been changed to “Cycle 2-16”. 
To align with the Cohort C1 Q2W dosing. 
The assessment of troponin level has been 
added. 
For footnote “d”, the following sentence 
“Information on the first subsequent anticancer 
treatment, best reported response, and date of 
progression will also be collected” has been 
deleted. 
To allow assessment of any potential 
cardiotoxicity. 
Reduction in protocol complexity and 
patient/site burden. 
Footnote “e” has been newly added for 
clarification on C1D2, D3 visits. Other footnotes 
are re-numbered accordingly. 
For footnote “f” (previous footnote e) and footnote 
“h” (previous footnote g), C1D15 visit has been 
removed. 
For footnote “h” (previous footnote g), data 
collection for blood chemistry/ hematology on Day 
For clarity. 
To align with the Cohort C1 Q2W dosing. 
To align with the Cohort C1 Q2W dosing. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1 of every cycle up to Cycle 12 has been change 
to “up to Cycle 24”. 
For footnote “i” (previous footnote h), tumor lysis 
laboratory tests on C1D1 have been changed 
from “for all participants” to “for safety run-in 
participants or participants who are hospitalized”. 
For clarity. 
1.3 Schedule of 
Activities (SOA), and 
10.7 Appendix 7: 
Country-Specific 
Requirements 
Requirement of human immunodeficiency virus 
(HIV) has been added at screening for participants 
in France and specified in SOA newly added 
footnote “m” and country-specific requirements 
sections. 
Regulatory Authority (ANSM) request. 
1.5 Pharmacokinetic 
flowcharts 
ADA sampling on C1D15 has been changed to 
C1D8. 
To align with the Cohort C1 Q2W dosing. 
2.2.1 Pre-clinical trials 
Rationale behind changing the dosing schedule 
from every 21 days to every 14 days for Cohort 
C1 has been added. 
A new reference (Reference 4) has been added 
and the subsequent references have been 
renumbered. 
To update 
 and 
rationale of dose changing. 
5.1 Inclusion criteria 
For I01 cancer diagnosis at study entry, 
“cytologically” has been removed from confirmed 
diagnosis of DLBCL. 
Typographical error corrected. 
5.1 Inclusion criteria 
For I02 Prior anticancer therapy, “patients must 
have BOR of stable disease (SD) or progressive 
disease (PD) after a Health Authority approved 
CD19-directed CAR-T therapy” has been added. 
“If more than 3 months have passed since the 
CAR-T therapy the Investigator can discuss the 
patient on a case by case basis with the Sanofi 
Medical Monitor.” Has been added to the second 
bullet. “No other systemic anti-lymphoma therapy 
may have been administered between the 
completion of CAR-T therapy” has been changed 
to  “… between the infusion of CAR-T therapy”. 
For clarity. 
5.1 Inclusion criteria 
The following sentence has been added "For I04 
in the master protocol, the contraception period for 
female participant who is a WOCBP can be during 
the intervention period (to be effective before 
Shorten the minimum contraception period to 
1 week for female participants with 
SAR444245 monotherapy. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
starting the intervention) and for at least 7 days 
[corresponding to the time needed to eliminate 
any study intervention(s)] after the last dose of 
study intervention" to specify  the contraception 
requirement for women who is a WOCBP for 
Cohort C1. 
5.2 Exclusion criteria 
Specific requirement for Cohort C1 has been 
added for E11 related criteria in the master 
protocol. 
To allow a participant with Grade 2 cytopenia 
or Grade 2 hypogammaglobinemia to be 
included in substudy 03. 
6.1.1 Investigational 
medicinal product 
The table for overview of IMP administered has 
been added without referring to the master 
protocol. 
To align with the Cohort C1 Q2W dosing. 
6.5.2 Dose delay and 
dose omission 
The section has been updated to clarify the 
treatment windows within a cycle, and the dose 
delay and omission rules. The title of the section 
has been renamed as “Dose delay and dose 
omission” accordingly.  
To align with the Cohort C1 Q2W dosing. 
1.4 Biomarker flowchart, 
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome 
(CRS); 6.5.4.4 Immune 
cell-associated 
neurotoxicity syndrome 
(ICANS) 
The following statement “alternative therapies per 
site practice in CRS management” has been 
added to “tocilizumab”. 
For flexibility following tocilizumab availability. 
6.5.4.3 Fever, flu-like 
symptoms and cytokine-
release syndrome 
(CRS) 
In Table 4, the following sentence has been 
deleted 
i
 
For consistency with instructions given in 
Section 6.5.1 General rules. 
Regulatory Authority (ANSM) request. 
6.5.4.6 Tumor Lysis 
Syndrome (TLS) 
Tumor lysis laboratory tests on C1D1 have been 
changed from “for all participants” to “for safety 
run-in participants or participants who are 
hospitalized”. 
For clarity and consistency. 
9.4.4 Exploratory 
endpoint(s) 
Section has been newly added with subsection of 
. 
For consistency. 
10.1.6 Dissemination of 
clinical study data 
The following sentence has been added “Study 
participants results summaries will be provided in 
any one of the clinical trial portals after completion 
of the substudy, until the end of study”.   
Per CTFG guidance 2019: Recommendation 
Paper on the Initiation and Conduct of 
Complex Clinical Trials. 
10.8 Appendix 8: 
Criteria for response 
Reference to master protocol has been deleted 
and Table 8 - Overall disease response has been 
For clarity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
assessment response 
was added 
added. 
Throughout 
The duration for each cycle has been changed 
from “21 days” to “14 days”. 
The total number of cycles has been changed 
from “35 cycles” to “52 cycles”. 
To align with the Cohort C1 Q2W dosing. 
Throughout 
“Study Committee” has been changed to “Study 
Board”.  
Harmonization per Sanofi standard 
terminology. 
Throughout 
Minor editorial updates. 
For clarity and consistency. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 (SUBSTUDY 03) .................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 16 
1.2.1 
Study design for Cohort C1 ............................................................................................................ 16 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 17 
1.4 
BIOMARKER FLOWCHARTS ....................................................................................................... 29 
1.5 
PHARMACOKINETIC FLOWCHARTS .......................................................................................... 30 
2 
INTRODUCTION ............................................................................................................................ 31 
2.1 
STUDY RATIONALE...................................................................................................................... 31 
2.2 
BACKGROUND ............................................................................................................................. 31 
2.2.1 
Pre-clinical trials ............................................................................................................................. 31 
2.2.2 
Rationale for B cell lymphoma and selected participant population .............................................. 31 
2.2.3 
Current standard of care in DLBCL ................................................................................................ 32 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 32 
2.3.1 
Risk assessment ............................................................................................................................ 32 
2.3.2 
Benefit assessment ........................................................................................................................ 32 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 32 
2.3.4 
Benefits and risks assessment in the context of COVID-19 pandemic ......................................... 32 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 33 
4 
STUDY DESIGN ............................................................................................................................ 34 
4.1 
OVERALL DESIGN ........................................................................................................................ 34 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 34 
4.2.1 
Participant input into design ........................................................................................................... 34 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 34 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 34 
5 
STUDY POPULATION .................................................................................................................. 35 
5.1 
INCLUSION CRITERIA .................................................................................................................. 35 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 36 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 36 
5.4 
SCREEN FAILURES...................................................................................................................... 36 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 36 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 37 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 37 
6.1.1 
Investigational medicinal product ................................................................................................... 37 
6.1.2 
Non-investigational medicinal products ......................................................................................... 38 
6.1.3 
Hydration guidelines for SAR444245 administration ..................................................................... 38 
6.1.4 
Readiness for treatment of severe cytokine release syndrome ..................................................... 38 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 38 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 38 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 38 
6.5 
DOSE MODIFICATION .................................................................................................................. 38 
6.5.1 
General rules .................................................................................................................................. 38 
6.5.2 
Dose delay and dose omission ...................................................................................................... 39 
6.5.3 
General guidelines for the management of treatment-related adverse events ............................. 39 
6.5.4 
Guidelines for the management of specific adverse events .......................................................... 40 
6.5.4.1 
Infusion-related reactions (IRR) ..................................................................................................... 40 
6.5.4.2 
Anaphylaxis .................................................................................................................................... 42 
6.5.4.3 
Fever, flu-like symptoms and cytokine-release syndrome (CRS) .................................................. 42 
6.5.4.4 
Immune Cell-Associated Neurotoxicity Syndrome (ICANS) .......................................................... 44 
6.5.4.5 
Vascular Leak Syndrome (VLS) ..................................................................................................... 45 
6.5.4.6 
Tumor Lysis Syndrome (TLS) ........................................................................................................ 47 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 47 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 47 
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6.8 
CONCOMITANT THERAPY .......................................................................................................... 47 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 48 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 48 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 49 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 49 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 49 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 49 
8.4 
PHARMACOKINETICS .................................................................................................................. 49 
8.5 
PHARMACODYNAMICS ............................................................................................................... 49 
8.6 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 49 
8.7 
BIOMARKERS ............................................................................................................................... 49 
8.8 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 50 
8.9 
HEALTH ECONOMICS .................................................................................................................. 50 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 50 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 51 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 51 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 51 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 52 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 52 
9.4.1 
General considerations .................................................................................................................. 52 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 52 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 52 
9.4.3.1 
Complete response rate (CRR) ..................................................................................................... 52 
9.4.4 
Exploratory endpoint(s) .................................................................................................................. 52 
9.4.4.1 
 ................................................................................................................................ 52 
9.5 
INTERIM ANALYSES .................................................................................................................... 53 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 54 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 54 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 54 
10.1.2 
Financial disclosure........................................................................................................................ 54 
10.1.3 
Informed consent process .............................................................................................................. 54 
10.1.4 
Data protection ............................................................................................................................... 54 
10.1.5 
Committees structure ..................................................................................................................... 54 
10.1.6 
Dissemination of clinical study data ............................................................................................... 54 
10.1.7 
Data quality assurance .................................................................................................................. 54 
10.1.8 
Source documents ......................................................................................................................... 54 
10.1.9 
Study and site start and closure ..................................................................................................... 55 
10.1.10 Publication policy ........................................................................................................................... 55 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 55 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 55 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 55 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 55 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 55 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 55 
10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT........................................................ 56 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 56 
10.10 
APPENDIX 10: RISK ASSESSMENT ............................................................................................ 56 
10.11 
APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS .................................................. 56 
10.12 
APPENDIX 12: GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS SYNDROME 
(TLS) .............................................................................................................................................. 57 
10.13 
APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE .................................. 57 
10.14 
APPENDIX 14: ABBREVIATIONS ................................................................................................. 57 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY ................................................................ 57 
11 
REFERENCES ............................................................................................................................... 58 
 
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LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 33 
Table 2 - Overview of IMP administered ....................................................................................................... 37 
Table 3 - SAR444245 Infusion-related reaction dose modification and treatment guidelines ...................... 41 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS) ........................ 42 
Table 5 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome (ICANS) ... 44 
Table 6 - Guidelines for the management of Vascular Leak Syndrome (VLS) ............................................. 46 
Table 7 - Cohort C1: Estimated objective response rate (ORR) depending on number of responders ....... 51 
Table 8 – Overall disease response .............................................................................................................. 56 
 
LIST OF FIGURES 
Figure 1 - Overall study schema ................................................................................................................... 14 
Figure 2 - Graphical study design-Cohort C1 ................................................................................................ 16 
 
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1 
PROTOCOL SUMMARY 
Please refer to the Master Protocol for description of common protocol elements. Substudy 
specific protocol elements are described below. 
1.1 
SYNOPSIS 
Protocol title:  
A Phase 2 non-randomized, open-label, multi-cohort, multi-center study assessing the clinical 
benefit of SAR444245 (THOR-707) as monotherapy for the treatment of adults and adolescents 
with relapsed or refractory diffuse large B-cell lymphoma 
Brief title: 
A study of SAR444245 monotherapy for the treatment of adults and adolescents 
with DLBCL 
Rationale: 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 as 
monotherapy in trial participants with diffuse large B-cell lymphoma (DLBCL). Trial participants 
in this study must have received at least 2 lines of systemic therapy and have either stable or 
progressive disease 1-3 months after receiving a Health Authority approved CAR-T therapy.  
Objectives and endpoints  
Please refer to the master protocol for descriptions of common objectives and endpoints. 
Substudy-specific objectives and endpoints are summarized below. 
  
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245. 
• 
Objective response rate (ORR) defined as the 
proportion of participants who have complete 
response (CR) or partial response (PR) determined 
by Investigator per Lugano response criteria 2014 
(1). 
Secondary 
 
• 
To assess other indicators of antitumor activity. 
• 
Complete response rate (CRR) defined as the 
proportion of participants who have a CR 
determined by Investigator per Lugano response 
criteria 2014 (1). 
 
 
 
 
 
 
Overall design: 
Please refer to the master protocol. 
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Brief summary:  
Cohort C1: This substudy will include approximately 25 participants with DLBCL who have 
received at least 2 lines of systemic therapy and have either stable or progressive disease 1-3 
months after receiving a Health Authority approved CAR-T therapy. The substudy will assess 
SAR444245 monotherapy as at least 3rd line of therapy. 
A graphical presentation of the substudy schema is shown in Figure 1. 
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Figure 1 - Overall study schema  
 
a The DLT observation period is 28 days for Cohort C1. 
b Including participants enrolled in the safety run-in at the confirmed safe dose. 
Abbreviations: 3L: third-line; CAR-T: chimeric antigen receptor T-cell immunotherapy; DLBCL: diffuse large B cell lymphoma; DLT: dose-limiting toxicities; N: number. 
 
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Number of participants: 
Overall, 25 participants will be treated in Cohort C1. 
Intervention groups and duration: 
Please refer to the master protocol for common descriptions of the study duration. For Cohort C1, 
the maximum cycles allowed are 52 cycles. 
Study interventions 
Cohort C1: DLBCL participants with stable disease or progressive disease 1-3 months after 
receiving a Health Authority approved CAR-T as at least 3L therapy 
Dosing sequence: premedication for SAR444245 (30 to 60 minutes prior to start of SAR444245 
infusion), and SAR444245. 
Investigational medicinal products 
SAR444245  
SAR444245 formulation and route of administration as described in the master protocol.  
• 
Dose regimen: 24 μg/kg administered (or reduced to 
 μg/kg or another lower dose level 
recommended by Study Board) as an IV infusion over 30 minutes every 2 weeks on Day 1 
of each cycle (14 days per cycle) for up to 52 cycles. 
Non-investigational medicinal products 
Please refer to the master protocol. 
Statistical considerations: 
Please refer to the master protocol for descriptions of common statistical considerations. 
Substudy-specific analyses are summarized below. 
• 
Analysis of primary endpoint:  
- 
The objective response rate (ORR) will be summarized for the efficacy population 
with descriptive statistics. In addition, two-sided 90% CIs for ORR will be computed 
using the Clopper-Pearson method. 
• 
Analysis of secondary efficacy endpoints: 
- 
The complete response rate (CRR) will be summarized for the efficacy population with 
descriptive statistics. In addition, two-sided 90% CIs for CRR will be computed using 
the Clopper-Pearson method. 
Data Monitoring/Other Committee: Yes 
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1.2 
SCHEMA 
1.2.1 Study design for Cohort C1 
Figure 2 - Graphical study design-Cohort C1 
 
 
C=Study cycle (1 cycle = 14 days); D=Study Day; EOT=end of treatment; IMP=Investigational medicinal product; FDG-PET=fluorodeoxyglucose-positron emission tomography; Q9W=every 9 weeks; Q12W=every 12 
weeks. 
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Informed 
consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT contact 
X 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Demography, 
medical/surgica
l and disease 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See 
Section 8 
in the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Performance 
status (ECOG 
or Lansky 
Scale) 
X 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
 
 
 
See 
Appendix 
13 in the 
master 
protocol 
Body 
weight/Heightg 
X 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Full physical 
examination  
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Directed 
physical 
examination 
 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
See 
Section 
8.2.1 in 
the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
See 
Section 
8.2.2 in 
the 
master 
protocol 
SpO2h 
X 
As clinically indicated 
 
 
 
 
 
 
Bone marrow 
biopsy 
  
As clinically indicated to confirm complete response 
 
 
 
See 
Section 
8.1 in the 
master 
protocol  
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Spleen 
measurement 
X 
As clinically indicated to evaluate response 
 
 
 
See 
Section 
8.1 in the 
master 
protocol 
12-Lead ECG   
X 
As clinically indicated 
 
 
 
See 
Section 
8.2.3 in 
the 
master 
protocol 
LVEF 
X 
As clinically indicated 
 
 
 
See 
Section 
8.2.3 in 
the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Troponin 
X 
As clinically indicated 
X 
 (Cycle 4 Day 1) 
As clinically indicated 
 
 
 
See 
Section 
8.2.3 and 
Section 
10.2 in 
the 
master 
protocol 
Pregnancy test 
X 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
 
See 
Section 
8.2.5 and 
Section 
10.2 in 
the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Blood 
chemistryh 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
See 
Section 
10.2 in 
the 
master 
protocol 
Tumor Lysis 
Laboratory 
Testsi 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Hematologyh 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
T3, FT4, TSH 
and cortisolj  
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
See 
Section 
10.2 in 
the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Coagulationk 
X 
As clinically indicated 
X 
 
 
 
See 
Section 
10.2 in 
the 
master 
protocol 
Urinalysisl  
X 
On C1D1 and C2D1, then as clinically indicated 
X 
 
 
 
See 
Section 
10.2 in 
the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Hepatitis 
serology, CD4+ 
counts and viral 
load 
Xm 
As clinically indicated 
 
 
 
See 
Section 
10.2 in 
the 
master 
protocol 
IMP 
 
X 
 
 
 
X 
 
X 
 
 
 
 
 
 
Hospitalizationo  
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
AE/SAE 
assessmentp 
X 
Continuous throughout treatment period 
X 
 
 
 
See 
Section 
8.3 in the 
master 
protocol 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Prior/Concomit
ant Meds 
Xn 
Continuous throughout treatment period 
 
 
 
 
See 
Section 
6.8 in the 
master 
protocol 
First 
subsequent 
anti-cancer 
therapy 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pharmacokinetic (PK) / Pharmacodynamic (PD) / Immunogenicity assessments 
 
PK 
See PK Flow-Charts in Section 1.5 
 
ADA 
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
PDy - Blood 
and tumor 
tissue 
collectionr 
See Biomarker Flow-Chart in Section 1.4 
 
Tumor assessment  
 
CT/MRIq 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
X 
 
See 
Section 
8.1.1 in 
the 
master 
protocol  
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Evaluationa 
Screenin
g  
 
Treatment Periodb 
End of 
treatment 
Observation periodc 
Surviva
l phone 
call 
follow-
up 
periodd 
Notes 
 
Cycle 1 
Cycle 2-16 
Cycle  
17 – 52 
EOT visit 
Follow-
up visit 1 
Follow-
up visit 2 
Follow-
up visit 3 
and 
beyond 
Phone 
call 
Follow-
up 
Cycle day  
D-28 to D-1 
D
1 
D
2e 
D
3e 
D
8f 
 
D1(±
2 
days) 
D
8 
 
D1(±
2 
days) 
 
30 (±7) days 
after last IMP 
admin or 
prior to 
initiation of 
further 
therapy 
3 months 
(±7 
days) 
after last 
IMP 
admin 
6 months 
(±7 days) 
after last 
IMP 
admin 
Every 3 
months 
±7 days 
Every 3 
months 
±14 
days  
 
Brain imagings 
If clinically 
indicated 
 
 
 
 
 
 
 
 
 
 
 
 
See 
Section 
8.1.1 in 
the 
master 
protocol  
FDG-PETq 
X 
As clinically indicated, and must be performed for the 9-week and 18-week on-treatment assessments  
 
 
 
See 
Section 
8.1.1 in 
the 
master 
protocol  
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 2 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. 
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b Cycle: A treatment cycle is 14 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 study treatment discontinuation. See Section 4.1 of the master 
protocol. For participant’s convenience, all Follow-up assessments may occur during the same visit as that when tumor assessment is performed. 
d Survival Phone Call Follow-Up Period: Once the participant stops the tumor assessments due to PD or starts a new antineoplastic therapy, the participant moves into the Survival Follow-up Period and should be 
contacted by telephone approximately every 3 months ±14 days to assess for survival status. Updated survival status may be requested by the Sponsor at any time during the study. 
e Visits on C1D2, D3 are for safety-run in participants only. 
f 
C1D8 visit must be performed on site only for participants enrolled in the Safety run-in and participants scheduled to have blood draws for biomarker assessment on Day 8. For all other participants, this on-site 
visit 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. Study Board may 
decide to cancel safety assessment on C1D8, upon agreement with Sponsor, if safety data justify it.  
g Weight/Height: Height is required at baseline only for patients > or =18 years old. For trial participants <18 years old, height should be assessed on day 1+/-1 of each cycle. Weight is required at Screening and 
prior to starting each infusion. The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a reasonable time frame according to 
Investigator assessment. Study sites should make every effort to measure body weight as close to the infusion day as possible considering the variability of local process from site to site. If the infusion is prepared 
with the most recent weight assessed in a reasonable time frame, this will not prevent to assess the weight on D1 of each cycle. 
h Blood chemistry/ hematology will be performed weekly on D1 pre-dose and D8 during Cycle 1, then on Day 1 of every cycle up to Cycle 24, then every other cycle during Treatment Phase. Visits and assessments 
on C1D2-D3 are only for participants in the safety run-in or participants who are hospitalized because of high tumor burden or at investigator’s discretion.  For these participants, vital signs, SpO2 and complete 
blood counts (CBC) and differentials, chemistries (blood urea nitrogen (BUN), creatinine (Cr), alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (Alk Phos), total bilirubin (TBil) will 
be obtained daily. 
i 
Tumor lysis laboratory tests (corrected calcium, magnesium, phosphate, uric acid, and lactate dehydrogenase [LDH] levels) will be obtained every 8 hours on C1D1 for safety run-in participants or participants who 
are hospitalized, and C1D2-D3 for safety run in or participants who are hospitalized because of high tumor burden or at Investigator’s discretion.  
j 
Endocrine function tests will be performed every 2 cycles throughout the entire treatment period and at EOT. During the Observation Period, they will be performed at Follow-Up Visit 1. They can also be performed 
as clinically indicated. 
k Coagulation includes international normalized ratio (INR), prothrombin time (PT) and activated partial thromboplastin time (aPTT). 
l 
Urinalysis will be performed on C1D1 and C2D1, then as clinically indicated during the treatment period, and will be performed at Follow-Up Visit 1. 
m For participants with known HIV, hepatitis B and hepatitis C infection under antiviral treatment to confirm controlled infection, and for all participants in France (see details and specific instructions in Section 10.2 
and Section 10.7 in the master protocol, and Section 10.6 in this substudy 03). 
n Prior medications that are received within 30 days before the first dose of IMP. 
o Hospitalization for 48 h for safety run-in participants or for participants with a high tumor burden or at investigator’s discretion. 
p AE/SAE assessment: Severity will be graded according to NCI-CTCAE v 5. ICANS and CRS will be graded using ASTCT criteria integrated with central laboratory cytokine results (2).   
q The initial tumor imaging FDG-PET CT and/or MRI 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. FDG-PET 
must be performed for the 9-week and 18-week on-treatment assessments. 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 and follow-up assessments.  
r 
If a tumor biopsy was obtained from a target lesion during eligibility assessment, it is preferred to obtain a new baseline scan. Tumor biopsy should be considered for new lesions if their pathologic etiology is 
ambiguous. 
s Brain CT/MRI: To be performed if clinically indicated.   
Abbreviations: ADA = Anti-drug antibodies; AE = Adverse event; ASTCT = American Society for Transplantation and Cellular Therapy; C = Cycle; CT = Computed tomography; D = Day; ECG = Electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = End-of-treatment; FDG-PET = fluorodeoxyglucose-positron emission tomography; 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; PD = Progressive disease; PDy = 
Pharmacodynamic; PK = Pharmacokinetic; Q2W = Every 2 weeks; SAE = Serious adverse event; TSH = Thyroid stimulating hormone. 
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1.5 
PHARMACOKINETIC FLOWCHARTS 
Cycle 
Treatment Cycle 1 
Treatment Cycle 2, 4, 
7, 10 + every 5th cycle 
EOT visit 
Day 
D1 
D2 
D3 
D8 
D1 
30 (±7) days after last 
IMP administration 
Time after start of 
SAR444245 dosing 
[h] 
SOI 
EOI  
4h post 
EOI  
At any time 
At any time 
At any time 
SOI 
EOI 
At any time 
SAR444245 PK 
sample  
 
P00b  
P01 
P02c 
P03c 
 
 
P00b  
 
SAR444245 ADA 
sample  
AB00a 
 
 
 
AB01 
AB00a 
 
ABF00 
 
 
 
 
 
 
a Samples collected strictly before start of infusion (SOI). ADA sampling may be discontinued by the Sponsor once sufficient data have been collected. 
b PK sample must be taken at the end of infusion (EOI) after flush.  
c P02 and P03 to be collected during safety run-in and when participants are hospitalized. 
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 4 h after interruption. If infusion is resumed, a (further) PK sample should be drawn at end of resumed infusion and subsequent sample should be 
drawn at 0.5 h after end of resumed infusion. PK sampling may be discontinued by the Sponsor once sufficient data have been collected. 
Abbreviations: ADA: anti-drug antibodies; D: day; EOT: end of treatment; PK: pharmacokinetic. 
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2 
INTRODUCTION 
Study ACT16941 is developed as a master protocol in order to accelerate the investigation of 
SAR444245 with or without various anticancer therapies by identifying early signals. The 
information that is common to all cohorts is included in the master protocol, and this substudy 
provides details specific to Cohort C1 (participants with DLBCL who have received at least 2 
lines of systemic therapy and have either stable or progressive disease 1-3 months after receiving 
a Health Authority approved CAR-T therapy) for SAR444245 monotherapy. 
Please refer to the master protocol for an introduction for ACT16941.    
2.1 
STUDY RATIONALE 
Preclinical studies demonstrated that treatment with SAR444245 leads to polyclonal expansion of 
CD8+ T cells in murine and NHP models. Furthermore, recombinant IL-2 has been shown to 
enhance T cell activation and proliferation. For these reasons, 
.  
2.2 
BACKGROUND 
2.2.1 Pre-clinical trials 
Additional preclinical studies support the role of IL-2 in promoting engineered T cells to eliminate 
tumors and demonstrate enhancement of antibody drug-dependent cellular cytotoxicity (ADCC). 
Studies in mouse models demonstrate that recombinant IL-2 (NKTR-214), given as a single agent, 
expands adoptively transferred T cells (engineered with TCR targeting murine melanoma antigen, 
p100) leading to a reduction in melanoma tumor burden in a mouse model (3).   
Based on these observations in 
vitro, as well on the previously reported results from pembrolizumab for B-cell lymphomas 
refractory or relapsed (BCL R/R) to CD19-directed CAR-T therapy (4),
 
2.2.2 Rationale for B cell lymphoma and selected participant population  
Please refer to Section 2.2.1 of the master protocol. 
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2.2.3 Current standard of care in DLBCL 
At diagnosis, patients usually receive multiagent chemoimmunotherapy including an 
anthracycline, rituximab, and prednisone (eg, R-CHOP, dose adjusted R-EPOCH, or R-ICE) with 
or without radiotherapy.  For refractory disease, or at first relapse, transplant-eligible patients are 
referred for autologous stem cell transplant.  Transplant-ineligible patients will be offered 
rituximab containing combinations, such as RGemOx or the recently approved combinations: 
polatuzumab vedotin (Polivy)+bendamustine+rituximab or rituximab+tafasitamab (Monjuvi), or 
are offered participation in a clinical trial. Eligible patients with relapsed or refractory disease, 
following two or more lines of therapy, are offered CD19-directed CAR-T cell therapy, (eg.  
tisagenlecleucel [Yescarta], axicatbtagene ciloleucel [Kymriah], or lisocabtagene maraleucel 
[Breyanzi]), selinexor (Xpovio), or autologous or allogeneic stem cell transplantation, or 
enrollment in a clinical trial (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 
Please refer to the master protocol. 
2.3.2 Benefit assessment 
Please refer to the master protocol.  
The regimen proposed to be evaluated in this substudy is anticipated to bring benefit to patients 
with DLBCL post CAR-T. 
2.3.3 Overall benefit: risk conclusion 
Please refer to the master protocol.  
2.3.4 Benefits and risks assessment in the context of COVID-19 pandemic 
Please refer to the master protocol.   
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3 
OBJECTIVES AND ENDPOINTS 
Please refer to the master protocol for descriptions of common objectives and endpoints. 
Substudy-specific objectives and endpoints are summarized below. 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To determine the antitumor activity of SAR444245. 
• 
Objective response rate (ORR) defined as the 
proportion of participants who have complete 
response (CR) or partial response (PR) 
determined by Investigator per Lugano response 
criteria 2014 (1). 
Secondary 
 
• 
To assess other indicators of antitumor activity. 
• 
Complete response rate (CRR) defined as the 
proportion of participants who have a CR 
determined by Investigator per Lugano response 
criteria 2014 (1). 
 
 
Exploratory  
 
 
                                                                                             
 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
Please refer to the master protocol. 
 
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This substudy will include approximately 25 participants with diffuse large B cell lymphoma 
(DLBCL) who have received at least 2 lines of systemic therapy and have either stable or 
progressive disease 1-3 months after receiving a Health Authority approved CAR-T therapy. The 
substudy will assess SAR444245 monotherapy as at least 3rd line of therapy.  
Please refer to the master protocol for a full description of the study design, and for details 
applicable to all therapy cohorts. 
A graphical presentation of the study schema is shown in Figure 1. 
The dose-limiting toxicity (DLT) observation period is 28 days for Cohort C1. The maximum 
cycles allowed in this substudy for Cohort C1 are 52 cycles.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The proposed study aims to establish proof-of-concept that non-alpha IL-2 SAR444245 as 
monotherapy in trial participants with DLBCL. 
The design of the study is a non-randomized study where the monotherapy will be assessed in a 
single cohort, using historical data for single agent as a benchmark to show outstanding objective 
response rate. The ORR will be assessed using Lugano response criteria 2014 for participants with 
DLBCL.  
Please refer to the master protocol for more information. 
4.2.1 Participant input into design 
Please refer to the master protocol. 
4.3 
JUSTIFICATION FOR DOSE 
Please refer to the master protocol.  
4.4 
END OF STUDY DEFINITION 
Please refer to the master protocol. 
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5 
STUDY POPULATION 
See the master protocol for a full list of common inclusion and exclusion criteria and the 
subsections below for Cohort C1 specific criteria. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply (in 
addition to the criteria listed in the master protocol): 
Type of participant and disease characteristics 
I 01. Cancer diagnosis at study entry:  
Histologically confirmed diagnosis of diffuse large B Cell lymphoma (DLBCL), according 
to the WHO 2016 classification. 
I 02. Prior anticancer therapy:  
- 
Must have received at least two prior lines of systemic therapy for DLBCL, including 
one containing a combination of anthracycline and rituximab (or another anti-CD20 
agent), with the last line of therapy a Health Authority approved CD19-directed CAR-
T therapy.   
- 
Patients must have BOR of stable disease (SD) or progressive disease (PD) 
after a Health Authority approved CD19-directed CAR-T therapy. 
- 
1 to 3 months must have passed between the administration of the Health 
Authority approved CAR-T therapy and start of treatment in this trial. If more 
than 3 months have passed since the CAR-T therapy the Investigator can 
discuss the patient on a case by case basis with the Sanofi Medical Monitor.  
- 
No other systemic anti-lymphoma therapy may have been administered 
between the infusion of CAR-T therapy and enrollment in the trial.  
- 
All CAR-T related adverse events must have resolved to grade 1 or less, and 
participant must meet all other eligibility criteria.   
- 
May have received a prior autologous or allogeneic stem cell transplant but must be at 
least ≥100 days post-auto-transplant, and all transplant- related adverse events must 
have resolved to grade 1 or less, and meet all other eligibility criteria. 
Sex, contraceptive/barrier method and pregnancy testing requirements 
For I04 in the master protocol, the contraception period for female participant who is a WOCBP 
can be during the intervention period (to be effective before starting the intervention) and for at 
least 7 days [corresponding to the time needed to eliminate any study intervention(s)] after the last 
dose of study intervention. 
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5.2 
EXCLUSION CRITERIA  
Please refer to the master protocol.  
Due to the nature of the disease and prior treatment, a participant with Grade 2 cytopenia or Grade 
2 hypogammaglobinemia, who should be excluded per E11 in the master protocol, will be allowed 
to be included. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Please refer to the master protocol. 
5.4 
SCREEN FAILURES 
Please refer to the master protocol. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION 
Please refer to the master protocol. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Please refer to the master protocol. 
The maximum cycles allowed in this substudy for Cohort C1 are 52 cycles.  
Dosing sequence: premedication for SAR444245 (30 to 60 minutes prior to start of SAR444245 
infusion), and SAR444245. 
6.1.1 Investigational medicinal product 
Investigational medicinal product (IMP) is defined as SAR444245 administered as described in 
Section 4.1 of the master protocol. Details of are shown in Table 2.  
Preparation and administration of IMP are detailed in the pharmacy manual. Hydration is required 
for SAR444245 infusions. Details are provided in Section 6.1.3 of the master protocol. 
Table 2 - Overview of IMP administered 
Intervention name 
SAR444245 
Type 
Biologic 
Dose formulation 
Concentrate for solution for infusion 
Unit dose strength(s) 
2.0 mg/mL 
Dosage level(s)a  
24 μg/kg (or reduced to 
 μg/kg or another lower dose level recommended by Study Board) 
Q2W 
Route of 
administration 
IV infusion 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and 
labeling 
Supplied in a single-dose vial in a treatment box. Each vial contains 2 mg/mL with an extractable 
volume of 1 mL. Each vial and treatment box will be labeled as required per country requirement. 
Current/Former 
name(s) or alias(es) 
NA 
a The total dose will be calculated based on the weight on the day of the infusion or the most recent weight assuming it was assessed in a 
reasonable time frame according to Investigator assessment. Study sites should make every effort to measure body weight as close to the 
infusion day as possible considering the variability of local process from site to site. If the infusion is prepared with the most recent weight 
assessed in a reasonable time frame, the participant must still be weighed on D1 of each cycle, and the weight recorded in the e-CRF. Study 
sites should make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted.
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6.1.2 Non-investigational medicinal products 
Please refer to the master protocol. 
6.1.3 Hydration guidelines for SAR444245 administration  
Please refer to the master protocol. 
6.1.4 Readiness for treatment of severe cytokine release syndrome  
Please refer to the master protocol. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Please refer to the master protocol. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
Please refer to the master protocol. 
6.5 
DOSE MODIFICATION 
6.5.1 General rules  
Dose modification for SAR444245 is permitted according to the guidelines described in this 
section. 
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor, unless required for immediate participant safety. 
Cycle delay (ie, Day 1 should be delayed for the IMP) is permitted in case of treatment-emergent 
adverse event (TEAE). Dose modification will be made according to the worst grade of toxicity 
observed within a cycle. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative recommended dose adjustment should be followed. 
Once a dose has been decreased, intra-patient re-escalation back to the previous dose level is not 
permitted. 
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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. 
All changes to study treatment administration must be recorded in the electronic case report form 
(e-CRF). 
6.5.2 Dose delay and dose omission 
Within a cycle, the treatment windows are: 
• For the Q2W administration, the Cn+1 (±2 days), dose is deemed to have been delayed if 
the treatment is ≥3 days beyond the theoretical day of treatment.  
• The reason for the dose delay will be captured. If the reason for the dose delay is an 
adverse event, the participant will receive the next infusion after recovery of the AE as 
described in Section 6.5.2 and Section 6.5.3 
Participants may have dose omission if an AE occurs and does not recover according to following 
rules: 
• If an AE occurs and the participant does not recover on the day of planned infusion or 
within the following 2 days, infusion of SAR444245 may be omitted for participants. 
• In case of consecutive dose omissions/delay for the recovery of AE, the following rules 
should be followed for restart or discontinuation of the treatment: 
- 
Dose delay (cycle delay) up to 9 days, it is per Investigator’s decision to restart the 
study treatment. 
- 
After dose delay of >9 days and ≤84 days, it is per Investigator’s decision to restart 
the study treatment, if a clear benefit from treatment is observed and after 
consultation with the Sponsor. 
- 
Treatment must be permanently discontinued if the delay is longer than 84 days. 
Cycle may be delayed for situations other than TEAEs such as medical / surgical events or 
logistical reasons not related to study therapy. Participants should be placed back on study therapy 
within 14 days of the scheduled delay, unless otherwise discussed with the Sponsor (for example 
for national or regional emergencies). The reason for this delay should be documented in the 
participant’s study record. 
6.5.3 General guidelines for the management of treatment-related adverse events  
Participants who experience Grade ≥3 treatment-related adverse events (TRAEs) at any time of 
the study (including clinically significant Grade 3 laboratory abnormalities as defined in Section 
10.3.1 of the master protocol) will be required to cycle delay the IMP, unless specified otherwise 
in the protocol, and with the exception of the TRAEs resolving within 5 days. After cycle delay, 
such participants may be considered for treatment resumption once the TRAE resolves or 
improves to Grade 1 or baseline or is stable and manageable through supportive/medical therapy. 
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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 withheld for more than 84 days from the last scheduled dose.  
The cycle delay of treatment for Grade 2 events is left at the discretion of the Investigator unless 
otherwise specified in this protocol.  
No cycle delay of treatment or dose modification is required for Grade 1 events. 
Dose reduction for SAR444245 from 
 µg/kg to 
 µg/kg (or another lower dose level 
recommended by Study Board) may be decided when specified in the protocol or following 
discussions with the Sponsor. 
The final decision on dose modification and/or corrective therapy will be based on the 
Investigator’s judgment, in the best interest of the participant. 
Recommended guidelines for the management of specific adverse events including irAE, CRS, 
vascular leak syndrome (VLS) and IRR are presented in Section 6.5.4. 
6.5.4 Guidelines for the management of specific adverse events  
Specific adverse events described in sections below may classify as adverse events of special 
interests (AESIs), depending on grading according to National Cancer Institute- Common 
Terminology Criteria for Adverse Event (NCI-CTCAE) V5.0 (see Section 8.3.8 of the master 
protocol). In case a specific adverse event meets the AESI definition it must be documented in the 
electronic case report form (e-CRF). 
6.5.4.1 Infusion-related reactions (IRR)  
Participants should routinely receive premedication as detailed in Section 6.1.2.1 of the master 
protocol, prior to SAR444245 administration, to prevent or reduce the incidence or severity of 
IRRs. 
An infusion-related reaction (IRR) in this study is defined as any signs or symptoms which 
develop during the infusion or up to 24 hours after the completion of the infusion. The term IRR 
indicates only a specific temporal relationship with the infusion and does not specify a particular 
mechanism underlying the signs or symptoms.  
Guidelines for the management of SAR444245 IRR events are provided in Table 3. Participants 
who develop Grade 2 IRR should have the next SAR444245 infusion given at half the infusion 
rate. For instructions on premedication at subsequent dosing, please see Section 6.1.2.1 of the 
master protocol.   
 
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Table 3 - 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. 
SAR444245 infusion should be interrupted if applicable.  
If symptoms resolve within 1 hour of interrupting drug infusion, the infusion may 
be restarted at 50% of the original infusion rate. Otherwise dosing will be held 
until symptoms resolve and the participant should be premedicated for the next 
scheduled dose according to Section 6.1.2.1 of the master protocol. 
The next infusion should be given at half the infusion rate. 
During or after completion of infusion, additional appropriate medical therapy 
may include but not limited to IV fluids, antihistamines, NSAIDs, acetaminophen, 
narcotics.  
Increase monitoring of vital signs will be as medically indicated until the 
participant recovers. 
Grade 3 
Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for other clinical 
sequelae  
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be prematurely 
permanently discontinued. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
Grade 4 
Life-threatening; pressor or ventilator support 
indicated 
SAR444245 infusion should be interrupted if applicable. 
If IRR is clearly attributable to SAR444245, SAR444245 should be prematurely 
permanently discontinued. 
During or after completion of infusion, additional appropriate medical therapy 
may include but is not limited to epinephrineb, IV fluids, antihistamines, NSAIDs, 
acetaminophen, narcotics, oxygen, vasopressors, corticosteroids. 
Increase monitoring of vital signs as medically indicated until the participant 
recovers. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
b In cases of anaphylaxis, epinephrine should be used immediately 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IRR = Infusion-related reaction; NCI = National Cancer Institute; 
NSAIDs: nonsteroidal anti-inflammatory drugs. 
 
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6.5.4.2 Anaphylaxis  
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of SAR444245 being administered. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers (see guidelines)  
(6, 7, 8). 
6.5.4.3 Fever, flu-like symptoms and cytokine-release syndrome (CRS)  
Fever can frequently happen with infusion of IL-2 and may possibly evolve into flu-like 
symptoms or could be an early manifestation of CRS. Fever or flu-like symptoms should be 
graded according to CTCAE V5.0 and managed according to institutional standards.  
Cytokine-release syndrome (CRS) should be graded as per American Society for Transplantation 
and Cellular Therapy (ASTCT) criteria integrated with central laboratory cytokine results, and 
managed per guidelines in Table 4. If any grade of CRS is suspected, sites should make every 
efforts to draw an additional blood sample for cytokines levels (by central laboratory), prior to the 
administration of tocilizumab, as well as for C-reactive protein (CRP) and ferritin (by local 
laboratory).  
Sites should have at least 2 full doses of tocilizumab available, or alternative therapies per site 
practice in CRS management, 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 4. 
ASTCT CRS consensus grading scale is provided in Section 10.11 of the master protocol. 
Table 4 - Guidelines for the management of suspected cytokine release syndrome (CRS)  
Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Grade 1 
• 
Fever (Temperature ≥38°C)b 
• 
No hypotension 
• 
No hypoxia  
No dose modification of SAR444245a. 
Appropriate symptomatic treatment may include but is not limited to IV 
fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen.  
Close direct monitoring of the participant’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less 
frequently as the participant improves. 
Grade 2 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension not requiring vasopressors  
• 
and/orc hypoxia requiring low-flow 
nasal cannulad or blow-by. 
Temporarily interruption of SAR444245, if event occurs during infusion 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as 
medically indicated should be increased until the participant recovers. 
Transfer to ICU may be required. 
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Event severity (ASTCT CRS 
Consensus Grading) 
Recommended SAR444245  
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 or alternative therapies per site practice 
in CRS management should be considered, as per guidance for Grade 3 
events.  
SAR444245 may be resumed when clinical symptoms have resolved or 
improved to Grade 1 and corticosteroid taper. No dose modification is 
required but decreasing to half the infusion rate can be considered. 
Grade 3 
• 
Feverb (Temperature ≥38°C)  
• 
Hypotension requiring a vasopressor 
with or without vasopressin  
• 
And/orc hypoxia requiring high-flow 
nasal cannulad, face mask, 
nonrebreather mask, or Venturi mask 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
• 
Feverb (Temperature ≥38°C) 
• 
Hypotension requiring multiple 
vasopressors (excluding vasopressin) 
• 
And/orc hypoxia requiring positive 
pressure (eg, CPAP, BiPAP, intubation 
and mechanical ventilation) 
If CRS Grade 3, SAR444245 should be temporarily 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.  
 
If CRS Grade 4, SAR444245 should be permanently discontinued, as 
clinically indicated.  
If CRS Grade 3 or Grade 4, IV corticosteroids should be initiated (outside 
of the context of CAR-T cells, corticosteroids alone maybe initiated in first 
intention) and tocilizumab or alternative therapies per site practice in CRS 
management should be 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), or alternative therapies per 
site practice in CRS management, should be administered, and steroids 
should be administered concurrently. If still no improvement in 
oxygenation, hypotension, fever and other manifestations is observed 
after the first dose of tocilizumab, or alternative therapies per site practice 
in CRS management, it may be repeated after an interval of at least 8 
hours and should not exceed 4 doses in total. 
For participants with severe CRS who fail to improve after repetitive 
treatment with both tocilizumab or alternative therapies per site practice in 
CRS management and steroids, alternative options should be discussed 
with clinical site specialists 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
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b Fever is defined as temperature ≥38°C not attributable to any other cause. In patients who have CRS then receive antipyretic or anticytokine 
therapy such as tocilizumab or alternative therapies per site practice in CRS management or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
c CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a patient with 
temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is classified as Grade 3 CRS. 
d Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in 
pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute. 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= Bilevel Positive Airway 
Pressure; CPAP= Continuous Positive Airway Pressure; CRS= cytokine release syndrome; ICU=intensive care unit; IL = Interleukin; 
IMP=investigational medicinal product; IV = Intravenous; NSAIDs=Non-steroidal anti-inflammatory drugs. 
 
 
6.5.4.4 Immune Cell-Associated Neurotoxicity Syndrome (ICANS)  
Immune cell-associated neurotoxicity syndrome (ICANS) is a neuropsychiatric syndrome which 
is frequently associated with CRS; however, it is specifically excluded from the definition of CRS 
and can occur during the course of CRS, after its resolution, or independently from CRS. Clinical 
findings can be progressive and may include aphasia, altered level of consciousness, impairment 
of cognitive skills, motor weakness, seizure, and cerebral edema. Severity is evaluated using the 
ASTCT Consensus grading scale, with ICE score for encephalopathy assessment (Section 10.11 
of the master protocol). Recommendations for ICANS management mainly include the use of 
steroids, whereas tocilizumab, or alternative therapies per site practice in CRS management, 
should only be used in the context of CRS, as outlined in Table 5. The proposed management 
should be considered only as recommendations and in light of recommendations from site 
specialist. 
Table 5 - Guidelines for the management of immune Cell-Associated Neurotoxicity Syndrome 
(ICANS)  
Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
ICE score 7-9. Awakens spontaneously 
No intervention required other than close clinical monitoring.  
Moderate 
Grade 2 
ICE score 3-6. Awakens to voice. 
SAR444245a should be delayed. 
Treatment with IV corticosteroids should be initiated as needed.  
SAR444245 may be resumed only after participant recovery or 
improvement to Grade 1 after corticosteroid taper. Consideration for 
reduction of SAR444245 dose to 
 µg/kg as per Investigator with 
Sponsor consultation. 
Severe or Life-threatening 
Grade 3 
ICE score 0-2. Awakens only to tactile stimulus.  
Any clinical seizure focal or generalized that 
resolves rapidly or nonconvulsive seizures on 
EEG that resolve with intervention. 
Grade 4  
If Grade 3 ICANS, SAR444245 should be delayed. 
When symptoms have resolved or improved to Grade 1 after 
corticosteroid taper, SAR444245 can be either restarted at 
 µg/kg or 
permanently discontinued, as clinically indicated, and upon discussions 
between the Investigator and Sponsor.  
If Grade 4 ICANS, SAR444245 should be permanently discontinued.  
Treatment with IV corticosteroids should be initiated. Concomitant CRS 
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Event severity 
(ASTCT Consensus Grading criteria) 
Recommended SAR444245  
dose modification and supportive care guidelines 
ICE score: 0 (participant is unarousable and 
unable to perform ICE). 
Participant is unarousable or requires vigorous or 
repetitive tactile stimuli to arouse. Stupor or 
coma. 
Life-threatening prolonged seizure (>5 min): or 
Repetitive clinical or electrical seizures without 
return to baseline in between. 
Deep focal motor weakness such as hemiparesis 
or paraparesis. 
Diffuse cerebral edema on neuroimaging; 
decerebrate or decorticate posturing; or cranial 
nerve VI palsy; or papilledema; or Cushing’s triad. 
may require tocilizumab, or alternative therapies per site practice in CRS 
management, and should be handled as described in Table 4. 
Corticosteroids can then be administered IV or orally every 8 hours for up 
to 3 days, then tapered over 4 days.  
For both Grade 3 and Grade 4 ICANS 
If there is no clinical improvement within 24 to 72 hours, then re-evaluation 
for other contributing conditions should be done. Administration of 
IV Tocilizumab at 8 mg/kg (for participants weighing ≥30 kg, total dose 
should not exceed 800 mg) or alternative therapies per site practice in 
CRS management, should be considered, and steroids should be 
administered concurrently and repeated as previously mentioned for CRS.  
Neurologist and other relevant clinical specialists should be involved 
whenever indicated. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual 
Abbreviations: AE = Adverse event; ASTCT=American Society for Transplantation and Cellular Therapy; CRS= cytokine release syndrome; 
IV = Intravenous; NCI = National Cancer Institute. 
6.5.4.5 Vascular Leak Syndrome (VLS)  
Vascular leak syndrome (VLS) is a disorder characterized by leakage of intravascular fluids into 
the extravascular space and can lead to generalized edema and multiple organ failure. This 
syndrome is observed in patients who demonstrate a state of generalized leaky capillaries 
following shock syndromes, low-flow states, ischemia-reperfusion injuries, toxemias, 
medications, or poisoning. In various human diseases, an increase in capillary permeability to 
proteins leads to the loss of protein-rich fluid from the intravascular to the interstitial space 
manifested by any of the following clinical presentations: diffuse pitting edema, exudative 
serous cavity effusions, noncardiogenic pulmonary edema, hypotension, and, in some cases, 
hypovolemic shock with multiple-organ failure. Fluid management is the cornerstone of VLS 
management; it is a balance between maintaining the intravascular volume to ensure organ 
perfusion to prevent organ failure, while avoiding volume overload. The management of VLS 
according to severity grading is described in Table 6. 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 (9).  
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Table 6 - Guidelines for the management of Vascular Leak Syndrome (VLS)  
Event severity 
(NCI-CTCAE V5.0) 
Recommended SAR444245  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Asymptomatic 
No intervention required other than clinical monitoring. 
Moderate 
Grade 2 
Symptomatic; medical intervention indicated 
SAR444245 should be delayed. Upon resolution of VLS or improvement to 
Grade 1, SAR444245a can be resumed at the reduced dose of
 µg/kg. 
The initial strategy is to administer boluses of crystalloids with a goal of 
providing the minimum effective volume that optimizes blood pressure 
together with a fluid-restrictive strategy is advocated to limit interstitial fluid 
volume expansion. 
Severe or Life-threatening 
Grade 3: 
Severe symptoms; intervention indicated 
Grade 4: 
Life-threatening consequences; urgent intervention 
indicated 
If Grade 3 or Grade 4 VLS, SAR444245 should be permanently 
discontinued.   
In participants with severe shock, blood pressure may be only partially 
responsive or refractory to IV crystalloid fluids.  
Severe or persistent hypotension is to be managed by the administration of 
vasopressors. A trial of 25% albumin IV is an additional option, although its 
efficacy is limited to those with a severe capillary leak. In those who remain 
with refractory shock in the setting of low filling pressures, high molecular 
weight starches such as hetastarch (MW 450 kDa) and pentastarch (MW 
264 kDa) may be effective in expanding the intravascular volume. 
Supportive care with invasive and noninvasive ventilation as well as renal 
replacement may be necessary in severe cases. When available, disease-
specific therapy should be initiated as soon as possible to facilitate 
recovery.  
During the recovery phase from severe capillary leak, the endothelial injury 
resolves and the capillary leak becomes less important, resulting in 
stabilization of blood pressure, at which time fluid overload symptoms and 
signs may predominate (eg, pulmonary edema, pleural effusions, acute 
respiratory distress syndrome, systemic edema, ascites). Volume removal 
with loop diuretics is the first-line therapy in these patients. In those with 
marginal blood pressure and fluid overload, the combination of loop 
diuretics and 25% albumin IV may facilitate volume removal. Patients with 
AKI refractory to diuretics will require renal replacement. 
a Information for preparation and storage of SAR444245 is provided in the pharmacy manual. 
Abbreviations: AE = Adverse event; CTCAE = Common terminology criteria for adverse events; IV = Intravenous; NCI = National Cancer 
Institute. 
   
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6.5.4.6 Tumor Lysis Syndrome (TLS) 
Tumor lysis laboratory tests (corrected calcium, magnesium, phosphate, uric acid, and lactate 
dehydrogenase [LDH] levels) will be obtained every 8 hours on C1D1 for safety run-in 
participants and participants who are hospitalized, and C1D2-D3 for safety run in or participants 
who are hospitalized because of high tumor burden or at Investigator’s discretion (refer to  
Section 1.3 SOA for details).  If it occurs, appropriate treatment will be initiated that will include 
correction of serum calcium, potassium, or phosphorus abnormalities, and treatment of 
hyperuricemia with allopurinol and/or rasburicase, as indicated in Appendix 12 of the master 
protocol (10). 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY 
Please refer to the master protocol. 
6.7 
TREATMENT OF OVERDOSE 
Please refer to the master protocol for definition and treatment of SAR444245 overdose. 
6.8 
CONCOMITANT THERAPY 
Please refer to the master protocol. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
Please refer to the master protocol. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Please refer to the master protocol. 
7.3 
LOST TO FOLLOW UP 
Please refer to the master protocol. 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Please refer to the master protocol. 
8.1 
EFFICACY ASSESSMENTS  
Please refer to the master protocol. 
 
8.2 
SAFETY ASSESSMENTS  
Please refer to the master protocol. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING 
Please refer to the master protocol. 
8.4 
PHARMACOKINETICS 
Please refer to the master protocol. 
8.5 
PHARMACODYNAMICS  
Please refer to the master protocol. 
8.6 
GENETICS AND/OR PHARMACOGENOMICS 
Please refer to the master protocol. 
8.7 
BIOMARKERS 
. 
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8.8 
IMMUNOGENICITY ASSESSMENTS 
Please refer to the master protocol. 
8.9 
HEALTH ECONOMICS 
Please refer to the master protocol. 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH 
Please refer to the master protocol. 
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9 
STATISTICAL CONSIDERATIONS 
9.1 
 STATISTICAL HYPOTHESES  
Please refer to the master protocol.  
9.2 
SAMPLE SIZE DETERMINATION 
The study will start with a safety run-in with 6-10 participants from Cohort C1. 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 Cohort C1. 
Sample size: 
The plan is to treat a total of 25 participants at the confirmed safe dose in Cohort C1. 
Table 7 lists estimated ORR and the corresponding 90% exact confidence interval (CI) by number 
of responders from a sample size of 25 participants in Cohort C1. 
Table 7 - Cohort C1: Estimated objective response rate (ORR) depending on number of responders 
 
Number of Responders 
(N=25) 
Objective Response Rate in % 
(90% Clopper-Pearson CI) 
1 
4 % (0.2% - 17.6%) 
3 
12 % (3.4% - 28.2%) 
4 
16 % (5.7% - 33%) 
5 
20 % (8.2% - 37.5%) 
6 
24 % (11% - 42%) 
8 
32 % (17% - 50.4%) 
9 
36 % (20.2% - 54.4%) 
 
With a sample size of 25 participants in Cohort C1, the probability of observing 1 or more 
instances of a specific AE with a true incidence rate of 1%, 2% or 5% is 22.2%, 39.7% or 72.3% 
respectively. 
This provides reasonable assurance that events occurring at ≥ 5% frequency can be identified in 
this substudy. 
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9.3 
POPULATIONS FOR ANALYSES 
Please refer to the master protocol. 
9.4 
STATISTICAL ANALYSES 
Please refer to the master protocol. 
9.4.1 General considerations 
Please refer to the master protocol. 
9.4.2 Primary endpoint(s) 
For Cohort C1, objective response rate (ORR) is defined as the proportion of participants who 
have a CR or PR per Investigator assessment (Lugano response criteria 2014). 
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 ORR and BOR will be summarized with descriptive statistics. In addition, two-sided 90% CIs 
will be computed for ORR from Clopper-Pearson exact method. 
9.4.3 Secondary endpoint(s) 
Please refer to the master protocol for descriptions of common secondary endpoints. Substudy-
specific analyses for secondary endpoints are summarized below. 
9.4.3.1 Complete response rate (CRR) 
The CRR is defined as the proportion of participants who have a CR per Investigator assessment 
(Lugano response criteria 2014). 
The CRR will be summarized with descriptive statistics. In addition, two-sided 90% CIs will be 
computed for CRR from Clopper Pearson exact method. 
9.4.4 Exploratory endpoint(s) 
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9.5 
INTERIM ANALYSES  
Please refer to the master protocol. 
The cohort cut-off for the primary endpoint analysis is estimated to be approximately 8 months 
from the date of the last participant’s first infusion. This would allow the possibility to observe the 
response of the last participant for 6 months, assuming there is a response at first treatment 
assessment. 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1.1 Regulatory and ethical considerations 
Please refer to the master protocol. 
10.1.2 Financial disclosure 
Please refer to the master protocol. 
10.1.3 Informed consent process 
Please refer to the master protocol.  
10.1.4 Data protection 
Please refer to the master protocol. 
10.1.5 Committees structure 
Please refer to the master protocol. 
10.1.6 Dissemination of clinical study data 
Please refer to the master protocol. 
Study participants results summaries will be provided in any one of the clinical trial portals after 
completion of the substudy, until the end of study.  
10.1.7 Data quality assurance 
Please refer to the master protocol. 
10.1.8 Source documents 
Please refer to the master protocol. 
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10.1.9 Study and site start and closure 
Please refer to the master protocol. 
10.1.10 
Publication policy 
Please refer to the master protocol. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
Please refer to the master protocol. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING 
Please refer to the master protocol. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE 
Please refer to the master protocol. 
10.5 
APPENDIX 5: GENETICS 
Please refer to the master protocol. 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS 
Please refer to the master protocol. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Please refer to the master protocol, and in addition to the requirements listed in the master 
protocol: 
France 
Section 1.3 Schedule of Activities (SoA) (Section 1.3)  
In France, serology for HIV will be tested at screening. 
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10.8 
APPENDIX 8: CRITERIA FOR RESPONSE ASSESSMENT 
 
Overall disease response for Cohort C1 is provided in Table 8. 
Table 8 – Overall disease response 
Overall raiological 
response 
Bone marrow 
biopsy/aspirate 
Clinical findings 
Overall disease 
response  
CR/PR/SD 
Negative at baseline or 
negative ± 28 days from 
assessment 
Any except new or recurrent 
lymphoma involvement 
CR/PR/SD 
CR 
Positive at baseline and either 
positive (without new or 
recurrent involvement) or not 
done ± 28 days from 
assessment 
Any except new or recurrent 
lymphoma involvement 
PR 
PR/SD 
Positive at baseline and either 
positive (without new or 
recurrent involvement) or not 
done ± 28 days from 
assessment 
Any except new or recurrent 
lymphoma involvement 
PR/SD 
PD 
Any 
Any 
PD 
Any 
New or recurrent involvement 
Any 
PD 
Any 
Any  
New or recurrent lymphoma 
involvement 
PD 
 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY 
Please refer to the master protocol. 
 
10.10 APPENDIX 10: RISK ASSESSMENT 
Please refer to the master protocol. 
10.11 APPENDIX 11: ASTCT ASSESSMENT FOR ICANS AND CRS  
Please refer to the master protocol.    
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10.12 APPENDIX 12: GUIDELINES FOR THE MANAGEMENT OF TUMOR LYSIS 
SYNDROME (TLS) 
Please refer to the master protocol. 
10.13 APPENDIX 13: ECOG PERFORMANCE STATUS AND LANSKY SCALE 
Please refer to the master protocol. 
10.14 APPENDIX 14: ABBREVIATIONS 
 
ADCC: 
antibody drug-dependent cellular cytotoxicity 
BOR: 
best overall response 
CAR-T: 
chimeric antigen receptor T-cell immunotherapy 
CRF: 
case report form 
CRR: 
complete response rate 
CRS: 
cytokine-release syndrome  
DLBCL: 
diffuse large B-cell lymphoma 
DLT: 
dose-limiting toxicity 
ICANS: 
immune cell-associated neurotoxicity syndrome 
IMP: 
investigational medicinal product 
IRR: 
infusion-related reaction 
ORR: 
objective response rate 
PR: 
partial response 
TRAE: 
treatment-related adverse event 
VLS: 
vascular leak syndrome 
 
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). 
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11 
REFERENCES 
1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and 
Non-Hodgkin Lymphoma: The Lugano Classification. J Clin Oncol. 2014;32(27):3059-68. 
2. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT 
consensus grading for cytokine release syndrome and neurologic toxicity associated with 
immune effector cells. Biol Blood Marrow Transplant. 2019;25(4):625-38. 
3. Parisi G, Saco JD, Salazar FB, Tsoi J, Krystofinski P, Puig-Saus C, et al. Persistence of 
adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist. Nat 
Commun. 2020;11(1):660. 
4. Chong EA, Alanio C, Svoboda J, Nasta SD, Landsburg DJ, Lacey SF, et al. Pembrolizumab 
for B-cell lymphomas relapsing after or refractory to CD19-directed CAR T-cell therapy. 
Blood. 2022; 139 (7): 1026–1038. 
5. National Comprehensive Cancer Network (NCCN). B-cell Lymphomas, Version 4.2020. 
NCCN Clinical Practice Guidelines in Oncology. 2020 August [cited 2021 Jul 16]. Available 
from: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf 
6. Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report-
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117(2):391-7. 
7. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K. Management of infusion 
reactions to systemic anticancer therapy: ESMO clinical practice guidelines. Ann Oncol. 
2017;28(suppl 4):iv100-18.  
8. Muraro A, Roberts G, Worm M, Bilò MB, Brockow K, Fernández Rivas M, et al. 
Anaphylaxis: guidelines from the European Academy of Allergy and Clinical Immunology. 
Allergy. 2014;69(8):1026-45. 
9. Siddall E, Khatri M , Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, 
and management. Kidney Int. 2017 Jul;92(1):37-46. 
10. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. 
Br J Haematol. 2004;127(1):3-11. 
 
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