Clinical trial NCT03769181
Conditions: Lymphoma
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2018-12-11; Completion date: 2022-11-08
Enrollment: 58 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objectives:

Phase 1

-To characterize the safety and tolerability of isatuximab in combination with cemiplimab in participants with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) or peripheral T-cell lymphoma (PTCL), and to confirm the recommended Phase 2 dose (RP2D).

Phase 2

* Cohort A1 (anti-programmed cell death protein 1/ligand 1 \[PD-1/PD-L1\] naïve cHL): To assess the complete remission (CR) rate of isatuximab in combination with cemiplimab.
* Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) and C (PTCL): To assess the objective response rate (ORR) of isatuximab in combination with cemiplimab.

Secondary Objectives:

* To evaluate the safety of the RP2D of the combination of isatuximab with cemiplimab.
* To evaluate the safety of the combination of isatuximab with cemiplimab and radiotherapy in participants with cHL.
* To evaluate the immunogenicity of isatuximab and cemiplimab when given in combination.
* To characterize the pharmacokinetic (PK) profile of isatuximab and cemiplimab when given in combination.
* To assess overall efficacy of isatuximab in combination with cemiplimab and isatuximab in combination with cemiplimab and radiotherapy.

Detailed description:
The total study duration per participant was up to 28 months, including an up to 28-day screening period, an up to 96-week treatment period, and a 90-day safety follow up period.

Arms: arm 1: Classic Hodgkin's lymphoma (cHL), anti-programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitor naïve participants received isatuximab 10 milligrams per kilogram (mg/kg), intravenous (IV) infusion once a week (QW) in Cycle 1 and then every 2 weeks (Q2W) from Cycle 2 to Cycle 6 (each cycle of 28 days), and then every 3 weeks (Q3W) from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 milligrams (mg) Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable adverse events (AEs) or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of complete response \[CR\], whichever was longer) of delivery of investigational medicinal product(s) without documented progressive disease (PD), or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks). arm 2: cHL, anti-PD-1/PD-L1 inhibitor progressor participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30, with optional radiotherapy until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks). arm 3: Diffuse large B-cell lymphoma (DLBCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks). arm 4: Peripheral T-cell lymphoma (PTCL), anti PD-1/PD-L1 naïve participants received isatuximab 10 mg/kg, IV infusion, QW in Cycle 1 and then Q2W from Cycle 2 to Cycle 6 (each cycle of 28 days) and Q3W from Cycle 7 to Cycle 30 (each cycle of 21 days) along with cemiplimab 250 mg Q2W, IV infusion from Cycle 1 to 6 and then 350 mg Q3W from Cycle 7 to Cycle 30 until, unacceptable AEs or participant's decision to stop the treatment, or at least 96 weeks (at least 48 weeks from initial signal of CR, whichever was longer) of delivery of investigational medicinal product(s) without documented PD, or study cut-off date, whichever occurs first (maximum duration: up to 103 weeks).
Interventions: intervention 1: isatuximab SAR650984 intervention 2: cemiplimab REGN2810
Intervention descriptions: intervention 1: Pharmaceutical form: solution for infusion

Route of administration: intravenous intervention 2: Pharmaceutical form: solution for infusion

Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: Version Sanofi dated 12-OCT-2017 based on TransCelerate CPT version 4 
Property of the Sanofi Group - strictly confidential 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 02  
 
Protocol title: 
A Phase 1/2 open-label, multi-center, safety, preliminary 
efficacy and pharmacokinetic (PK) study of isatuximab in 
combination with other anti-cancer therapies in 
participants with lymphoma 
Protocol number: 
ACT15320  
Amended Protocol: 
02 
Compound number 
(INN/Trademark): 
SAR650984 
isatuximab 
Short title: 
A study of isatuximab-based therapy in participants with 
lymphoma  
Sponsor name: 
 
Legal registered 
address: 
 
Monitoring Team’s 
Representative Name 
and Contact 
Information 
  
 
Regulatory agency identifying number(s): 
EudraCT number: 
2018-002442-37 
IND number: 
103217 
WHO number: 
U1111-1211-9010 
NCT number: 
NCT03769181 
Approval Date: 
15-Dec-2020 
Total number of pages: 
138 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02 
All 
15 December 2020, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 01 
All 
19 September 2019, version 1 (electronic 4.0) 
Original Protocol 
 
14 September 2018, version 1 (electronic 5.0) 
Amended protocol 02 (15 December 2020) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
This amendment includes clarifications requested by the French Health Authority (ANSM). In 
addition, this amendment is to make provisions for data collection from patients still on treatment 
if the sponsor decides to stop the study prematurely. Other modifications or editorial changes are 
included to correct inconsistencies and improve operational feasibility.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Added IND number 
Administrative change. 
Section 1.1 Synopsis, Section 1.3 
SoA (footnote a), Section 4.1 Overall 
design and Section 6.1.4. 
Radiotherapy (for Cohorts A1 and A2) 
(optional)  
Numbering of exclusion criteria corrected 
to E01, E06, E08, E021, E30, E32, instead 
of E01, E06, E08, E021, E29, E31.  
Wording has been corrected for exclusion 
criteria: "does not meet exclusion criteria" 
instead of "meet exclusion criteria".  
Correction. 
Section 1.1 Synopsis and Section 1.3 
SoA (footnote “f”) 
Text has been added to clarify that there 
will be no survival follow-up period for the 
cohorts with negative interim analysis 
results. 
Clarification. 
Section 1.1 Synopsis, Section 2.3.4. 
Preventive measures to minimize the 
risk from the combination, Section 6.1 
Study intervention(s) administered, 
Section 6.1.2 Non-investigational 
medicinal products and Section 
6.1.2.2 Ranitidine 50 mg IV or 
equivalent 
Use of ranitidine or equivalent as 
premedication is left to medical judgement 
of the investigator. 
To provide option to adapt the 
premedication depending on 
individual situation. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis and Section 
10.1.5 Committees structure 
Text in the Study Committee (SC) section 
has been updated to clarify the 
composition of the SC during Phase 1 and 
during Phase 2 for participants who 
undergo radiotherapy after Cycle 10. 
Clarification. 
Section 1.3 SoA (footnote “b”), 
Section 5.2 Exclusion criteria (E33.), 
Section 6.4 Concomitant therapy, 
Section 6.5.6 Guidance in case of 
hepatitis B reactivation occurring 
under study treatment, and Section 
10.2 Appendix 2: Clinical laboratory 
tests  
New text added for prevention of viral 
reactivation risk. 
To complement hepatitis B virus 
(HBV) investigation. 
Section 1.3 SoA 
The wording “Continuous” was added for 
the adverse event (AE)/serious adverse 
event (SAE) assessment during the 
treatment period. 
Follow-up of concomitant medication was 
modified from 31 days to 90 days when 
related to AEs/SAEs. 
Correction. Clarification. 
Section 1.3 SoA, footnote “d” and 
Section 8.1.1 FDG-PET-CT/CT 
Tumor assessment frequency updated to 
Year 1: Fluorodeoxyglucose (FDG) 
positron emission tomography (PET)-
computed tomography (CT)/ CT scans 
every 12 weeks, Year 2 and beyond: CT 
scan every 12 weeks, and FDG PET-CT 
scan when clinically indicated. 
Wording of spleen size measurement, 
standardized uptake value (SUV) max, 
and 5-point scale (5PS) score were 
clarified. 
To optimize scan frequency in the 
context of disease setting and 
response to study treatment. 
Section 2.3.4. Preventive measures to 
minimize the risk from the 
combination  
E08 was corrected as follows: Known 
seropositive and requiring anti-viral 
therapy for human immunodeficiency virus 
(HIV), known HBV, or hepatitis C virus 
(HCV), unless they are controlled or 
negative when tested by polymerase chain 
reaction (PCR) or equivalent. Active 
tuberculosis, or severe infection requiring 
parenteral antibiotic treatment". 
Correction. Clarification. 
Section 2.3.4 Preventive measures to 
minimize the risk from the 
combination, 
Section 6.1.1 Investigational 
medicinal product(s), and Section 
6.5.5 General guidelines for the 
management of IRs 
Improvement in isatuximab administration. 
Switching to faster infusion 
schedule with a fixed distribution 
volume will reduce hospital chair 
time (particularly in some specific 
challenging situations like 
pandemic restrictions) and increase 
convenience for patients and sites.  
Section 2.3.4 Preventive measures to 
minimize the risk from the 
combination and Section 6.5.5 
General guidelines for the 
management of IRs 
Updated management guidelines on 
Grade 3 IR including permanent 
discontinuation of study treatment at third 
IR. 
Clinical management of Grade 3 
infusion reaction was updated to 
align with isatuximab IB ed11. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion criteria 
Inclusion criterion number 6 (I 06.) 
updated. 
Clarification. 
Section 5.2 Exclusion criteria 
Exclusion criterion number 15 (E15.): 
Cohort A1 and A2 were added.  
Richter syndrome, a high-grade 
transformation of chronic 
lymphocytic leukemia (CLL) or low-
grade lymphoma, will not be 
allowed. 
Section 6. Study intervention, Section 
6.5.2 Dose delay and dose omission, 
Section 7.1 Discontinuation of study 
intervention, Section 8 Study 
assessments and procedures, Section 
9.3 Populations for analyses, Section 
10.1.3 Informed consent process, 
Section 10.14 Appendix 14: 
Contingency Measures for a regional 
or national emergency that is declared 
by a governmental agency.   
 
Contingency measures for a regional or 
national emergency such as Covid-19 are 
added. 
 
To include instructions for the team 
to add flexible language in the 
protocol that may be implemented 
during regional or national 
emergencies. 
  
Section 8.3 Adverse events and 
serious adverse events 
Wordings related to reporting of SAEs and 
adverse events of special interest (AESIs) 
has been revised. 
Clarification. 
Section 8.11 Data collection after 
premature stop of the study 
Details are provided for data collection 
from patients still on treatment if the 
sponsor decides to prematurely stop the 
study  
Provisions for data collection after 
the premature stoppage of the 
study are included.  
Section 9.3 Population of analyses  
The text has been updated to: 
"The response evaluable population will 
include all participants in the all treated 
population who fulfilled all inclusion and 
exclusion criteria without any major or 
critical deviation with an evaluable 
baseline assessment and at least one 
evaluable post-baseline assessment 
during the treatment period. This 
population is the secondary analysis 
population for efficacy.” 
The definition of response 
evaluable population was clarified.  
Section 10.1.7 Data quality assurance 
Addition of wordings regarding monitoring 
techniques as per the latest template 
version. 
Correction. 
Section 10.6 Appendix 6: Disease 
assessment and Lugano classification 
Replaced the blurry Lugano 2014 tumor 
assessment table with clear table for 
better readability.  
Clarification  
Section 11 References 
Addition of missing references 25 to 27. 
Correction. 
Throughout the document 
In addition, editorial corrections for 
consistency and clarity, and document 
formatting revisions have been made. 
Standardization of wordings as per the 
latest template version. 
To improve readability and be 
compliant with the latest template. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02  ............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 20 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  ............................................................................................. 21 
1.4 
PHARMACOKINETIC/PHARMACODYNAMICS FLOW CHART .................................................. 27 
1.4.1 
Intervention period: Cycle 1 (Rich sampling) ................................................................................. 27 
1.4.2 
Intervention period: from Cycle 2 and beyond (Sparse sampling) ................................................. 28 
2 
INTRODUCTION ............................................................................................................................ 29 
2.1 
STUDY RATIONALE...................................................................................................................... 29 
2.2 
BACKGROUND ............................................................................................................................. 31 
2.2.1 
Isatuximab ...................................................................................................................................... 31 
2.2.2 
Cemiplimab .................................................................................................................................... 31 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 32 
2.3.1 
Benefits .......................................................................................................................................... 32 
2.3.2 
Potential and identified risks .......................................................................................................... 32 
2.3.3 
Potential risk related to the combination ........................................................................................ 33 
2.3.4 
Preventive measures to minimize the risk from the combination .................................................. 33 
2.3.5 
Conclusion ..................................................................................................................................... 35 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 36 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 37 
4 
STUDY DESIGN ............................................................................................................................ 38 
4.1 
OVERALL DESIGN ........................................................................................................................ 38 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 41 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 41 
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4.4 
END OF STUDY DEFINITION ....................................................................................................... 42 
5 
STUDY POPULATION .................................................................................................................. 43 
5.1 
INCLUSION CRITERIA .................................................................................................................. 43 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 45 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 48 
5.4 
SCREEN FAILURES...................................................................................................................... 49 
6 
STUDY INTERVENTION ............................................................................................................... 50 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 50 
6.1.1 
Investigational Medicinal Product(s) .............................................................................................. 51 
6.1.2 
Non-Investigational Medicinal Products: ........................................................................................ 53 
6.1.3 
Dosing sequence ........................................................................................................................... 54 
6.1.4 
Radiotherapy (for Cohorts A1 and A2) (optional) .......................................................................... 55 
6.1.5 
Blinding procedures ....................................................................................................................... 56 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 56 
6.2.1 
General rules .................................................................................................................................. 56 
6.2.2 
Storage conditions ......................................................................................................................... 57 
6.2.3 
Preparation, reconstitution and administration: ............................................................................. 57 
6.3 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 58 
6.4 
CONCOMITANT THERAPY .......................................................................................................... 58 
6.5 
DOSE MODIFICATION .................................................................................................................. 60 
6.5.1 
General rules .................................................................................................................................. 60 
6.5.2 
Dose delay and dose omission ...................................................................................................... 61 
6.5.3 
Dose modifications ......................................................................................................................... 62 
6.5.4 
General guidelines for the management of Immune-Related Adverse Events ............................. 63 
6.5.5 
General guidelines for the management of IRs ............................................................................. 64 
6.5.6 
Guidance in case of hepatitis B reactivation occurring under study treatment .............................. 67 
6.5.7 
Guidelines for the management of potential Tumor Lysis Syndrome ............................................ 67 
6.6 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 67 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 68 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 68 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 70 
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7.3 
LOST TO FOLLOW-UP ................................................................................................................. 70 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 72 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 72 
8.1.1 
FDG-PET-CT/CT ............................................................................................................................ 72 
8.1.2 
Bone marrow biopsy & aspirate: .................................................................................................... 74 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 74 
8.2.1 
Physical examinations ................................................................................................................... 74 
8.2.2 
Vital signs ....................................................................................................................................... 75 
8.2.3 
Electrocardiograms ........................................................................................................................ 75 
8.2.4 
ECHO or MUGA ............................................................................................................................. 75 
8.2.5 
Pulmonary function test: ................................................................................................................ 75 
8.2.6 
Clinical safety laboratory assessments .......................................................................................... 75 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 78 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 80 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 81 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 81 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 81 
8.3.5 
Pregnancy ...................................................................................................................................... 82 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 82 
8.3.7 
Guidelines for reporting product complaints .................................................................................. 83 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 83 
8.5 
PHARMACOKINETICS .................................................................................................................. 83 
8.5.1 
Sampling time ................................................................................................................................ 83 
8.6 
PHARMACODYNAMICS ............................................................................................................... 85 
8.7 
GENETICS ..................................................................................................................................... 85 
8.8 
BIOMARKERS ............................................................................................................................... 86 
8.8.1 
RNA transcriptome research .......................................................................................................... 86 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 86 
8.10 
[HEALTH ECONOMICS] OR [MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS]  ............................................................................................................................... 87 
8.11 
DATA COLLECTION AFTER PREMATURE STOP OF THE STUDY .......................................... 87 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 89 
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9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 89 
9.2 
SAMPLE SIZE DETERMINATION  ................................................................................................ 89 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 90 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 91 
9.4.1 
Efficacy analyses ........................................................................................................................... 91 
9.4.2 
Safety analyses .............................................................................................................................. 92 
9.4.3 
Other analyses ............................................................................................................................... 93 
9.5 
INTERIM ANALYSES  ................................................................................................................... 94 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 95 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 95 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 95 
10.1.2 
Financial disclosure........................................................................................................................ 95 
10.1.3 
Informed consent process .............................................................................................................. 96 
10.1.4 
Data protection ............................................................................................................................... 96 
10.1.5 
Committees structure ..................................................................................................................... 97 
10.1.6 
Dissemination of clinical study data ............................................................................................... 97 
10.1.7 
Data quality assurance .................................................................................................................. 98 
10.1.8 
Source documents ......................................................................................................................... 98 
10.1.9 
Study and site closure .................................................................................................................... 99 
10.1.10 Publication policy ........................................................................................................................... 99 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 99 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 101 
10.4 
APPENDIX 4: RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC CEMIPLIMAB DRUG RELATED 
ADVERSE EVENTS..................................................................................................................... 105 
10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 115 
10.6 
APPENDIX 6: DISEASE ASSESSMENT AND LUGANO CLASSIFICATION ............................. 119 
10.7 
APPENDIX 7: MITIGATING THE ANTI-CD38 INTERFERENCE WITH SEROLOGIC 
TESTING ...................................................................................................................................... 122 
10.8 
APPENDIX 8: GENETICS ........................................................................................................... 126 
10.9 
APPENDIX 9:  MODIFICATION OF DIET IN RENAL DISEASE (MDRD) EQUATION ............... 126 
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10.10 
APPENDIX 10: DEFINITION OF LINE OF THERAPY ................................................................ 127 
10.11 
APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS .......................................................... 127 
10.11.1 Amendment for France ................................................................................................................ 127 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 128 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 130 
10.13.1 Amended protocol 01 (19 September 2019) ................................................................................ 130 
10.14 
APPENDIX 14: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 135 
11 
REFERENCES ............................................................................................................................. 136 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 36 
Table 2 - Overview of study interventions administered ............................................................................... 51 
Table 3 - Isatuximab and cemiplimab dose modification guidelines ............................................................. 62 
Table 4 - General guidelines for immune-related adverse events ................................................................ 64 
Table 5 - IR management .............................................................................................................................. 66 
Table 6 - Laboratory and clinical abnormalities possibly consistent with TLS .............................................. 67 
Table 7 - Bioanalytical methods for isatuximab and functional cemiplimab pharmacokinetic ...................... 84 
Table 8 - List of pharmacokinetic parameters and definitions ....................................................................... 84 
Table 9 - Bioanalytical methods for immune response assessment ............................................................. 87 
Table 10 - Determination of sample size in Phase 2 ..................................................................................... 90 
Table 11 - Populations for analyses .............................................................................................................. 90 
Table 12 - Efficacy analyses ......................................................................................................................... 92 
Table 13 - Safety analyses ............................................................................................................................ 92 
Table 14 - Protocol-required safety laboratory assessments ...................................................................... 100 
Table 15 - Colitis adverse event management ............................................................................................ 105 
Table 16 - Endocrine adverse event management ..................................................................................... 108 
Table 17 - Pneumonitis adverse event management .................................................................................. 109 
Table 18 - Renal adverse event management ............................................................................................ 110 
Table 19 - Dermatologic adverse event management ................................................................................ 111 
Table 20 - Hepatitis adverse event management ....................................................................................... 112 
Table 21 - Ophthalmology (uveitis) adverse event management ............................................................... 113 
Table 22 - Nausea and vomiting adverse event management ................................................................... 114 
Table 23 - Highly effective contraceptive methods ..................................................................................... 117 
Table 24 - Revised Criteria for Response Assessment .............................................................................. 119 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 20 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A Phase 1/2 open-label, multi-center, safety, preliminary efficacy and 
pharmacokinetic (PK) study of isatuximab in combination with other anti-
cancer therapies in participants with lymphoma 
Short title: 
A study of isatuximab-based therapy in participants with lymphoma  
Rationale:  
Monoclonal antibodies (mAb) that block the programmed cell death/programmed cell 
death-ligand (PD-1, PD-L1) axis alone have demonstrated benefit in lymphoma therapy. 
Isatuximab, an anti-cluster of differentiation CD38 (CD38) mAb, has shown clinical response in 
relapsed refractory multiple myeloma (MM) participants as a single agent and in combination 
with other agents. Although isatuximab has not been tested in lymphoma, this study is designated 
to explore whether isatuximab may contribute to reshaping the tumor immune-environment and 
will enhance the activity of checkpoint inhibitor therapy. A recent report has shown that the 
combination of anti-PD-L1 and CD38 antibodies induces a greater anti-tumor immune response 
than anti-PD-L1 monotherapy in a mouse lung cancer model and possibly revert resistance to 
anti-PD-1/PD-L1 therapies, establishing the hypothesis of targeting CD38 to potentiate anti-PD-
1/PD-L1 therapies. 
Objectives and endpoints 
Responses will be determined per Lugano response criteria 2014, as assessed by the Investigators 
(1). All tumor assessment imaging data must be kept in sites for potential future use, including 
independent review.  
 
Objectives 
Endpoints 
Primary 
Phase 1:  
To characterize the safety and tolerability of isatuximab in 
combination with cemiplimab in participants with relapsed and 
refractory classic Hodgkin’s lymphoma (cHL), diffuse large 
B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma 
(PTCL), and to confirm the recommended Phase 2 dose 
(RP2D). 
Phase 1:  
Safety and tolerability will be assessed based on dose limiting 
toxicities (DLTs, in Cycle 1), adverse events (AEs)/serious 
adverse events (SAEs), and laboratory abnormalities. 
  
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Phase 2: 
1 - Cohort A1 (anti-PD-1/PD-L1 naive cHL): To assess the 
complete remission (CR) rate of isatuximab in combination 
with cemiplimab. 
 
2 - Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) 
and C (PTCL): To assess the objective response rate (ORR) 
of isatuximab in combination with cemiplimab. 
 
Phase 2:  
1 - Cohort A1: CR rate as defined by as the proportion of 
participants who have a CR as a best overall response during 
the isatuximab + cemiplimab therapy period using the Lugano 
response criteria 2014 (1) (Appendix 6 Section 10.6). 
2 - Cohorts A2, B, and C: 
ORR defined as the proportion of participants who have a CR 
or partial response (PR) as a best overall response during 
isatuximab + cemiplimab therapy period using the Lugano 
response criteria 2014 (1) (Appendix 6 Section 10.6). 
Secondary 
1 - To evaluate the safety of the RP2D of isatuximab in 
combination with cemiplimab.  
1 - AEs/SAEs and laboratory abnormalities for isatuximab+ 
cemiplimab. 
2 - To evaluate the safety of the combination of isatuximab 
with cemiplimab and radiotherapy in participants with cHL 
2 - AEs/SAEs and laboratory abnormalities in isatuximab + 
cemiplimab + radiotherapy treated participants (Cohort A1 
and A2). 
3 - To evaluate the immunogenicity of isatuximab and 
cemiplimab when given in combination. 
3 - Immunogenicity: Anti-drug antibody (ADA) against 
isatuximab and against cemiplimab. 
4 - To characterize the pharmacokinetic (PK) profile of 
isatuximab and cemiplimab when given in combination. 
4 - PK evaluation using non-compartmental analysis for both 
compounds using serum concentrations for cemiplimab and 
plasma concentrations for isatuximab. 
5 - To assess overall efficacy of: 
• 
isatuximab in combination with cemiplimab, 
And  
 
• 
isatuximab in combination with cemiplimab and 
radiotherapy. 
5 - Efficacy: 
• 
Tumor burden change, duration of response (DoR), 
disease control rate (DCR), defined as the 
percentage of participants who achieve CR, partial 
response (PR) or stable disease (SD) and 
progression-free survival (PFS). 
• 
For Cohort A1, ORR during isatuximab + 
cemiplimab ± radiotherapy periods. CR rate during 
isatuximab + cemiplimab + radiotherapy period. 
• 
For Cohort A2, ORR during   isatuximab + 
cemiplimab + radiotherapy period. CR rate during 
isatuximab + cemiplimab ± radiotherapy periods. 
Overall design: 
This is a Phase 1/2 open-label, non-comparative, multi-center, safety, preliminary efficacy and 
PK study of isatuximab in combination with other anti-cancer therapies in participants with 
lymphoma. This study will be conducted in 2 phases (see Section 1.2 for study design schema). 
Phase 1 (Safety run-in) 
Participants with classic Hodgkin’s lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), 
or peripheral T-cell lymphoma (PTCL) will be simultaneously enrolled in Phase 1. 
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Dose levels and schedules are described in the table below. 
Dose levels and schedules for Phase 1 
 
Dose level 
(DL) 
Isatuximab 
Cemiplimab 
Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond 
1 cycle = 21 days 
 Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond  
1 cycle = 21 days 
Starting dose 
10 mg/kg every week 
(QW) × 4 (Cycle 1) 
10 mg/kg every 2 weeks 
(Q2W) (Cycle 2 ~ Cycle 
6)  
 
10 mg/kg every 
3 weeks (Q3W) 
250 mg Q2W 
350 mg Q3W 
Minus -1 
(DL-1) 
5 mg/kg QW × 4 (Cycle 1) 
5 mg/kg Q2W 
(Cycle 2 ~ Cycle 6)  
5 mg/kg Q3W 
250 mg Q2W 
350 mg Q3W 
The dose limiting toxicity (DLT) observation period is the first cycle (28 days). 
To account for DLT non-evaluability because of AEs that do not qualify as DLTs, approximately 
6 participants may be enrolled without interruption to receive the starting dose. At the starting 
dose, DLTs will be assessed among the first 3 DLT evaluable participants provided that they will 
have received at least 90% of the planned cumulative doses of the first cycle (unless they 
discontinue investigational medicinal product (IMPs) due to DLT), based on the rules listed 
below. The totality of the adverse events (AEs) collected from all treated participants will be 
taken into consideration when deciding recommended Phase 2 dose (RP2D). 
• If 0/3 participants experience a DLT, the starting dose will be the RP2D. 
• If 1/3 participants experience a DLT, 3 additional participants will be enrolled at the 
starting dose level: 
- 
If a total of 1/6 participants treated at the starting dose experience a DLT, the starting 
dose will be the RP2D. 
- 
If a total of ≥2/6 participants experience a DLT, the dose will be de-escalated to dose 
level minus 1 (DL-1). 
• If ≥2/3 participants experience DLTs, the dose will be de-escalated to DL-1. 
At DL-1, the same DLT observation rules will be applied for selecting a RP2D, and if ≥2/6 or 
≥2/3 participants experience DLTs, an alternative dose/schedule might be considered from 
a safety viewpoint by the Sponsor after consulting with the Investigators who have recruited at 
least one participant for the Phase 1. 
Enrollment of participants within DL is to be staggered by at least 3 days. 
Following the identification of the RP2D, Phase 2 of the study will be initiated. 
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The National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) 
version 5.0 will be used to assess the severity of AEs. Causal relationships are to be determined 
by the Investigator (Section 8.3). The DLTs will be confirmed by the Sponsor and recruiting 
Investigators. 
Phase 2 (Efficacy signal/Simon 2-stage design): 
Phase 2 includes 4 cohorts: 
Cohort A1: cHL anti-PD-1/PD-L1 naïve. 
Cohort A2: cHL anti-PD-1/PD-L1 progressor.  
Cohort B: DLBCL anti-PD-1/PD-L1 naïve. 
Cohort C: PTCL anti-PD-1/PD-L1 naïve. 
The participants treated at the RP2D of isatuximab and cemiplimab in combination during Phase 1 
will be included in the efficacy analysis together with participants of the same indication in 
Stage 1 of Phase 2. 
In both Phases 1 and 2, participants with cHL who achieve best overall response of PR or stable 
disease (SD) at the disease assessment planned for Week 36, if deemed appropriate (and does not 
meet exclusion criteria E01, E06, E08, E21, E30, and E32) by the Investigator, may begin 
radiotherapy between D1 to D14 (preferably between D1 to D7) of the next immediate cycle.   
Number of participants: 
In Phase 1, approximately 3 to 12 DLT evaluable participants are expected to be enrolled. 
In Phase 2, participants will be screened to achieve approximately 118 treated participants with 
study intervention in Cohorts A1, A2, B, and C (see Section 9.2 for details of the sample size 
determination). 
Intervention groups and duration: 
The duration of the study for a participant will include a screening period (up to 28 days), 
a treatment period (up to 96 weeks), a post safety follow-up period up to 90 days and a survival 
follow-up period (except for the cohorts where the results of interim analysis are not positive) 
until death or study cut-off date. The data cut-off for the primary end-of-cohort analysis is up to 
24 weeks from the date the last participant treated in individual cohort. The data cut-off for the 
intermediate and final end-of-cohort analysis are up to 48 and 96 weeks, respectively, from the 
date the last participant treated in individual cohort. 
Treatment period: The cycle duration is 28 days during the 6 first cycles then 21 days. 
Participants will continue treatment until disease progression, unacceptable AE, participant’s 
decision to stop the treatment, 96 weeks (at least 48 weeks from initial signal of CR, whichever is 
longer) of delivery of IMP(s) without documented progressive disease (PD), or any other reason. 
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Safety follow-up period: After treatment discontinuation, participants will return to the study site 
30 days (±7 days) after the last dose of IMP(s), or when the participant receives another 
anti-cancer therapy, whichever is earlier, for end of treatment (EOT) assessments. In addition, 
there will be an extended safety follow-up period for 90 days after the last dose of IMP(s) 
including 60 days (±7 days) visit after the last IMP for safety assessment and 90 days (±7 days) 
visit after the last IMP for ADA assessment (only for isatuximab) and for safety assessment.  
Participants who discontinue the study treatment without PD will be followed at 90 days 
(±7 days) for disease assessment. 
Survival follow-up period: The further follow-up schedule beyond 90 days after last dose of 
IMP(s) is according to the disease progression status: 
• Participants who discontinue study treatment due to PD: phone call follow-up will be done 
every 90 days from the date of last IMP(s) administration until death or final study 
cut-off date. 
• Participants who discontinue the study treatment without PD: will be followed every 
90 days for disease assessment until confirmation of PD or start treatment with another 
anti-cancer therapy, or study cut-off date whichever comes first. After PD, participant will 
be followed by phone call until death or final study cut-off date. 
• Participants who are still on study treatment after study cut-off date: will continue to 
receive study treatment if they benefit, and will undergo planned study procedures (except 
PK and ADA) until confirmation of PD, or start with another anti-cancer therapy, or 
treatment period ended, whichever comes first.  
After EOT, all the ongoing related non-serious AEs, the ongoing SAEs and the new related 
AE/SAEs are to be followed until resolution or stabilization. Stabilization is defined as an event 
ongoing without any change for at least 3 months. 
Investigational medicinal product(s): Isatuximab with cemiplimab and radiotherapy 
(Cohorts A1 and A2) or isatuximab in combination with cemiplimab (Cohort B and C). 
Isatuximab and cemiplimab could be given up to 96 weeks (at least 48 weeks from initial signal of 
CR whichever is longer). 
Isatuximab: 
Formulation: 
• Drug product concentrated solution for infusion in vials containing 20 mg/mL 
(500 mg/25 mL) isatuximab in 20 mM histidine. 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0. 
Route(s) of administration: IV infusion. 
Dose regimen: Refer to the dose levels and schedule for Phase 1. Dose for Phase 2 will be 
determined based on safety data from Phase 1. 
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Cemiplimab: 
Formulation 
• Drug product concentrated solution 50 mg/mL in 10 mL vials with 5.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 0.2% (w/v) 
polysorbate 80, pH 6.0. 
Or 
• Drug product concentrated solution 50 mg/mL in 10 mL vials with 7.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 0.2% (w/v) 
polysorbate 80, pH 6.0. 
Route(s) of administration: IV infusion. 
Dose regimen: Refer to the dose levels and schedule for Phase 1. 
Non-investigational medicinal products: will be locally sourced and formulations may vary.  
Premedication 
All participants will receive the following premedications to prevent or reduce incidence or 
severity of infusion reactions (IRs), 30 to 60 minutes prior to isatuximab infusion (no longer than 
60 minutes). The standard premedication regimen will include see Section 6.1.2: 
• Acetaminophen (paracetamol) 650 to 1000 mg oral route (PO) (or equivalent). 
• Ranitidine 50 mg IV (or equivalent at Investigator’s discretion). 
• Diphenhydramine 25 to 50 mg IV (or equivalent). 
• Methylprednisolone 100 mg IV (or equivalent). 
• Montelukast 10 mg PO (or equivalent). 
Criteria for optional premedication for IRs: 
• For a patient who has no IR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
• If a patient develops an IR Grade ≤2 during their first infusion only and then experiences 
no further IRs during their next 3 infusions: The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion. 
If no IR is observed for the next infusion without premedication, premedication is optional 
for the subsequent infusions at the Investigator’s discretion. However, if during the next 
infusion without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
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Radiotherapy (for Cohorts A1 and A2) (optional): 
• Formulation: Not applicable. 
• Route(s) of administration: Stereotactic radiation therapy. 
• Dose regimen: see Section 6.1.4. 
Statistical considerations: 
The participants treated at the RP2D of isatuximab and cemiplimab in combination during Phase 1 
will be included in the efficacy analysis together with participants of the same indication Phase 2 
Stage 1. Data from cHL (Cohorts A1 and A2), DLBCL, and PTCL cohorts in Phase 2 will be 
analyzed and reported separately by cohort. 
• Analysis of primary efficacy endpoints: 
- 
For cHL Cohort A1: CR rate during isatuximab + cemiplimab period will be 
summarized with descriptive statistics. A 90% two-sided confidence interval will be 
computed using Clopper-Pearson method. The statistical inference will be based on the 
hypothesis and alpha level defined in the sample size calculation section. 
- 
For cHL Cohort A2, DLBCL and PTCL: ORR during isatuximab + cemiplimab period 
will be summarized with descriptive statistics. A 90% two-sided confidence interval 
will be computed using Clopper-Pearson method. The statistical inference will be 
based on the hypothesis and alpha level defined in the sample size calculation section. 
• Analysis of secondary endpoints: For each cohort, separate analyses of the following 
endpoints will be performed for all participants during isatuximab + cemiplimab period for 
all 4 cohorts, for participants in Cohorts A1 and A2 including the data from 
both isatuximab + cemiplimab and isatuximab + cemiplimab + radiotherapy periods, and 
for participants in Cohorts A1 and A2 who receive isatuximab + cemiplimab + 
radiotherapy. 
- 
Tumor burden change: the best percent-change from baseline in tumor burden for all 
target lesions will be summarized and presented graphically. 
- 
DoR and progression-free survival (PFS) will be summarized using Kaplan-Meier 
method. 
- 
DCR will be summarized with descriptive statistics. 
In addition, ORR during isatuximab + cemiplimab period will be summarized in a similar fashion 
as described in the primary efficacy analysis for participants in Cohort A1. Similar analyses will 
be provided for CR rate and ORR for all participants in Cohorts A1 and A2 including the data 
from both isatuximab + cemiplimab and isatuximab + cemiplimab + radiotherapy periods, and for 
participants in Cohorts A1 and A2 who receive isatuximab + cemiplimab + radiotherapy. 
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• Analysis of safety endpoints: 
In Phases 1, the DLTs will be listed by participant using the DLT evaluable population. 
In Phases 1 and 2, the AEs will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA). AEs and laboratory abnormalities will be graded according to NCI 
CTCAE version 5.0. 
- 
The number (%) of participants experiencing treatment-emergent AEs (TEAEs) by 
primary system organ class (SOC) and preferred term (PT) will be summarized by 
CTCAE grade (all grades and Grade ≥3) for the all-treated population. Same table will 
be prepared for treatment-related TEAEs, AEs of special interest (AESIs), TEAEs 
leading to treatment discontinuation, serious TEAEs and TEAEs with fatal outcome. 
The post-treatment AEs will be analyzed separately, 
- 
The number (%) of participants with laboratory abnormalities (ie, all grades and 
Grade ≥3) using the worst grade during the on-treatment period will be provided for 
the all-treated population. 
• Analysis of pharmacokinetic endpoints: 
- 
Individual concentrations and pharmacokinetic (PK) parameters of both isatuximab 
and cemiplimab will be descriptively summarized. 
• Analysis of immune response and pharmacodynamic endpoints: 
- 
Findings from immune markers and pharmacodynamics markers will be descriptively 
summarized and tabulated. 
Data Monitoring Committee: Yes 
Independent from the Sponsor and Investigators, the Data Monitoring Committee (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. During this exercise, the DMC will also institute any 
measures that may be required for ensuring the integrity of the study results during the execution 
of its primary mission.  
Study Committee: 
During Phase 1, the study committee (SC) will review clinical data approximately every 2 weeks. 
During Phase 1, composition of the SC will vary based on the matter discussed, but it will 
generally include Sponsor representatives and at least two Investigators with participants 
participating to Phase 1. For Phase 2, the SC will consist of Sponsor representatives and at least 
two Investigators participating in Phase 2 Stage 1 or Stage 2. A radiotherapist will be included in 
the SC meetings to discuss the radiotherapy option after Cycle 10. The SC meetings will occur on 
an as needed basis to review data and provide strategic recommendations on study medical 
decisions. 
 
 
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
 
Abbreviations: cHL = Classic Hodgkin’s lymphoma; DLBCL = Diffuse large B cell lymphoma; DLT = Drug toxicity limit, PTCL = Peripheral T-cell 
lymphoma 
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e Radiotherapy for “no fly zone”, 2Gy × 2 fractions in 2 consecutive days (eg, Monday and Tuesday) will be administered once a week every 3 weeks for 3 times (treatment lasts for a total of 9 weeks), starting in the 
same week when isatuximab and cemiplimab are administered. 
f 
Survival status follow-up should not be performed for the cohorts where the results of interim analysis are not positive.   
Abbreviations: 5PS = 5-point scale; ADA = Anti-drug antibody; AE = Adverse event; ALT = Alanine aminotransferase; AP = Plasma antibody; aPTT = Activated partial thromboplastin time; AS = Serum antibody; AST = 
Aspartate-Amino-Transferase; C = Cycle; CT = Computed tomography; D = Day; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; ECHO = Echocardiogram; ECOG = Eastern Cooperative Oncology Group; 
eCRF = electronic case report form; EOI = End of infusion (Actual EOI sample should be taken when the pump beeps (end of infusion) before flush); EOT = End of Treatment (Post-treatment Safety); FDG  = 
Fluorodeoxyglucose; FUP = Follow-up period (Post-treatment safety); HBc =Hepatitis B core antigen; HBV = Hepatitis B virus; HBsAg = Surface antigen of the hepatitis B; HCV = Hepatitis C virus; HIV = Human 
immunodeficiency virus; ID = Identification; Ig = Immunoglobulin; IMP = investigational medicinal product; INR = International normalized ratio; IV = Intravenous, MUGA = Multigated Acquisition; P = Plasma; PET = 
Positron emission tomography; PD = Progressive disease; PK = Pharmacokinetic; RNA = Ribonucleic acid; RNT = relative nominal time; SAE = Serious adverse event; S = Serum; SOI = Start of infusion; SUV = 
Standardized uptake value; TSH = Thyroid stimulating hormone; WOCBP = Women of child-bearing potential. 
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1.4 
PHARMACOKINETIC/PHARMACODYNAMICS FLOW CHART  
1.4.1 Intervention period: Cycle 1 (Rich sampling)  
 
 
 
Procedure 
Intervention period 
C1 
D1 
D2 
D5 
D8 
D15 
D22 
Cemiplimab 
IV infusion 
X------------X 
 
 
 
 
 
 
X---------------------X 
 
 
Sample RNT (hours)  
Ref. Cemiplimab SOI 
SOI 
EOI 
EOI+4h 
 
 
 
96h 
168h 
336h  
(SOI C1D15) 
EOI 
 
 
Sample time window 
[-24h,SOI] 
[-5 min,EOI] 
±30min 
 
 
 
±5h 
±24h 
[-24h,SOI] 
[-5 min,EOI] 
 
 
PK sample IDe 
S00 
S01 
S02 
 
 
 
S03 
S04 
S05b 
S06 
 
 
ADA sample IDc 
AS00 
 
 
 
 
 
 
 
 
 
 
 
 
 
C1 
 
 
D1 
D2 
D5 
D8 
D15 
D22 
 
IV infusion 
 
 
 
X-------------X 
 
 
X--- 
 
X------------X 
X--- 
Isatuximab 
Sample RNT(hours) 
Ref. isatuximab SOI 
 
 
 
SOI 
EOI 
EOI+4h 
72h 
144h  
(SOI C1D8) 
SOI 
 
EOI 
SOI 
Sample time window 
 
 
 
[-24h,SOI] 
±10min 
±30min 
±5h 
[-24h,SOI] 
[-24h,SOI] 
 
±10min 
[-24h,SOI] 
PK sample IDe 
 
 
 
P00 
P01 
P02 
P03 
P04b 
P05a 
 
P06 
P07 
ADA sample IDd 
 
 
 
AP00 
 
 
 
 
 
 
 
 
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2 
INTRODUCTION  
2.1 
STUDY RATIONALE  
Monoclonal antibodies that block the PD-1/PD-L1 axis have demonstrated clinical benefit in 
lymphoma therapy. Nivolumab and pembrolizumab were granted accelerated approval by the 
US Food and Drug Administration (FDA) for relapsed or refractory classic Hodgkin lymphoma 
(cHL). Despite their success, only approximately 20% of the participants achieved complete 
remission (CR) (2, 3). Cemiplimab monotherapy in an early phase study has demonstrated similar 
result (4). Combining nivolumab with brentuximab vedotin increased CR rate to 61% in the 
interim analysis of a Phase 1/2 study (5). However not all participants can tolerate brentuximab 
vedotin. For the participants who failed nivolumab or pembrolizumab, cytotoxic chemotherapy 
remains the only available treatment option (6). 
In diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), objective 
responses were observed in 4 out of 11 and 2 out of 5 heavily pre-treated participants, 
respectively, in a nivolumab monotherapy Ph1b study (7). Similarly, objective responses were 
observed in 3 (all CRs) out of 18 participants with DLBCL treated with cemiplimab monotherapy 
(4). Limited treatment options are available to participants with DLBCL who failed at least 3 lines 
of therapy and participants with PTCL who have failed frontline therapy. Tisagenlecleucel 
(a chimeric antigen receptor T-cell immunotherapy) is recently approved by US Food and Drug 
Administration for the treatment of adult participants with relapsed or refractory DLBCL. 
Nevertheless, tisagenlecleucel may not be accessible to all participants. 
Many participants will require checkpoint inhibitor combination therapies to improve outcome, 
despite checkpoint inhibitor monotherapy is an effective treatment strategy. Numerous clinical 
studies are currently evaluating anti-PD-1/PD-L1 antibodies in combination with chemotherapy, 
targeted therapies, other immunotherapies and radiotherapy in participants with lymphoma. 
A recent report has shown that the combination of anti-PD-L1 and CD38 antibodies induces 
a greater anti-tumor immune response than anti-PD-L1 monotherapy in a mouse lung cancer 
model and possibly revert resistance to anti-PD-1/PD-L1 therapies, establishing the hypothesis of 
targeting CD38 to potentiate anti-PD-1/PD-L1 therapies (8, 9). 
CD38 expression is well-documented in hematological cancers, including MM and certain types 
of lymphomas and leukemia (10). The role of CD38 in tumor environment is not completely 
understood, but there are several findings indicating that CD38 can contribute to the 
immune-suppressive tumor microenvironment: 
A) CD38 catalyzes the conversion of nicotinamide adenine dinucleotide into 
immunosuppressive adenosine (10). 
B) CD38 expression is highly correlated with the expression of PD-1 and its ligands in solid 
tumor biopsies. 
C) CD38 is found upregulated in tumor models that have acquired resistance to anti-PD-L1 
(8, 9). 
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D) CD38 expressing myeloid derived suppressor cells promote growth of human tumors in 
mice (11). 
E) CD38 expressing mouse tumor cells inhibit the proliferation of autologous T cells (12). 
Isatuximab (anti-CD38 antibody) can induce different immune-modulatory mechanisms that can 
contribute to reshape the tumor microenvironment and enhance the anti-tumor activity of 
anti-PD-1 antibodies: 
A) Isatuximab decreases circulating regulatory T cell counts and increases total T cell counts 
in MM participants (12). 
B) Isatuximab restores T cell function inhibited by regulatory T cells (12). 
C) Isatuximab induces activation of natural killer (NK) cells and increases their cytolytic 
activity (13).  
D) Isatuximab increases macrophage phagocytic activity and M1 polarization. 
In lymphomas, CD38 is found expressed on the tumor cells of Hodgkin’s lymphoma (HL), 
DLBCL, and PTCL (14, 15). 
Hodgkin Lymphoma (HL) 
It has been shown that a considerable fraction of infiltrating CD4+ T cells in HL represented by 
T regulatory cells (Treg) have immunosuppressive activity on infiltrating cytotoxic T-cells (16, 
17, 18). Gaetano et al. reported that in 108 HL participant samples, 43% of CD4+ T-cells also 
expresses CD38, and is significantly higher than that detected in benign reactive lymphoid 
hyperplasia (14). The majority of activated CD4+CD38+ T-cells are also found to be CD26-, 
which represents a phenotype that contribute to tumor escape by increasing levels of 
immunosuppressive adenosine and evasion of the host antitumor response. 
Diffuse Large B-Cell Lymphoma (DLBCL) 
Depending on the cut-off applied, up to 61% and 69% of DLBCL cases were reported to have 
PD-L1+ tumor cells and PD-1+ tumor infiltrating lymphocytes, respectively (19). CD38 
expression was observed in both germinal center B cell-like (GCB) and activated B cell-like 
(ABC) DLBCL samples, where prevalence and receptor density was higher in GCB than ABC. 
Through direct targeting of CD38, isatuximab was also shown to induce apoptosis in vitro and in 
vivo in SU-DHL-8 DLBCL models (13). 
Peripheral T-Cell Lymphoma (PTCL) 
CD38, PD-1, and PD-L1 are expressed in certain subtypes of PTCL (eg, 80% and 70% of 
angioimmunoblastic T-cell lymphoma [AITL] samples are CD38 and PD-1 positive, respectively) 
(15). 
Based on the above rationale, it is hypothesized that isatuximab (anti-CD38) in combination with 
cemiplimab (anti-PD-1) may be effective in participants with HL, DLBCL, and PTCL. 
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Furthermore, emergent clinical data suggests that radiotherapy, in combination with 
anti-PD-1/PD-L1, elicits immune-mediated anti-neoplastic effects locally as well as systemically 
(abscopal) in solid tumors (20, 21, 22). A recent report of a participant with refractory HL who 
was enrolled in a Phase 1 pembrolizumab study describes an abscopal effect after local radiation 
administered concurrently with pembrolizumab (6). In an effort to improve CR rate (CRR) and 
enhance response duration in HL and cutaneous T-cell lymphoma participants, several studies are 
ongoing combing anti-PD-1 with radiotherapy (NCT03179917, NCT03480334, NCT03385226). 
The coupling of radiotherapy with immune checkpoint inhibition provides an opportunity for 
synergistic abscopal anti-tumor effects. The hypothesis of coupling radiotherapy with isatuximab 
and cemiplimab will be evaluated in the current study.  
2.2 
BACKGROUND  
2.2.1 Isatuximab  
Isatuximab (SAR650984) is a mAb that binds selectively to a unique epitope on the human 
surface antigen CD38. Isatuximab kills tumor cells via multiple biological mechanisms; 
antibody-dependent cellular-mediated cytotoxicity, antibody-dependent cellular-mediated 
phagocytosis, complement-dependent cytotoxicity and direct induction of apoptosis 
(pro-apoptosis) without crosslinking. Isatuximab treatment of CD38-expressing cells also results 
in inhibition of CD38 enzymatic activity. 
At the cut-off date of 05 January 2018, a total of 675 participants were treated with isatuximab 
single agent or in combination in 10 studies. All participants had hematological malignancy. 
Refer to the isatuximab Investigator’s Brochure for the most updated nonclinical and clinical 
studies of isatuximab. 
2.2.2 Cemiplimab  
Cemiplimab (REGN2810) is a high affinity hinge-stabilized IgG4P human antibody to the PD-1 
receptor (PDCD1, CD279) that blocks PD-1/PD-L1-mediated T cell inhibition. Cemiplimab 
displayed a robust, dose-dependent suppression of MC38.Ova tumors in the syngeneic mouse 
tumor model. The nonclinical activity of cemiplimab is similar to two in-house generated 
anti-PD-1 comparator antibodies with identical amino acid sequence to nivolumab and 
pembrolizumab (based on publicly available sequence data). On 28 Sep 2018, the US FDA 
approved cemiplimab-rwlc for patients with metastatic cutaneous squamous cell carcinoma 
(CSCC) or locally advanced CSCC. 
Refer to the cemiplimab Investigator’s Brochure for the most updated nonclinical and clinical 
studies of cemiplimab. 
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2.3 
BENEFIT/RISK ASSESSMENT  
Detailed information about the known and expected benefits and risks associated with the 
treatments to be used in study ACT15320 may be found in the Investigator’s Brochure of 
isatuximab and the Investigator’s Brochure of cemiplimab. 
2.3.1 Benefits  
Refer to Section 2.1. 
2.3.2 Potential and identified risks  
2.3.2.1 Isatuximab  
Isatuximab has been investigated either as monotherapy or in combination in participants with 
hematological malignancies. The safety profile of isatuximab monotherapy has been best 
characterized in study TED10893 (Phase 1 and Phase 2, including 186 participants with MM), 
where the most common TEAEs, excluding the AEs corresponding to laboratory abnormalities, 
include IRs, fatigue, nausea, upper respiratory infection, cough, back pain and diarrhea. Infusion 
reactions occurred in 49.4% of the participants from the TED10893 Phase 1 study. 
The IRs associated with isatuximab in participants who are administered appropriate primary 
prophylaxis (see also Section 2.3.4) are most common with the first administration of the drug, are 
not dose-dependent, are Grade 1 to 2 in severity, are manageable with standardized precautions 
detailed in each study protocol, are resolved either spontaneously or with standard medication by 
the next day following the infusion, and the participants do not appear to sustain sequelae. The 
IRs generally do not cause treatment discontinuation, and do not tend to recur at subsequent 
administrations of isatuximab. 
In addition to the occurrence of IRs, cytokine release syndrome, influenza-like illness, and fever 
have also been observed in participants treated with isatuximab; these reactions may involve 
immunogenicity mechanisms (human antihuman antigen) and hypersensitivity reactions. These 
adverse reactions, whether acute or delayed, may be serious and systemic (eg, anaphylactic 
reaction). 
Please refer to the current version of the isatuximab Investigator’s Brochure. 
2.3.2.2 Cemiplimab  
Cemiplimab has been generally well tolerated, and the reported AEs have been similar to what 
have been observed with other PD-1 inhibitors.  
As of 27 March 2018, pooled data from the non-randomized studies (R2810-ONC-1423, 
R2810-ONC-1540, R2810- ONC-1606, R2810-ONC-1620, R2810-ONC-1622, R2810-ONC-
1655, and R1979-ONC-1504) were analyzed. A total of 757 participants have been treated with 
cemiplimab either as monotherapy or in combination with radiotherapy and/or other cancer 
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therapy in seven of the ongoing studies. A total of 512 participants (67.6%) experienced at least 
1 treatment-related AE, of which 96 participants (12.7%) experienced Grade 3 or higher 
treatment-related AEs. Sixty-four participants (8.5%) experienced investigator-attributed 
treatment-related SAEs. Seven participants (0.9%) experienced fatal treatment-related AEs: 
hepatic failure (1 participant with hepatocellular carcinoma) and acute hepatic failure 
(1 participant with DLBCL), paraneoplastic encephalomyelitis (1 participant with soft tissue 
sarcoma), toxic epidermal necrolysis (1 participant with follicular lymphoma [FL]), nosocomial 
pneumonia secondary to Grade 4 mucositis (1 participant with FL), and pneumonitis 
(2 participants: 1 with NSCLC and 1 with cervical cancer). 
Treatment-related AEs were characterized as potential immune-related AEs (irAEs). A total of 
339 participants (44.8%) experienced potential irAEs including 123 participants (16.2%) with 
identified irAEs. The majority of potential irAEs were mild to moderate in severity. Sixty-three 
participants (8.3%) experienced potential irAEs of Grade 3 or higher including 53 (7.0%) with 
identified irAEs. Forty-nine participants (6.5%) experienced serious potential irAEs including 
41 participants (5.4%) with serious identified irAEs. Six participants (0.8%) experienced fatal 
irAE including hepatic failure, toxic epidermal necrolysis, pneumonitis, and paraneoplastic 
encephalomyelitis. 
As of 27 March 2018, 71 (9.4%) participants experienced IRs including 2 (0.3%) with Grade 3 IR. 
The remaining participants experienced Grade 1 or Grade 2 IRs. The most common symptoms 
reported were pyrexia (14 [1.8%] participants), chills (11 [1.5%] participants), nausea (9 [1.2%] 
participants), and abdominal pain, vomiting, and rash (4 [0.5%] participants each). 
Please refer to the current version of the cemiplimab Investigator’s Brochure. 
2.3.3 Potential risk related to the combination  
Based on the available pre-clinical and clinical data from each individual drug, no serious adverse 
drug reactions potentially overlapping are anticipated with the isatuximab and cemiplimab 
combination. 
There are 2 ongoing Phase 1/2 clinical studies (Study ACT15319 and Study TCD14906) of 
isatuximab in combination with cemiplimab in participants with MM (TCD14906), prostate 
cancer or lung cancer (ACT15319). Both studies have completed their respective Phase 1 
components. Recommended Phase 2 doses were confirmed without DLT observed. Recruitment 
in the Phase 2 components is in progress. 
2.3.4 Preventive measures to minimize the risk from the combination  
To minimize the risk of IRs, all participants treated with isatuximab should routinely receive 
primary prophylactic treatment with diphenhydramine 25 to 50 mg IV (or equivalent), 
methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent at 
investigator’s discretion), acetaminophen (paracetamol) 650 to 1000 mg orally (or equivalent), 
and montelukast 10 mg orally (or equivalent), 30 to 60 minutes (and never longer than 60 
minutes) prior to the isatuximab infusion to minimize the incidence and severity of IR commonly 
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observed with certain mAb. In an attempt to further mitigate the incidence and severity of IRs, it 
is recommended that the initial infusion rate should not exceed 200 mL of isatuximab per hour. In 
the absence of IRs after 1 hour of infusion, the first infusion rate can be increased by 25 mL/hour 
increments every 30 minutes, to a maximum of 150 mL/hour. In the event of a moderate 
hypersensitivity reaction, the isatuximab infusion should be interrupted and may subsequently 
resume after recovery, at a slower infusion rate (one half of the initial infusion rate, 
ie, 12.5 mL/hour), under close monitoring and with supportive care as needed. Prior to restarting 
the infusion, participants may receive additional medication per the judgment of the Investigator; 
recommended medications consist of diphenhydramine 25 mg IV and methylprednisolone 100 mg 
IV (or equivalent). In the event of a severe hypersensitivity reaction, treatment with isatuximab is 
to be immediately discontinued until resolution or until improvement of the AE to Grade 1. If 
a severe infusion-related AE (Grade 3) occurs for a 3rd time or in case of life-threatening 
consequences (Grade 4), treatment with isatuximab will be definitively and permanently 
discontinued. Detailed guidelines for the management of the IRs are provided in Section 6.5.5. 
Criteria for optional premedication for IRs: 
• For a patient who has no IR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
• If a patient develops an IR Grade ≤2 during their first infusion only and then experiences 
no further IRs during their next 3 infusions: The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion. 
If no IR is observed for the next infusion without premedication, premedication is optional 
for the subsequent infusions at the Investigator’s discretion. However, if during the next 
infusion without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
To minimize the risk of potential immune-related treatment-emergent adverse events related to 
cemiplimab, the exclusion criteria in the Study ACT15320 include: 
• E 05. Comorbidity requiring systemic corticosteroid therapy (>10 mg prednisone/day or 
equivalent) within 14 days of study intervention initiation. Physiologic replacement doses 
are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are 
not being administered for immunosuppressive intent.  
• E 07. 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 for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). 
Vitiligo, hypothyroidism, or Sjogren’s syndrome are eligible. 
• E 08. Known seropositive and requiring anti-viral therapy for human immunodeficiency 
virus (HIV), known hepatitis B virus (HBV), or known hepatitis C virus (HCV), unless 
they are controlled or negative when tested by polymerase chain reaction (PCR) or 
equivalent. Active tuberculosis or severe infection requiring parenteral antibiotic 
treatment. 
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• E 11. History of or current interstitial lung disease or pneumonitis that requires oral or IV 
glucocorticoids to assist with management (radiation pneumonitis in the radiation field is 
permitted). 
• E 18. Prior treatment with idelalisib. 
• E 24. Treatment-related immune-mediated (or immune-related) AEs from 
immune-modulatory agents (including anti PD-1/PD-L1 agents for Cohort A2) that caused 
permanent discontinuation of the agent, or that were Grade 3 or 4 in severity, or that have 
not resolved or improved to baseline at least 3 months prior to initiation of study 
intervention. For other agents, treatment related immune mediated (or immune related) 
AEs that were Grade 2 or above. 
Additionally, careful monitoring of AEs and laboratory abnormalities, continuous direct 
communication between the Investigators and the monitoring team, and the adherence to the dose 
modification rules specified in the study protocol, are the measures that will continue to be 
implemented to minimize the risks in study participants. 
General guidelines for the management of irAEs, including some specific irAEs such as colitis, 
endocrine AEs, pneumonitis, renal AEs, dermatologic AEs, hepatitis, ophthalmologic AEs 
(eg, uveitis) are also provided in the study protocol Section 10.4. 
2.3.5 Conclusion  
Overall, the anticipated benefit/risk ratio of isatuximab in combination with cemiplimab supports 
the conduct of study ACT15320 in participants with lymphoma. 
More detailed information about the known and expected benefits and risks associated with the 
treatments to be used in study ACT15320 may be found in the Investigator’s Brochure of 
isatuximab and the Investigator’s Brochure of cemiplimab. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
Phase 1:  
To characterize the safety and tolerability of isatuximab in 
combination with cemiplimab in participants with relapsed and 
refractory classic Hodgkin’s lymphoma (cHL), diffuse large 
B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma 
(PTCL), and to confirm the recommended Phase 2 dose 
(RP2D). 
Phase 1:  
Safety and tolerability will be assessed based on dose limiting 
toxicities (DLTs, in Cycle 1), adverse events (AEs)/serious 
adverse events (SAEs), and laboratory abnormalities. 
Phase 2: 
1 - Cohort A1 (anti-PD-1/PD-L1 naive cHL): To assess the 
complete remission (CR) rate of isatuximab in combination 
with cemiplimab. 
 
2 - Cohort A2 (cHL progressing from PD-1/PD-L1), B (DLBCL) 
and C (PTCL): To assess the objective response rate (ORR) 
of isatuximab in combination with cemiplimab. 
 
Phase 2:  
1 - Cohort A1: CR rate as defined by as the proportion of 
participants who have a CR as a best overall response during 
the isatuximab + cemiplimab therapy period using the Lugano 
response criteria 2014 (1) (Appendix 6 Section 10.6). 
2 - Cohorts A2, B, and C: 
ORR defined as the proportion of participants who have a CR 
or partial response (PR) as a best overall response during 
isatuximab + cemiplimab therapy period using the Lugano 
response criteria 2014 (1) (Appendix 6 Section 10.6). 
Secondary 
 
1 - To evaluate the safety of the RP2D of isatuximab in 
combination with cemiplimab.  
1 - AEs/SAEs and laboratory abnormalities for isatuximab+ 
cemiplimab. 
2 - To evaluate the safety of the combination of isatuximab 
with cemiplimab and radiotherapy in participants with cHL 
2 - AEs/SAEs and laboratory abnormalities in isatuximab + 
cemiplimab + radiotherapy treated participants (Cohort A1 
and A2). 
3 - To evaluate the immunogenicity of isatuximab and 
cemiplimab when given in combination. 
3 - Immunogenicity: Anti-drug antibody (ADA) against 
isatuximab and against cemiplimab. 
4 - To characterize the pharmacokinetic (PK) profile of 
isatuximab and cemiplimab when given in combination. 
4 - PK evaluation using non-compartmental analysis for both 
compounds using serum concentrations for cemiplimab and 
plasma concentrations for isatuximab. 
5 - To assess overall efficacy of: 
• 
Isatuximab in combination with cemiplimab, 
And  
 
• 
Isatuximab in combination with cemiplimab and 
radiotherapy. 
• 
- Efficacy: 
• 
Tumor burden change, duration of response (DoR), 
disease control rate (DCR), defined as the 
percentage of participants who achieve CR, partial 
response (PR) or stable disease (SD) and 
progression-free survival (PFS). 
• 
For Cohort A1, ORR during isatuximab + 
cemiplimab ± radiotherapy periods. CR rate during 
isatuximab + cemiplimab + radiotherapy period. 
• 
For Cohort A2, ORR during   isatuximab + 
cemiplimab + radiotherapy period. CR rate during 
isatuximab + cemiplimab ± radiotherapy periods. 
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Tertiary/exploratory 
1 - To explore the preliminary overall efficacy. 
1 - Overall survival (OS) and time to response (TTR) for all 
treated participants;  
• 
For Cohorts A1 and A2, time to CR (TTCR) for all 
treated participants 
• 
For Cohorts A1 and A2, OS, TTR, TTCR during 
isatuximab + cemiplimab period and for participants 
who receive isatuximab + cemiplimab + 
radiotherapy 
2 - To evaluate the relationships between clinical response 
and biomarkers in tumor tissue. 
2 - The relationship between clinical response and analyses 
in tumor tissue of:  
• 
CD38, PD-L1, MHC-II expression,   
• 
Possibly beta-2-microglubulin, and MHC-I 
expression, 
• 
Genomic and genetic analysis,   
• 
Immune contexture. 
3 - To explore immune genetic markers in blood. 
3 - Immune genetic determinants (including polymorphisms in 
FcγR receptors) in blood at baseline. 
 
4 - To perform PK/pharmacodynamics analysis if possible 
with any relevant pharmacodynamics markers mentioned 
above, and correlation with safety/efficacy endpoints. 
4 - PK/pharmacodynamics analysis: 
• 
Pharmacodynamic biomarkers in response to 
investigational medicinal product (IMPs): immune 
contexture and possibly transcriptomic analyses in 
tumor tissue at baseline and upon treatment. 
• 
Determination of exposure-response relationships 
with efficacy, safety, and biomarkers, if possible. 
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 a hematology setting. In addition, suitable steps have been built into 
each of these assessments to ensure their reliability and accuracy and to minimize any risks to 
participant safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 1/2 open-label, non-comparative, multi-center, safety, preliminary efficacy and 
PK study of isatuximab in combination with other anti-cancer therapies in participants with 
lymphoma. This study will be conducted in 2 parts (see Section 1.2 for study design schema). 
Phase 1 (safety run-in): 
Participants with cHL, DLBCL, or PTCL will be enrolled in the Phase 1.  
Dose levels and schedules are described in the table below. 
Dose levels and schedules for Phase 1  
Dose level 
(DL) 
Isatuximab 
Cemiplimab 
Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond 
1 cycle = 21 days 
Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond  
1 cycle = 21 days 
Starting dose 
10 mg/kg every week 
(QW) × 4 (Cycle 1) 
10 mg/kg every 2 weeks 
(Q2W) (Cycle 2 ~ Cycle 6)  
10 mg/kg every 3 weeks 
(Q3W) 
250 mg Q2W 
350 mg Q3W 
Minus - 1 (DL-1) 
5 mg/kg QW × 4 (Cycle 1) 
5 mg/kg Q2W 
(Cycle 2 ~ Cycle 6)  
5 mg/kg Q3W 
250 mg Q2W 
350 mg Q3W 
The DLT observation period is 1 cycle (28 days). 
To account for DLT non-evaluability because of AEs that do not qualify as DLTs, approximately 
6 participants may be enrolled without interruption to receive the starting dose. At the starting 
dose, DLTs will be assessed among the first 3 DLT evaluable participants provided that they will 
have received at least 90% of the planned cumulative doses of the first cycle (unless they 
discontinue IMP[s] due to DLT), based on the rules listed below. The totality of the AEs collected 
from all treated participants will be taken into consideration when deciding RP2D. 
• If 0/3 participants experience a DLT, the starting dose will be the RP2D. 
• If 1/3 participants experience a DLT, 3 additional participants will be enrolled at the 
starting dose level: 
- 
If a total of 1/6 participants treated at the starting dose experience a DLT, the starting 
dose will be the RP2D. 
- 
If a total of ≥2/6 participants experience a DLT, the dose will be de-escalated to dose 
level minus 1 (DL-1). 
• If ≥2/3 participants experience DLTs, the dose will be de-escalated to DL-1. 
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At DL-1, the same DLT observation rules will be applied for selecting a RP2D, and if ≥2/6 or 
≥2/3 participants experience DLTs, an alternative dose/schedule might be considered from 
a safety viewpoint by the Sponsor after consulting with the Investigators who have recruited 
participants for Phase 1.  
Enrollment of participants within DL is to be staggered by at least 3 days. 
Following the identification of the RP2D, the Phase 2 of the study will be initiated. 
The NCI CTCAE version 5.0 will be used to assess the severity of AEs. Causal relationships are 
to be determined by the Investigator. The DLTs will be confirmed by the Sponsor and recruiting 
Investigators. 
Dose limiting toxicity is defined as: 
All AEs specified below occurring during the first cycle of treatment, unless due to disease 
progression or to a cause obviously unrelated to IMP. The duration of the DLT observation period 
will be longer for participants who delay initiation of Cycle 2 due to treatment-related AE whose 
duration must be assessed in order to determine if that AE meets the definition of a DLT. 
Hematological abnormalities are defined as any of the following: 
• Grade 4 neutropenia for 7 or more consecutive days. 
• Grade 3 to 4 neutropenia complicated by fever (temperature ≥38.5°C on more than 
1 occasion) or microbiologically or radiographically documented infection. 
• Grade 3 to 4 thrombocytopenia associated with clinically significant bleeding requiring 
clinical intervention. 
Non-hematological abnormalities 
• Grade 4 non-hematologic AE. 
• Grade ≥2 uveitis. 
• Grade 3 non-hematological AE lasting >3 days despite optimal supportive care, except: 
- 
Grade 3 fatigue, 
- 
Allergic reaction/hypersensitivity attributed to isatuximab or cemiplimab, 
- 
Grade 3 or 4 laboratory abnormalities that are not clinically significant per recruiting 
Investigators and Sponsor. 
• Treatment-related laboratory abnormalities/AEs that lead to delay in initiation of Cycle 2 
>14 days. 
• In addition, any other AE that the recruiting Investigators and Sponsor deem to be dose 
limiting, regardless of its grade, may also be considered as DLT. 
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Phase 2: (Efficacy signal/Simon 2-stage design): 
Phase 2 includes 4 cohorts: 
Cohort A1: cHL anti-PD-1/PD-L1 naïve. 
Cohort A2: cHL anti-PD-1/PD-L1 progressor.  
Cohort B: DLBCL anti-PD-1/PD-L1 naïve. 
Cohort C: PTCL anti-PD-1/PD-L1 naïve. 
The participants treated at the RP2D of isatuximab and cemiplimab in combination during Phase 1 
will be included in the efficacy analysis together with participants of the same indication in 
Stage 1 of Phase 2. 
Interim analysis will be performed based on the number of CR (for Cohort A1) or objective 
responses (for Cohorts A2, B, and C) and the totality of data observed (up to 24 weeks after the 
last ongoing participant receives first dose of IMP) within a treatment cohort in Phase 2 Stage 1; 
based on the available data, the Sponsor may decide to advance such a treatment cohort to Phase 2 
Stage 2 after consulting with Investigators. 
The Sponsor may decide to proceed to Phase 2 Stage 2 without enrollment hold based on the 
available data.  
Based on the positive efficacy signal and the totality of data observed at the end of Phase 2 
Stage 2, the Sponsor may decide to open additional cohorts to study isatuximab in combination 
with radiotherapy, or cemiplimab in combination with radiotherapy in participants with cHL in 
this study. The Sponsor may also decide to test alternative IMP doses and schedules in case of 
inadequate efficacy and PK results. 
In both Phases 1 and 2, participants with cHL who achieve best overall response of PR or SD at 
the disease assessment planned for Week 36, if deemed appropriate (and does not meet exclusion 
criteria E01, E06, E08, E21, E30, and E32) by the Investigator, may begin radiotherapy between 
D1 to D14 (preferably between D1 to D7) of the next immediate cycle.   
The data cut-off for the primary end-of-cohort analysis is up to 24 weeks from the date the last 
participant treated in individual cohort. The data cut-off for the intermediate and final end-of-cohort 
analysis is up to 48 and 96 weeks, respectively, from the date the last participant treated in individual 
cohort. 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
Treatment beyond the first in those 3 indications remains challenging with a significant unmet 
need for participants with advanced lymphomas. Combination strategies with immunotherapy 
agents have a potential to increasing their individual effectiveness in these participants. 
Phase 1 is designed to assess the safety and tolerability of isatuximab in combination with 
cemiplimab in participants with classic Hodgkin’s lymphoma (cHL), diffuse large B-cell 
lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), and to confirm the recommended 
Phase 2 dose (RP2D). 
Phase 2 is designed to assess the CR rate of isatuximab in combination with cemiplimab in 
participants with cHLPD-1 naïve (Cohort A1) and objective response rate (ORR) of isatuximab in 
combination with cemiplimab in participants with cHL progressing from PD-1/PD-L1 (Cohort 
A2), DLBCL (Cohort B), and PTCL (Cohort C). 
4.3 
JUSTIFICATION FOR DOSE  
The proposed isatuximab dose is selected based on the clinical data from the participants with 
MM. In participants with MM, isatuximab exhibits non-linear PK due to the presence of 
target-mediated drug disposition. In addition, tumor burden impacts the PK of isatuximab. 
Based on safety, efficacy, PK, and PK/pharmacodynamic analyses, the dosing schedule selected 
for isatuximab when used in combination with other therapies for the treatment of MM is 
10 mg/kg QW × 4 followed by Q2W. The half-life of isatuximab associated to the linear 
elimination is 18 days. Since it is hypothesized that the immuno-modulatory mechanisms of 
isatuximab would also be involved in the pharmacological activity of isatuximab and because 
10 mg/kg Q2W ×2, Q4W have shown some activity in MM (Study TED10893). The current 
10 mg/kg QW ×4 followed by Q2W schedule was adapted for this study ACT15320 for the first 
6 cycles: 10 mg/kg QW ×4 followed by Q2W, and then maintained by 10 mg/kg Q3W from 
Cycle 7. Of note, based on updated pharmacokinetic characterization of isatuximab in 2019, the 
plasma half-life has been re-estimated to 28 days. 
To support the development program of isatuximab in pediatrics, simulations of isatuximab 
exposure were conducted in children for different body weight categories with showing 
comparable exposure to those observed in adults (Study ACT14596) up to 12.2 kg corresponding 
to 2-year-old children (OMS classification). 
The proposed cemiplimab dosing schedule of 250 mg Q2W for the first 6 cycles and maintained 
by 350 mg Q3W from Cycle 7 is selected in this study for participants with lymphoma to better 
align with the dosing schedule of planned concurrent treatment with isatuximab. The cemiplimab 
dose of 350 mg Q3W is also selected for ongoing pivotal Phase 3 studies in participants with 
NSCLC. Cemiplimab dosing regimen of 3 mg/kg Q2W was well tolerated by participants with 
lymphoma in ongoing Study R1979-ONC-1504.  
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A flat cemiplimab dose of 350 mg Q3W is selected based on population PK modeling and 
simulation, as it is expected to provide exposure that closely replicates that observed in 
participants (mean weight: 80 kg) for the 3 mg/kg Q2W regimen in the ongoing first-in-human 
study R2810-ONC-1423 (NCT02383212). Simulations of cemiplimab exposure in 
1000 participants using population PK analyses indicated that: 
• A 350 mg Q3W dose in participants resulted in similar (≤20% difference) Ctrough, area 
under the curve (AUC)12 weeks, and Cmax as compared to the 3 mg/kg Q2W dose in the 
first-in-human participant population (80 kg), and exceeded those observed at the 1 mg/kg 
Q2W dose. 
• The variability in cemiplimab exposure (coefficient of variation) was similar for 
body-weight adjusted doses as compared to flat doses. Given the similar predicted 
exposure for 350 mg Q3W when compared to the 3 mg/kg Q2W regimen, a similar 
efficacy/safety profile is also expected. Therefore, the 350 mg Q3W IV dose of 
cemiplimab is being proposed across the cemiplimab program. 
To support the development program of cemiplimab in pediatrics, simulations of cemiplimab 
exposure were conducted in children for different body weight categories with mean values of 
8 kg to 80 kg and a distribution around these mean values similar to that observed in the adult 
population in first-in-human study (R2810-ONC-1423). 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all periods of the 
study including the last follow-up visit  or the last scheduled procedure shown in the Schedule of 
Activities (SoA). 
The end of study will occur at the final study cut-off planned at 96 weeks after the last participant 
enters the study whichever the cohort or when all participants have had the opportunity to 
complete the EOT visit 30 days after the last study treatment administration, whichever is the 
latest. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
I 01. Age: Participant must be ≥12 years of age inclusive (or the age deemed appropriate per 
local health authority or IRB approval), at the time of signing the informed consent. 
Specific to France: refer to Appendix 11 (Section 10.11.1). 
I 02. Disease location amenable to mandatory tumor biopsy at baseline (unless clinically 
unfeasible and after discussion with Sanofi Medical Monitor for Phase 1 and 
Phase 2 Stage 1; mandatory for Phase 2 Stage 2), and possibly at Cycle 2 Day 1. If disease 
location is in a superficial lymph node, excisional biopsy or resected tissue is required if 
clinically feasible; otherwise, core needle biopsy is acceptable. Fine needle aspirates are 
not acceptable. Archival tumor biopsy sample may be used to replace mandatory baseline 
biopsy, if the sample was obtained after progression from immediate prior therapy. 
I 03. 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 an LDi >1 cm 
according to Lugano criteria 2014 (1). Tumor sites that are considered measurable must 
not have received prior radiotherapy, unless among them at least one is FDG-avid. 
For Phase 1 and Cohort A1 (cHL anti-PD-1/PD-L1 naïve): 
I 04. Histologically confirmed advanced cHL that has relapsed or progressed after:  
• At least 3 lines of systemic therapies that may include auto-hematopoietic stem cell 
transplantation (HSCT)(See Appendix 10 Section 10.10 for definition of one line of 
therapeutic regimen) OR 
• Auto-HSCT and Brentuximab vedotin.  
For Phase 1 and Cohort A2 (cHL anti-PD-1/PD-L1 inhibitor progressor): 
I 05. Histologically confirmed advanced cHL which has relapsed or progressed after one 
previous anti-PD-1/PD-L1 containing regimen as the most recent prior therapy. 
I 06. In Cohort A2 Phase 1: Documentation of benefit (defined as CR, PR or SD ≥6 months at 
≥1 radiographic imaging scans) but subsequent progression during or after the prior 
anti-PD1/PD-L1 containing regimen. Progression has to occur within 6 months from 
last dose of the prior anti-PD1/PD-L1 containing regimen. IMP must be started within 
4 months from progression. The site’s study team must confirm that radiographic 
progression has occurred per IWG response criteria for malignant lymphoma following 
initiation of the anti PD-1/PD-L1 containing regimen. 
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In Cohort A2 Phase 2: Participants who achieved CR are excluded unless they relapsed on 
an anti-PD1/PD-L1 containing regimen. Documentation of benefit (defined as PR or SD 
≥6 months at ≥1 radiographic imaging scans) but subsequent progression during or after 
the prior anti-PD1/PD-L1 containing regimen. Progression has to occur within 6 months 
from last dose of the prior anti-PD1/PD-L1 containing regimen. IMP must be started 
within 4 months from progression. The site’s study team must confirm that radiographic 
progression has occurred per IWG response criteria for malignant lymphoma following 
initiation of the anti PD1/PD-L1 containing regimen.  
For Phase 1 and Cohort B (DLBCL): 
I 07. Histologically confirmed advanced DLBCL that has relapsed or progressed after: 
• 2 lines of systemic therapy including auto-HSCT, OR 
• 2 lines of systemic therapy for participants who are not eligible for auto-HSCT. 
For Phase 1 and Cohort C (PTCL): 
I 08. Histologically confirmed advanced PTCL that has relapsed or progressed after: 
• Chemotherapy and auto-HSCT as consolidation of first remission, OR 
• First-line chemotherapy if participants are ineligible for auto-HSCT. 
Weight 
I 09. Body weight of >45 kg for patients with age <18 years. 
Sex 
I 10. Male or Female 
Male participants: A male participant must agree to use contraception as detailed in Appendix 5 
(Section 10.5) 2 weeks before study intervention first administration, during the intervention 
period and for at least 6 months, after the last dose of study intervention and refrain from donating 
sperm during this period. 
Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 5 Section 10.5), not breastfeeding, and at least one of the following conditions 
applies: 
• Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 (Section 10.5) 
OR 
• A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 (Section 10.5) 
2 weeks before study intervention first administration, during the intervention period and 
for at least 6 months after the last dose of study intervention. 
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Informed Consent 
I 11. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. In countries where the legal age of majority is 
above 18 years and for participants less than 18 years, a specific ICF must also 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: 
Medical conditions 
E 01. Eastern Cooperative Oncology Group (ECOG) performance status of ≥2. 
E 02. Predicted life expectancy <3 months. 
E 03. Central nervous system lymphoma, active brain metastases or leptomeningeal metastases. 
Participants with asymptomatic central nervous system metastases which have been stable 
(defined as without evidence of progression by magnetic resonance imaging [MRI] or 
other imaging modality for at least 28 days prior to initiation of study intervention and any 
neurologic symptoms have returned to baseline) following treatment with surgery or 
radiation therapy are allowed. 
E 04. Symptomatic or impending cord compression at study entry. 
E 05. Comorbidity requiring systemic corticosteroid therapy (>10 mg prednisone/day or 
equivalent) within 14 days of study intervention initiation. Physiologic replacement doses 
are allowed even if they are >10 mg of prednisone/day or equivalent, as long as they are 
not being administered for immunosuppressive intent.  
E 06. Significant cardiac dysfunction (defined as left ventricular ejection fraction [LVEF] of 
<50%), New York Heart Association classification for chronic heart failure III-IV, 
symptomatic coronary artery disease, major clinically significant electrocardiogram (ECG) 
abnormality, significant ventricular arrhythmias; myocardial infarction within 6 months; 
unstable or poorly controlled angina pectoris. 
E 07. 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 for replacement therapy (eg, thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc). 
Vitiligo, hypothyroidism, or Sjogren’s syndrome are eligible. 
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E 08. Known seropositive and requiring anti-viral therapy for HIV, known HBV, or HCV, unless 
they are controlled or negative when tested by polymerase chain reaction (PCR) or 
equivalent. Active tuberculosis, or severe infection requiring parenteral antibiotic treatment 
(Section 10.2). 
E 09. Diffusing capacity of the lungs for carbon monoxide (DLCO) <60% for participants 
previously treated with bleomycin. 
E 10. Known second malignancy either progressing or requiring active treatment within the 
last 3 years (except for basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, DICT or in situ cervical cancer that has undergone potentially curative therapy). 
E 11. History of or current interstitial lung disease or pneumonitis that requires oral or 
IV glucocorticoids to assist with management (radiation pneumonitis in the radiation field 
is permitted). 
E 12. Participant has undergone major surgery ≤3 weeks prior to starting study treatment or has 
not recovered from the side effects of major surgery. 
E 13. Primary mediastinal large B-cell lymphoma. 
Phase 1 and Cohorts A1 and A2 
E 14. Nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) subtype is not allowed. 
Phase 1 Cohorts A1, A2, and B 
E 15. Transformed follicular lymphoma (tFL) and chronic lymphocytic leukemia (CLL) Richter 
transformation subtypes are not allowed. 
Phase 1 and Cohort C 
E 16. Cutaneous T-cell lymphoma subtype is not allowed. 
Prior/concomitant therapy 
E 17. Prior treatment with an agent (approved or investigational) that blocks CD38 (participants 
who joined a study with an anti-CD38 but have written confirmation they were on control 
arm are allowed providing that therapy is allowed). 
E 18. Prior treatment with idelalisib. 
E 19. Prior allogeneic HSCT. 
E 20. Auto-HSCT less than 90 days prior to initiation of study intervention. Carmustine (BCNU) 
≥600 mg/m² received as part of the pre-transplant conditioning regimen. 
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E 21. Receipt of a live-virus vaccination within 28 days of planned treatment start. Seasonal flu 
vaccines that do not contain a live virus are permitted. 
E 22. Wash out period of less than 2 weeks from previous antitumor chemotherapy, tyrosine 
kinase inhibitor immunotherapy, or any palliative radiotherapy; less than 4 weeks from 
previous antitumor biological therapy (eg, rituximab and brentuximab vedotin). 
E 23. Participant has received wide field radiotherapy ≤4 weeks prior to starting study treatment, 
or limited field radiation for palliation ≤2 weeks prior to starting study treatment, or has 
not recovered from the side effects of such therapy. 
E 24. Treatment-related immune-mediated (or immune-related) AEs from immune-modulatory 
agents (including but not limited to anti-PD-1/PD-L1 agents, anti-CTLA-4 monoclonal 
antibodies, and PI3K δ inhibitors) that caused permanent discontinuation of the agent, or 
that were Grade 3 or 4 in severity, or that have not resolved or improved to baseline at 
least 3 months prior to initiation of IMP. For other agents, treatment-related 
immune-mediated (or immune-related) AEs that were Grade 2 or above. 
Cohorts A1, B, and C: 
E 25. Prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, anti CTLA-4 
antibody or LAG-3 (or any other antibody or drug specifically targeting T-cell 
costimulation or checkpoint pathways). 
Phase 1 and Cohort A2 
E 26. Participants with anti-cancer therapy including radiotherapy or auto-HSCT between failure 
of anti-PD-1/PD-L1 therapy and initiation of IMP.  
Prior/concurrent clinical study experience 
E 27. Last dose of prior investigational agent within 28 days from initiation of study 
intervention. 
Diagnostic assessments 
E 28. Not applicable. Removed by Protocol Amendment 01. 
E 29. Ongoing AEs (excluding alopecia and fatigue) caused by any prior anti-cancer therapy 
≥ Grade 2 (NCI CTCAE version 5.0). 
E 30. Inadequate organ and bone marrow function prior to IMP administration: 
a) Absolute neutrophil count (ANC)<1000/mm3 (1.0 × 103/mm3; after at least 2 weeks 
without WBC growth factors). 
b) Platelets <50 000/mm3 (50 × 103/ mm3; after at least a week without platelet 
transfusion). 
c) Hemoglobin <9 g/dL (<5.6 mmol/L; after at least a week without transfusion). 
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d) Total bilirubin >2 upper limit of normal (ULN), except for participants with Gilbert's 
syndrome. 
e) Aspartate aminotransferase and/or alanine aminotransferase >3 × ULN (or >5 × ULN 
for participants with liver metastases). 
f) Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 using Modified Diet 
in Renal Disease Formula (MDRD). 
E 31. Known intolerance or hypersensitivity to any component of isatuximab and/or cemiplimab. 
E 32. History or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the participant’s participation for the full 
duration of the study, or is not in the best interest of the participant to participate, in the 
opinion of the treating Investigator. 
E 33.  
a) Uncontrolled or active HBV infection: Patients with positive surface antigen of the 
hepatitis B (HBsAg) and/or HBV deoxyribonucleic acid (DNA). Of note: 
• Patient can be eligible if anti-hepatitis B core antigen (HBc) immunoglobulin (Ig) 
G positive (with or without positive anti-HBs) but HBsAg and HBV DNA are 
negative.  
• If anti-HBV therapy in relation with prior infection was started before initiation of 
IMP, the anti-HBV therapy and monitoring should continue throughout the study 
treatment period (see Section 1.3). 
• Patients with negative HBsAg and positive HBV DNA observed during screening 
period will be evaluated by a specialist for start of anti-viral treatment: study 
treatment could be proposed if HBV DNA becomes negative and all the other 
study criteria are still met. 
b) Active HCV infection: positive HCV ribonucleic acid (RNA) and negative anti-HCV.  
• Patients with antiviral therapy for HCV started before initiation of IMP and 
positive HCV antibodies are eligible. The antiviral therapy for HCV should 
continue throughout the treatment period until seroconversion. 
• Patients with positive anti-HCV and undetectable HCV RNA without antiviral therapy for 
HCV are eligible. 
5.3 
LIFESTYLE CONSIDERATIONS  
Not applicable. 
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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 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 details, eligibility criteria, 
and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. A different participant identification will be issued, while the other identification for 
this participant should be recorded as Screen Failure. There is no requirement for a waiting period 
between a screen failure date and the rescreening date. Participants that are rescreened must sign 
a new consent form and all screening procedures must be repeated. 
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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 14 (see Section 10.14). 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Investigational medicinal product(s): Isatuximab with cemiplimab and radiotherapy 
(Cohorts A1 and A2) or isatuximab in combination with cemiplimab (Cohort B and C). 
Isatuximab and cemiplimab could be given up to 96 weeks (at least 48 weeks from initial signal of 
CR whichever is longer). 
Isatuximab: 
Formulation: 
• Drug product concentrated solution for infusion in vials containing 20 mg/mL 
(500 mg/25 mL) isatuximab in 20 mM histidine. 10% (w/v) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0. 
Route(s) of administration: IV infusion. 
Dose regimen: Refer to the dose levels and schedule for Phase 1. Dose for Phase 2 will be 
determined based on safety data from Phase 1. 
Cemiplimab: 
Formulation 
• Drug product concentrated solution 50 mg/mL in 10 mL vials with 5.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 0.2% (w/v) 
polysorbate 80, pH 6.0. 
Or 
• Drug product concentrated solution 50 mg/mL in 10 mL vials with 7.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 1.5% (w/v) L-proline, and 0.2% (w/v) 
polysorbate 80, pH 6.0. 
Route(s) of administration: IV infusion. 
Dose regimen: Refer to the dose levels and schedule for Phase 1. 
Non-investigational medicinal products: will be locally sourced and formulations may vary.  
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Premedication 
All participants will receive the following premedications to prevent or reduce incidence or 
severity of infusion reactions (IRs), 30 to 60 minutes prior to isatuximab infusion (no longer than 
60 minutes). The standard premedication regimen will include see Section 6.1.2: 
• Acetaminophen (paracetamol) 650 to 1000 mg oral route (PO) (or equivalent). 
• Ranitidine 50 mg IV (or equivalent at Investigator’s discretion). 
• Diphenhydramine 25 to 50 mg IV (or equivalent). 
• Methylprednisolone 100 mg IV (or equivalent). 
• Montelukast 10 mg PO (or equivalent). 
Criteria for optional premedication for IRs: 
• For a patient who has no IR for the first 4 infusions: Premedication for the subsequent 
infusions is optional at the Investigator’s discretion. However, if during the subsequent 
infusions without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
• If a patient develops an IR Grade ≤2 during their first infusion only and then experiences 
no further IRs during their next 3 infusions: The Investigator should discuss with the 
Sponsor Medical Monitor when considering omitting premedication for the next infusion. 
If no IR is observed for the next infusion without premedication, premedication is optional 
for the subsequent infusions at the Investigator’s discretion. However, if during the next 
infusion without premedication the patient experiences an IR (any grade), premedication 
must be restarted for all subsequent infusions. 
Radiotherapy (for Cohorts A1 and A2) (optional): 
• Formulation: Not applicable. 
• Route(s) of administration: Stereotactic radiation therapy. 
• Dose regimen: see Section 6.1.4. 
6.1.1  Investigational Medicinal Product(s)  
Table 2 - Overview of study interventions administered  
Study 
intervention 
name 
Isatuximab 
Cemiplimab 
Dosage 
formulation 
Concentrate for solution for intravenous infusion 
Concentrate for solution for intravenous infusion  
Unit dose 
strength(s)/Dosage 
level(s) 
20 mg/mL (500 mg/25 mL) isatuximab in 20 mM 
histidine, 10% (w/V) sucrose, 0.02% (w/v) 
polysorbate 80, pH 6.0 
50 mg/mL in 10 mL vials with 5.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 
1.5% (w/v) L-proline, and 0.2% (w/v) polysorbate 
80 pH, pH 6.0  
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OR 
50 mg/mL in 10 mL vials with 7.0 mL withdrawable, 
containing 10 mM histidine, 5% (w/v) sucrose, 
1.5% (w/v) L-proline, and 0.2% (w/v) polysorbate 
80, pH 6.0. 
Route of 
administration and 
duration 
Intravenous infusion over 30 minutes per 
administration  
Intravenous infusion over 30 minutes per 
administration  
Dosing instructions 
Phase 1 
Starting dose: 
Isatuximab: 10 mg/kg every week (QW) × 4 on Cycle 1, then every 2 weeks (Q2W) from Cycle 2 to 
Cycle 6, then every 3 weeks (Q3W) from Cycle 7 to Cycle 30  
Cemiplimab (administrated before isatuximab): 250 mg every 2 weeks (Q2W) from Cycle 1 to Cycle 6, 
then 350 mg every 3 weeks (Q3W) from Cycle 7 to Cycle 30 
Dose Level -1 may be implemented if ≥2/3 with DLT or if ≥2/6 participants with DLT at starting dose: 
Isatuximab: 5 mg/kg every week (QW) × 4 on Cycle 1, then every 2 weeks (Q2W) from Cycle 2 to 
Cycle 6, then every 3 weeks (Q3W) from Cycle 7 to Cycle 30 
Cemiplimab (administrated before isatuximab): 250 mg every 2 weeks (Q2W) from Cycle 1 to Cycle 6, 
then 350 mg every 3 weeks (Q3W) from Cycle 7 to Cycle 30 
Phase 2: 
For the combination Cohorts A1, A2, B, and C, cemiplimab will be administered first followed by 
isatuximab. Isatuximab will be administered at the RP2D determined based on safety data from Phase 1. 
Packaging and 
labeling 
In single dose vials 
30 mL (C1P2F2) glass vials fitted with elastomeric 
closure. 
The label contents will be in accordance with the 
local regulatory specifications and requirements. 
ISATUXIMAB It will be supplied for parenteral 
administration as a sterile, nonpyrogenic, 
injectable, 20 mg/mL concentrate for solution for 
infusion, essentially free of visible particulates. 
Each vial will contain a nominal content of 500 mg 
isatuximab C1P2F2. The fill volume will be 
established to ensure removal of 25 mL. 
For participant administration, the appropriate 
volume of isatuximab will be diluted in an infusion 
bag of 0.9% sodium chloride solution. The final 
infusion volume corresponding to the dose of 
isatuximab will be administered for a period of time 
that will depend on the dose administered and will 
be based on protein amount given per hour. 
Preferred diluents are: 
0.9% Sodium chloride for injection 100 mL, 
250 mL or 500 mL bags in polyolefins (so covers 
also polyethylene (PE) or polypropylene (PP)) or 
polyvinyl chloride (PVC) (with DEHP) Or Dextrose 
Cemiplimab is packaged in USP Type 1 clear 
glass, 10 mL vial with 20 mm gray chlorobutyl 
rubber stopper with FluroTec® coating and 20 mm 
red flip-off seal.  
The content of the labeling at vial and box level is 
in accordance with the local regulatory 
specifications and requirements. 
Cemiplimab concentrated solution for infusion will 
be diluted in an infusion bag with 0.9% sodium 
chloride solution to achieve the appropriate drug 
concentration for infusion 
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Rate and duration of infusion: 
The duration of infusion for cemiplimab is 250 mg or 350 mg (based on cycle number) over 
30 minutes per administration.  
Following Investigator’s Brochure (IB) ed11 isatuximab release in which the registered flat 
infusion administration has been added, patients still receiving isatuximab will switch to the 
registered infusion rate as described below after amended protocol 02 has been approved. 
• First isatuximab infusions post amended protocol 02: Initiate infusion at 25 mL/hour. 
In the absence of IRs after 1 hour of infusion, increase infusion rate by 25 mL/hour 
increments every 30 minutes, to a maximum of 150 mL/hour. In case of grade 2 IR during 
first infusion, infusion could be restarted at one-half (12.5 mL/hour) of the initial infusion 
rate when the IR improves to Grade ≤1. If symptoms do not recur after 30 minutes, the 
infusion rate may be increased by 25 mL/hour increments every 30 minutes, until the total 
volume is infused. 
• Second infusion post amended protocol 02: Initiate infusion at 50 mL/hour. In the 
absence of Grade 2 IR after 30 minutes of infusion, increase rate to 100 mL/hour for 
30 minutes, then, to 200 mL/hour until the total volume is infused. 
• In case of Grade 2 IR during second infusion, infusion could be restarted at one-half 
(25 mL/hour) of the initial infusion rate when the IR improves to Grade ≤1. If symptoms 
do not recur after 30 minutes, the infusion rate may be increased by 50 mL/hour 
increments every 30 minutes, until the total volume is infused. 
• Third and subsequent infusions post amended protocol 02: Initiate infusion at a fixed 
infusion rate of 200 mL/hour, until the total volume is infused. In case of Grade 2 IR 
during third infusion, infusion could be restarted at one-half (100 mL/hour) of the infusion 
rate when the IR improves to Grade ≤1. If symptoms do not recur after 30 minutes, the 
infusion rate may be increased by 50 mL/hour increments every 30 minutes, until the total 
volume is infused. 
Guidelines for patients who develop IRs are provided in Section 6.5.5. 
6.1.2 Non-Investigational Medicinal Products:  
They will be locally sourced and formulations may vary.  
Premedication 
All participants will receive the following premedication to prevent or reduce incidence or 
severity of IRs, 30 to 60 minutes prior to isatuximab infusion (no longer than 60 minutes). The 
standard premedication regimen will include: 
• Acetaminophen (paracetamol) 650 to 1000 mg PO (or equivalent). 
• Ranitidine 50 mg IV (or equivalent at Investigator's discretion). 
• Diphenhydramine 25 to 50 mg IV (or equivalent). 
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• Methylprednisolone 100 mg IV (or equivalent). 
• Montelukast 10 mg PO (or equivalent). 
6.1.2.1 Acetaminophen (paracetamol) 650 or 1000 mg PO or equivalent  
Commercial supplies of acetaminophen (paracetamol) or equivalent will be used for this study. 
Please refer to the package insert for further details as regards to formulation, storage, and 
handling purposes. 
6.1.2.2 Ranitidine 50 mg IV or equivalent  
The use of ranitidine or equivalent to be part or not of IR premedication is left to the medical 
judgement of the Investigator. 
Ranitidine is presented as a solution for IV infusion. Commercial supplies of ranitidine or 
equivalent will be used for this study. Please refer to the package insert for further details as 
regards to formulation, storage, and handling purposes. Equivalents are other approved 
H2 antagonists (eg, cimetidine) and oral proton pump inhibitors (eg, omeprazole, esomeprazole). 
6.1.2.3 Diphenhydramine 25 to 50 mg IV or equivalent  
Diphenhydramine is presented as a solution for IV infusion. Commercial supplies of 
diphenhydramine or equivalent will be used for this study. Please refer to the package insert for 
further details as regards to formulation, storage, and handling purposes. Equivalents are, 
eg, cetirizine, promethazine, and dexchlorpheniramine according to local approval and 
availability. Intravenous route is preferred for at least the first 4 infusions. 
6.1.2.4 Methylprednisolone 100 mg IV or equivalent  
Methylprednisolone is presented as a solution for IV infusion. Commercial supplies of 
methylprednisolone or equivalent will be used for this study. Please refer to the package insert for 
further details as regards to formulation, storage, and handling purposes.  
6.1.2.5 Montelukast 10 mg PO or equivalent  
Commercial supplies of montelukast will be used for the study. Please refer to the package insert 
for further details as regards to formulation, storage and handling purposes. 
6.1.3 Dosing sequence  
All participants will receive isatuximab in combination with cemiplimab. 
Emergency equipment and medication for the treatment of IRs (eg, antihistamines, 
bronchodilators, IV saline, corticosteroids, acetaminophen [paracetamol], and/or epinephrine) 
must be available for immediate use. 
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Premedication will be administered 30 to 60 minutes prior to isatuximab infusion (no more than 
60 minutes prior). 
Only at Cycle 1, cemiplimab will be administered on D1 and isatuximab on D2. 
When isatuximab and cemiplimab are to be administered on the same day, the administration 
sequence is: premedication, followed by cemiplimab, followed by isatuximab. 
When only isatuximab is to be administered on a day, the administration sequence is: 
premedication, followed by isatuximab. 
When only cemiplimab is administered on a day, no premedication is recommended. 
Participants will continue treatment until disease progression, unacceptable AE, consent 
withdrawal, treatment period of 96 weeks (at least 48 weeks from initial signal of CR, whichever 
is longer) without documented PD, or any other reason. 
6.1.4 Radiotherapy (for Cohorts A1 and A2) (optional)  
The participants with cHL who achieve best response of PR or SD at the disease assessment 
planned for Week 36, if deemed appropriate (and does not meet exclusion criteria E01, E06, E08, 
E21, E30, and E32) by the Investigator, may begin radiotherapy between D1 to D14 (preferably 
between D1 to D7) of the next immediate cycle.  
• Formulation: Not applicable. 
• Route(s) of administration: Stereotactic radiation therapy. 
• Dose regimen: Plan for radiotherapy is summarized as below:  
1. Irradiation will start with up to 2 lesions. The other lesions (up to the maximum of 
5 lesions) will be irradiated only if no response is observed after the initial 
radiotherapy. 
2. For lesions that have not been previously irradiated and are in the “safe zone”, a total 
of 12 Gy will be administered as 3 doses of 4 Gy over 1 week (ie, 4 Gy × 3 fractions, 
eg, Monday, Wednesday, and Friday) in the same week when isatuximab and 
cemiplimab are administered. 
3. For lesions that have been previously irradiated or any lesions that are in the “no fly 
zone” (23), 2 Gy × 2 fractions in 2 consecutive days (eg, Monday and Tuesday) will be 
administered once a week every 3 weeks for 3 times (treatment lasts for a total of 
9 weeks), starting in the same week when isatuximab and cemiplimab are 
administered. 
4. When multiple lesions are treated with radiotherapy in parallel, treatment for 
radiotherapy -naïve lesions will follow the schedule as per point #2, while treatment 
for previously irradiated lesions will follow schedule as per point #3. 
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5. Decision to perform radiotherapy or not will be made by the treating Investigator based 
on his/her evaluation of the specific participant’s situation. Overall safety monitoring 
will be performed throughout the conduct of the study. 
6.1.5 Blinding procedures  
This is an open-label study; therefore, blinding procedures are not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
6.2.1 General rules  
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. 
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. 
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). 
Partially-used and used study treatments will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the pharmacist). A detailed treatment log form of the destroyed study 
treatment will be established with the Investigator (or the pharmacist) and countersigned by the 
Investigator and the Monitoring Team. 
The Investigator must not destroy the unused IMP unless Sanofi provides written authorization 
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. 
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 IMPs to a third party (except for a duties and 
taxes paid shipment, for which a courier company has been approved by the Sponsor), allow the 
IMPs to be used other than as directed by this clinical trial protocol, or dispose of IMPs in any 
other manner. 
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6.2.2 Storage conditions  
6.2.2.1 Isatuximab  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing isatuximab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures. 
Control of isatuximab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the Sanofi compound 
should be managed according to the rules provided by the Sponsor. 
Isatuximab is to be stored at +2°C to +8°C (36°F to 46°F), is not to be frozen and protected from 
light. All vials must be kept in their box until use. No protection from light is required for storage 
in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
6.2.2.2 Cemiplimab  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing cemiplimab 
in a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures. 
Control of cemiplimab storage conditions, especially control of temperature (eg, refrigerated 
storage), and information on in-use stability and instructions for handling the compound should be 
managed according to the rules provided by the Sponsor. 
Cemiplimab is to be stored at +2°C to +8°C (36°F to 46°F), is not to be frozen, and protected 
from light. All vials must be kept in their box until use. No protection from light is required for 
storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
6.2.3 Preparation, reconstitution and administration:  
6.2.3.1 Isatuximab  
For patient administration, the appropriate volume of isatuximab will be diluted in a 250-mL 
infusion bag of 0.9% sodium chloride solution or 5% dextrose solution to achieve the appropriate 
drug concentration for infusion. 
Infusion via a central line is preferred if available. In case of participants with local intolerance 
after peripheral IV infusion, the decision to use a central line is left to the Investigator. The final 
infusion volume corresponding to the dose of isatuximab will be administered by IV infusion for 
the period of time that depends on total dose administered. 
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Prior to dosing, each participant's dose will be individually prepared by the study pharmacist and 
labeled with the protocol number, participant number, and treatment description. The participant’s 
weight should be measured prior to each treatment to allow calculation of the isatuximab dose. 
For infusion, an IV tubing administration set with a 0.20 μm in-line filter will be used; if 
an in-line filter is unavailable, a 0.20 μm filter unit may be attached to the administration set 
before administration. Further details are provided in the Pharmacy Manual. 
6.2.3.2 Cemiplimab  
Cemiplimab concentrate for solution for infusion will be diluted in an infusion bag with 
0.9% sodium chloride solution to achieve the appropriate drug concentration for infusion. 
Infusion via a central line is preferred if available. In case of participants with local intolerance 
after peripheral IV infusion, the decision to use a central line is left to the Investigator. The final 
infusion volume corresponding to the dose of cemiplimab will be administered by IV infusion for 
the period of time that will depend on total dose administered. 
Prior to dosing, each participant's dose will be individually prepared by the study pharmacist and 
labeled with protocol number, participant number, and treatment description.  
For infusion, an IV tubing administration set with a 0.20 μm in-line filter will be used; if 
an in-line filter is unavailable, a 0.20 μm filter unit may be attached to the administration set 
before administration. Further details are provided in the Pharmacy Manual. 
6.3 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMP will be supervised by the Investigator or Sub-investigator. The person 
responsible for drug dispensing is required to maintain adequate records of the IMPs. These 
records (eg, drug movement form) include the date the IMPs are received from the Sponsor, 
dispensed to the participant and destroyed or returned to the Sponsor. The packaging batch 
number (IP number) and the treatment number on the vial must be recorded on the drug 
accountability form. The person responsible for drug administration to the participant will record 
precisely the date and the time of the drug administration to the participant. 
6.4 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) 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. 
• Dosage information including dose and frequency. 
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Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the follow-up visit, unless, in the opinion of the Investigator and Sponsor, the 
medication will not interfere with the study.  
• All treatments being taken by the participant 21 days prior to the first study treatment, at 
any time during the study in addition to the IMP are regarded as concomitant treatments 
and the type, dose and route of administration must be documented on the appropriate 
pages of the eCRF. 
• Concomitant medications should be kept to a minimum during the study. However, if 
these are considered necessary for the participant's welfare and are unlikely to interfere 
with the IMP, they may be given at the discretion of the Investigator and recorded in the 
eCRF. 
• Supportive treatment as medically indicated for the participant’s well-being may be 
prescribed at the Investigator’s discretion. Every medication or treatment taken by the 
participant during the trial and the reason for its administration must be recorded on the 
eCRF. 
Hepatitis B vaccination could be considered, following Investigator’s discretion, for patients with 
negative HBsAg, total anti-HBc, anti-HBs and HBV-DNA. At least 3 doses of vaccine will be 
administered at monthly intervals, the first one 1 to 2 weeks before start of study treatment. 
Anti-HBs should be monitored at 1, 2 and 3 months after end of vaccination. Anti-HBs above 
100 mU/mL will indicate a good seroconversion, between 10 and 100 mU/mL moderate 
seroconversion that can be limited in time, less than 10 mU/mL will indicate no response to 
vaccination. 
If antiviral therapy for HBV or HCV was started before initiation of IMP and patient was eligible 
for the trial, the antiviral therapy for HBV or HCV should continue throughout the treatment 
period as recommended by specialist. In case of trial testing combo, to check that there is no drug-
drug interaction (DDI) with the drug associated with isatuximab. 
In case of viral reactivation during study treatment (greater than 1log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection*), 
study treatment will be held and specialist consulted for initiation of anti-viral treatment and 
monitoring of the patient. Re-start of study treatment should be agreed between Sponsor, 
Investigator and specialist (hepatologist) if controlled infection. Close monitoring of alanine 
aminotransferase (ALT), aspartate-aminotransferase (AST) every month, up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
*previous known history of acute or chronic hepatitis B or the presence of total anti-HBc 
with/without anti-HBs; HBsAg negative; undetectable serum HBV DNA; normal ALT levels. 
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Prohibited concomitant treatments: 
• Concurrent treatment with any other anti-lymphoma therapy not specified in the protocol, 
including immunotherapy, hormonal therapy, targeted therapy or biological therapies, or 
other investigational drug, or curative radiotherapy.  
• Investigational therapy (other than protocol-mandated study treatment) is prohibited 
within 28 days prior to initiation of study treatment and during study treatment. 
• Concomitant systemic corticosteroids are prohibited, except for: 
- 
Use in premedication defined in the study protocol, 
- 
Treatment of an irAE, 
- 
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). 
• Live vaccines should be avoided. However, giving the increased risk of infection, routine 
vaccinations are recommended for the participants and their contacts. Prophylactic 
vaccination is recommended for influenza A and B virus, pneumococci and hemophilus 
influenza. 
• Prophylactic use of hematopoietic growth factors (eg, G-CSF, GM-CSF, and 
erythropoietin) during the DLT observation period. Curative treatment is allowed.  
6.5 
DOSE MODIFICATION  
6.5.1 General rules  
Dose modifications are 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. 
Dose adjustment and/or cycle delay are permitted in case of adverse reaction. Dose adjustments 
will be made according the worst grade of adverse reaction observed within a cycle. If 
a participant experiences several adverse reactions and there are conflicting recommendations, the 
most conservative dose adjustment recommended should be followed. 
Administration of the study treatment will be discontinued in the event of a TEAE that persists 
despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, 
warrants discontinuation. 
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If one of the 2 drugs (cemiplimab or isatuximab) is prematurely permanently discontinued, the 
other drug can be continued until disease progression, unacceptable adverse reaction, participant’s 
refusal of further treatment, or in the absence of a clear benefit from therapy. The EOT assessment 
in this case will be 30 days after the date of the last IMP administration. 
All changes to study treatment administration must be recorded in the eCRF.  
6.5.2 Dose delay and dose omission  
Within a cycle, the treatment windows are: 
• For the weekly administrations during the Cycle 1: ±1 day. A dose is deemed to have been 
delayed if the treatment is ≥2 days beyond the theoretical day of treatment for weekly 
dose. 
• For the Q2W administrations (D15): ±2 days from Cycle 2 to Cycle 6. A dose is deemed 
to have been delayed if the treatment is ≥3 days beyond the theoretical day of treatment. 
• For the 4-week cycle D1 (from Cycle 2 to Cycle 6) and the 3-week cycle D1 (from 
Cycle 7 to Cycle 30): ±3 days. A dose is deemed to have been delayed if the treatment is 
≥4 days beyond the theoretical day of treatment. 
• The reason for dose delay will be captured. The participant will receive the next infusion 
after recovery of the AE as described in Section 6.5.3.  
• If infusion has been delayed within a cycle, next study treatment should be administered at 
the planned time interval between 2 administrations (eg, if infusion has been delayed by 
2 days, Day 15 Cycle 1 administration is actually administered on Day 17, the planned 
Day 22 should be administered on Day 24).  
Participants may have dose omission if an AE occurs and does not recover according to following 
rules: 
• In Cycle 1 if AE occurs and does not recover on the day of planned infusion or within the 
following 3 days, infusion of isatuximab and/or cemiplimab (D8 or D15) may be omitted.  
• From Cycle 2 to Cycle 6, if an AE occurs and does not recover on the day of planned 
infusion or within the following 7 days, infusion of isatuximab and/or cemiplimab may be 
omitted for participants on Q2W (D15) dose schedule.  
In case of consecutive dose omissions/delay for the recovery of AE, following rules should be 
followed for restart or discontinue the treatment:  
• Dose delay (cycle delay) up to 14 days, it is per Investigator’s decision to restart the 
treatment of cemiplimab and isatuximab. 
• After dose delay of >14 days and ≤84 days, it is per Investigator’s decision to restart the 
treatment of cemiplimab and isatuximab, if a clear benefit from therapy is observed and 
after consultation with the Sponsor. 
• Treatment with isatuximab and cemiplimab must be definitely discontinued if the delay is 
longer than 84 days. 
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During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Appendix 14 (see Section 10.14) should be considered for screening, enrollment, and 
administration of study intervention. 
6.5.3 Dose modifications  
Guidelines for isatuximab and cemiplimab dose modifications and treatment discontinuation due 
to hematological and non-hematological adverse reactions in general are outlined in the table 
below. 
See Table 3 and Appendix 4 (Section 10.4) for guidance for irAEs correlated with cemiplimab, 
and Section 6.5.5 for IRs correlated with isatuximab and cemiplimab. 
The final decision will be per Investigator’s judgment for the best interest of the participant. 
Table 3 - Isatuximab and cemiplimab dose modification guidelines  
Adverse Events 
NCI CTCAE V5.0 
Isatuximab dose 
management  
Cemiplimab Dose 
management  
Action and Guidelines  
Hematological adverse events  
Grade 1, 2, and 3 
No change in dose  
Participant should be given 
supportive care and monitored 
closely. 
Grade 3 
thrombocytopenia 
lasting >7 days or 
associated with 
bleeding 
Delay the dose until bleeding is controlled and platelet 
>50 000/mm3. Restart treatment with same dose and schedule. 
 
Participant should be given 
supportive care and monitored 
closely. 
Permanent discontinuation should 
be considered if the abnormality 
does not resolve within 84 days of 
last infusion. 
 
Grade 4  
Delay the cycle until absolute neutrophil count >1000/mm3, and 
platelet >50 000/mm3. Restart with same dose and schedule. 
Grade 4 lymphopenia: no change in dose. 
Febrile neutropenia 
and/or neutropenic 
infection 
Delay the dose until fever and infection recover and 
ANC>1000/mm3. Restart with same dose and schedule. 
 
Non-hematological adverse events (other than irAE and IR)   
Grade 1 
 
No Change in Dose 
 
N/A 
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Adverse Events 
NCI CTCAE V5.0 
Isatuximab dose 
management  
Cemiplimab Dose 
management  
Action and Guidelines  
Grade 2 (except 
alopecia) 
Grade 3 
Delay the dose until improves to Grade ≤1 or baseline. 
Restart treatment at same dose and schedule. 
Delay the dose until improves to Grade ≤1 or baseline.  
Restart treatment at same dose and schedule. 
 
It is up to the Investigator’s 
judgment whether to restart the 
treatment of isatuximab and 
cemiplimab if the delay is within 
14 days. 
If the treatment delay is longer 
than 14 days, before restarting the 
treatment, the Investigator must 
discuss with the Sponsor; if it is 
determined that it is to the best 
interest of the participant, the 
treatment may be restarted. 
If the delay is longer than  
84 days, the treatment must be 
definitely discontinued. 
Grade 4 
Permanent discontinue treatment for treatment-related AEs 
Immune-related AE (irAE): see Table 4 and Appendix 4 (Section 10.4) for dose modification and participant management guideline). 
6.5.4 General guidelines for the management of Immune-Related Adverse Events  
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.   
• Detailed guidance for the management of specific irAEs (Colitis, Endocrine AE, 
Pneumonitis, Renal AE, Dermatologic AE, Hepatitis, Ophthalmologic AE [Uveitis]), plus 
Nausea and Vomiting is provided in Appendix 4 (Section 10.4). 
• General guidance is provided in Table 4.  
• If a participant experiences several irAEs which involve different recommendations, the 
most conservative recommendation should be followed.   
The recommendations provided in Table 4 should be seen as guidelines, and the treating physician 
should exercise clinical judgment based on the symptoms and condition of the individual 
participant. 
Any participant currently receiving cemiplimab who was previously treated with a PI 3-K 
inhibitor and who develops stomatitis or mucositis should temporarily suspend study treatment. If 
this or any other immune-related AE occurs among these participants, the Sponsor should be 
informed as soon as possible to discuss further management of the participant. An irAE of any 
grade in a participant previously treated with a PI 3-K inhibitor should be reported as an adverse 
event of special interest (AESI). 
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Table 4 - General guidelines for immune-related adverse events  
Severity 
Withhold/Restart 
/Discontinue 
isatuximab Treatment 
Withhold/Restart/Discontinue 
cemiplimab Treatment 
Supportive Care 
Grade 1 
No action 
No action 
Provide symptomatic 
treatment. 
Grade 2 
No action 
May delay the dose until Grade ≤1 
Consider systemic 
corticosteroids (Prednisone 
0.5 to 1 mg/kg/day or 
equivalent) in addition to 
appropriate symptomatic 
treatment. 
Grade 3 and 
Grade 4 
Delay the cycle until when toxicity improves to Grade ≤1 or baseline. 
Discontinue prematurely cemiplimab if unable to reduce corticosteroid 
dose to <10 mg/day prednisone equivalent within 84 days of toxicity.  
For any Grade 3-4 
immune-related adverse 
event, if symptoms worsen 
or do not improve on 
adequate corticosteroids 
(Prednisone 1 to 2 
mg/kg/day or equivalent) 
within 48 to 72 hours), 
consider additional 
immunosuppressive agents 
(to be selected from agents 
such as: infliximab, 
cyclophosphamide, 
cyclosporine, and 
mycophenolate mofetil). 
Referral of the participant to 
a specialized unit for 
assessment and treatment 
should be considered. 
6.5.5 General guidelines for the management of IRs  
Participants should routinely receive premedication prior to isatuximab infusion as detailed in 
Section 8.2 to reduce the risk and severity of IRs commonly observed with mAbs.  
Infusion reactions typically occur within 24 hours from the start of the infusion. If an IR is 
observed, the participants must be informed of the potential risk of recurrent IRs at subsequent 
infusions. 
Summary of IR management is provided in Table 5. 
Participants who experience Grade 2 IRs may resume cemiplimab/isatuximab infusion after 
temporary interruption, under close monitoring and with therapy as needed. Participants may 
receive additional medication per the judgment of the Investigator. Additional recommended 
medications are: diphenhydramine 25 mg IV (or equivalent) and methylprednisolone 100 mg 
IV (or equivalent). 
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Once a Grade 2 IR or first/second Grade 3 IR has improved or resolved to Grade ≤1, the infusion 
may be restarted: 
• For cemiplimab, the infusion should be restarted at one half the original infusion rate. 
• For isatuximab, the infusion should be restarted at one half the original infusion rate,  
see Section 6.1.1 for infusion rate.  
- 
First infusion:  Infusion could be restarted at one-half (12.5 mL/hour) of the initial 
infusion rate when the IR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 25 mL/hour increments 
every 30 minutes, until the total volume is infused or reaching 150 mL/hour, 
whichever is earlier. 
- 
Second infusion:  Infusion could be restarted at one-half (25 mL/hour) of the initial 
infusion rate when the IR improves to Grade ≤1. If symptoms do not recur after 
30 minutes, the infusion rate may be increased by 50 mL/hour increments 
every 30 minutes, until the total volume is infused or reaching 200 mL/hour, 
whichever is earlier. 
- 
Third and subsequent infusions:  Infusion could be restarted at one-half (100 mL/hour) 
of the initial infusion rate when the IR improves to Grade ≤1. If symptoms do not recur 
after 30 minutes, the infusion rate may be increased by 50 mL/hour increments 
every 30 minutes, until the total volume is infused or reaching 200 mL/hour, 
whichever is earlier. 
Participants with Grade 3 IR (third Grade 3, or do not fulfil criteria to restart infusion as 
per Table 5) or Grade 4 IR must have cemiplimab and/or isatuximab permanently discontinued 
and appropriate therapy should be administered. 
If a Grade 3 or high IR occurred during cemiplimab infusion, cemiplimab should be permanently 
discontinued. The participant can continue treatment with isatuximab. 
Grade 2 or higher IRs must be reported as AESIs (see Section 8.3). Study personnel should 
consult the Medical Monitor for further guidance regarding retreatment of participants with IRs 
and regarding issues of premedication management (eg, alternative medications for participants 
allergic or intolerant to premedication agents) or to determine if locally used equivalent 
medications are acceptable. 
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Table 5 - IR management  
Infusion Related Reaction grading (NCI 
CTCAE v5.0 criteria) 
Recommendation 
Mild 
Grade 1 
Transient reaction; infusion interruption or intervention 
not indicated 
Continuation of cemiplimab/ isatuximab infusion is per the 
judgment of the Investigator following close direct monitoring of the 
participant’s clinical status. 
Cemiplimab/isatuximab infusion may be stopped at any time if 
deemed necessary. If stopped, IR will be classified as Grade 2 as 
per NCI CTCAE definition. 
Moderate  
Grade 2 
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for ≤24 hours). 
Stop cemiplimab/isatuximab infusion. Give additional medication(s) 
with IV diphenhydramine 25 mg IV (or equivalent) and/ or 
IV methylprednisolone 100 mg (or equivalent) as needed. 
Cemiplimab*/isatuximab** may be resumed only after participant 
recovery, with close monitoring.  
Severe or Life-threatening. 
Grade 3: Prolonged (eg, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for clinical 
sequelae. 
Stop cemiplimab/isatuximab infusion. Give additional medication(s) 
with diphenhydramine 25 mg IV (or equivalent) and/or 
IV methylprednisolone 100 mg (or equivalent) and/or epinephrine 
as needed until the resolution of the AE or until the AE improves to 
Grade 1.  Only then, the infusion may be restarted at the 
Investigator’s discretion; if so, the infusion rate should be half of the 
initial infusion rate before the interruption, and it may be increased 
subsequently, at the Investigator’s discretion. 
If the severity of an infusion-related AE returns to Grade 3 after the 
restart of the infusion, the same procedure described above may 
be repeated at the Investigator’s discretion.  If a Grade 3 infusion-
related AE occurs for a 3rd time, treatment with isatuximab will be 
definitively discontinued for that participant. 
If symptoms do not resolve rapidly, do not improve after 
interruption of the isatuximab infusion, they recur after initial 
improvement with appropriate medications, or they require 
hospitalization, treatment with isatuximab should be definitively 
discontinued. 
Grade 4: Life-threatening consequences; urgent 
intervention indicated. 
If IR occurred during cemiplimab infusion, permanently discontinue 
cemiplimab. Continue treatment with isatuximab. 
If IR occurred after the start of isatuximab infusion, permanently 
discontinue both cemiplimab and isatuximab. 
*Cemiplimab: The prepared infusion bag should be kept no more than 8 hours at room temperature between +15°C to +25°C (59°F to 77°F), 
or no more than 24 hours at 5°C (with an acceptable operating range of 2°C to 8°C refrigerator). 
**Isatuximab: the resulting solution for infusion should be used within 16 hours at room temperature between +15°C to +25°C (59°F to 77°F) 
from the bag preparation to the end of IV infusion of the participant or a new infusion should be prepared with the remaining dose to be 
administered the same day. 
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6.5.6 Guidance in case of hepatitis B reactivation occurring under study treatment  
In case of viral reactivation during study treatment (greater than 1log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection*) 
study treatment will be held and specialist consulted for initiation of anti-viral treatment and 
monitoring of the patient. Re-start of study treatment should be agreed between Sponsor, 
Investigator and specialist (hepatologist) if infection is controlled. Close monitoring of ALT, AST 
every month, up to study treatment discontinuation. HBV DNA to be done as per specialist 
advice. 
* previous known history of acute or chronic hepatitis B or the presence of total anti-HBc 
with/without anti-HBs; HBsAg negative; undetectable serum HBV DNA; normal ALT levels. 
6.5.7 Guidelines for the management of potential Tumor Lysis Syndrome  
In case of tumor lysis syndrome (TLS), study treatment should be held until all serum chemistries 
have resolved. To ensure normal hydration, correct laboratory abnormalities, fluid overload, 
electrolyte, or acid-base deviation. Management must be done according to the local site 
guideline. Use of xanthine oxidase or urate oxidase is allowed. 
TLS complications including renal function should be monitored, and study treatment can be 
reinstituted at full doses after resolution. 
The laboratory abnormalities normally associated with TLS, and the possible clinical 
manifestations which can be associated with TLS are presented in Table 6. 
Table 6 - Laboratory and clinical abnormalities possibly consistent with TLS  
Laboratory  
 Clinical  
Uric acid >8 mg/dL (>475.8µmol/L) 
Potassium >6.0 mmol/L 
Phosphorus >4.5 mg/dL (>1.5mmol/L) 
Corrected calciuma <7.0 mg/dL(<1.75mmol/L) or ionized 
calcium <1.12 mg/dL (<0.3mmol/L) 
 
Acute kidney injury: increase in the serum creatinine level of 
0.3 mg/dL (26.5 μmol/L) or the presence of oliguria, defined as 
an average urine output of <0.5 mL/kg/hour for 6 hours. 
Seizures, cardiac dysrhythmia, neuromuscular irritability 
(tetany, paresthesia, muscle twitching, carpopedal spasm, 
Trousseau’s sign, Chvostek’s sign, laryngospasm, 
bronchospasm), hypotension, or heart failure probably or 
definitely caused by hypocalcemia. 
Dysrhythmias probably or definitely caused by hyperkalemia. 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 x 4-albumin in grams per 
deciliter 
6.6 
INTERVENTION AFTER THE END OF THE STUDY  
The IMPs will not be provided after the end of the treatment period. 
The participant’s treatment after discontinuation of last IMP will be at the discretion of the 
treating physician. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
The duration of the study for a participant will include a period for screening of up to 28 days. 
The cycle duration is 28 days from Cycle 1 to Cycle 6 then 21 days from Cycle 7 to Cycle 30. 
Participants will continue treatment until disease progression, unacceptable adverse events, 
consent withdrawal, treatment period of 96 weeks (at least 48 weeks from initial signal of CR, 
whichever is longer) without documented PD, or any other reason. 
After study treatment discontinuation, participants will return to the study site 30 days (+7 days) 
after the last dose of study treatments, for EOT.  
The post-treatment follow-up period includes an extended safety follow-up period of 90 days after 
the last dose of IMP, including 60 day (±7 days) and 90 day (±7 days) visits after the last IMP for 
safety and anti-drug antibody (ADA) isatuximab (90 day [±7 days] only) assessments and further 
follow-up period beyond 90 days after the last dose of study treatments until death or study cut-off 
date, whichever occurs first. The further follow-up schedule beyond 90 days after last treatment is 
adjusted according to the disease progression:  
• Participants who discontinue study treatment due to PD: phone call follow-up visit will be 
done every 90 days from the date of last study treatment administration until death or 
study cut-off date.  
• Participants who discontinue the study treatment without PD: will be followed every 
90 days for disease assessment until confirmation of PD or start of treatment with another 
anti-cancer therapy whichever comes first. PD participants will be followed every 
3 months as described just above until death or study cut-off date. 
• Participants who are still on study treatment after study cut-off date will continue to 
receive study treatment if they benefit, and will undergo planned study procedures (except 
PK and ADA) until confirmation of PD, or start with another anti-cancer therapy, or 
treatment period ended, whichever comes first. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
The IMPs should be continued whenever possible.  
In case the IMPs are stopped, it should be determined whether the stop can be made temporarily; 
definitive IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible until the documentation of PD. 
Temporary intervention discontinuation may be considered by the treating Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 10.14). For all temporary intervention discontinuations, 
duration should be recorded by the Investigator in the appropriate eCRF pages. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
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Definitive intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP whatever the reason. 
All efforts should be made to document the reason for discontinuation of treatment with the study 
treatment:  
• At the participant’s request, at any time and irrespective of the reason (consents 
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 
participant’s participation in the procedure(s) involved in the research. Withdrawal of 
consent for treatment should be distinguished from withdrawal of consent for follow-up 
visits and from withdrawal of consent for non-participant contact follow-up, eg, medical 
records check.  
Participants requesting withdrawal should be informed that withdrawal of consent for  
follow-up may jeopardize the public health value of the study. The Investigator should 
make every effort to re-contact the participant, to identify the reason why he/she decided 
to withdraw, and to determine his/her health status, including at least his/her vital status.  
• If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the participant’s wellbeing, such as: 
- 
Disease progression, 
- 
Unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as inter-current illness that prevents further administration of 
study treatment (will be specified), 
- 
Participant is lost to follow-up, 
- 
Completion of the 96-week treatment period. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
Handling of participants after definitive 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 definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
a pharmacokinetics sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or any other reason. 
• 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. 
• 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. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused.  
Isatuximab or cemiplimab can be discontinued prematurely. Participants will remain on study 
treatment until the last IMP (isatuximab or cemiplimab) is discontinued see Section 6.5.1. The 
reason for premature discontinuation will be captured in the appropriate eCRF page. 
7.3 
LOST TO FOLLOW-UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
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• 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.  
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 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. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 14 (see Section 10.14). 
• In exceptional cases, under regional or national emergencies (eg, natural disaster, epidemic 
disease, terrorist attack), onsite visits may be replaced with telephone/remote visits. For 
example, patient interview for medical history/prior medications could be performed by 
phone, local safety labs and some efficacy assessments could be performed off-site/at the 
participant's home (eg, home nursing) if agreed by patient and permissible per local 
regulations. In such circumstances, visit window may be expanded, if needed 
(eg, ±14 days for visits). 
8.1 
EFFICACY ASSESSMENTS  
Please refer to study SoA flow chart (Section 1.3). 
8.1.1 FDG-PET-CT/CT  
ORR is defined as the proportion of participants with complete response, and PR based on 
responses as assessed using the Lugano response criteria 2014. Uniform Response Criteria (see 
Appendix 6: Section 10.6). All enrolled participants must have at least one measurable lesion for 
inclusion (Section 5, I 03). 
Tumor assessment will include FDG-PET-CT scan in case of avid lymphomas and CT in case of 
non-avid lymphomas and they will be performed at fixed intervals as described in SoA, and the 
assessment window is not impacted by dose delay or dose omission. 
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For fluorodeoxyglucose (FDG) avid lesions, standardized uptake value (SUV) max is mandatory 
and should be reported for all lesions at each time point assessment. For purposes of the 5-point 
scale (5PS), SUV of a lesion is compared to the SUV of the liver and mediastinum. The 5PS is 
noted below: 
• 1. No uptake above background 
• 2. Uptake ≤ mediastinum 
• 3. Uptake > mediastinum but ≤ liver 
• 4. Uptake moderately higher than liver  
• 5. Uptake markedly higher than liver (> 2 × maximum SUV of the liver) and/or new 
lesions  
• X. New areas of uptake unlikely to be related to lymphoma (1). 
If CT and PET scans at Screening are negative for disease involvement in the neck, subsequent 
CT scans may not include neck. If PET or CT scan at Screening is positive for disease 
involvement of the neck, subsequent CT scans must include neck.  
Following screening, for the first year FDG-PET-CT and CT scans should be performed every 
12 weeks (3 months). For the second year and beyond, CT scans should be performed every 
12 weeks and FDG-PET-CT should be done when clinically indicated.   
Response assessments should occur at Screening (within 28 days prior to first IMP), and every 
12 weeks (±7 days), starting from C1D1. Imaging timing should follow calendar days and should 
not be adjusted for delays in cycle. For participants who discontinue for reasons other than PD, 
assessments should continue until the participant has documented PD or start a new anti-cancer 
therapy. The first assessment may be performed earlier than 12 weeks after C1D1 if in the opinion 
of the Investigator the participant is clinically progressing. 
Measurement of spleen size is mandatory and is to be assessed whenever response assessment is 
done.  
If participants have partial response (PR), or complete response, a repeat CT scan is not required 
for confirmation, they should continue on every 12-week assessment schedule. In the setting 
where a participant is clinically stable, but imaging shows PD at the Week 12 disease response 
assessment, study drug may be continued, at the discretion of the PI, until the next disease 
response assessment. However, imaging should occur at any time where there is clinical suspicion 
of progression. 
Assessment of lymphoma B symptoms should occur with each disease response assessment. 
In participants with PD at Week 12, who continued study therapy beyond Week 12 a radiological 
assessment should be performed at the time of treatment discontinuation. If previous scan was 
obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation is not mandatory. 
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8.1.2 Bone marrow biopsy & aspirate:  
All participants will have bone marrow biopsy/aspirate performed as clinically indicated as per 
Lugano 2014 criteria (Section 10.6). FDG-PET-CT is adequate for determination of bone marrow 
involvement and can be considered highly suggestive for involvement of bone marrow. Bone 
marrow biopsy confirmation can be considered if necessary at baseline (if the FDG-PET-CT is 
negative in the bone marrow site then biopsy/aspirate is performed to identify involvement as per 
the Investigator’s judgment and based on other factors consistent with advanced stage or poor 
prognosis). Subsequent bone marrow assessments will only be performed in participants who 
have bone marrow involvement at baseline. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. Please refer to study SoA 
flow chart (Section 1.3). 
The NCI CTCAE version 5.0 will be used in this study to grade the severity of clinical and 
laboratory AEs.  
The safety profile will be mainly based on incidence, severity, and cumulative nature of TEAEs. 
TEAEs are defined as AEs that develop or worsen in grade or become serious during the 
on-treatment period. 
Adverse events will be coded to a “Low Level Term (LLT)”, “Preferred Term (PT)”, “High Level 
Term (HLT)”, “High Group Level Term (HGLT)” and associated primary SOC” using Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be summarized with respect to the 
type, frequency, severity, seriousness, and relatedness. 
All the AEs, including AEs of new onset as well as worsening of baseline signs and symptoms are 
to be reported from the signing of the informed consent to 30 days following the 
last administration of study treatment. After the 30-day interval EOT, all the ongoing related 
non-serious AEs, the ongoing SAEs and the new related AE/SAEs are to be followed until 
resolution or stabilization. Stabilization is defined as an AE ongoing without any change for at 
least 3 months.  
The primary objective is to evaluate the safety of isatuximab and cemiplimab when administered 
as an IV infusion to participants with lymphoma.  The safety profile will be assessed from the 
findings of physical examination (preferably by the same physician), laboratory tests, etc, and will 
be based on incidence, severity, and cumulative nature of AEs. 
8.2.1 Physical examinations  
• A complete physical examination will include, at minimum, assessments of the major 
body systems. Height (only at baseline) and weight will also be measured and recorded. 
• To be performed at baseline (within 14 days from C1D1), then within 3 days prior to 
premedication and IMP administration, at the EOT visit, during follow-up, and as 
clinically indicated. 
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• Performance status as measured by the ECOG. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
• Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at baseline, 
to be taken just before starting infusion of IMP, 1 hour after the start of the infusion, at the 
end of infusion, and as clinically indicated during the infusion or during any interruption 
due to an infusion reaction. The measurements will also be performed at the EOT visit and 
post-treatment follow-up visits at 60 and 90 days after last treatment. 
• Blood pressure and pulse rate measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions (eg, television and cell 
phones). 
8.2.3 Electrocardiograms  
• 12-lead ECG at baseline and as clinically indicated during the study treatment period. 
• 12-lead ECG will be obtained as outlined in the SoA (Section 1.3), using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Clinically significant abnormalities should be reported as AE, except for at the screening 
assessment if the detected finding is linked to a preexisting condition. In that case, the 
diagnosis should be recorded in the participant’s medical history. 
8.2.4 ECHO or MUGA  
Left ventricular ejection fraction (LVEF) will be performed at baseline (within 90 days of Day 1) 
for participants previously treated with anthracyclines (Section 5.2). 
8.2.5 Pulmonary function test:  
Diffusing capacity of the lungs for carbon monoxide (DLCO) will be performed at baseline for 
participants previously treated with bleomycin (Section 5.2). 
8.2.6 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
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• The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition and that either leads to IMP(s) discontinuation or dose modification 
or fulfills a serious or AESI definition. 
• All laboratory tests with values considered clinically and significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or medical monitor: 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the system provided by the 
Sponsor.  
8.2.6.1 Blood Chemistry:  
To be done at baseline (within 14 days from C1D1), then within 3 days prior to premedication and 
IMP administration, at the EOT visit, during follow-up and as clinically indicated. Biochemistry 
should be performed every 7 days in case of Grade 3/4 abnormalities. Blood chemistry includes: 
aspartate aminotransferase, alanine aminotransferase, bilirubin (total and direct), Alkaline 
phosphatase, Lactate dehydrogenase, sodium, potassium, chloride, bicarbonate/carbon dioxide (to 
be performed as clinically indicated), calcium, magnesium, phosphate, uric acid, urea or blood 
urea nitrogen, serum creatinine, eGFR (MDRD formula; Appendix 9 [Section 10.9]), glucose 
(fasting), albumin and total protein.  
8.2.6.2 Hematology:  
To be done at Screening (within 14 days from C1D1), then within 3 days prior to premedication 
and IMP administration, at the EOT visit, during follow-up and as clinically indicated. 
Hematology includes: hemoglobin, hematocrit, red blood cells, white blood cells with differential, 
and platelet counts. If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC ≥0.5 × 109/L 
and at least weekly thereafter until ANC ≥1.0 × 109/L. Blood group card to be obtained before 
study entry. 
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8.2.6.3 Urinalysis  
Semi-quantitative (according to site practice and if such method can provide absolute numeric 
value of the parameters) (includes RBC, protein, glucose, pH, ketones, bilirubin, leucocytes, 
nitrates, and specific gravity) to be done at baseline (within 14 days from C1D1), then within 
3 days prior to Cycle 1 Day 1, EOT, during follow-up, and during the treatment period if 
hematuria is observed or clinically indicated. Dipstick will be performed on Day 1 of each new 
cycle if clinically indicated. In case of positive dipstick results, quantitative or semi-quantitative 
analysis would be required. 
Blood chemistry, hematology, and urinalysis are not required to be repeated prior to Cycle 1 
Day 1 if the baseline laboratory assessments were performed within 3 days prior to first IMP 
administration. 
8.2.6.4 TSH  
It will be assessed at baseline, within 3 days prior to every second ie, other cycle, EOT, during 
follow-up visits (60 and 90 days after last treatment); free T4 will be assessed if thyroid 
stimulating hormone (TSH) is outside of the normal range. 
8.2.6.5 Blood typing interference test  
At baseline: blood type (if not already done) and phenotype (according to the site protocol). 
Recommended phenotype includes Rh system (C/c and E/e), Kell system (K/k); Duffy system 
(Fya/Fyb); Kidd system (Jka/Jkb); MNS system (M/N, S/s), and indirect antiglobulin test 
(indirect Coombs test) if considered standard of care in the site. On Cycle 2 Day 1 and before 
each transfusion: IAT (indirect Coombs test or antibody screen). Blood type card will be kept by 
the participant with the study card. Blood transfusions are to be recorded in the eCRF. The blood 
bank needs to be informed that the participant is receiving a treatment with an anti-CD38 and 
a potential interference with the Coombs test is possible. During the treatment period the 
transfusion service should follow the recommendations issued in the AABB bulletin in case a red 
blood cell transfusion is needed. The web link to the AABB bulletin will be indicated on the study 
patient card. 
• The AABB Clinical Transfusion Medicine Committee has developed a bulletin 
(Appendix 7 Section 10.7) to provide background information and guidance to members 
regarding anti-CD38 interference with serologic testing. 
8.2.6.6 Serology HIV, HBV, and HCV  
Only for participants with prior history of these infections, including for viral genomes (PCR). 
8.2.6.7 Pregnancy test  
Urine or Serum Pregnancy Test for WOCBP only at baseline within 7 days prior to first dose, on 
Day 1 of each cycle prior to study treatment from Cycle 2, at EOT, and monthly up to 6 months 
following study treatment discontinuation. 
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8.2.6.8 Blood draw for biomarker analysis  
A sample of peripheral blood will be drawn at Cycle 1 Day1, prior to IMP administration. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
Adverse events 
All AEs regardless of seriousness or relationship to the IMP, spanning from the signature of the 
informed consent form (ie, occurring during the screening period even in the absence of any 
administration of IMP), up to 30 days following the last administration of study treatment, are to 
be recorded on the corresponding page(s) included in the eCRF. 
Whenever possible, a diagnosis or single syndrome should be reported instead Of symptoms (with 
the exception of IRs for which a main diagnosis and individual symptoms should be reported). 
The Investigator should specify the date of onset, severity (grade), action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, and 
his/her opinion as to whether there is a reasonable possibility that the AE was caused by the IMP. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
requiring corrective treatment and/or leading to treatment discontinuation and/or modification of 
dosing and/or fulfilling a seriousness criterion and/or is defined as an AESI. 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a seriousness criterion and/or are defined as an AESI. 
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to isatuximab, for which ongoing monitoring and immediate notification 
by the Investigator to the Sponsor is required. Such adverse 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 AEs are considered AESIs: 
• Grade ≥2 acute infusion reactions (IRs; Section 6.5.5 for manifestation/symptoms 
typical of an IR). An IR occurs typically within 24 hours from the start of the infusion. 
• Grade ≥3 immune-related TEAEs. 
• Immune-related AEs of any grade  in a participant previously treated with a PI 3-K 
inhibitor. 
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• Dose limiting toxicities (as defined in Section 4.1) are considered as AESIs, and as such, 
the Investigators will be required to report them to the Sponsor within 24 hours of the 
Investigator becoming aware of the event. The Investigator will attach the DLT-specific 
CRF page to the DLT/AESI form. 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in 
a female partner of a male subject 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, treatment with the 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 5 
Section 10.5).  
• Symptomatic overdose (serious or non-serious) with IMP/NIMP. An overdose 
(accidental or intentional) with the isatuximab is defined as increase of at least 30% of the 
intended administered dose at each infusion expressed in unit per body weight) 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 defined as increase of at least 
30% of the intended administered dose at each administration expressed in unit 
per body weight), 
- 
Cemiplimab symptomatic overdose: accidental or unintentional overdose of at least 
2 times the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
- 
In case of accidental or intentional overdose with the IMP/NIMP, even not fulfilling 
a seriousness criterion, is to be reported to the Sponsor immediately (within 24 hours) 
using the AE form together with the SAE complementary form to be entered in the 
eCRF.  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Information about AEs will be obtained from 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. 
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Serious Adverse Events , Adverse Events of Special Interest (including pregnancy and 
overdose) 
• In the case of a SAE or an AESI, the Investigator must report the SAE or AESI to the 
Sponsor within 24 hours of the initial receipt of the information about SAE or AESI. 
• The information about the SAE/AESI need to be entered in the appropriate sections of the 
eCRF; the system will automatically send the notification to the Monitoring Team after 
approval of the Investigator within the eCRF or after a standard delay. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In such case, care should be taken to ensure that the patient's identity is 
protected and the patient's identifiers in the study are properly mentioned on any copy of 
a source document provided to the Company. For laboratory results, include the laboratory 
normal ranges. 
• When cohorts of more than one participant begin accruing, the monitoring team will notify 
the study Investigators of the occurrence of DLTs and SAEs within 24 hours. 
• All further data updates should be recorded in the eCRF (or a system provided by the 
Sponsor) as appropriate, and further documentation as well as additional information (for 
laboratory data, concomitant medication, and participant status) should be sent (by fax or 
e-mail) to the Monitoring Team within 1 working day of knowledge. In addition, any 
effort should be made to further document each Serious Adverse Event that is fatal or life-
threatening within the week (7 days) following initial notification. 
• A back-up plan is used (using paper flow) when the eCRF system does not work 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs will be collected from the signing of the ICF until the follow-up visit. 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee within 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 AE or SAE 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. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 Section 10.3. 
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8.3.2  Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
• The Investigator should take all appropriate measures to ensure the safety of the 
participants, notably he/she should follow-up the outcome of any AEs (clinical signs, 
laboratory values or other, etc.) until the return to normal or consolidation of the 
participant's condition. Ongoing related AEs at the end of study treatment will be followed 
until resolution or stabilization. 
• In case of any SAE/AESI, the participant must be followed up until clinical recovery is 
complete and laboratory results have returned to normal, or until outcome has been 
stabilized. This may imply that follow-up may continue after the participant has 
discontinued study treatment or has left the clinical trial and that additional investigations 
may be requested by the monitoring team. 
• In case of any AE or AESI brought to the attention of the Investigator at any time after the 
end of the study for the participant and considered by him/her to be caused by the IMP 
with a reasonable possibility, should be reported to the monitoring team. 
Follow-up information for any adverse events entered in the pharmacovigilance database will be 
entered in the pharmacovigilance database at any time irrespective of the clinical database lock. 
GPV may also request follow-up on Individual Case Safety Reports received for entry in the 
pharmacovigilance database. 
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 
non-serious AEs of special interest (as defined in Section 8.2), will be followed until resolution, 
stabilization, or the participant is lost to follow-up. Further information on follow-up procedures 
is given in Appendix 3, Section 10.3. 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
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• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• Adverse events that are considered expected are specified in the reference safety 
information. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants, will be collected after the start of study intervention and the follow-up will be 
no longer than 6 to 8 weeks following the estimated delivery date. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of learning 
of the pregnancy and should follow the procedures outlined in Appendix 5 (Section 10.5). 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
• Of a female subject entered in a study as well as pregnancy occurring in a female partner 
of a male subject 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. 
• In the event of pregnancy in a female participant, treatment with the 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. 
8.3.6 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
The following disease-related events (DREs) are common in participants with cancer and can be 
serious: 
• Progression of underlying disease, as it is the study endpoint. 
• Death due to progression of underlying disease, if it occurs after 30 days of the last IMP 
administration. The causes for all other deaths that occur within 30 days of last IMP 
administration, however, should be reported as SAEs. 
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Because these DREs are typically associated with the disease under study, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the event 
may meet the definition of an SAE.  
8.3.7 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP/device 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 
TREATMENT OF OVERDOSE  
There is no information on specific recommendations regarding overdose with isatuximab or 
cemiplimab. In case of overdose, participants should be closely monitored for signs or symptoms 
of adverse reactions, and appropriate symptomatic treatment should be instituted. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
8.5.1 Sampling time  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. The dates and times of drug administration should also 
be precisely recorded. 
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The cemiplimab and isatuximab PK sampling times for blood collection can be found in the 
PK/PD Flow Chart (Section 1.4). For isatuximab, samples for PK assessment are to be collected 
during the course of the study; however, collection can be stopped earlier upon notification from 
the Sponsor based on the updated knowledge of PK. 
For both cemiplimab and isatuximab, PK samples will be collected over C1 to C4 and from C5, 
both compounds will be collected at predose each cycle until C11 then every third cycle, ie, C14, 
C17, and C20 till the last study treatment or at the primary analysis cutoff date whichever comes 
first. For cemiplimab only, further samples to be collected at the end of treatment and at the 
follow-up treatment visit at 60 (±7) days or at the primary analysis cut-off date, whichever comes 
first. No PK collection will occur after the primary analysis cut-off date. 
8.5.1.1 Pharmacokinetic sample handling procedure  
Special procedures for collection, storage, and shipment will be provided in a separate laboratory 
manual. 
8.5.1.2 Bioanalytical Methods  
Bioanalytical methods are summarized in Table 7. 
Table 7 - Bioanalytical methods for isatuximab and functional cemiplimab pharmacokinetic  
Analyte 
Isatuximab 
Cemiplimab 
Matrix 
Plasma 
Serum 
Analytical technique 
Immunoassay 
Immunoassay 
Lower limit of quantification 
5.00 µg/mL 
78.0 ng/mL 
Site of bioanalysis 
Covance Harrogate, UK 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
8.5.1.3 Pharmacokinetic parameters  
Not applicable. 
8.5.1.4 Non-compartmental analysis  
The following PK parameters will be calculated with PKDMS software (Pharsight), using 
non-compartmental methods, from plasma concentrations of isatuximab and serum concentrations 
of cemiplimab. The parameters will include, but may not be limited to, the following in Table 8: 
Table 8 - List of pharmacokinetic parameters and definitions  
Parameters 
Definition 
Ceoi 
Concentration observed at the end of intravenous (IV) infusion 
Cmax 
Maximum concentration observed after the first infusion 
tmax 
Time to reach Cmax 
Clast 
Last concentration observed above the lower limit of quantification after the first infusion 
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8.8 
BIOMARKERS  
This section refers to additional analyses and future use of samples:  
• During the study additional analyses, not specified in the protocol but related to the drug 
action and/or effect of isatuximab/cemiplimab, may be conducted on samples pending 
evolving literature. 
• After study completion, for participants who have consented to it, remaining samples will 
be kept for other possible exploratory analyses. Results of these analyses will not be 
included in the clinical study report but in a stand-alone report, if applicable. 
• These other research analyses will help to understand either disease subtypes or drug 
response, or to develop and/or validate a bioassay method, or to identify new drug targets 
or biomarkers. 
• These samples will remain labeled with the same identifiers used during the study 
(ie, participant ID).  
• They will be transferred to a Sanofi site (or a subcontractor site) which can be located 
outside of the country where the study is conducted. The Sponsor has included safeguards 
for protecting participant confidentiality and personal data (Section 10.1.4). These samples 
maybe stored for a period of up to 5 years after completion of the final study report. After 
that period, any samples remaining will be destroyed. 
8.8.1 RNA transcriptome research  
Transcriptome studies will be conducted using NGS (RNAseq) or by Nanostring and/or 
alternative equivalent technologies, which facilitates the simultaneous measurement of the relative 
abundances of thousands of ribonucleic acid (RNA) species resulting in a transcriptome profile 
for each and tumor biopsy sample. This analysis will be performed on available tumor sample 
(such as FFPE or RNA later preserved tumor samples). This analysis will particularly enable 
discrimination between different subtypes of DLBCL. This might also enable the evaluation of 
changes in transcriptome profiles (such as immune related genes) that may correlate with 
biological response relating to disease or the action of study intervention. 
The same samples may also be used to confirm findings by application of alternative 
technologies. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications for collection, storage, and shipment as defined in a separate laboratory manual. 
Samples missed or lost, for any reason, should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. The dates and times of drug administration should also 
be precisely recorded. 
The cemiplimab and isatuximab ADA sampling times for blood collection can be found in the 
PK/PD Flow Chart (Section 1.4). 
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• No isatuximab and cemiplimab ADA collection will be done after primary analysis cut-off 
date. 
• For isatuximab during intervention period, samples for immunogenicity assessment will be 
collected at each cycle from C1 to C5 then every third Cycle (ie, on D1 of C5, C8, C11, 
C14, etc) until the last study treatment, and at FUP 90 (±7) days after last isatuximab 
administration or at the primary analysis cut-off date, whichever comes first. However, 
collection can be stopped earlier upon notification of the Sponsor based on the updated 
knowledge of isatuximab immunogenicity. After FUP 90 (±7) days after last isatuximab 
administration no further ADA will be sampled even if the status is positive or 
inconclusive. 
• For cemiplimab during intervention period, samples for immunogenicity assessment will 
be collected at C1, C2, then every third cycle from C5 Cycle (ie, D1 of Cycle 5, 8, 11, 14, 
etc.) till the last study treatment, and at EOT or at the primary analysis cut-of date, 
whichever comes first. During the intervention period, if isatuximab is stopped and 
cemiplimab treatment continues cemiplimab ADA samples should be collected as planned 
per PK/PD flow chart. In response to AE’s of special interest, such as anaphylaxis or 
hypersensitivity, ADA samples may be collected closer to the event, based on the 
judgment of the Investigator and/or medical monitor.  
Bioanalytical methods used for immunogenicity assessment are summarized in Table 9. 
Table 9 - Bioanalytical methods for immune response assessment  
Analyte 
ANTI ISATUXIMAB ANTIBODY 
ANTI CEMIPLIMAB ANTIBODY 
Matrix 
Plasma 
Serum 
Analytical technique 
PandA method 
Non-quantitative bridging immunoassay 
Lower Limit of Quantification 
Not applicable 
Not applicable 
Site of bioanalysis 
Covance Harrogate (UK)) 
Regeneron Pharmaceuticals, Inc. 
(Tarrytown, NY) 
 
8.10 
[HEALTH ECONOMICS] OR [MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS]  
Not applicable. 
8.11 
DATA COLLECTION AFTER PREMATURE STOP OF THE STUDY  
If the sponsor decides to stop prematurely the study, eg,  not to open Phase 2 Stage 2 if the interim 
analysis met protocol criteria. All participants still on treatment after premature stop of the study 
may continue to receive treatment if they accept as far as they continue to benefit from it as per 
investigator assessment until disease progression, unacceptable AE, participant's decision to stop 
the treatment, 96 weeks of delivery of IMP(s) without documented progressive disease (PD), or 
48 weeks of treatment after achieving a complete response to study treatment (whichever is 
longer), or any other reason.  
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Procedure and data collection for these patients will be as follows: 
• Study treatment administration (SAR650984, Cemiplimab, premedications) 
• ECOG PS 
• Pregnancy test (urine sample or approximately 1 teaspoon [ie, 5 mL] of blood sample will 
be collected) on D1 of each cycle from cycle 2, at EOT and monthly up to 6 months 
following study treatment discontinuation for women who can become pregnant. 
• All SAEs regardless of relationship, ongoing and new related AEs and AESIs are to be 
collected until stabilization or resolution and all associated concomitant medication. 
Stabilization is defined as an AE ongoing without any change for at least 3 months 
• All laboratory values leading to treatment modification should be reported 
• No more PK, ADA and BM to be collected 
• No efficacy data including FDG PET CT and CT Scan will be collected   
• EOT visit should be done approximately 30 days after last study drugs 
• After EOT visit, no follow up visit will be performed 
Patients with ongoing related AEs/AESIs and ongoing SAEs after treatment discontinuation will 
be followed until resolution or stabilization of the AEs/AESIs/SAEs. 
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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
Phase 1 
There is no formal statistical hypothesis in Phase 1 safety run-in. 
Phase 2 
For Cohort A1 (cHL anti-PD-1/PD-L1 naïve), the null hypothesis is that the true CR during 
isatuximab + cemiplimab period is ≤20%, and the alternative hypothesis is that the true CR is 
≥40%. 
For Cohort A2 (cHL anti-PD-1/PD-L1 inhibitor progressor), the null hypothesis is that the true 
ORR during isatuximab + cemiplimab period is ≤20%, and the alternative hypothesis is that the 
true ORR is ≥45%. 
For Cohort B (DLBCL), the null hypothesis is that the true ORR is ≤35%, and the alternative 
hypothesis is that the true ORR is ≥60%. 
For Cohort C (PTCL), the null hypothesis is that the true ORR is ≤25%, and the alternative 
hypothesis is that the true ORR is ≥50%. 
9.2 
SAMPLE SIZE DETERMINATION   
Phase 1 
For RP2D assessment, up to between 3 (assuming 3 participants for the starting dose) and 
12 (assuming 6 participants for the starting dose plus 6 participants for DL-1) DLT evaluable 
participants are needed. For 3 DLT evaluable participants on starting dose, approximately 
6 participants could be enrolled without interruption. The actual sample size will vary depending 
on DLTs observed and the number of dose levels explored. 
Phase 2 
Approximately 118 participants are expected to be enrolled (assuming all cohorts complete 
2 stages), including approximately 57 participants in Phase 2 Stage 1 and approximately 
61 participants in Phase 2 Stage 2.  
The participants who are treated with RP2D in Phase 1 will be counted as Phase 2 participants. 
The efficacy evaluation is based on Simon’s 2-stage design with 85% power at 1-sided alpha level 
of 5% for each cohort, respectively. The assumption of response rate, the required sample sizes, 
and the number of responders at each stage are provided in Table 10: 
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Table 10 - Determination of sample size in Phase 2  
Indication 
H0 
H1 
Sample size 
Number of 
required response 
Stage 1 
Final 
Stage 1 
Final 
Cohort A1 (cHL anti-PD-1/PD-
L1 naïve) 
20% (2, 3) 
40% 
17 
37 
≥4 CR 
≥12 CR 
Cohort A2 (cHL anti-PD-1/PD-
L1 progressor) 
20% (6) 
45% 
12 
25 
≥3 
≥9 
Cohort B (DLBCL anti-PD-
1/PD-L1 naïve) 
35% (20, 21) 
60% 
18 
29 
≥8 
≥15 
Cohort C (PTCL anti-PD-1/PD-
L1 naïve) 
25% (22, 24, 11) 
50% 
10 
27 
≥3 
≥11 
Abbreviations: H0 = Null hypothesis; H1 = Alternative hypothesis; cHL = Classic Hodgkin’s lymphoma; DLBCL = Diffuse large B-cell 
lymphoma; PTCL = Peripheral T-cell lymphoma. 
 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined: 
Table 11 - Populations for analyses  
Population 
Description 
All treated  
For both Phase 1 and Phase 2 of the study, the all-treated population will include all 
participants who have given their informed consent and received at least 1 dose 
(even incomplete) of either isatuximab or cemiplimab  
Dose limiting toxicity (DLT) evaluable 
(Phase 1) 
The DLT evaluable population is defined as participants in Phase 1 who received at 
least 90% of the planned doses of isatuximab and cemiplimab during Cycle 1, and 
completed the DLT observation period after the first IMP administration, unless they 
discontinued the study treatment(s) due to DLT. The dose recommended for Phase 
2 will be determined on the DLT evaluable population. 
Response evaluable population 
The response evaluable population will include all participants in the all treated 
population who fulfilled all inclusion and exclusion criteria without any major or 
critical deviation with an evaluable baseline assessment and at least one evaluable 
post-baseline assessment during the treatment period. This population is the 
secondary analysis population for efficacy. 
Pharmacokinetics (PK) 
The PK population will include all participants from the all treated population with at 
least 1 drug concentration after drug administration. 
Anti-drug antibody (ADA) evaluable 
The ADA evaluable population includes all participants from the all treated 
population with at least 1 non-missing ADA result after the drug administration. 
Pharmacodynamics (PDy) 
The pharmacodynamics population will include all participants from the all treated 
population with at least 1 pharmacodynamic marker result after the first dose of 
study treatment. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 14 (see Section 10.14). 
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9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 
The participants treated at the RP2D of isatuximab and cemiplimab in combination during Phase 1 
will be included in the efficacy analysis together with participants of the same indication in 
Stage 1 of Phase 2. Data from cHL (Cohorts A1 and A2), DLBCL, and PTCL cohorts in Phase 2 
will be analyzed and reported separately by cohort. 
Planned date for analysis cut-off: 
The data cut-off for the primary end-of-cohort analysis is up to 24 weeks from the date the 
last participant treated in individual cohort. The data cut-off for the intermediate and final 
end-of-cohort analysis are up to 48 and 96 weeks, respectively, from the date the last participant 
treated in individual cohort. 
9.4.1 Efficacy analyses  
All treated population will be the primary analysis population for efficacy endpoints. In addition, 
similar analysis will be performed using the response evaluable population as a secondary 
analysis. 
Analysis of primary efficacy endpoints 
For cHL Cohort A1: CR rate during isatuximab + cemiplimab period will be summarized with 
descriptive statistics. A 90% two-sided confidence interval will be computed using 
Clopper-Pearson method. The statistical inference will be based on the hypothesis and alpha level 
defined in the sample size calculation section. 
For cHL Cohort A2, DLBCL and PTCL: ORR during isatuximab + cemiplimab period will be 
summarized with descriptive statistics. A 90% two-sided confidence interval will be computed 
using Clopper-Pearson method. The statistical inference will be based on the hypothesis and alpha 
level defined in the sample size calculation section. 
Analysis of secondary efficacy endpoints 
For each cohort, separate analyses of the following endpoints will be performed for all 
participants during isatuximab + cemiplimab period for all 4 cohorts, for participants in 
Cohorts A1 and A2 including the data from both isatuximab + cemiplimab and isatuximab + 
cemiplimab + radiotherapy periods, and for participants in Cohorts A1 and A2 who receive 
isatuximab + cemiplimab + radiotherapy. 
• Tumor burden change: the best percent-change from baseline in tumor burden for all target 
lesions will be summarized and presented graphically. 
• DoR and PFS will be summarized using Kaplan-Meier method. 
• DCR will be summarized with descriptive statistics. 
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In addition, ORR during isatuximab + cemiplimab period will be summarized in a similar fashion 
as described in the primary efficacy analysis for participants in Cohort A1. Similar analyses will 
be provided for CR rate and ORR for all participants in Cohorts A1 and A2 including the data 
from both isatuximab + cemiplimab and isatuximab + cemiplimab + radiotherapy periods, and for 
participants in Cohorts A1 and A2 who receive isatuximab + cemiplimab + radiotherapy. 
Table 12 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
 
cHL Cohort A1: CR rate during isatuximab+cemiplimab period 
Descriptive statistics and Clopper-Pearson method 
cHL Cohort A2, DLBCL and PTCL: ORR during 
isatuximab+cemiplimab period 
Descriptive statistics and Clopper-Pearson method 
Secondary 
 
Tumor burden change 
Descriptive statistics 
DoR and PFS 
Kaplan-Meier method 
DCR 
Descriptive statistics 
cHL Cohort A1: ORR during isatuximab+cemiplimab period 
Descriptive statistics and Clopper-Pearson method 
cHL Cohort A1 & Cohort A2: CR rate and ORR including the data 
from both isatuximab + cemiplimab and isatuximab + cemiplimab 
+ radiotherapy periods, and for participants in Cohorts A1 and A2 
who receive isatuximab + cemiplimab + radiotherapy. 
Descriptive statistics and Clopper-Pearson method 
Exploratory 
Will be described in the statistical analysis plan finalized 
before database lock 
Abbreviations: cHL = Classic Hodgkin’s lymphoma; CR = Complete remission; DCR = Disease control rate; DLBCL = Diffuse large B cell 
lymphoma; DoR = Duration of response, ORR = Objective response rate; PFS = Progression free survival; PTCL = Peripheral T-cell 
lymphoma 
9.4.2 Safety analyses  
All safety analyses will be performed on the all treated population.  
Table 13 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
DLTs, AEs/SAEs, and laboratory abnormalities in Phase 1 
Descriptive statistics 
Secondary 
AEs/SAEs and laboratory abnormalities in Phase 2 
Descriptive statistics 
AEs/SAEs and laboratory abnormalities in isatuximab + cemiplimab 
+ radiotherapy treated participants for Cohort A1 and A2 
Descriptive statistics 
ADA against isatuximab and against cemiplimab 
Descriptive statistics 
Exploratory 
Will be described in the statistical analysis plan finalized 
before database lock 
ADA = Anti-drug antibody; AE = Adverse event; DLT = Dose limiting toxicity; SAE = Serious adverse event. 
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Dose limiting toxicities 
In Phases 1, the DLTs will be listed by participant using the DLT evaluable population. 
Analyses of adverse events 
In Phases 1 and 2, the AEs will be coded according to MedDRA. Adverse events and laboratory 
abnormalities will be graded according to NCI CTCAE version 5.0. 
The number (%) of participants experiencing TEAEs by primary SOC and PT will be summarized 
by CTCAE grade (all grades and Grade ≥3) for the all treated population. Same table will be 
prepared for treatment-related TEAEs, AESIs, TEAEs leading to treatment discontinuation, 
serious TEAEs and TEAEs with fatal outcome. The post-treatment AEs will be analyzed 
separately. 
Clinical laboratory evaluations 
All the laboratory abnormalities will be graded according to NCI CTCAE version 5.0, when 
applicable. The number (%) of participants with laboratory abnormalities (ie, all grades and Grade 
≥3) using the worst grade during the on-treatment period will be provided for the all treated 
population. 
Immunogenicity 
The findings from the analyses of immunogenicity for isatuximab and cemiplimab will be 
summarized. 
9.4.3 Other analyses  
Pharmacokinetic, pharmacodynamic, and biomarker exploratory analyses will be described in the 
SAP finalized before database lock. The population PK analysis and pharmacodynamic analyses 
will be presented separately from the main clinical study report (CSR).  
Analysis of PK endpoints 
Individual concentrations and PK parameters of isatuximab and cemiplimab will be summarized 
by descriptive statistics (such as mean, geometric mean, median, standard deviation, standard 
error of the mean, coefficient of variation, and minimum and maximum) under the responsibility 
of Sanofi, Pharmacokinetic, Dynamic & Metabolism department. Individual and mean profiles 
will be presented graphically. 
Analysis of pharmacodynamic endpoints 
Findings from pharmacodynamics markers will be descriptively summarized and tabulated. 
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9.5 
INTERIM ANALYSES   
The Statistical Analysis Plan will describe the planned interim analyses in greater detail. An 
interim analysis will be performed for cHL PD-1/PD-L1 naïve cohort A1, cHL PD-1/PD-L1 
progressors cohort A2, DLBCL and PTCL cohorts when the first 17, 12, 18, and 10 participants, 
respectively, in Phase 2 have been treated and followed-up for 24 weeks. 
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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. 
• The protocol, protocol amendments, ICF, Investigator’s 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.  
• 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, 
- 
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. 
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. 
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10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
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, 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
• Participants who are rescreened are required to sign a new ICF. 
• The ICF will contain a separate section that addresses the participation in the post-dose 
PK assessment sub-study. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory 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. A separate signature will be required to document a participant's 
agreement to allow any remaining specimens to be used for exploratory research. 
Participants who decline to participate in this optional research will not provide this 
separate signature. 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Appendix 14 (see Section 10.14). 
10.1.4  Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation).  
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. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.  
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• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant.  
• 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. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
DMC (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. During this exercise, the DMC will also institute any measures that may be required 
for ensuring the integrity of the study results during the execution of its primary mission.  
Study committee:  
During Phase 1, the study committee (SC) will review clinical data approximately every 2 weeks. 
During Phase 1, composition of the SC will vary based on the matter discussed, but it will 
generally include Sponsor representatives and at least two Investigators with participants 
participating to Phase 1. For Phase 2, the SC will consist of Sponsor representatives and at least 
two Investigators participating in Phase 2 Stage 1 or Stage 2. A radiotherapist will be included in 
the SC meetings to discuss the radiotherapy options after Cycle 10. The SC meetings will occur 
on an as needed basis to review data and provide strategic recommendations on study medical 
decisions. 
10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinical trial register (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance, and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
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Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or eCRF 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 CRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• 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.  
• 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.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the end of the clinical study 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 eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
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• The informed consent form will include a statement by which the participant allowing the 
Sponsor’s duly authorized personnel, the ethics committee (IRB/IEC), and the regulatory 
authorities to have direct access to original medical records which support the data in the 
eCRF (eg, participant's medical file, appointment books, and original laboratory records). 
These personnel, bound by professional secrecy, must maintain the confidentiality of all 
personal identity or personal medical information (according to confidentiality rules). 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study 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 the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 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 recruitment of participants by the Investigator. 
• Discontinuation of further study intervention development. 
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 14 will be performed by the local laboratory. 
• The results must be entered into a system provided by the Sponsor. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
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Table 14 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematologya 
Platelet count  
Red blood 
cell (RBC) 
count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
 
Blood chemistrya 
Urea or  
Blood urea 
nitrogen 
(BUN)b 
Uric acid 
Potassium 
Chloride 
Bicarbonate/carbon  
Dioxide (to be 
performed as clinically 
indicated) 
Aspartate 
aminotransferase (AST)/ 
Serum glutamic-
oxaloacetic 
transaminase (SGOT) 
Total and direct bilirubin 
Lactate dehydrogenase (LDH) 
 
Creatinine 
eGFR 
(MDRD) 
 
Glucose 
fasting 
Sodium 
Magnesium 
Phosphate  
 
Calcium 
Alanine 
aminotransferase 
(ALT)b/ Serum glutamic-
pyruvic transaminase 
(SGPT) 
 
Alkaline phosphatase 
Total protein 
Albumin 
Thyroid stimulating hormone 
(TSH), free T4c, (baseline), 
every other cycle thereafter, 
end of treatment, during 
follow-up visits (60 and 
90 days after last treatment) 
Routine urinalysis 
Semi-quantitative urinalysis (including RBC, protein, glucose, pH, ketones, bilirubin, leucocytes, 
nitrates, and specific gravity). 
Semi-quantitative analysis is required at baseline, end of treatment (EOT), during follow-up, and 
during the treatment period if hematuria is observed. Dipstick will be performed on Day 1 of each new 
cycle if clinically indicated. Subsequent urinalysis may be performed; in case of positive dipstick 
results, semi-quantitative analysis would be required. 
Other screening 
tests 
Serum (at baseline) or urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential).(urine pregnancy test on Day 1 of each cycle, EOT and monthly up 
to 6 months following study treatment discontinuation) 
Coagulation: prothrombin time or international normalized ratio (INR)b and partial thromboplastin time 
(PTT) 
Blood typing interference test 
Only for participants with prior history of these infections, including for viral genomes (PCR). 
Serologyd (HIV antibody, hepatitis B surface antigen [HBsAg], anti-HBc total and IgM, (HBV DNA 
testing by PCR in case of anti-HBc positive), anti-HBs, anti-HCV and HCV RNA) 
The results of each test must be entered into the CRF. 
Definitions: 
1. Controlled human immunodeficiency virus (HIV) infection is defined as undetectable viral load and 
CD4+ >200 cells/mm3. 
2. Controlled hepatitis B virus (HBV) infection is defined as anti-HBV therapy started before initiation 
of IMP, and HBV viral load <2000 IU/mL (104 copies/mL). The anti-HBV therapy should continue 
throughout the treatment period. 
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NOTES : 
a Blood chemistry, hematology: assessments are not required to be repeated prior to Cycle 1 Day 1 if the screening laboratory 
assessments were performed within 3 days prior to first IMP administration and met entry criteria. 
b All events of ALT ≥3 × ULN and bilirubin ≥2 × ULN (>35% direct bilirubin) or ALT ≥3 × ULN and INR >1.5, if INR measured which 
may indicate severe liver injury must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). INR = (PT test /PT 
normal) (international sensitivity index [ISI] value). 
c Free T4: will be assessed if TSH is outside of the normal range. 
d For patients with positive anti-HBc IgG and negative HBsAg and undetectable (under limit of quantification) HBV DNA at study entry 
(HBV carriers: past resolved infection, resolving acute infection or receiving antiviral treatment with controlled infection), specialist 
advice should be requested, close monitoring of viral reactivation (greater than 1log10 IU/mL increase in HBV DNA or reappearance 
of HBsAg or HBV DNA in patients with resolved infection) throughout and following the end of study treatment should be proposed 
(ALT, AST and HBV DNA at least every 3 months, up to 6 months after treatment discontinuation or initiation of further anticancer 
therapy). 
In case of viral reactivation during study treatment (greater than 1log10 IU/mL increase in HBV DNA or reappearance of HBsAg or 
detection of HBV DNA in patients with resolved infection*), close monitoring of ALT, AST every month, up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
In case HBV vaccination will be started before first study treatment administration, anti-HBs should be monitored at 1, 2 and 3 months 
after end of vaccination. 
* previous known history of acute or chronic hepatitis B or the presence of total anti-HBc with/without anti-HBs; HBsAg negative; 
undetectable serum HBV DNA; normal ALT levels. 
 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition: 
• An AE is any untoward medical occurrence in a 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, if they are symptomatic, require corrective 
treatment, lead to treatment discontinuation, or dose modification, fulfill a serious 
criterion, or the 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. 
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• 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” (eg, disease 
progression) will be reported as a DRE not 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.  
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. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death, 
b) Is life-threatening, 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization, 
In general, hospitalization signifies that the participant has been detained (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. When 
in doubt as to whether “hospitalization” occurred, 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 disability/incapacity, 
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- 
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 in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but 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. 
- 
Examples of such events include second primary invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
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 CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sanofi in lieu of completion of the Sanofi/AE/SAE CRF page. 
• 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 severity (grade)  
The Investigator will make an assessment of severity (grade) for each AE and SAE reported 
during the study and assign it to one of the categories according to NCI CTCAE v.5.0. 
An adverse 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. 
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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 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 Monitoring team. 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 Monitoring team. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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 the follow-up period, the 
Investigator will provide the Sponsor with a copy of any post-mortem findings including 
histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The Investigator will submit any updated SAE data to the monitoring team within 24 hours 
of receipt of the information. 
REPORTING OF SAES 
SAE reporting to Monitoring team via an electronic data collection tool 
• The primary mechanism for reporting an SAE to Monitoring team will be the electronic 
data collection tool. 
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• If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section). 
• 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 monitoring team by fax or e-mail. 
10.4 
APPENDIX 4: RECOMMENDED DOSE MODIFICATION OR DISCONTINUATION AND 
SUPPORTIVE CARE GUIDELINES FOR SPECIFIC CEMIPLIMAB DRUG RELATED 
ADVERSE EVENTS  
Table 15 - Colitis adverse event management  
Colitis 
events 
CTCAE 
version 5.0 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Bowel 
obstruction 
Colitis 
Colitis 
microscopic 
No change in 
dose 
No change in 
dose 
For diarrhea, treat symptomatically 
(loperamide, oral hydration, electrolyte 
substitution and ADA colitis diet). 
Endoscopy is recommended if symptoms 
persist. 
Grade 1 diarrhea that persists for >1 week 
should be treated with the addition of oral 
diphenoxylate hydrochloride and atropine 
sulfate 4 times daily and budesonide 
9 mg daily. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or parasitic 
infection, 
gastroenteritis or 
the first 
manifestation of an 
inflammatory bowel 
disease by 
examination for 
stool leukocytes, 
stool cultures, and 
a Clostridium 
difficile titer. 
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Colitis 
events 
CTCAE 
version 5.0 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 2 
Enterocolitis 
hemorrhagic 
GI perforation 
Necrotizing 
colitis 
Diarrhea: all 
participants who 
experience 
diarrhea should 
be advised to 
drink liberal 
quantities of 
clear fluids. If 
sufficient oral 
intake is not 
feasible, fluid 
and electrolytes 
should be 
substituted via 
IV infusion. 
Delay or omit 
dose until 
≤Grade 1 
(See 
Section 6.5.2) 
Delay or omit 
dose until 
≤Grade 1 
(See 
Section 6.5.2) 
GI consultation and endoscopy is 
recommended to confirm or rule out colitis 
for Grade 2 diarrhea that persists >1 week 
or Grade 1-2 diarrhea with rectal bleeding 
(additional guidelines for the treatment of 
persistent colitis are provided below). 
Grade 2 diarrhea should be treated with 
addition of oral diphenoxylate hydrochloride 
and atropine sulfate 4 times daily and 
budesonide 9 mg daily. 
Grade 2 diarrhea with diffuse ulceration and 
bleeding seen on endoscopy may require 
oral steroids with prolonged taper and 
represent an increased risk for the 
development of bowel perforation. 
When symptoms improve to Grade 1 or less, 
steroid taper should be started and 
continued over no less than 4 weeks. 
In participants with Grade 2 enterocolitis, 
cemiplimab should be withheld and 
anti-diarrheal treatment should be started. If 
symptoms are persistent for more than 
1 week, systemic corticosteroids should be 
initiated (eg, 0.5 mg/kg/day of prednisone or 
equivalent). When symptoms improve to 
Grade 1 or less, corticosteroid taper should 
be started and continued over at least 
1 month. 
 
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Colitis 
events 
CTCAE 
version 5.0 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3 and 
Grade 4 
Grade 3: delay 
or omit dose 
until ≤Grade 1 
(See 
Section 6.5.2) 
Grade 4: 
discontinue 
treatment 
Delay or omit 
dose until 
≤Grade 1 (See 
Section 6.5.2) 
Discontinue if 
unable to reduce 
corticosteroid 
dose to 
<10 mg/day 
prednisone 
equivalent within 
12 weeks of 
adverse event 
Participants with Grade 3 enterocolitis, drug 
will be permanently discontinued and 
treatment with systemic corticosteroids 
should be initiated at a dose of 1 to 2 
mg/kg/day prednisone or equivalent. When 
symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and 
continued over at least 1 month. 
For Grade 3-4 diarrhea (or Grade 2 diarrhea 
that persists after initial steroid treatment): 
Rule out bowel perforation. Imaging with 
plain films or CT can be useful. 
Consider consultation with 
gastroenterologist and confirmation biopsy 
with endoscopy. 
Treat with IV steroids (methylprednisolone 
125 mg) followed by high-dose oral steroids 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours). When 
symptoms improve to Grade 1 or less, 
corticosteroid taper should be started and 
continued over no less than 4 weeks. Taper 
over 6 to 8 weeks in participants with diffuse 
and severe ulceration and/or bleeding. 
If IV steroids followed by high-dose oral 
steroids does not reduce initial symptoms 
with 48 to 72 hours, consider treatment with 
infliximab at 5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom relief 
and initiate a prolonged steroid taper over 
45 to 60 days. If symptoms worsen during 
steroid reduction, initiate a re-tapering of 
steroids starting at a higher dose of 80 or 
100 mg followed by a more prolonged taper 
and administer infliximab. CAUTION: 
Infliximab is contraindicated in participants 
with bowel perforation or sepsis. 
If symptoms persist despite the above 
treatment a surgical consult should be 
obtained. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial 
or parasitic 
infection, 
gastroenteritis or 
the first 
manifestation of 
an inflammatory 
bowel disease by 
examination for 
stool leukocytes, 
stool cultures, and 
a Clostridium 
difficile titer. 
 
If symptoms are 
persistent and/or 
severe, endoscopic 
evaluation should 
be considered. 
Abbreviations: CT = Computed tomography; CTCAE = Common terminology criteria for adverse events; GI = Gastrointestinal; IV = 
Intravenous. 
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Table 16 - Endocrine adverse event management  
Endocrine 
events 
CTCAE 
version 5.0 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1-2 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
No change in dose 
No change in 
cemiplimab dose 
Monitor thyroid function or other 
hormonal level tests and serum 
chemistries more frequently 
(every 3 to 6 weeks) until 
returned to baseline values. 
Replacement of thyroid 
hormone or thyroid suppression 
therapy as indicated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. 
An endocrinology 
consultation is 
recommended. 
Grade 3-4 
Hyperthyroidism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Delay or omit dose 
until resolves to 
Grade ≤2 (see 
Section 6.5.2) 
Delay or omit dose 
until on stable 
replacement dose 
as determined by 
resolution of 
symptoms and 
normalization of 
hormone levels 
(see Section 6.5.2) 
Consider endocrine 
consultation. 
Rule out infection and sepsis 
with appropriate cultures and 
imaging. 
Replacement of thyroid 
hormone or thyroid suppression 
therapy as indicated. 
Grade 1-4 
Adrenal 
insufficiency 
Hypophysitis 
Hypopituitarism 
Pan-
hypopituitarism 
Grade 1, 2: no 
change in dose, 
Grade 3, 4: delay or 
omit dose until 
resolves to 
Grade ≤2 (see 
Section 6.5.2) 
Delay or omit dose 
until on stable 
replacement dose 
(see Section 6.5.2) 
Thyroid hormone and/or steroid 
replacement therapy to manage 
adrenal insufficiency. 
If Grade 1-2 hypophysitis is 
considered, pituitary gland 
imaging should be considered 
(MRI with gadolinium and 
selective cuts of the pituitary 
can show enlargement or 
heterogeneity and confirm the 
diagnosis). 
Grade 3-4 hypophysitis with 
clinically significant adrenal 
insufficiency and hypotension, 
dehydration, and electrolyte 
abnormalities (such as 
hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis. Hospitalization 
and IV methylprednisolone 
should be initiated. 
All attempts should be 
made to rule out other 
causes such as brain 
metastases, sepsis, 
and/or infection. 
An endocrinology 
consultation is 
recommended 
Abbreviations: CTCAE = Common terminology criteria for adverse events; IV = Intravenous; MRI = Magnetic resonance imaging. 
 
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Table 17 - Pneumonitis adverse event management  
Pneumonitis 
events 
CTCAE 
version 5.0Grade 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 1 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
No change in 
dose 
Consider delay 
or omit dose 
(see 
Section 6.5.2). 
Cemiplimab may 
be continued 
with close 
monitoring. 
Radiological findings should be 
followed on serial imaging studies at 
least every 3 weeks. 
Monitor for symptoms every 2 to 
3 days. 
Consider pulmonary consultation 
and/or bronchoscopy if clinically 
indicated. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial or 
viral infection. 
Grade 2 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.5.2) 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.5.2) 
To rule out other causes such as 
infection: 
Consider pulmonary consultation with 
bronchoscopy and biopsy/BAL. 
Consider pulmonary function tests 
Follow radiological findings on serial 
imaging studies every 1 to 3 days 
If the participant is determined to have 
study treatment-associated 
pneumonitis 
Monitor symptoms daily, consider 
hospitalization 
Treat with systemic corticosteroids at a 
dose of 1 to 2 mg/kg/day prednisone or 
equivalent. When symptoms improve 
to Grade 1 or less, steroid taper should 
be started and continued over no less 
than 4 weeks. 
Treatment with cemiplimab may be 
resumed if the event improves to 
≤Grade 1 within 12 weeks and 
corticosteroids have been reduced to 
the equivalent of methylprednisolone 
10 mg by mouth daily or less. Repeat 
chest imaging monthly as clinically 
indicated. 
For Grade 2 pneumonitis that improves 
to ≤Grade 1 within 12 weeks, the 
following rules should apply: 
First episode of pneumonitis: may 
decrease the dose to 1 mg/kg in 
subsequent cycles. 
Second episode of pneumonitis: 
Discontinue cemiplimab if upon 
re-challenge the participant develops 
a second episode of ≥Grade 2 
pneumonitis. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial or 
viral infection 
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Pneumonitis 
events 
CTCAE 
version 5.0Grade 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
considerations 
Grade 3-4 
Pneumonitis 
Interstitial lung 
disease 
Acute interstitial 
pneumonitis 
Grade 3: delay 
or omit dose 
until resolves to 
Grade ≤1 (see 
Section 6.5.2) 
Grade 4: 
discontinue 
treatment 
Discontinue 
cemiplimab 
Consider pulmonary function tests with 
pulmonary consult. 
Bronchoscopy with biopsy and/or BAL 
is recommended. 
Treat with IV steroids 
(methylprednisolone 125 mg). When 
symptoms improve to Grade 1 or less, 
a high-dose oral steroid (prednisone 1 
to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) 
taper should be started and continued 
over no less than 4 weeks. 
Add prophylactic antibiotics for 
opportunistic infections. 
If IV steroids followed by high-dose 
oral steroids does not reduce initial 
symptoms with 48 to 72 hours, 
consider treatment with infliximab at 
5 mg/kg once every 2 weeks. 
Discontinue infliximab upon symptom 
relief and initiate a prolonged steroid 
taper over 45 to 60 days. If symptoms 
worsen during steroid reduction, 
initiate a re-tapering of steroids starting 
at a higher dose of 80 or 100 mg 
followed by a more prolonged taper 
and administer infliximab. 
All attempts should 
be made to rule out 
other causes such 
as metastatic 
disease, bacterial or 
viral infection 
Abbreviations: BAL = Bronchoalveolar lavage; CTCAE = Common terminology criteria for adverse events; IV = Intravenous. 
Table 18 - Renal adverse event management  
Renal events 
CTCAE 
version 5.0 
Grade 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
Considerations 
Grade 1 
Nephritis 
Nephritis 
autoimmune 
No change in 
dose 
Consider delay 
or omit dose if 
event does not 
improve with 
symptomatic 
treatment (see 
Section 6.5.2) 
Provide symptomatic treatment. 
Monitor creatinine weekly: when it 
returns to baseline, resume routine 
creatinine monitoring per protocol. 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents. A renal 
consultation is 
recommended. 
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Renal events 
CTCAE 
version 5.0 
Grade 
Isatuximab 
Dose 
Management 
Cemiplimab 
Dose 
Management 
Actions and Guidelines 
Diagnostic 
Considerations 
Grade 2 
Renal failure 
Delay or omit 
dose until 
resolves to 
Grade ≤1 (see 
Section 6.5.2) 
Consider delay 
or omit dose (see 
Section 6.5.2) 
Systemic corticosteroids at a dose of 
1 to 2 mg/kg/day of prednisone or 
equivalent may be indicated. When 
symptoms improve to Grade 1 or less, 
corticosteroid taper should be started 
and continued for at least 1 month. 
Consider prophylactic antibiotics for 
opportunistic infections. 
Consider renal biopsy. 
If elevations persist >7 days or worse, 
treat as Grade 4. 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents. A renal 
consultation is 
recommended. 
Grade 3-4 
Renal failure 
acute 
Grade 3: delay 
or omit dose 
until resolves to 
Grade ≤1 (see 
Section 6.5.2) 
Grade 4: 
discontinue 
treatment 
Discontinue 
cemiplimab 
Renal consultation with consideration of 
ultrasound and/or biopsy as appropriate. 
Monitor creatinine daily. 
Treat with systemic corticosteroids at 
a dose of 1 to 2 mg/kg prednisone or 
equivalent once per day. 
When symptoms improve to Grade 1 or 
less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
All attempts should be 
made to rule out other 
causes such as 
obstructive uropathy, 
progression of 
disease, or injury to 
other chemotherapy 
agents. A renal 
consultation is 
recommended. 
Abbreviations: CTCAE = Common terminology criteria for adverse events; irAEs = Immune-related adverse events. 
Table 19 - Dermatologic adverse event management  
Skin events 
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Managment 
Cemiplimab 
Dosing 
Managemnt 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1, 2 
No change in 
dose 
No change in 
dose 
Symptomatic treatment should be given 
such as topical glucocorticosteroids 
(eg, betamethasone 0.1% cream or 
hydrocortisone 1%) or urea-containing 
creams in combination with oral 
antipruitics (eg, diphenhydramine HCl or 
hydroxyzine HCl) 
Treatment with oral steroids is at 
Investigator discretion for Grade 2 events. 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
infectious, or allergic 
dermatitis. 
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Skin events 
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Managment 
Cemiplimab 
Dosing 
Managemnt 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 3 
No change in 
dose 
Delay or omit 
dose until 
Grade ≤2 (see 
Section 6.5.2) 
Consider dermatology consultation and 
biopsy for confirmation of diagnosis. 
Treatment with oral steroids is 
recommended, starting with 1 mg/kg 
prednisone or equivalent once daily or 
dexamethasone 4 mg 4 times per day. 
When symptoms improve to Grade ≤1, 
steroids taper should be started and 
continue over no less than 4 weeks. 
 
Grade 4 
Delay or omit 
dose until 
Grade ≤3 (see 
Section 6.5.2) 
Discontinue 
treatment 
Dermatology consultation and 
consideration of biopsy and clinical 
dermatology photograph. Initiate with oral 
steroids with 1 mg/kg prednisone or 
equivalent. When symptoms improve to 
Grade ≤1, steroids taper should be started 
and continue over no less than 4 weeks. 
 
Abbreviations: CTCAE = Common terminology criteria for adverse events. 
Table 20 - Hepatitis adverse event management  
Hepatitis 
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Management 
Cemiplimab 
Dosing 
Management 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1, 2 
No change in 
dose 
Delay or omit dose if 
there is a treatment-
emergent concurrent 
elevation of ALT and 
bilirubin that 
corresponds to 
an upward shift of 
2 or more grades in 
both parameters (see 
Section 6.5.2) 
Monitor liver function tests more 
frequently until returned to 
baseline values 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
progressive liver 
disease, viral hepatitis, 
alternative drug 
adverse event, 
infectious causes 
and/or myositis 
Grade 3, 4 
Delay or omit 
dose until 
Grade ≤2 (see 
Section 6.5.2) 
Discontinue 
treatment if: AST or 
ALT ≥5 x ULN 
Bilirubin ≥3 x ULN 
Consider appropriate consultation 
and liver biopsy to establish 
etiology of hepatic injury, if 
necessary. 
Treat with high-dose IV 
glucocorticosteroids for 24 to 
48 hours. When symptoms 
improve to Grade ≤1, a steroid 
taper with dexamethasone 4 mg 
every 4 hours or prednisone at 1 
to 2 mg/kg should be started and 
continued over no less than 
4 weeks. 
If AST/ALT levels do not decrease 
48 hours after initiation of systemic 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
progressive liver 
disease, viral hepatitis, 
alternative drug 
adverse event, 
infectious causes 
and/or myositis 
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Hepatitis 
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Management 
Cemiplimab 
Dosing 
Management 
Action and Guidelines 
Diagnostic 
Considerations 
steroids, oral mycophenolate 
mofetil 500 mg every 12 hours 
may be given. Infliximab is not 
recommended due to its potential 
for hepatotoxicity. 
Several courses of steroids taper 
may be necessary as symptoms 
may worsen when the steroids 
dose is decreased. 
Abbreviations: ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; CTCAE = Common terminology criteria for adverse 
events; ULN = Upper limit of normal. 
Table 21 - Ophthalmology (uveitis) adverse event management  
Uveitis 
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Management 
Cemiplimab 
Dosing 
Management 
Action and Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in dose 
Discontinue 
treatment if 
symptoms persist 
despite treatment 
with topical 
immunosuppressive 
therapy 
Evaluation by 
an ophthalmologist is strongly 
recommended 
Treat with topical steroids such 
as 1% prednisolone acetate 
suspension and iridocyclitis 
All attempts should be 
made to rule out other 
causes such as 
metastatic disease, 
infection, or other 
ocular disease 
(eg, glaucoma or 
cataracts) 
Grade 2 
No change in dose 
Discontinue 
treatment if 
symptoms persist 
despite treatment 
with topical 
immunosuppressive 
therapy, and do not 
improve to Grade 1 
within the retreatment 
period or requires 
systemic treatment 
Grade ≥3 
Delay or omit dose 
until Grade ≤2 (see 
Section 6.5.2) 
Discontinue 
treatment 
Treatment with systemic 
corticosteroids such as 
prednisolone at a dose of 1 to 
2 mg/kg/day. When symptoms 
improve to Grade ≤1, steroid 
taper should be started and 
continued over no less than 
4 weeks 
Abbreviations: CTCAE = Common terminology criteria for adverse events. 
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Table 22 - Nausea and vomiting adverse event management  
Nauea and 
Vomiting  
CTCAE 
version 5.0 
Isatuximab 
Dosing 
Management 
Cemiplimab Dosing 
Management 
Action and 
Guidelines 
Diagnostic 
Considerations 
Grade 1 
No change in dose 
No change in dose 
Nausea and vomiting 
should be treated 
aggressively, and 
consideration should be 
given in subsequent 
cycles to the 
administration of 
prophylactic antiemetic 
therapy according to 
standard institution 
practice. Participants 
should be strongly 
encouraged to maintain 
liberal oral fluid intake. 
 
Grade 2 
Delay or omit dose 
until ≤Grade 1 (see 
Section 6.5.2) 
Restart treatment at 
same dose level 
Delay or omit dose until 
≤Grade 1 (see 
Section 6.5.2) 
May increase dosing 
interval by 1 week if it takes 
more than 4 weeks for 
toxicities for resolve. 
 
 
Grade 3 
Delay or omit dose 
until ≤Grade 1 (see 
Section 6.5.2) 
Restart at same dose 
level. 
Delay or omit until 
≤Grade 1 (see 
Section 6.5.2) 
May increase dosing 
interval by 1 week if it takes 
more than 4 weeks for 
toxicities for resolve. 
Discontinue if adverse 
event does not resolve 
within 12 weeks. 
 
 
Grade 4 
Discontinue treatment 
Abbreviations: CTCAE = Common terminology criteria for adverse events. 
 
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10.5 
APPENDIX 5: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 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). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-estrogen hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
Reproductive potential 
- 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy and bilateral 
oophorectomy. 
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CONTRACEPTION GUIDANCE 
Male participants 
• Male participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following during the protocol-defined time frame:  
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent. 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 23 when having penile-vaginal intercourse 
with a woman of childbearing potential who is not currently pregnant. 
• In addition, male participants must refrain from donating sperm for the duration of the 
study and for 6 months after study completion or the last dose of study intervention. 
• Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame.  
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 23. 
In addition, WOCBP must refrain from donating ova for the duration of the study and for 
6 months after study completion or the last dose of study intervention. 
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Table 23 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
Highly effective methods that are user independent 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
• 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 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. 
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. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the efficacy of the contraceptive 
method. In this case, two highly effective methods of contraception should be utilized during the intervention period and for at least [X, 
corresponding to time needed to eliminate study intervention plus 30 days for study interventions with genotoxic potential] after the last 
dose of study intervention. 
PREGNANCY TESTING: 
• WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine or serum pregnancy test. 
• Additional pregnancy testing is required during the intervention period and after the last 
dose of study intervention during 6 months of the follow-up period. 
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
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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. 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 will be reported as 
an AE or SAE. A spontaneous abortion 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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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 lesions. 
a 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). 
b 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. 
Imaging timing should follow calendar days and should not be adjusted for delays in cycle. For 
participants who discontinue for reasons other than PD, assessments should continue until the 
participant has documented PD. The first assessment may be performed earlier than 12 weeks if in 
the opinion of the Investigator the participant is clinically progressing. 
 
 
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10.7 
APPENDIX 7: MITIGATING THE ANTI-CD38 INTERFERENCE WITH SEROLOGIC 
TESTING  
 
Association Bulletin #16-02 
Date: 
January 15, 2016 
To: 
AABB Members 
From: 
 
 
 
Re: 
Mitigating the Anti-CD38 Interference with Serologic Testing 
Summary 
A new class of therapeutic agents for multiple myeloma, CD38 monoclonal antibodies, can result 
in interference with blood bank serologic tests and thereby cause delays in issuing Red Blood Cell 
(RBC) units to patients receiving these agents. To minimize these delays, hospitals should set up 
procedures to inform the transfusion service when patients start receiving these agents. 
Considerations for the transfusion service, both before and after initiation of anti-CD38 therapy, 
are detailed below. 
The AABB Clinical Transfusion Medicine Committee has developed this bulletin to provide 
background information and guidance to members regarding anti-CD38 interference with 
serologic testing. The bulletin includes recommendations for its prevention and treatment. 
Association Bulletins, which are approved for distribution by the AABB Board of Directors, may 
include announcements of standards or requirements for accreditation, recommendations on 
emerging trends or best practices, and/or pertinent information. This bulletin contains information 
and recommendations. No new standards are proposed. 
Background 
CD38 monoclonal antibodies are a new treatment for multiple myeloma 
CD38, an integral membrane protein that is highly expressed on myeloma cells, has been 
identified as an effective target antigen for monoclonal antibody therapies. In November 2015, the 
first therapeutic CD38 monoclonal antibody [daratumumab (Darzalex, Janssen Biotech, Horsham, 
PA)] was approved by the Food and Drug Administration.1 Other CD38 monoclonal antibodies 
are under development. 
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CD38 monoclonal antibodies interfere with blood bank serologic tests 
CD38 is weakly expressed on red cells. Anti-CD38 binds to CD38 on reagent RBCs, causing 
panreactivity in vitro.2, 3 Plasma samples from anti-CD38-treated patients consistently cause 
positive reactions in indirect antiglobulin tests (IATs), antibody detection (screening) tests, 
antibody identification panels, and antihuman globulin (AHG) crossmatches. Agglutination due to 
anti-CD38 may occur in all media (eg, saline, low ionic strength saline, polyethylene glycol), and 
with all IAT methods (eg, gel, tube, solid phase). Agglutination reactions caused by anti- CD38 
are usually weak (1+), but stronger reactions (up to 4+) may be seen in solid-phase testing. 
However, anti-CD38 does NOT interfere with ABO/RhD typing or with immediate-spin 
crossmatches. 
Other notes on anti-CD38 serologic interference: 
• Adsorptions using either untreated or ZZAP-treated cells fail to eliminate the interference. 
• Anti-CD38 variably interferes with direct antiglobulin tests (DATs) and antibody 
identification panel autocontrols. 
• Some rare Lu(a–b–) cells are not reactive in the presence of anti-CD38, potentially giving 
the false impression that the patient has a Lutheran-related antibody4, 5. 
• Positive IATs can be observed for up to six months after anti-CD38 is discontinued1, 3. 
• Anti-CD38 may cause a small decrease in hemoglobin in vivo (~1 g/dL), but severe 
hemolysis has not been observed among treated patients3, 6. 
Anti-CD38 interference can cause delays in issuing RBCs 
If the transfusion service is unaware that a patient has received anti-CD38, the following scenario 
may occur when the patient’s sample is tested: 
1. ABO/RhD typing: no issues. 
2. Antibody detection (screening) test: all cells positive. 
3. Antibody identification panel: all cells positive (autocontrol may be negative). 
4. DAT: positive or negative. 
5. AHG crossmatches: positive with all RBC units tested. 
6. Adsorptions: panreactivity cannot be eliminated. 
This leads to delays in issuing RBCs to the patient. In some cases, the anti-CD38 interference 
could mask the presence of a clinically significant alloantibody. 
Recommendations 
To avoid problems with transfusion, hospitals should set up procedures to inform the transfusion 
service whenever any patient is scheduled to begin taking anti-CD38. 
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BEFORE a patient begins taking anti-CD38: 
• A baseline type and screen should be performed. 
• In addition, a baseline phenotype or genotype is recommended. 
AFTER a patient begins taking anti-CD38: 
• ABO/RhD typing can be performed normally. 
• For antibody detection (screening) and identification, dithiothreitol (DTT)-treated cells can 
be used to eliminate the interference2, 7. 
- 
Because DTT treatment destroys Kell antigens, K-negative units should be provided 
unless the patient is known to be K-positive. 
- 
Antibodies against other DTT-sensitive blood group antigens (anti-k, anti-Yta, 
anti-Doa/Dob, etc) will not be detectable when the antibody screen with DTT-treated 
cells is performed; such antibodies are encountered infrequently, however. 
Crossmatch 
• For patients with a negative antibody screen using DTT-treated cells, an electronic or 
immediate-spin crossmatch with ABO/RhD-compatible, K-matched units may be 
performed. 
• For patients with known alloantibodies, phenotypically or genotypically matched RBC 
units may be provided6, 8. 
- 
As some typing antisera require the use of AHG, phenotyping should be performed 
before the patient receives anti-CD38. 
- 
Genotyping can be performed either before or after the patient receives anti-CD38. 
- 
AHG crossmatches with phenotypically or genotypically matched units will still be 
incompatible. 
- 
Some clinically significant antibodies may be missed with the use of uncrossmatched 
phenotypically or genotypically matched units, although this will occur infrequently. 
• Alternatively, an AHG crossmatch may be performed using DTT-treated donor cells. 
• If an emergency transfusion is required, uncrossmatched ABO/RhD-compatible RBCs 
may be given per local blood bank practices. 
Future/alternative approaches to mitigating the anti-CD38 interference 
It is possible to neutralize anti-CD38 in plasma and eliminate the interference using either 
recombinant soluble human CD38 or daratumumab idiotype antibody2, 3. Neither reagent is widely 
available at this time, and additional validation would be needed. In principle, soluble CD38 could 
be used to neutralize any anti-CD38, while different idiotype antibodies would be needed to 
neutralize different CD38 therapeutic antibodies. Finally, antigen-typed cord cells have been used 
for the antibody screen as an alternative to DTT-treated cells9. 
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References 
1. Darzalex package insert. Horsham, PA: Janssen Biotech, 2015. [Available at: 
http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf 
(accessed January 7, 2016).] 
2. Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. 
Resolving the daratumumab interference with blood compatibility testing. Transfusion 
2015;55(6pt2):1545-54. 
3. Oostendorp M, Lammerts van Bueren JJ, Doshi P, Khan I, Ahmadi T, Parren PW, et al. 
When blood transfusion medicine becomes complicated due to interference by monoclonal 
antibody therapy. Transfusion 2015;55(6pt2):1555-62. 
4. Velliquette RW, Shakarian G, Jhang J, et al. Daratumumab-derived anti-CD38 can be 
easily Mistaken for clinically significant antibodies to Lutheran antigens or to Knops 
antigens (abstract). Transfusion 2015;55(3S):26A. 
5. Aye T, Arndt PA, Leger RM, et al. Myeloma patients receiving daratumumab (anti-CD38) 
can appear to have an antibody with Lutheran-related specificity (abstract). Transfusion 
2015;55(3S):28A. 
6. Chari A, Satta T, Tayal A, Jagannath S, Cho HJ,  Parekh S, et al. Outcomes and 
management of red blood cell transfusions in multiple myeloma patients treated with 
daratumumab (oral and poster abstract presented Monday, December 7, 2015, 6:00 PM-
8:00 PM at 57th Annual American Society of Hematology meeting). Blood 
2015;26(Suppl):Abstract 3571. 
7. Chapuy CI, Aguad MD, Nicholson RT, et al. International validation of a dithiothreitol 
(DTT)-based method to resolve the daratumumab interference with blood compatibility 
testing (oral and poster abstract presented Monday, December 7, 2015, 6:00 PM-8:00 PM 
at 57th Annual American Society of Hematology meeting). Blood 
2015;126(Suppl):Abstract 3567. 
8. Hannon JL, Caruk B, Clarke G. Serological findings related to treatment with a human 
monoclonal antibody (daratumumab) in patients with advanced plasma cell myeloma 
(abstract). Transfusion 2014;54(2S):162A. 
9. Schmidt AE, Kirkley S, Patel N, Masel D, Bowen R, Blumberg N, et al. An alternative 
method to dithiothreitol treatment for antibody screening in patients receiving 
daratumumab (abstract). Transfusion 2015;55(3S):2292-3. 
 
 
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10.8 
APPENDIX 8: GENETICS  
Use/Analysis of DNA 
Genetic variation may impact a participant’s response to study intervention, susceptibility to, and 
severity and progression of disease. Variable response to study intervention may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; mechanism of 
action of the drug; disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting participants. 
DNA samples will be used for research related to IMP and related diseases. They may also be 
used to develop tests/assays including diagnostic tests related to IMP administration. Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome or analysis of the entire exome (as appropriate). 
DNA samples will be analyzed for immune genetic markers (such as FcγRIII polymorphism). 
Additional analyses may be conducted if it is hypothesized that this may help further understand 
the clinical data. 
DNA samples may be analyzed for additional analyses if it is hypothesized that this may help 
resolve issues with the clinical data.  
The samples may be analyzed as part of a multi-study assessment of genetic factors involved in 
the response to IMP or study interventions of this class to understand study disease or related 
conditions. 
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The Sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. 
The samples will be retained while research on study intervention or study interventions of this 
class or indication continues but no longer than 5 years or other period as per local requirements. 
10.9 
APPENDIX 9:  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). 
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10.10 APPENDIX 10: 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.  
(See: 
https://www.cibmtr.org/DATAMANAGEMENT/TRAININGREFERENCE/MANUALS/DATA
MANAGEMENT/DOCUMENTS/APPENDIX%20T_PRE-
HCT%20TREATMENT%20FOR%20LYMPHOMA.PDF) 
10.11  APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS  
10.11.1 
Amendment for France  
Section 5.1 Inclusion Criteria (I01.) 
I 01. Age: Participant must be ≥18 years of age inclusive at the time of signing the informed 
consent. 
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10.12 APPENDIX 12: ABBREVIATIONS  
 
5PS: 
5-point scale  
ABC: 
activated B cell-like 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
AITL: 
angioimmunoblastic T-cell lymphoma 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophil count 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
CD38: 
cluster of differentiation CD38 
cHL: 
classic Hodgkin's lymphoma 
CLL: 
chronic lymphocytic leukemia 
CONSORT: 
Consolidated Standards of Reporting Trials 
CR: 
complete remission 
CSR: 
clinical study report 
CT: 
computed tomography 
CTCAE: 
common terminology criteria for adverse events 
CTLA-4: 
cytotic T-lymphocyte-associated protein 4 
DCR: 
disease control rate 
DDI: 
drug-drug interaction 
DLBCL: 
diffuse large B-cell lymphoma 
DLCO: 
diffusing capacity of the lungs for carbon monoxide  
DLT: 
dose limiting toxicity 
DMC: 
Data Monitoring Committee 
DNA: 
deoxyribonucleic acid 
DoR: 
duration of response 
DRE: 
disease related event 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOI: 
end of infusion 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
FDG: 
Fluorodeoxyglucose 
FFPE: 
formalin-fixed paraffin-embedded 
FL: 
follicular lymphoma 
GCB: 
germinal center B cell-like 
HBc: 
hepatitis B core antigen 
HBsAg: 
surface antigen of the hepatitis B 
HBV: 
hepatitis B virus 
HCV: 
hepatitis C virus 
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HGLT: 
high group level term 
HIV: 
human immunodeficiency virus 
HL: 
Hodgkin’s lymphoma 
HSCT: 
hematopioetic stem cell transplantation 
IB: 
Investigator’s Brochure  
ICF: 
informed consent form 
ICH: 
International Committee of Harmonization 
Ig: 
immunoglobulin 
IHC: 
immunohistochemistry 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IR: 
infusion reaction 
irAE: 
immune-related adverse event 
LLT: 
low level term 
LVEF: 
left ventricular ejection fraction  
mAb: 
monoclonal antibodies 
MDRD: 
modified diet in renal disease formula 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MRI: 
magnetic resonance imaging 
NCI: 
National Cancer Institute 
NIMP: 
noninvestigational medicinal product 
NK: 
natural killer 
NLPHL: 
nodular lymphocyte predominant Hodgkin’s lymphoma  
NSCLC: 
non-small cell lung cancer 
ORR: 
objective response rate 
PCR: 
polymerase chain reaction 
PD: 
progressive disease 
PD-L1: 
programmed cell death-ligand 1 
PD-L2: 
programmed cell death-ligand 2 
PET: 
positron emission tomography 
PFS: 
progression-free survival  
PK: 
pharmacokinetic 
PP: 
polypropylene 
PR: 
partial response 
PT: 
preferred term/prothrombin time (depends on contex) 
PTCL: 
peripheral T-cell lymphoma  
Q2W: 
once every 2 weeks 
Q3W: 
every 3 weeks 
RNA: 
ribonucleic acid 
RNT: 
relative nominal time 
RP2D: 
Recommended Phase 2 dose 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
study committee 
SD: 
stable disease 
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SoA: 
schedule of activities 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
SUV: 
standardized uptake value 
TEAE: 
treatment-emergent adverse event 
tFL: 
transformed follicular lymphoma 
TLS: 
tumor lysis syndrome 
TSH: 
thyroid stimulating hormone 
ULN: 
upper limit of normal 
WOCBP: 
woman of child-bearing potential 
 
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.13.1 
Amended protocol 01 (19 September 2019)  
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 reason for this amendment is to include clarifications requested by the French Health 
Authority (ANSM). Other modifications or editorial changes are included to correct 
inconsistencies and improve operational feasibility.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Protocol Summary: Study 
Objectives: Primary endpoints 
Section 3: Objectives and 
endpoints 
Section 5.1: Inclusion criteria 
Section 8.1.1: FDG-PET-CT/CT 
5-point scale per the Lugano 
classification changed to “Lugano 
criteria” regarding the response 
criteria.” 
Original wording in primary objective was 
clarified and corrected because the response 
criteria based on the 2014 Lugano criteria are 
not only based on the 5-point scale resulting 
of the PET-CT assessment for FDG-avid 
lymphoma but also on CT assessment for non 
FDG-avid lymphoma.  
Protocol Summary: Data 
Monitoring Committee 
Section 10.1.5: Committees 
structure 
Clarified that data monitoring 
committee to provide recommendations 
to the Sponsor. 
For clarification 
Section 1.3 Schedule of Activities 
Time window for cycles adjusted. 
Adjusted according to cycles, as time window 
is different. 
Section 1.3 Schedule of Activities: 
Physical examination 
Screening period updated from 7 days 
to 14 days prior to first dose. 
To maintain consistency with the protocol 
body. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of Activities: 
Urinalysis 
“As clinically indicated” area extended 
to include C1D1. 
To maintain consistency with other laboratory 
testing schedules. 
Section 1.3 Schedule of Activities 
Freshly collected Tumor Biopsy for 
biomarker analyses 
Section 8.6 Pharmacodynamics 
 
Specified that on treatment biopsy on 
C2D1 to be obtained within 7 days prior 
to IMP administration on C2D1 as 
opposed to ±7 days earlier. 
In order to obtain the tumor biopsy prior to the 
start of the Cycle 2. 
Section 1.3: Schedule of Activities: 
Radiotherapy 
Added footnote to clarify “no fly zone”, 
2 Gy × 2 fractions in 2 consecutive 
days (eg, Monday and Tuesday) will be 
administered once a week every 
3 weeks for 3 times (treatment lasts for 
a total of 9 week), starting in the same 
week when isatuximab and cemiplimab 
are administered. 
The second radiotherapy schedule option was 
added in the SoA as already stated in the 
initial protocol Section 6.1.4. 
Section 1.3: Schedule of Activities: 
Urine or Serum Pregnancy Test 
Section 8.2.6.7: Pregnancy test 
Section 10.2: Clinical laboratory 
tests 
Section 10.5: Contraceptive 
guidance and collection of 
pregnancy information 
 
Amended to indicate that females of 
child-bearing potential will be required 
to be tested for pregnancy monthly for 
6 months after discontinuation of study 
treatment. 
Change due to re estimation of isatuximab 
plasma half-life 
Section 1.4.2: Intervention period: 
from Cycle 2 and beyond (Sparse 
sampling); footnote “d” 
Section 7: Discontinuation of study 
intervention and participant 
discontinuation/withdrawal  
Section 8.9: Immunogenicity 
assessments 
Clarification added about ADA 
sampling done systematically at FUP 
90 (±7) days rather than depending on 
result of last sample collected during 
last treatment. 
To specify that isatuximab ADA samples are 
systematically collected at FUP 90 (±7) days 
and to simplify monitoring of immunogenicity. 
Protocol Summary 
Section 2.3.4: Preventive 
measures to minimize risk from the 
combination 
Section 6.1.2: Non Investigational 
Medicinal Products 
Section 6.1.2.5: Montelukast 
Montelukast 10 mg orally added as 
primary prophylactic treatment. 
Montelukast 10 mg orally or equivalent was 
added as a premedication based on recent 
references (25, 26, 27) that this addition may 
decrease incidence and respiratory symptoms 
of IR. 
 
Protocol Summary 
Section 2.3.4: Preventive 
measures to minimize risk from the 
combination 
Section 6.1.2: Non Investigational 
Medicinal Products 
Section 6.1.2.5: Montelukast 
Premedication requirements were 
modified. 
Change based on data from completed and 
ongoing studies to allow patients with 
Grade ≤2 infusion reactions (IRs) to omit 
premedications at Investigators’ discretion. 
Section 2.2.2 Cemiplimab 
US FDA approval for cemiplimab added 
Updated as per the latest information 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.4: Preventive 
measures to minimize risk from the 
combination 
Deleted “mild” hypersensitivity 
reactions from the below statement “In 
the event of mild or moderate 
hypersensitivity reaction, the 
isatuximab infusion should be 
interrupted and may be subsequently 
resumed after recovery, at a slower 
infusion rate, under close monitoring 
and with supportive care as needed.” 
To maintain consistency with the protocol 
body Section 6.5.5, transient reaction; infusion 
interruption or intervention not indicated in 
mild hypersensitivity reactions.  
Section 2.3.4: Preventive 
measures to minimize risk from the 
combination 
Primary prophylactic treatment time 
changed from 15 to 30 minutes prior to 
isatuximab infusion to 30 to 60 minutes 
prior to the isatuximab infusion  
To maintain consistency with the protocol 
body for the premedication in Section 6.1.2 
Section 2.3.4: Preventive 
measures to minimize risk from the 
combination 
Section 5.2 Exclusion criteria E05 
“Inhaled or topical steroids are 
permitted, provided that they are not for 
treatment of an autoimmune disorder” 
was removed from Section 2.3.4 and 
E05. 
Specified that the exclusion of patients 
with comorbidity requiring corticosteroid 
therapy refers to systemic 
corticosteroid therapy only 
For clarification as participants with active, 
known or suspected autoimmune disorder are 
ineligible as per E07.  
Section 4.3: Justification for dose 
Re-estimation of isatuximab half-life of 
28 days is included 
Re-estimation of isatuximab half-life of 
28 days. 
Section 5.1: Inclusion criteria I01 
Section 10.11.1: Amendment for 
France 
The lower limit of age for patient 
inclusion in France will be 18 years old, 
inclusive. 
Clarification based on feedback received from 
French Health Authorities (ANSM). 
Section 5.1: Inclusion criteria I03: 
Inclusion criteria 03 modified to add 
that if the only measurable lesion is 
previously irradiated; the lesion should 
also be FDG-avid. 
FDG-avid lesions previously irradiated can be 
used as measurable lesion as the disease 
assessment is based on FDG-PET-CT and no 
impact on the assessment is expected in this 
case. 
Section 5.1: Inclusion criteria I10: 
Male and female participants to start 
using contraceptive measures 2 weeks 
before study intervention. 
Clarification based on feedback received from 
French Health Authorities (ANSM) 
Section 5.2: Exclusion criteria E13 
Specified primary mediastinal large B-
cell lymphoma to be more specific 
For clarification 
Section 5.2: Exclusion criteria E26 
Modified from “No anti-cancer therapy 
including radiotherapy or auto-HSCT 
between failure of anti-PD-1/PD-L1 
therapy and initiation of IMP” to 
“Participants with anti-cancer therapy 
including radiotherapy or auto-HSCT 
between failure of anti-PD-1/PD-L1 
therapy and initiation of IMP”. 
To make it consistent with other exclusion 
criteria and for better readability. 
Section 5.2: Exclusion criteria E28 
Exclusion criteria 28 replaced with “Not 
applicable. Removed by Protocol 
Amendment 01” 
Criteria removed. 
Section 5.2: Exclusion criteria E30 
Inadequate organ and bone marrow 
function was modified from at the 
Screening visit to prior to IMP 
administration. 
For clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.4 Concomitant therapy 
Clarified exceptions for use of systemic 
corticosteroids (including management 
of irAEs). 
Previous guidance on prohibited use of 
corticosteroids was inconsistent with 
management guidelines. 
Section 6.5.2: Dose delay and 
dose omission 
Treatment windows clarified with ±1 
day during Cycle 1, ±2 days during 
Q2W, and ±3 days for Q3W and Q4W 
cycles. 
The original wording describing the dose 
delay was confusing, therefore wordings was 
clarified to indicate that the treatment window 
is ±3 days for both the 4 week administration 
cycles (Cycle 1 to Cycle 6) and the 3 week 
administration cycles (Cycle 7 and beyond). 
Section 6.5.3: Dose modifications 
Table 3 Isatuximab and 
cemiplimab dose modification 
guidelines  
Management of Grade 4 hematological 
AEs added. 
This text was removed from original protocol 
in error and is being reinstated. 
Section 7: Discontinuation of study 
intervention and participant 
discontinuation/withdrawal 
Added following text “The cycle 
duration is 28 days from Cycle 1 to 
Cycle 6 then 21 days from Cycle 7 to 
Cycle 30”. 
For clarity 
Section 7: Discontinuation of study 
intervention and participant 
discontinuation/withdrawal 
Participants who discontinued the study 
treatment without PD are followed 
every 90 days instead of every month. 
To maintain consistency with the protocol 
body. 
Section 7: Discontinuation of study 
intervention and participant 
discontinuation/withdrawal 
Participants who are still on study 
treatment after study cut-off date: will 
continue to receive study treatment if 
they benefit, and will undergo planned 
study procedures (except PK and ADA) 
until confirmation of PD, or start with 
another anti-cancer therapy, or 
treatment period ended, whichever 
comes first, added in the body of the 
protocol according to the synopsis. 
To maintain consistency with body of the 
protocol and the synopsis. 
Section 8.1.2 Bone Marrow Biopsy 
and Aspirate 
Language added to specify that if the 
FDG-PET-CT is negative in the bone 
marrow site then biopsy/aspirate is 
performed to identify involvement as 
per the investigator’s judgment and 
based on other factors consistent with 
advanced stage or poor prognosis 
For more clarity 
Section 8.2.2 Vital Signs 
Vital signs monitoring during isatuximab 
infusion was modified 
To simplify monitoring of vital signs during the 
isatuximab infusion, and clarification when it is 
clinically indicated 
Section.8.2.6.7: Pregnancy Test 
Appendix 10.5: Contraceptive 
Guidance and Collection of 
Pregnancy information 
Clarified that pregnancy testing must 
be performed on Day 1 of each cycle 
prior to the study treatment and at the 
EOT visit. This will be applicable to all 
countries. 
Per French Health Authorities (ANSM) 
request, the current protocol is unclear to 
investigators whether the more frequent tests 
are a legal requirement in France according to 
the phrase “in countries where required by 
local regulations”. In order to meet the legal 
requirement, ANSM is requesting to indicate 
that pregnancy testing (urine or serum) must 
be performed on Day 1 of each cycle prior to 
the study treatment and at the EOT visit. This 
will be applicable to all countries. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.5: Pregnancy 
Changed pregnancy follow-up 
guidance from 6 months after the last 
administration of study treatment to no 
longer than 6 to 8 weeks following the 
estimated delivery date. 
Typographical error 
Appendix 10.4: From Table 16 to 
Table 23  
CTCAE version changed from 4.03 to 
5.0. 
Typographical error. To maintain consistency 
in the protocol body. 
Appendix 10.4: Table 18 Renal 
adverse event management 
Deleted text regarding discontinuation 
of Cemiplimab if unable to reduce 
corticosteroid dose for irAEs to 
≤10 mg. 
To avoid repetition, cemiplimab 
discontinuation is already in the column 
cemiplimab management. 
Appendix 10.4: Table 18 Renal 
adverse event management 
For patients with Grade 3-4 renal 
events, under Isatuximab Dose 
Management, “Grade 3: discontinue 
treatment” is corrected to “Grade 4: 
discontinue treatment” (as Grade 3 is 
already noted as “delay or omit dose 
until resolves to Grade ≤1”) 
Typographical error 
Appendix 10.10: definition of line of 
therapy 
Clarification was added regarding the 
definition of line of therapy.  
To clarify the definition of line of therapy, a 
reference to Center for International Blood 
and Morrow Transplant Research (CIBMRT) 
website added (cibmrt.org). 
Throughout the document 
Minor editorial, typographical error 
corrections, and document formatting 
revisions have been made throughout 
the document. 
Minor changes, therefore have not been 
summarized. 
Abbreviations: ADA = Anti-drug antibody; AEs = adverse events; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events; EOT = End of Treatment; FDG = Fluorodeoxyglucose; FUP = Follow-up; HSCT = Hematopoetic stem cell transplant; IMP = 
Investigational medicinal product; IR = Infusion reaction; PD = Progressive disease; PD-L1 = Programmed cell death-ligand 1; PET = Positron 
emission tomography; PK = Pharmacokinetics; Q2W = every 2 weeks; Q3W = every 3 weeks; Q4W = every 4 weeks; SOA = Schedule of 
Activities. 
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10.14 APPENDIX 14: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency 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 and in Section 6, Section 6.5.2, Section 7.1, 
Section 8, Section 9.3, and Section 10.1.3 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, alternative treatment outside the clinical trial should be proposed, and screening and 
administration of study intervention may be temporarily delayed.  
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data. For 
example, patient interview for medical history/prior medications could be performed by 
phone, local safety labs and some efficacy assessments could be performed off-site/at the 
participant’s home (eg, home nursing) if agreed by patient and permissible per local 
regulations. 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely, if needed (eg, ±14 days for visits). 
Contingencies implemented due to emergency will be documented.  
The impact of the 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. 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. 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). 
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11 
REFERENCES  
 
1. Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. 
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2016;17(9):1283-94. 
3. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study of the 
Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. 
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4. Topp M, Borchmann P, Wagner-Johnston N, Provencio M, Cordoba R, Papadopoulos K, et al. 
Safety and Preliminary Antitumor Activity of the Anti-PD-1 Monoclonal Antibody 
Cemiplimab (REGN2810) Alone or in Combination with REGN1979, an Anti-CD20 x Anti-
CD3 Bispecific Antibody, in Patients with B-Lymphoid Malignancies. Poster presented at the 
2017 American Society of Hematology Annual Meeting, December 9–12, Atlanta, Georgia. 
5. Herrera AF, Moskowitz AJ, Bartlett NL, Vose JM, Ramchandren R, Feldman TA, et al. 
Interim results of brentuximab vedotin in combination with nivolumab in patients with 
relapsed or refractory Hodgkin lymphoma. Blood. 2018;131(11):1183-94. 
6. Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, et al. A Phase 2 
multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. 
Blood. 2011;118(19):5119-25. 
7. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in 
Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a 
Phase Ib Study. J Clin Oncol. 2016;34(23):2698-704. 
8. Chen L, Diao L, Yang Y, Yi X, Rodriguez J, Fan Y, et al. CD38 blockade Overcomes the 
immune resistance to anti-PD-L1 therapy by boosting CD8 T cell response. Cancer Res. 2017; 
77(Suppl 13):abstract number 567. 
9. Chen L, Byers LA, Ullrich S, Wistuba II, Qin X, Gibbons DL. CD38 as a novel immune 
checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis. J Clin 
Oncol. 2017;35(Suppl 7S):abstract number 79. 
10. van de Donk NW, Janmaat ML, Mutis T, Lammerts van Bueren JJ, Ahmadi T, Sasser AK, et 
al. Monoclonal antibodies targeting CD38 in hematological malignancies and beyond. 
Immunol Rev. 2016;270(1):95-112. 
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Page 136 
11. Karakasheva TA, Waldron TJ, Eruslanov E, Kim SB, Lee JS, O’Brien S, et al. CD38-
expressing myeloid-derived suppressor cells promote tumor growth in a murine model of 
esophageal cancer. Cancer Res. 2015;75(19):4074-85. 
12. Feng X, Zhang L, Acharya C, An G, Wen K, Qiu L, et al. Targeting CD38 Suppresses 
Induction and Function of T Regulatory Cells to Mitigate Immunosuppression in Multiple 
Myeloma. Clin Cancer Res. 2017;23(15):4290-300. 
13. Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher VS, Vallée F, et al. (2014) 
SAR650984, A Novel Humanized CD38-Targeting Antibody, Demonstrates Potent Antitumor 
Activity in Models of Multiple Myeloma and Other CD38þ Hematologic Malignancies. Clin 
Cancer Res. 2014;20(17):4574-83. 
14. Gaetano RD, Gasparetto V, Padoan A, Callegari B, Candiotto L, Sanzari MC, et al. Flow 
cytometry CD4+CD26−CD38+ lymphocyte subset in the microenvironment of Hodgkin 
lymphoma-affected lymph nodes.  Ann Hematol. 2014;93(8):1319-26. 
15. Zaja F, Tabanelli V, Agostinelli C, Calleri A, Chiappella A, Varettoni M, et al. CD38, BCL-2, 
PD-1, and PD-1L expression in nodal peripheral T-cell lymphoma: Possible biomarkers for 
novel targeted therapies? Am J Hematol. 2017;92(1):E1-E2. 
16. Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. The classical Hodgkin’s 
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Pathol. 2010;221(3):248-63. 
17. Marshall NA, Christie LE, Munro LR, Culligan LR, Jonston PW, Barker RN, et al. 
Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin 
lymphoma. Blood. 2004;103(5):1755–62. 
18. Schreck S, Friebel D, Buettner M, Distel L, Grabenbauer G, Young LS, et al. Prognostic 
impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. 
Hematol Oncol. 2009;27(1):31-9. 
19. Gravelle P, Burroni B, Péricart S, Rossi C, Bezombes C, Tosolini M, et al. Mechanisms of 
PD-1/PD-L1 expression and prognostic relevance in non-Hodgkin lymphoma: a summary of 
immunohistochemical studies. Oncotarget. 2017;8(27):44960-75. 
20. Baues C, Trommer-Nestler M, Jablonska K, Bröckelmann PJ, Schlaak M, von Bergwelt-
Baildon M, et al. Short review of potential synergies of immune checkpoint inhibition and 
radiotherapy with a focus on Hodgkin lymphoma: radio-immunotherapy opens new doors.  
Immunotherapy. 2017;9(5):423-33. 
21. Weichselbaum RR, Liang H, Deng L, Fu YX. Radiotherapy and immunotherapy: a beneficial 
liaison? Nat Rev Clin Oncol. 2017;14(6):365-79. 
22. Luke JJ, Lemons JM, Karrison TG, Pitroda SP, Melotek JM, Zha Y, et al. Safety and Clinical 
Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With 
Advanced Solid Tumors. J Clin Oncol. 2018;36(16):1611-8. 
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Page 137 
23. Oskan F. The Quality of Toxicity Reporting and the Story of the Lung SBRT "No-Fly Zone".  
Int J Radiat Oncol Biol Phys. 2015;92(3):514-5. 
24. Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, et al. Higher 
response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal 
center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011;117(22):5058-
66. 
25. Chari A, Mark TM, Krishnan A, Stockerl-Goldstein K, Usmani SZ, Londhe A, et al. Use of 
Montelukast to Reduce Infusion Reactions in an Early Access Program (EAP) of 
Daratumumab in United States Patients with Relapsed or Refractory Multiple Myeloma 
[abstract]. Blood. 2016;128:2142. 
26. Nooka AK, Gleason C, Sargeant MO, Walker M, Watson M, Panjic EH, Lonial S. Managing 
Infusion Reactions to New Monoclonal Antibodies in Multiple Myeloma: Daratumumab and 
Elotuzumab. J Oncol Pract. 2018;14(7):414-22. 
27. Reece DE, Phillips MJ.  Infusion Reactions With Monoclonal Antibody Therapy in Myeloma: 
Learning From Experience.  J Oncol Pract. 2018;14(7):425-6.  
 
 
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According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1 
 
STATISTICAL ANALYSIS PLAN  
A Phase 1/2 open-label, multi-center, safety, preliminary efficacy and 
pharmacokinetic (PK) study of isatuximab (SAR650984) in combination with other 
anti-cancer therapies in participants with lymphoma 
SAR650984-ACT15320  
STATISTICIAN: 
 
Statistical Project Leader: 
  
DATE OF ISSUE: 24-Apr-2020 
 
 
Total number of pages: 
46 
 
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Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................. 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.1.1 
Phase 1 (safety run-in) ..................................................................................................................... 7 
1.1.1.1 
Starting dose and de-escalation design ........................................................................................... 7 
1.1.1.2 
Dose limiting toxicity ......................................................................................................................... 8 
1.1.1.3 
Recommended Phase 2 dose .......................................................................................................... 8 
1.1.2 
Phase 2 (efficacy signal search with a 2-stage design in each cohort) ............................................ 8 
1.2 
OBJECTIVES ................................................................................................................................... 9 
1.2.1 
Primary objectives ............................................................................................................................ 9 
1.2.2 
Secondary objectives ....................................................................................................................... 9 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 9 
1.4 
STUDY PLAN ................................................................................................................................. 10 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN...................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ..................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................ 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) .............................................. 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 13 
2.1.3.1 
Primary efficacy endpoint(s) ........................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 13 
2.1.3.3 
Tertiary/Exploratory efficacy endpoint(s) ........................................................................................ 14 
2.1.4 
Safety endpoints ............................................................................................................................. 15 
2.1.4.1 
Dose limiting toxicities (DLTs) ........................................................................................................ 15 
2.1.4.2 
Adverse events variables ............................................................................................................... 15 
2.1.4.3 
Infusion reactions ........................................................................................................................... 16 
2.1.4.4 
Deaths ............................................................................................................................................ 16 
2.1.4.5 
Laboratory safety variables ............................................................................................................ 16 
2.1.4.6 
Vital signs variables ........................................................................................................................ 18 
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2.1.4.7 
Electrocardiogram variables ........................................................................................................... 18 
2.1.4.8 
Immunogenicity variables ............................................................................................................... 18 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 20 
2.1.6 
Biomarker endpoints ...................................................................................................................... 20 
2.1.6.1 
Microsatellite instability ................................................................................................................... 20 
2.1.6.2 
PD-L1 expression singleplex IHC .................................................................................................. 21 
2.1.6.3 
Cluster of differentiation 38 (CD38) expression singleplex IHC ..................................................... 21 
2.1.6.4 
Immune cell subpopulation tumor infiltration and markers co-expression multiplex 
immunofluorescence ...................................................................................................................... 21 
2.1.7 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 21 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 21 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 22 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 22 
2.3.1 
All-treated population ..................................................................................................................... 22 
2.3.2 
DLT-evaluable population .............................................................................................................. 23 
2.3.3 
Pharmacokinetic population ........................................................................................................... 23 
2.3.4 
Biomarker Population ..................................................................................................................... 23 
2.3.5 
Immunogenicity population............................................................................................................. 23 
2.3.6 
Response evaluable population ..................................................................................................... 23 
2.4 
STATISTICAL METHODS ............................................................................................................. 23 
2.4.1 
Demographics and baseline characteristics .................................................................................. 24 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) .............................................. 24 
2.4.3 
Anticancer therapies ...................................................................................................................... 24 
2.4.4 
Extent of investigational medicinal product exposure and compliance .......................................... 24 
2.4.4.1 
Extent of investigational medicinal product exposure .................................................................... 24 
2.4.4.2 
Isatuximab exposure ...................................................................................................................... 26 
2.4.4.3 
Cemiplimab exposure .................................................................................................................... 27 
2.4.5 
Analyses of efficacy endpoints ....................................................................................................... 28 
2.4.5.1 
Analysis of primary efficacy endpoint(s) ......................................................................................... 28 
2.4.5.2 
Analyses of secondary efficacy endpoints ..................................................................................... 29 
2.4.5.3 
Analyses of exploratory efficacy endpoints .................................................................................... 29 
2.4.5.4 
Multiplicity issues ............................................................................................................................ 29 
2.4.6 
Analyses of safety data .................................................................................................................. 29 
2.4.6.1 
Analyses of DLTs (Phase 1 only) ................................................................................................... 30 
2.4.6.2 
Analyses of adverse events ........................................................................................................... 30 
2.4.6.3 
Deaths ............................................................................................................................................ 32 
2.4.6.4 
Analyses of laboratory variables .................................................................................................... 32 
2.4.6.5 
Analyses of vital sign variables ...................................................................................................... 32 
2.4.6.6 
Analyses of electrocardiogram variables ....................................................................................... 33 
2.4.6.7 
Analysis of Immunogenicity ............................................................................................................ 33 
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2.4.7 
Analyses of pharmacokinetic variables .......................................................................................... 33 
2.4.7.1 
Cycle 1 non-compartmental analysis: following the 1st administration ........................................... 34 
2.4.7.2 
Over treatment concentrations: Ctrough and Ceoi .............................................................................. 34 
2.4.7.3 
Immunogenicity impact on PK ........................................................................................................ 34 
2.4.8 
Analyses of biomarker variables .................................................................................................... 35 
2.4.9 
Analyses of quality of life/health economics variables ................................................................... 35 
2.4.10 
Further therapy after discontinuation of investigational medicinal product administration 
during the study .............................................................................................................................. 35 
2.5 
DATA HANDLING CONVENTIONS............................................................................................... 35 
2.5.1 
General conventions ...................................................................................................................... 35 
2.5.2 
Data handling conventions for secondary efficacy variables.......................................................... 36 
2.5.3 
Missing data ................................................................................................................................... 36 
2.5.4 
Windows for time points ................................................................................................................. 39 
2.5.5 
Unscheduled visits ......................................................................................................................... 39 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 40 
2.5.7 
Statistical technical issues ............................................................................................................. 40 
3 
INTERIM ANALYSIS ..................................................................................................................... 41 
4 
DATABASE LOCK ........................................................................................................................ 42 
5 
SOFTWARE DOCUMENTATION .................................................................................................. 43 
6 
REFERENCES ............................................................................................................................... 44 
7 
LIST OF APPENDICES ................................................................................................................. 45 
APPENDIX A 
GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY 
PARAMETERS............................................................................................................................... 46 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA: 
anti-drug antibodies  
ADI: 
actual dose intensity 
AEs: 
adverse events 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
ATC: 
anatomic therapeutic category 
AUC: 
area under the curve 
BOR: 
best overall response 
BUN: 
blood urea nitrogen 
CD38: 
cluster of differentiation 38 
CR: 
complete response 
DCR: 
disease control rate 
DLT: 
dose limiting toxicity 
DoR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
eastern cooperative oncology group 
eCRF: 
electronic case report form 
EOC: 
epithelial ovarian cancer 
GBM: 
glioblastoma multiforme 
HCC: 
hepatocellular carcinoma 
IAR: 
infusion associated reaction 
INR: 
international normalized ratio 
IV: 
intravenous 
LDH: 
lactate dehydrogenase 
MDRD: 
modified diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NIMP: 
non-investigational medicinal product 
PCSA: 
potentially clinically significant abnormality 
PFS: 
progression-free survival 
PFS-6: 
progression free survival rate at 6 months 
PK: 
pharmacokinetic 
PR: 
partial response 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
Q3W: 
once every 3 weeks 
QW: 
once weekly 
RBC: 
red blood cell 
RDI: 
relative dose intensity 
ROI: 
region of interest 
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RP2D: 
recommended phase 2 dose 
RR: 
response rate 
SAEs: 
serious adverse events 
SCCHN: 
squamous cell carcinoma of the head and neck 
SD: 
stable disease 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TSH: 
thyroid stimulating hormone 
TTR: 
time to response 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
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Statistical Analysis Plan  
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a Phase 1/2 open-label, non-randomized, multi-center, safety, preliminary efficacy, and 
PK study of isatuximab in combination with other anti-cancer therapies in participants with 
lymphoma. The study will be conducted in 2 phases. 
1.1.1 Phase 1 (safety run-in)  
Participants with relapsed and refractory classic Hodgkin’s lymphoma (cHL), diffuse large B cell 
lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL) will be enrolled in Phase 1. 
1.1.1.1 Starting dose and de-escalation design  
Starting dose is isatuximab given 10 mg/kg once weekly (QW) for the first cycle, once every 
two weeks (Q2W) for Cycle 2 - Cycle 6, followed by once every 3 weeks (Q3W) for Cycle 7 and 
beyond, with cemiplimab at 250 mg once every 2 weeks (Q2W) for the first six cycles then 
350 mg once every 3 weeks (Q3W) for Cycle 7 and beyond. Dose de-escalation will be performed 
if necessary as defined in Table 1 below: 
Table 1 - Dose modification for Phase 1  
 
Isatuximab 
Cemiplimab 
Dose level 
(DL) 
Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond 
1 cycle = 21 days 
Cycle 1 ~ Cycle 6 
1 cycle = 28 days 
Cycle 7 and 
beyond 
1 cycle = 21 days 
Starting dose 
10 mg/kg QW x 4 (Cycle 1) 
10 mg/kg Q2W  
(Cycle 2 - Cycle 6) 
 
10 mg/kg Q3W 
 
250 mg Q2W 
 
350 mg Q3W 
Minus -1 
(DL-1) 
5 mg/kg QW x 4 (Cycle 1) 
5 mg/kg Q2W  
(Cycle 2 - Cycle 6) 
 
5 mg/kg Q3W 
 
250 mg Q2W 
 
350 mg Q3W 
Abbreviations: DL: Dose level; QW: once weekly, Q2W: once every 2 weeks Q3W: once every 3 weeks. 
The dose limiting toxicity (DLT) observation period is 1 cycle (28 days).  
To account for DLT non-evaluability because of AEs that do not qualify as DLTs, approximately 
6 participants may be enrolled without interruption to receive the starting dose. At the starting dose, 
DLTs will be assessed among the first 3 DLT evaluable participants provided that they will have 
received at least 90% of the planned cumulative doses of the first cycle (unless they discontinue IMP(s) 
due to DLT), based on the rules listed below. The totality of the AEs collected from all treated 
participants will be taken into consideration when deciding recommended Phase 2 dose (RP2D). 
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 If 0/3 participants experiences a DLT, the starting dose will be the RP2D. 
 If 1/3 participants experiences a DLT, 3 additional participants will be enrolled at the 
starting dose level: 
- 
If a total of 1/6 participant treated at starting dose experiences a DLT, the starting dose 
will be the RP2D, 
- 
If a total of ≥2/6 participants experience a DLT, the dose will be de-escalated to dose 
level minus 1 (DL-1). 
 If ≥2/3 participants experience DLTs, dose will be de-escalated to DL-1. 
At DL-1, the same DLT observation rules will be applied for selecting a RP2D, and if ≥2/6 or 
≥2/3 participants experience DLTs, an alternative dose/schedule might be considered from a safety 
viewpoint by the Sponsor after consulting with the Investigators who have recruited participants 
for Phase 1. 
Enrollment of participants within DL and between cohorts is to be staggered by at least 3 days. 
Following the identification of the RP2D, the Phase 2 of the study will be initiated. 
1.1.1.2 Dose limiting toxicity  
Dose limiting toxicity (DLT) is defined in Section 4.1 in the protocol. 
1.1.1.3 Recommended Phase 2 dose  
The RP2D is defined as the dose selected for the Phase 2 portion. 
1.1.2 Phase 2 (efficacy signal search with a 2-stage design in each cohort)  
Phase 2 will include 4 cohorts: Cohorts A1, A2, B, and C will be initiated in parallel. 
 Cohort A1: cHL anti-PD-1/PD-L1 naïve, isatuximab and cemiplimab combination. 
 Cohort A2: cHL anti-PD-1/PD-L1 progressor, isatuximab and cemiplimab combination. 
 Cohort B: DLBCL, isatuximab and cemiplimab combination. 
 Cohort C: PTCL, isatuximab and cemiplimab combination. 
A 2-stage design will be used in each cohort. 
The participants treated at the RP2D of isatuximab and cemiplimab in combination during 
Phase 1 will be included in the efficacy analysis together with participants of the same tumor type 
in Phase 2 Stage 1. Based on the predefined number of objective responses in participants with 
cHL anti-PD-1/PD-L1 naïve, cHL anti-PD-1/PD-L1 progressor, DLBCL, or PTCL, as well as any 
other relevant data observed within a treatment cohort in Phase 2 Stage 1, the study will proceed 
with Phase 2 Stage 2. After enrollment completion of Phase 2 Stage 1, if efficacy results do not 
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warrant initiation of Stage 2, enrollment will be paused until sufficient results or analyses warrant 
initiation of Phase 2 Stage 2. In the case of inadequate efficacy for a cohort at interim analyses, the 
Sponsor will notify study sites regarding modification or termination of study 
procedures/scheduled activities for patients in that specific cohort. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
Phase 1: 
 To characterize the safety and tolerability of isatuximab in combination with cemiplimab 
in participants with relapsed and refractory classic Hodgkin’s lymphoma (cHL), diffuse 
large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), and to confirm 
the recommended Phase 2 dose (RP2D). 
Phase 2: 
 Cohort A1 (anti-PD-1/PD-L1 naïve cHL): To assess the complete remission (CR) rate of  
isatuximab in combination with cemiplimab. 
 Cohort A2 (anti-PD-1/PD-L1 progressor cHL), B (DLBCL) and C (PTCL): To assess the 
objective response rate (ORR) of isatuximab in combination with cemiplimab. 
1.2.2 Secondary objectives  
 To evaluate the safety of the RP2D of isatuximab in combination with cemiplimab.  
 To evaluate the safety of the combination of isatuximab with cemiplimab and radiotherapy 
in participants with cHL. 
 To evaluate the immunogenicity of isatuximab and cemiplimab when given in 
combination. 
 To characterize the pharmacokinetic (PK) profile of isatuximab and cemiplimab when 
given in combination. 
 To assess overall efficacy of:  
- 
isatuximab in combination with cemiplimab  
and 
- 
isatuximab in combination with cemiplimab and radiotherapy. 
1.3 
DETERMINATION OF SAMPLE SIZE  
Phase 1 
For RP2D assessment, up to between 3 (assuming 3 participants for the starting dose) and 
12 (assuming 6 participants for the starting dose plus 6 participants for DL-1) DLT evaluable 
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participants are needed. For 3 DLT evaluable participants on starting dose, approximately 
6 participants could be enrolled without interruption. The actual sample size will vary depending 
on DLTs observed and the number of dose levels explored.  
Phase 2 
Approximately 118 participants are expected to be treated (assuming all cohorts complete 
2 stages), including approximately 57 participants in Phase 2 Stage 1 and approximately 
61 participants in Phase 2 Stage 2.  
The participants who are treated with RP2D in Phase 1 will be counted as Phase 2 participants. 
The efficacy evaluation is based on Simon’s 2-stage design with 85% power at 1-sided alpha level 
of 5% for each cohort, respectively. The assumption of response rate, the required sample sizes, 
and the number of responders at each stage for each of the four cohorts are provided in Table 2: 
Table 2 - Sample size calculation for Phase 2  
Indication 
H0 
H1 
Sample size 
Number (%) of 
responses to reject H0 
Stage 1 
Final 
Stage 1 
Final 
A1 (cHL anti-PD-1/PD-L1 naive) 
A2 (cHL anti-PD-1/PD-L1 progressor) 
B (DLCBL anti-PD-1/PD-L1 naive) 
C (PTCL anti-PD-1/PD-L1 naive) 
20% 
20% 
35% 
25% 
40% 
45% 
60% 
50% 
17 
12 
18 
10 
37 
25 
29 
27 
≥4 CR 
≥3 
≥8 
≥3 
≥12 CR 
≥9 
≥15 
≥11 
Abbreviations: H0=null hypothesis; H1=alternative hypothesis; cHL=classic Hodgkin lymphoma; DLBCL=diffuse large B-cell lymphoma; 
PTCL=peripheral T-cell lymphoma. 
Note: Based on the number of complete or objective responses and the totality of data observed within a treatment cohort in Phase 2 Stage 1, 
the Sponsor may decide to advance such a treatment cohort to Phase 2 Stage 2 after consulting with the Investigators. 
1.4 
STUDY PLAN  
The complete study plan is presented in Section 1.2 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Not applicable. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
Patients treated at the RP2D in Phase 1 will be included in the analysis with patients of the same 
tumor type in Phase 2. If the RP2D is the starting dose, all data from the patients in Phase 1 will 
be summarized together with the data from the patients of the same tumor type in Phase 2 except 
for the DLT analysis.  
Data from cHL anti-PD-1/PD-L1 naive, cHL anti-PD-1/PD-L1 progressor, DLBCL, and PTCL 
cohorts (Cohorts A1, A2, B, and C) in Phase 2 will be analyzed and reported separately by cohort.  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last assessment for this parameter before first administration 
of study treatments unless otherwise noted. 
All baseline safety and efficacy parameters (apart from those listed below) will be presented along 
with summary statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.6). 
Demographic characteristics 
Demographic variables include race (American Indian or Alaska Native, Asian, Black or African 
American, Native Hawaiian or Other Pacific Islander, White, Not reported, Unknown), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), age in years, weight (kg), 
height (cm), and eastern cooperative oncology group (ECOG) performance status.  
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor under study.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) in effect at Sanofi at the time of database lock. 
Disease characteristics at diagnosis 
The following disease characteristics at initial diagnosis will be summarized: 
 Time from initial diagnosis to first study treatment administration (in years). 
 Histology (diagnosis as collected in electronic case report form [eCRF]). 
 Histopathology type (as collected in eCRF). 
 Stage of the disease (as collected in eCRF). 
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Disease characteristics at study entry  
The following disease characteristics at study entry will be described: 
 Patient with FDG-avid histology. 
 Ann Arbor Staging. 
 Designation applicable to the stage. 
 International Prognostic score. 
 FDG bone marrow uptake. 
Prior anticancer therapies 
Prior anti-cancer treatments are collected by regimen in the eCRF. The following variables will be 
summarized for each cohort: 
 Number of prior regimens (by category). 
 Prior radiation therapy: number (%) of patients with any prior radiation therapy by curative 
or palliative intent.  
 Prior surgery related to disease: number (%) of patients with any prior surgery by type of 
procedure (Preferred Term).  
 Time from completion of last regimen of treatment to first study treatment (months) 
 Best overall response to last regimen 
 Reason for discontinuation of last regimen 
 Duration of last regimen (months) 
 Prior transplant (Yes/No) 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications (other than anticancer therapies)  
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD), 
using the version currently in effect at Sanofi at the time of database lock. 
 Prior medications are those the patient used prior to first study treatment administration. 
Prior medications can be discontinued before first dosing or can be ongoing during 
treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to the 
study treatment from first administration to the last administration +30 days. A given 
medication can be classified both as a prior medication and as a concomitant medication.  
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Infusion reaction (IR) medications 
As defined in Section 6.1 of the study protocol, all participants will receive premedications to 
prevent or reduce incidence or severity of infusion reactions (IRs), 30 to 60 minutes prior to 
isatuximab infusion (no longer than 60 minutes). For participants who do not experience an IR 
during the first 4 administrations of isatuximab, subsequent premedication is optional  at the 
Investigator’s discretion. Premedications are defined in the protocol as non-investigational 
medicinal product(s). Premedications are reported on a specific eCRF page. 
Any technical details related to computation, dates, imputation for missing dates are described 
in Section 2.5. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint(s)  
The primary efficacy endpoint for the Phase 2 part of the study is CR rate for cHL anti-PD-1/PD-L1 
naïve patients, or ORR for cHL anti-PD-1/PD-L1 progressor, DLBCL, and PTCL patients.  
For cHL anti-PD-1/PD-L1 naïve patients, the CR rate is defined as the proportion of patients with 
complete remission as best overall response (BOR), assessed by investigators per Lugano response 
criteria 2014(1), relative to the total number of patients in the all treated  population. For cHL anti-
PD-1/PD-L1 progressor, DLBCL, and PTCL patients, the ORR is defined as the proportion of 
patients with CR or PR as BOR, assessed by investigators per Lugano response criteria 2014, 
relative to the total number of patients in the analysis population. 
2.1.3.2 Secondary efficacy endpoint(s)  
The secondary efficacy endpoints are: 
 Tumor burden change: Tumor burden change is defined as the best percent-change from 
baseline in a sum of product of lesion diameters (longest for non-nodal lesion, short axis 
for nodal lesions) for all target lesions. 
 Area under the curve (AUC) of percent-change from baseline in tumor burden is defined as 
the area under the percent-change from baseline versus time curve calculated using the 
trapezoidal method from the date of the first post-baseline assessment to the date of the 
last assessment. 
 The time-adjusted AUC of percent-change from baseline in tumor burden is defined as 
AUC of percent-change from baseline in tumor burden divided by the duration of the 
assessment. 
 Disease control rate (DCR): DCR is defined as the sum of the complete response (CR), 
partial response (PR) and stable disease (SD) rates. CR, PR, and SD are assessed by 
Investigator per Lugano response criteria 2014. 
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 Duration of response (DoR): DoR is the date of first response (CR for cohort A1, PR or 
CR whichever is first for cohort A2, B, and C) to the first date that recurrent or 
radiologically progressive disease progression is objectively documented, or the date of 
death, whichever occurs first. First disease progression refers to radiographic disease 
progression. The Lugano response criteria 2014 will be followed for assessment of 
radiographic disease progression. In the absence of disease progression or death before the 
analysis cut-off date or the date of initiation of a further anticancer treatment, the DoR will 
be censored at the date of the last valid response assessment not showing disease 
progression performed prior to initiation of a further anticancer treatment or the analysis 
cut-off date, whichever is earlier. DoR will not be calculated for patients who do not 
achieve a response. 
Progression-free survival (PFS): PFS is defined as the time from first study treatment 
administration to the date of first documented radiographic progression per Lugano 
criteria, or the date of death from any cause, whichever occurs first.  
For patients who did not experience documented radiographic progression or death before 
the analysis cut-off date or the date of initiation of new anticancer treatment, PFS will be 
censored at the date of the last valid disease assessment not showing radiographic 
progression performed prior to initiation of a further anticancer treatment or the analysis 
cut-off date, whichever comes first. In addition, patient without PFS event (death or 
documented radiographic progression) and without any valid post-baseline disease 
assessments will be censored at the date of first treatment (Day 1).  
 For cohort A1: ORR, defined as percent of number of patients achieving BOR of CR or 
PR, relative to the total number of patients in analysis population, during isatuximab 
+ cemiplimab ± radiotherapy periods; CR rate, defined as percent of number of patients 
achieving BOR of CR, relative to the total number of patients in analysis population, 
during isatuximab + cemiplimab + radiotherapy period. 
For cohort A2: ORR, defined as percent of number of patients achieving BOR of CR or 
PR, relative to the total number of patients in analysis population, during isatuximab 
+ cemiplimab + radiotherapy periods; CR rate, defined as percent of number of patients 
achieving BOR of CR, relative to the total number of patients in analysis population, 
during isatuximab + cemiplimab ± radiotherapy periods. 
2.1.3.3 Tertiary/Exploratory efficacy endpoint(s)  
The following tertiary/exploratory efficacy endpoints will be summarized: 
 Overall survival (OS) for all treated participants: OS is defined as the time from first study 
treatment administration to death from any cause. Patients without death prior to the 
analysis cut-off date will be censored at the last date the patient was known to be alive or 
the cut-off date, whichever comes first. 
 Time to response (TTR) for all treated participants: TTR is defined as the time from first 
study treatment administration to the first response (PR or CR whichever is first) per 
Lugano response criteria 2014. When performing descriptive statistics, the patients who 
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responded will be used as the analysis population; when doing the KM analysis, the all 
treated population will be used, for non-responders, the censoring rule is that, for patients 
who had a PFS event (PD or death), censored at the maximum follow-up time; Otherwise, 
censored at the date of last adequate tumor assessment. 
 Time to CR (TTCR) for all treated participants in Cohort A1 and A2. 
 OS, TTR, and TTCR during isatuximab + cemiplimab period and for participants who 
receive isatuximab + cemiplimab + radiotherapy. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, vital signs, weight, electrocardiogram (ECG), and 
Eastern Cooperative Oncology Group (ECOG) performance status. 
Observation period  
The observation period starts from the time when the patient gives informed consent and is 
divided into 3 periods: 
 The pre-treatment period is defined as the time informed consent is signed until the first 
dose of study treatments administration. 
 The treatment-emergent adverse event (TEAE) period is defined as the time from the 
first dose of study treatments up to 30 days after last dose of study treatments. 
 The post-treatment period is defined as the time starting from 31 days after the last dose 
of study treatments to the end of the study (as defined in the protocol). 
2.1.4.1 Dose limiting toxicities (DLTs)  
For the Phase 1 part dose limiting toxicities will be listed by patient using the DLT evaluable 
population. 
2.1.4.2 Adverse events variables  
AEs (including serious adverse events [SAEs] and AEs of special interest [AESIs]) will be 
collected from the time of signed informed consent until the end of study. 
Adverse event observation period 
 Pre-treatment AEs are defined as any adverse event reported during the pre-treatment 
period. 
 TEAEs are adverse events that developed or worsened or became serious during the 
TEAE period. 
 Post-treatment AEs are adverse events that developed or worsened or became serious 
during the post-treatment period. 
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All AEs (including SAEs and AESIs) will be graded according to NCI-CTCAE v5.0 and coded to 
a lower-level term, preferred term (PT), high-level term, high-level group term and associated 
primary system organ class (SOC) using the version of MedDRA currently in effect at Sanofi at 
the time of database lock. 
Adverse events of special interest 
Specific analyses will be performed for the following AEs: 
 DLTs. 
 Grade ≥2 acute infusion reactions.  
 Grade ≥3 immune-related TEAEs. 
 Immune-related TEAEs of any grade in a participant previously treated with a PI3K 
inhibitor. 
 Pregnancy of a female patient entered in a study as well as pregnancy occurring in a 
female partner of a male patient entered in a study with IMP/non-investigational medicinal 
product (NIMP). 
 Symptomatic overdose (serious or non-serious) with isatuximab/NIMP. 
2.1.4.3 Infusion reactions  
Infusion reactions (IRs) typically occur within 24 hours from the start of each 
isatuximab/cemiplimab infusion. 
Whenever possible, a diagnosis of the IR will be reported by the investigator in a specific AE 
page. In addition, symptoms of the IRs will be reported on a separate eCRF form. 
IRs will be analyzed based on the investigator reported term collected in the specific AE pages. 
2.1.4.4 Deaths  
The deaths will be summarized as follows: 
 Deaths in TEAE period: includes all deaths occurring from the first IMP up to the end of 
treatment +30 days. 
 Deaths in post-treatment period: includes all deaths occurring after the end of TEAE 
period up to study closure. 
2.1.4.5 Laboratory safety variables  
All protocol-required laboratory assessments, as defined in Section 10.2 of the protocol, will be 
performed and to the Schedule of Activities for the timing and frequency. 
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The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. Remaining 
laboratory tests are reported in eCRF pages for Hematology and Biochemistry. 
All laboratory tests with values considered clinically significantly abnormal during participation in 
the study or after the last dose of study intervention should be repeated until the values return to 
normal or baseline or are no longer considered clinically significant by the Investigator or Medical 
Monitor. If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified.  
Clinical laboratory data consists of blood and urine analysis including hematology, biochemistry, 
and urinalysis. Clinical laboratory values will be converted into standard international units that 
will be used in all listings and tables. 
Parameters measured on the day of the first study treatment infusion will be considered as part of 
the baseline measurements.. 
For laboratory safety variables, the treatment period is defined as the time from the first dose of 
study treatment (irrespective of treatment) administration to the last dose of study treatments 
+30 days. 
Blood and urine samples for clinical laboratories parameters will be taken as defined in the study 
flow charts and as clinically indicated. The laboratory parameters will be classified as follows:   
 Hematology  
- 
Hemoglobin and coagulation: hemoglobin, hematocrit, red blood cell (RBC) count, 
platelet counts, prothrombin time or international normalized ratio (INR) and activated 
partial thromboplastin time (PTT). 
- 
White blood cells (WBCs): leukocytes, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils. 
 Biochemistry 
- 
Metabolism: fasting glucose, total protein, 
- 
Electrolytes: sodium, potassium, chloride, calcium, albumin, magnesium, phosphate, 
bicarbonate/carbon dioxide, 
- 
Renal function: uric acid, serum creatinine, estimated creatinine clearance by 
modified diet in renal disease (MDRD) formula, urea or blood urea nitrogen (BUN), 
- 
Liver parameters: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total and direct bilirubin, lactate dehydrogenase (LDH). 
- 
Hormonal: thyroid stimulating hormone (TSH) and free T4. 
 Urinalysis  
- 
Semi-quantitative urinalysis: RBC, protein, glucose, pH, leukocytes. 
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2.1.4.6 Vital signs variables  
Vital signs include: weight, temperature, pulse rate, systolic and diastolic blood pressure, and 
respiratory rate.  
Thus, parameters measured pre-infusion on the day of the first study treatment infusion will be 
considered as part of the baseline measurements.  
For a given parameter, a patient (respectively a cycle) will be considered as evaluable if at least 
one measure of this parameter is available during the on-treatment period. 
2.1.4.7 Electrocardiogram variables  
12-lead ECG assessments will be described as normal or abnormal. 
2.1.4.8 Immunogenicity variables  
Anti-drug antibodies (ADA) against isatuximab and cemiplimab will be collected according to the 
pharmacokinetics/pharmacodynamics (PK/PD) flowcharts in Section 1.4 of the protocol.  
ADA attributes 
Pre-existing ADA is defined as ADA reactive with the biotherapeutic present in subjects before 
treatment (or before initiation of the clinical study). 
Treatment boosted ADA is defined as pre-existing ADAs that were boosted to a higher level 
following administration of biotherapeutic (ie, any time after the initial drug administration) the 
ADA titer is significantly higher than the baseline titer. A low serial dilution schema (2-fold or 
3-fold) should be applied during titration. A difference in titer values of two titer steps between 
treatment or follow-up sample and its baseline sample is considered significant. For examples, at 
least a 4-fold increase in titers for 2-fold serial dilution schema (or 9-fold increase in titers for 
3-fold serial dilution schema). If no titer could be determined for a positive sample, the titer will 
be reported as the minimal required dilution of the assay. 
Treatment-induced ADA is defined as ADAs developed de novo (seroconversion) following 
administration of the biotherapeutic (ie, formation of ADAs any time after the initial drug 
administration in a subject without pre-existing ADAs). If the baseline ADA sample is missing or 
non-reportable and at least one reportable ADA sample is available during the treatment 
(including follow-up period) the baseline sample will be considered as “negative” for data 
analysis. This is considered being a conservative approach for ADA assessment. 
Subject status 
Among evaluable population for immunogenicity (described in Section 2.3.5), following patient 
status will be defined: 
 ADA-positive subject: A subject with at least one treatment induced or treatment boosted 
ADA-positive sample at any time during the treatment or follow-up observation period. 
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 ADA-negative subject: Subject without any treatment induced or treatment boosted 
ADA-positive sample during the treatment or follow-up observation period. 
 ADA-inconclusive subject: A subject who cannot irrefutably be classified as 
ADA negative (eg, all post baseline samples inconclusive). 
Overview of the ADA response 
Two main categories can be reported for the epidemiology of an ADA immune response: ADA 
prevalence and ADA incidence: 
 ADA prevalence defines the proportion of all subjects tested positive for ADAs (including 
preexisting antibodies, treatment boosted ADAs and treatment induced ADAs) at any point 
in time. 
 In contrast the term ADA incidence only defines the proportion of subjects found to either 
have seroconverted (treatment induced ADAs) or boosted their pre-existing ADA response 
during the study. Only evaluable subjects (described in Section 2.3.5) are considered for 
computing ADA incidence. 
Kinetics of the immune response 
 Onset of ADA: refers to the time period between the initial drug administration and the 
first instance of treatment induced ADAs. The use of real-elapsed days should be used for 
the calculations. The “median time to ADA development” and the quartiles Q1 and Q3 
should be reported. 
 Duration of ADA: ADA duration will be calculated as the date of last treatment induced ADA 
sample minus date of first treatment induced or treatment boosted ADA sample +1; ADA 
duration will be calculated only for patients with at least two ADA positive samples. Median 
duration of an induced ADA response and the quartiles Q1 and Q3 should be reported. 
 Transient ADA response is defined by: 
- 
Treatment induced ADA detected only at one sampling time point during the treatment 
or follow-up observation period  (excluding the last sampling time point), OR 
- 
Treatment induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the patient’s last sampling time point is ADA negative. 
 Persistent ADA response is defined by: 
- 
Treatment induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples are separated by at least 16 weeks (irrespective of any negative samples in 
between).  
 Indeterminate ADA is defined by: 
- 
Treatment induced ADA detected only at the last sampling time point, OR 
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- 
The last two samples being ADA-positive and separated by a period of less than 16 weeks. 
Treatment-boosted ADAs are excluded from the analysis of ADA kinetics. 
2.1.5 Pharmacokinetic variables  
PK analysis will be done separately for isatuximab and cemiplimab.  
The PK sampling times for isatuximab and cemiplimab were provided in the PK/PD flowchart in 
Section 1.4 of the protocol. 
The following PK parameters (listed in Table 3) will be calculated with pharmacokinetic data 
management system (PKDMS) software (Pharsight) V3.0, using non-compartmental analysis 
(NCA) from isatuximab and cemiplimab concentrations after the first administration on Cycle 1.  
The parameters will include, but may not be limited to the following: 
Table 3 - List of pharmacokinetic parameters and definitions  
Parameters 
Analyte 
Definition 
 
cemiplimab 
Isatuximab 
 
Ceoi 
X 
X 
Concentration observed at the end of intravenous (IV) infusion 
Cmax 
X 
X 
Maximum concentration observed 
tmax 
X 
X 
Time to reach Cmax 
Clast  
X 
X 
Last concentration observed above the lower limit of 
quantification 
tlast 
X 
X 
Time of Clast 
AUC0-14d 
X 
 
Area under the concentration versus time curve calculated 
using the trapezoidal method over the dosing interval (14 days)  
AUC0-6d 
 
X 
Area under the concentration versus time curve calculated 
using the trapezoidal method over the dosing interval (6 days)  
 
For isatuximab and cemiplimab: Ctrough defined as sample collected just before treatment 
administration during repeated dosing and Ceoi will be measured over the study period.  
In addition, population PK approaches may be used for both compounds. If done, the data 
generated will be reported in a standalone report(s). 
2.1.6 Biomarker endpoints  
2.1.6.1 Microsatellite instability  
Microsatellite instability will be analyzed on tumor samples collected at screening or baseline: 
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 
Results will be of the form of MSI-H (ie, high microsatellite instability) or no-MSI-H 
(ie, low microsatellite instability or microsatellite stable). 
2.1.6.2 PD-L1 expression singleplex IHC  
PD-L1 expression on tumor and immune cells will be assessed using tumor tissue (freshly 
collected tumor biopsy or archival tissue) biopsy at Screening/Baseline and (unless clinically 
unfeasible) at C2D1. 
2.1.6.3 Cluster of differentiation 38 (CD38) expression singleplex IHC  
CD38 expression on tumor and immune cells will be assessed using tumor tissue (freshly 
collected tumor biopsy or archival tissue) biopsy at Screening/Baseline and (unless clinically 
unfeasible) at C2D1. 
2.1.6.4 Immune cell subpopulation tumor infiltration and markers co-expression 
multiplex immunofluorescence  
Immune cell subpopulation tumor infiltration and markers co-expression on different cell 
sub-populations will be assessed on tumor tissue (freshly collected tumor biopsy or archival tissue) 
biopsy at Screening/Baseline and (unless clinically unfeasible) at C2D1. Cell sub-populations will 
be determined by multiplex Immunofluorescence based on the expression of 12 different cell 
markers. The results will be provided per region of interest (ROI) and the number of cell 
sub-populations will be provided for 3 regions (total, within tumor, outside tumor). 
Per cell sub-population, an average of the results provided per ROI will be calculated for the 
totality of tumor tissue. 
2.1.7 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
Further therapies after discontinuation of study treatment will be collected on a specific eCRF 
page. The following information will be collected: drug/medication (brand or generic name), start 
date and end date (if available)/ongoing (otherwise). 
2.2 
DISPOSITION OF PATIENTS  
Patient disposition will be summarized by cohort based on the analysis population defined 
in Section 2.3.  
Screened patients are defined as any patients who signed the study informed consent. 
Enrolled patients are screened patients who are planned to receive the study treatment, ie, for 
whom the investigator ticked “Yes” to the question “Will the patient continue into the study?” at 
the end of the screening period.  
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For patient study status, the total number of patients for each of the following categories will be 
presented in the clinical study report using a flow-chart diagram or a summary table: 
 Screened patients. 
 Enrolled patients. 
 Enrolled and not treated patients. 
 Enrolled and treated patients. 
 Patients still on treatment. 
 Patients completed treatment. 
 Patients who discontinued the study treatments period and reasons for permanent 
discontinuation. 
The number and percentage of patients in analysis population (defined in Section 2.3) will be 
provided in a summary table. 
A summary of the reasons for definitive and premature treatment discontinuation for either 
treatment will be provided.  Definitive treatment discontinuation is defined as the discontinuation 
of all the study treatments. Premature treatment discontinuation is defined as the discontinuation 
of one of the study treatments but the other one continued. Listing of the reasons for treatment 
discontinuation will be provided. 
The number (%) of patients treated by country and center will be summarized using the all-treated 
population (defined in Section 2.3). 
All critical or major deviations potentially impacting efficacy and safety analyses will be 
summarized by cohort separately.  Critical or major protocol deviations will be listed. 
2.2.1 Randomization and drug dispensing irregularities  
This is an open-label, non-randomized study; therefore, randomization and dispensing 
irregularities are not applicable.  
2.3 
ANALYSIS POPULATIONS  
2.3.1 All-treated population  
For both Phase 1 and Phase 2 parts of the study, the all-treated population will include all patients 
who signed the study informed consent and received at least 1 dose (even incomplete) of the study 
treatment, either isatuximab or cemiplimab. 
This population is the primary population for the analyses of efficacy and safety parameters except 
for DLT evaluation. All analyses using this population will be based on the dose level actually 
received in the first cycle. 
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2.3.2 DLT-evaluable population  
The DLT evaluable population is defined as patients in the Phase 1 part receiving the planned 
doses of isatuximab and cemiplimab during Cycle 1, and who completed the DLT observation 
period after the first IMP administration as per Section 4.1 from protocol, unless they discontinue 
the study treatment(s) due to DLT. The dose recommended for Phase 2 will be determined on the 
DLT evaluable population. 
2.3.3 Pharmacokinetic population  
The PK population will be defined independently for isatuximab and cemiplimab, and include 
patients from the all treated population who received at least one dose of the drug even if 
incomplete with at least one reportable concentration after the study drug administration.  
2.3.4 Biomarker Population  
The biomarker population will include all treated patients who submitted at least one baseline 
biomarker sample.       
2.3.5 Immunogenicity population  
The immunogenicity population will be defined independently for isatuximab and cemiplimab, 
and include subjects from the all treated population who received at least one dose of the drug 
even if incomplete with at least one sample, taken post-baseline after drug administration during 
the treatment or follow-up observation period, with a reportable result (positive, negative or 
inconclusive).  
2.3.6 Response evaluable population  
The response evaluable population will include all patients in the all-treated population who 
fulfilled all inclusion and exclusion criteria without any major or critical deviations with an 
evaluable baseline assessment and at least one evaluable post-baseline disease assessment during 
the treatment period. 
2.4 
STATISTICAL METHODS  
Continuous data will be summarized using number of available data, mean, standard deviation, 
median, minimum and maximum for each dose level (if applicable). Categorical and ordinal data 
will be summarized using number and percentage of patients. 
Data listings will be provided separately by cohort and sorted by patient number, unless otherwise 
specified. 
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2.4.1 Demographics and baseline characteristics  
Demographics and baseline characteristics will be summarized on the all-treated population.  
Parameters described in Section 2.1.1 will be summarized using descriptive statistics. 
The medical and surgical history will be summarized according to the SOC and PT (SOC will be 
sorted according to the internationally agreed order and PT by overall decreasing frequency).  
Disease characteristics at diagnosis and at study entry will be described. 
2.4.2 Prior or concomitant medications (other than anticancer therapies)  
The prior, concomitant and post-treatment medications will be presented for the all-treated 
population. The anti-cancer therapy will be presented separately.  
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomic therapeutic category (ATC) class and the first 3 digits of the ATC class 
(therapeutic category).  All ATC codes corresponding to a medication will be summarized, and the 
patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore, the patients may be counted several times for the same medication.  
The tables for medications (prior, concomitant and post-treatment) will be sorted by decreasing 
frequency of ATC followed by all other therapeutic classes based on the overall incidence.  In case 
of equal frequency regarding ATCs, alphabetical order will be used. 
IR medications 
Number (%) of patients with IR medications as defined in Section 2.1.2 will be provided. 
2.4.3 Anticancer therapies  
Prior anti-cancer treatments will be summarized for the all-treated population. Number (%) of 
patients with the anti-cancer treatments described in Section 2.1.1 will be summarized.  
2.4.4 Extent of investigational medicinal product exposure and compliance  
The extent of study treatment exposure will be assessed and summarized on the all-treated 
population. 
2.4.4.1 Extent of investigational medicinal product exposure  
The overall extent of exposure will be assessed as: 
 Overall number of cycles started, defined as maximum number of cycles started on 
isatuximab or cemiplimab. 
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 Duration of overall exposure (weeks): defined as (last day of last cycle - first day of 
first cycle)/7. The first day of first cycle is defined as the date of the first dose of study 
treatments. The last day of last cycle is defined as the later date among the following: 
- 
Date of last dose of isatuximab +7 days if last cycle is QW cycle, or date of last dose of 
isatuximab +14 days if last cycle is Q2W cycle, or date of last dose of 
isatuximab +21 days if last cycle is Q3W cycle, 
- 
Date of last dose of cemiplimab +14 days if last cycle is Q2W cycle, or date of last 
dose of cemiplimab +21 days if last cycle is Q3W cycle. 
Total number of cycles started, number of cycles started by patient as a continuous variable and by 
category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), duration of 
overall exposure will be summarized using descriptive statistics. 
To describe overall dose modification, the cycle delay will be summarized. Within a cycle, the 
treatment windows are: 
 for the weekly administrations during Cycle 1: ±1 day. A dose is deemed to have been 
delayed if the treatment is ≥2 days beyond the theoretical day of treatment for weekly dose. 
 For the Q2W administrations (D15): ±2 days from Cycle 2 to Cycle 6. A dose is deemed to 
have been delayed if the treatment is ≥3 days beyond the theoretical day of treatment. 
 For the 4-week cycle D1 (from Cycle 2 to Cycle 6) and the 3-week cycle D1 (from Cycle 7 
to Cycle 30):  ±3 days. A dose is deemed to have been delayed if the treatment is ≥4 days 
beyond the theoretical day of treatment.  
The cycle start date is defined by the earlier date of isatuximab or cemiplimab administration 
within a cycle. Cycle delay is not defined for the first cycle. 
Cycle delay will be summarized at both the patient and cycle levels as follows: 
 Patient level: 
- 
Number of patients treated, 
- 
Number (%) of treated patients with at least 1 cycle delayed,  
- 
Number (%) of treated patients with a cycle delayed between 4 and 7 days, 
- 
Number (%) of treated patients with a cycle delayed between 8 and 14 days, 
- 
Number (%) of treated patients with a cycle delayed more than 14 days. 
 Cycle level: 
- 
Number of cycles started, 
- 
Number (%) of cycles delayed, 
- 
Number (%) of cycles delayed between 4 and 7 days, 
- 
Number (%) of cycles delayed between 8 and 14 days, 
- 
Number (%) of cycles delayed more than 14 days. 
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2.4.4.2 Isatuximab exposure  
The isatuximab exposure will be summarized as follows: 
 Total number of cycles started. 
 Number of cycles started by patient as a continuous variable and by category. 
 Number of infusions. 
 Duration of isatuximab exposure (weeks) is defined as: 
- 
[date of last dose of isatuximab + 7 days - first dose of isatuximab] / 7 if last cycle is 
QW cycle or [date of last dose of isatuximab + 14 days - first dose of isatuximab] / 7 if 
last cycle is Q2W cycle, or [date of last dose of isatuximab + 21 days - first dose of 
isatuximab] / 7 if last cycle is Q3W cycle, 
 Actual dose (mg/kg): is defined as the actual dose (mg) administered divided by the body 
weight at the time. 
 Cumulative dose (mg/kg): the cumulative dose is the sum of all actual doses (mg/kg) of 
isatuximab given from the first to the last administration. 
 Actual dose intensity (ADI, mg/kg/week): is defined as the cumulative dose (mg/kg) 
divided by the duration of isatuximab exposure (weeks).  
 Relative dose intensity (RDI, %): 
k)
(mg/kg/wee
Intensity 
 
Dose
 
Planned
 
k)
(mg/kg/wee
 
ADI
100
. 
Planned dose intensity (mg/kg/week) corresponds to the planned dose (mg/kg) multiplied 
by the theoretical total number of doses during the started cycles (3 for QW cycle and 1 for 
Q3W cycle) and divided by the theoretical cycle duration (weeks), ie, 3 weeks per cycle 
started. 
The total number of cycles started, number of cycles started by patients as a continuous variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), 
duration of isatuximab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
The following variables will be derived to describe dose delay and modification: 
 Dose delay within Cycle as described in Section 2.4.4.1. 
 Infusion interruption: an infusion is considered to be interrupted (as collected on eCRF) if 
the isatuximab administration is stopped during an infusion before it is completed 
regardless of whether it is further restarted or not. 
 Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are dose(s) administered afterwards.  
Dose delay and modification will be summarized at the patient and infusion levels as follows: 
 Patient level: 
- 
Number (%) of patients with at least 1 dose delay within cycle, 
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- 
Number (%) of patients with at least 1 dose omission, 
- 
Number (%) of patients with at least 1 infusion interrupted, 
- 
Number (%) of patients with at least 1 infusion interrupted and re-started, 
- 
Number (%) of patients with at least 1 infusion interrupted and not re-started. 
 Infusion level: 
- 
Number of isatuximab infusions, 
- 
Number (%) of infusions interrupted, 
- 
Number (%) of infusions interrupted and re-started, 
- 
Number (%) of infusions interrupted and not re-started, 
- 
Number (%) of infusions interrupted more than once, 
- 
Number (%) of infusions interrupted at 1st infusion, 2nd infusion, subsequent infusions, 
- 
Time from infusion start to first interruption in minutes summarized as a continuous 
variable and by category (<5 minutes, 5-10 minutes, etc). 
2.4.4.3 Cemiplimab exposure  
The cemiplimab exposure will be summarized as follows: 
 Total number of cycles started. 
 Number of cycles started by patient as a continuous variable and by category. 
 Duration of cemiplimab exposure (weeks) is defined as [Date of last dose of cemiplimab 
+ 14 days - first dose of cemiplimab] / 7 if last cycle is Q2W cycle, or [date of last dose of 
cemiplimab + 21 days - first dose of isatuximab] / 7 if last cycle is Q3W cycle. 
 Actual dose (mg): is defined as actual dose administered. 
 Cumulative dose (mg): the cumulative dose is the sum of all actual cemiplimab doses. 
 ADI (mg/week): is defined the cumulative dose (mg) divided by the duration of 
cemiplimab exposure (weeks). 
 RDI (%): 
(mg/week)
Intensity 
 
Dose
 
Planned
 
(mg/week)
 
ADI
100
, where the planned dose intensity is 
250 mg for Q2W schedule, and 350mg for Q3W schedule. 
The total number of cycles started, number of cycles started by patients as a continuous variable 
and by category (ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles, etc), 
duration of cemiplimab exposure, cumulative dose, ADI and RDI will be summarized by 
descriptive statistics. 
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The following variables will be derived to describe dose delay and modification: 
 Infusion interruption: An infusion will be considered to be interrupted (as collected on 
eCRF) if the cemiplimab administration is stopped during an infusion before it is 
completed regardless of whether it is further restarted or not. 
 Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
Dose delay and modification will be summarized at the patient and infusion levels as follows: 
 Patient level: 
- 
Number (%) of patients with at least 1 dose omission, 
- 
Number (%) of patients with at least 1 infusion interrupted, 
- 
Number (%) of patients with at least 1 infusion interrupted and re-started, 
- 
Number (%) of patients with at least 1 infusion interrupted and not re-started. 
 Infusion level: 
- 
Number of cemiplimab infusions, 
- 
Number (%) of infusions interrupted, 
- 
Number (%) of infusions interrupted and re-started, 
- 
Number (%) of infusions interrupted and not re-started, 
- 
Number (%) of infusions interrupted more than once, 
- 
Number (%) of infusions interrupted at 1st infusion, 2nd infusion, subsequent infusions, 
- 
Time from infusion start to first interruption in minutes summarized as a continuous 
variable and by category (<5 minutes, 5-10 minutes, etc). 
2.4.5 Analyses of efficacy endpoints  
All efficacy analysis will be performed using the all-treated population. In addition, efficacy 
analysis will be performed using the response evaluable population. 
The data cut-off for the primary end-of-cohort analysis is up to 24 weeks from the date the last 
participant treated in individual cohort. The data cut-off for the intermediate and final end-of-
cohort analysis are up to 48 and 96 weeks respectively, from the date the last participant treated in 
individual cohort. 
2.4.5.1 Analysis of primary efficacy endpoint(s)  
For cHL cohort A1: CR rate during isatuximab + cemiplimab period will be summarized with 
descriptive statistics. A 90% two-sided confidence interval will be computed using 
Clopper-Pearson method. The statistical inference will be based on the hypothesis and alpha level 
defined in the sample size calculation section. 
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For cHL cohort A2, DLBCL and PTCL: ORR during isatuximab + cemiplimab period will be 
summarized with descriptive statistics. A 90% two-sided confidence interval will be computed 
using Clopper-Pearson method. The statistical inference will be based on the hypothesis and apha 
level defined in the sample size calculation section. 
2.4.5.2 Analyses of secondary efficacy endpoints  
For each cohort, separate analyses of the following endpoints will be performed for all participants 
during isatuximab + cemiplimab period for all 4 cohorts, for participants in Cohorts A1 and A2 
including the data from both isatuximab + cemiplimab and isatuximab + cemiplimab 
+ radiotherapy periods, and for participants in Cohorts A1 and A2 who receive isatuximab 
+ cemiplimab + radiotherapy. 
 
Tumor burden change: the best percent-change from baseline in tumor burden for all target 
lesions will be summarized and presented graphically. 
 
DoR and PFS will be summarized using Kaplan-Meier method. 
 
DCR will be summarized with descriptive statistics. 
In addition, ORR during isatuximab + cemiplimab period will be summarized in a similar fashion 
as described in the primary efficacy analysis for participants in Cohort A1. Similar analyses will 
be provided for CR rate and ORR for all participants in Cohorts A1 and A2 including the data 
form both isatuximab + cemiplimab and isatuximab + cemiplimab + radiotherapy periods, and for 
participants in Cohorts A1 and A2 who receive isatuximab + cemiplimab + radiotherapy. 
2.4.5.3 Analyses of exploratory efficacy endpoints  
OS and TTR for all treated patients will be summarized by descriptive statistics by cohort. 
For cohorts A1 and A2, CR (TTCR) for all treated patients will be summarized by descriptive 
statistics by cohort. 
For cohorts A1 and A2, OS, TTR, TTCR during isatuximab + cemiplimab period and for 
participants who receive isatuximab + cemiplimab + radiotherapy will be summarized by 
descriptive statistics by cohort. 
2.4.5.4 Multiplicity issues  
Not applicable. 
2.4.6 Analyses of safety data  
The all-treated population will be used for all safety analyses except for the DLT analysis in 
Phase 1, which will be performed based on the DLT-evaluable population.  
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2.4.6.1 Analyses of DLTs (Phase 1 only)  
The DLTs will be listed by patient using the DLT-evaluable population in Phase 1. 
2.4.6.2 Analyses of adverse events  
The primary focus of adverse event reporting will be on treatment-emergent adverse events. 
Pre-treatment and post-treatment adverse events will be described separately.  
If an AE date of onset (occurrence, worsening, or becoming serious) is incomplete, an imputation 
algorithm will be used to classify the AE as pretreatment, treatment-emergent, or post-treatment.  
The algorithm for imputing date of onset will be conservative and will classify an AE as treatment 
emergent unless there is definitive information to determine it is pretreatment or post-treatment.  
Details on classification of adverse events with missing or partial onset dates are provided 
in Section 2.5.3.  
Regarding treatment discontinuation, following definitions will be used: 
 Premature treatment discontinuation is defined when 1 of the IMPs is permanently 
discontinued, subjects will continue receiving the other IMP until study treatment 
permanent discontinuation. 
 Definitive treatment discontinuation is defined as the discontinuation of all the study 
drugs.  
The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same AE, the maximum (worst) severity grade by period of observation will be 
used. Summaries will be provided for all grades and for Grade ≥3 (including Grade 5). Missing 
grades handling is provided in Section 2.5.3.  
Sorting within tables should ensure the same presentation for the set of all AEs for each 
observation period (pre-treatment, treatment-emergent and post-treatment). For that purpose, 
tables of all TEAEs by SOC and PT will be sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs. This order will define the presentation order for all 
other tables unless otherwise specified.  
Overall summary of TEAEs 
An overall summary of TEAEs will be provided.  The number (%) of patients who experience any 
of the following will be provided: 
 TEAE. 
 TEAE of Grade ≥3. 
 TEAE of Grade 5. 
 Serious TEAE. 
 Treatment-related TEAEs (any grade). 
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 Treatment-related TEAEs of Grade ≥3. 
 Serious treatment-related TEAEs. 
 TEAE leading to definitive study treatment discontinuation. 
 TEAE leading to premature discontinuation of isatuximab. 
 TEAE leading to premature discontinuation of cemiplimab. 
 AESI. 
 AESI of Grade ≥3. 
Analysis of all TEAEs 
The number (%) of patients experiencing TEAEs by primary SOC and PT will be summarized by 
grade (all grades and Grade ≥3).  Similar tables will be presented for treatment-related TEAEs, 
serious TEAEs, and TEAEs leading to definitive/premature discontinuation. 
TEAEs with an incidence ≥5% will be summarized by PT for all grades and Grade ≥3.   
Listings of serious TEAEs, TEAEs leading to definitive or premature treatment discontinuation 
will be provided. 
Infusion reactions (IRs) 
IR analysis will include all adverse events regardless of relationship to isatuximab, cemiplimab or 
NIMP. The IRs will be summarized as follow: 
 Number (%) of patients experiencing IRs according to investigator reported AEs presented 
by primary SOC and PT will be summarized by grade. 
 Description of the IR diagnoses (using the diagnosis reported and excluding symptoms). 
- 
Number (%) of patients action taken, 
- 
Number (%) of patients with only 1, ≥1, ≥2, ≥3, ≥4 and ≥5 episodes, 
- 
Number (%) of patients with first occurrence of IR at the first infusion and subsequent 
infusions, 
- 
Number (%) of patients with IR at the first and subsequent infusions, 
- 
Number (%) of patients with at least two episodes of IRs at the same infusion, 
- 
Day of onset from infusion, 
- 
Duration (in days). 
 Number of patients with symptoms of IRs (as reported by investigator) by SOC and PT. 
Analysis of adverse events of special interest 
A listing of patients with at least one AESI described in Section 2.1.4.2 will be provided.  
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Analysis of pre-treatment and post-treatment adverse events  
The following analysis will be provided by grade (all grades and Grade ≥3).   
 All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
 All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
2.4.6.3 Deaths  
The following summaries of deaths will be generated: 
 Number (%) of patients who died by study period (on-treatment, post-treatment) and 
reasons for death (disease progression, AE, other). 
 TEAEs with fatal outcome (on the AE eCRF page as reported by the Investigator), TEAEs 
that started as non-fatal during treatment period but became fatal during post-treatment 
period, and TEAEs with fatal outcome during the post-treatment period summarized by 
SOC and PT. 
2.4.6.4 Analyses of laboratory variables  
Each laboratory test result will be graded by CTCAE criteria (Version 5.0), when applicable. For 
hematological parameters and for some biochemistry parameters, Sanofi sponsor generic normal 
ranges will be used for the grading of laboratory abnormalities (see list of parameters in 
Table 6 and Table 7). For other biochemistry parameters (eg, for hepatic parameters), grading will 
be derived using the local laboratory normal ranges. 
The number (%) of patients with abnormal laboratory tests at baseline and during the on-treatment 
period will be presented by all grades and each grade. For patients with multiple occurrences of 
the same laboratory variable during the on-treatment period, the maximum grade (worst) per 
patient will be used. 
The denominator used for percentage calculation is the number of patients with at least 
1 evaluation of the laboratory test during the considered observation period.  
When appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with Grade 3-4 abnormal laboratory tests. 
2.4.6.5 Analyses of vital sign variables  
The incidence of vital signs potentially clinically significant abnormality (PCSA) (Table 4) any 
time during the on-treatment period will be summarized by treatment group irrespective of the 
baseline level and/or according to the following baseline status categories:  
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 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
Table 4 - Potentially clinically significant abnormalities criteria for vital signs  
Parameter 
PCSA 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline ≥20 bpm 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
Temperature and respiratory rate will be summarized at baseline and end of treatment. A listing of 
patients with at least one PCSA will be provided. 
2.4.6.6 Analyses of electrocardiogram variables  
A listing of patients with ECG results will be provided.  
2.4.6.7 Analysis of Immunogenicity  
Immunogenicity analysis will be done separately for isatuximab and cemiplimab.  
Number of evaluable patients, number (%) of pre-existing ADA and negative patients at baseline, 
number (%) of boosted and induced patients (either transient, persistent or indeterminate) will be 
reported, along with descriptive statistics of titer, by cohort and possibly overall. Prevalence and 
incidence will also be presented. 
In addition, for positive ADA patients, time to onset, duration of ADA response, and the 
characterization of the immune response (transient, persistent, indeterminate) will be provided.  
An individual data listing with ADA samples status (positive, negative or inconclusive), the titer if 
applicable, date of first/last dose, duration of exposure, study period, cycle/day, time point and 
date/time of sampling along with Ctrough value of the drug will be provided for all patients.  
The impact on safety and efficacy endpoints may be further explored by graphical methods or 
descriptively, depending on the ADA prevalence. 
2.4.7 Analyses of pharmacokinetic variables  
PK analysis will be done separately for isatuximab and cemiplimab. 
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2.4.7.1 Cycle 1 non-compartmental analysis: following the 1st administration  
Following the first administration, individual concentrations and PK parameters of drug will be 
listed and summarized by descriptive statistics (such as the number of observations, arithmetic and 
geometric mean, median, standard deviation (SD), standard error (SE), coefficient of variation 
(CV)%, minimum, and maximum) by cohort and possibly overall. 
Individual and mean concentration profiles over time will be plotted by cohort and possibly 
overall under the responsibility of Sanofi, Pharmacokinetic, Dynamic and Metabolism (PKDM), 
Translational Medicine and Early Development (TMED) department.  
2.4.7.2 Over treatment concentrations: Ctrough and Ceoi  
Ctrough defined as a sample collected before dosing, in a time window of 6 to 8 days after the 
previous infusion for the QW administration (5 to 7 days after the first isatuximab infusion) , in a 
time window of 12 to 16 days after the previous infusion for the Q2W administration, and in a 
time window of 18 to 24 days after the previous infusion for the Q3W administration will be 
included in the descriptive analysis irrespectively of interruption of infusion. However Ctrough 
drawn outside time collection window described in the protocol PK/PD flowchart or collected 
after a dose deviation higher than ±50% from intended dose will be excluded from the analyses.  
Ceoi collected after significant infusion interruption, drawn outside collection of time window 
described in the PKPD flowchart of the protocol or collected after a dose deviation higher than 
±50% from intended dose will be excluded from the analyses. 
Individual Ctrough and Ceoi will be listed and summarized with same descriptive statistics as above 
by cohort and possibly overall.  
Mean (±SE) of Ctrough will be plotted over treatment phase by cohort and possibly overall for 
isatuximab and for cemiplimab. 
Individual Ctrough ratio and Ceoi ratio (described in Table 5) will be listed and summarized by 
descriptive statistics by cohort and possibly overall as described above.  
Table 5 - Ctrough and Ceoi ratio  
Analyte 
Ctrough 
Ceoi 
Isatuximab 
C2D1 vs C1D8 
C2D1 vs C1D2 
 
C4D1 vs C1D8 
C4D1 vs C1D2 
Cemiplimab 
C4D1 vs C1D15 
C4D1 vs C1D1 
NA = Not applicable. 
2.4.7.3 Immunogenicity impact on PK  
Immunogenicity impact on PK analysis may be explored, depending on the ADA prevalence.  
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A descriptive statistics of Ctrough as described above will be provided at each cycle in the subset of 
negative patients by cohort and possibly overall where positive or inconclusive patients will be 
observed.  
A graphical representation of individual Ctrough profile will be provided throughout the course of 
treatment by cohort and possibly overall where positive or inconclusive patients will be observed. 
Positive patients profile will be highlighted (eg, color or bold) and the concentration of the 
administered drug at the same time as ADA positive result will be notified.  
2.4.8 Analyses of biomarker variables  
The biomarker variables may be summarized by clinical group (eg, SD >6 months vs. others) and 
overall depending on availability of assessable tumor biopsy samples. Graphics will be provided 
as appropriate. The biomarker variables include, but not limited to, the following variables: 
 CD38 expression. 
 PDL1 expression. 
Additional biomarker analysis may be conducted in an exploratory manner. Additional analysis, 
not specified in the protocol but related to the drug action and/or effect of  
isatuximab/Cemiplimab, may be conducted on remaining samples pending evolving literature. 
2.4.9 Analyses of quality of life/health economics variables  
Not applicable. 
2.4.10 Further therapy after discontinuation of investigational medicinal product 
administration during the study  
A listing of further therapy after discontinuation of investigational medicinal product 
administration during the study may be provided. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Estimated glomerular filtration rate (eGFR) using the equation of MDRD formula: 
American)
African 
 
if 
(1.212
 x 
Female)
 
if 
(0.742
 x 
(Age)
 x 
 
(Scr)
 x 
175
 
GFR
-0 203
-1 154

 
with serum creatinine (sCr) in mg/dL and age in year. 
Corrected calcium formula using SI unit: 
Corrected Calcium = Calcium + 0.25* 0.8 (4 - Albumin / 10) 
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2.5.2 Data handling conventions for secondary efficacy variables  
Not applicable. 
2.5.3 Missing data  
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with 
non-missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
When incomplete or missing dates are found in the eCRF, attempts will be made to retrieve the 
complete date, especially for dates within the month prior to first dose. However, if some dates 
remain incomplete, the following rules will be applied: 
Handling of disease characteristics missing/partial dates 
 If the day is missing, it will be estimated by 1. 
 If the month is missing, it will be estimated by 1 (only for medical history variables). 
 If the year is missing, no estimation will be performed. 
Handling of medication missing/partial dates  
No imputation of medication (other than anti-cancer therapies) start/end dates or times will be 
performed. If a medication date is missing or partially missing and it cannot be determined 
whether it was taken prior or concomitantly, it will be considered a prior, concomitant, and 
post-treatment medication. 
For prior anti-cancer therapies, following rules will be applied: 
Missing/partial start date will be imputed as follows: 
 If year and month exist, day is missing, impute as the first day of the month. 
 If only year exists, month and day are missing, impute as the first day of the year. 
 If year, month, and day are all missing, no imputation will be applied. 
Missing/partial end date will be imputed in a two-step approach as follows: 
 Step 1: Use the following rule to impute end date: 
- 
If year and month exist, day is missing, impute as the first day of the month, 
- 
If only year exists, month and day are missing, impute as the first day of the year, 
- 
If year, month, and day are all missing, no imputation will be applied. 
 Step 2: If imputed end date is earlier than start date, set the imputed end date the same as 
start date. 
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Imputation of incomplete date for post anti-cancer treatment start date  
For post anti-cancer treatments, if the medication start date is missing, it will be imputed as 
follows: 
 If the medication start day and month are missing and the medication start year is the same 
as treatment end year, the medication start date will be set equal to treatment end date +1. 
 If the medication start day and month are missing and the medication start year is after the 
treatment end year, the medication start day and month will each be set to 01. 
 If the medication start day is missing and medication start year and month is the same as 
the treatment end year and month, the medication start day will be set equal to the 
treatment end day +1. 
 If the medication start day is missing and medication start month is before the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
 If the medication start day is missing and the medication start month is after the treatment 
end month and the medication start year is the same as treatment end year, the medication 
start day will be set to 01. 
 If the medication start day is missing and the medication start month is not missing and the 
medication start year is after the treatment end year, the medication start day will be set to 01. 
 If the medication start day, start month and start year is missing, the medication start date 
will be set equal to the treatment end date +1. 
No imputation will be done for the missing/partial end date. 
Handling of adverse events with missing or partial date of onset 
Missing or partial adverse event onset dates (occurrence or becoming serious) will be imputed so 
that if the partial adverse event onset date information or visit number does not indicate that the 
adverse event started prior to treatment or after the treatment-emergent adverse event period, the 
adverse event will be classified as treatment-emergent. In case of an AEs worsening during the 
study, the emergence will also be based on the cycle of worsening. No imputation of adverse event 
end dates will be performed. These data imputations are for categorization purpose only and will 
not be used in listings. No imputation is planned for date of adverse event resolution.   
Handling of death with missing or partial date of death 
The imputation for missing or partial death date will proceed as follows: 
 If the death day is missing and the death month and year are the same as the last month and 
year the patient was last known to be alive, the death day will be set equal to the last day 
the patient was known to be alive +1. 
 If the death day is missing and the death month is after the month the patient was last 
known to be alive and the death year is the same as the year the patient was last known to 
be alive, the death day will be set to 01. 
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 If the death day and month are missing and the death  year is the same as the year the 
patient was last known to be alive, the death date will be set equal to the date the patient 
was last known to be alive +1. 
 If the death day and month are missing and the death year is after the year the patient was 
last known to be alive, the death day and month will both be set to 01. 
If the date the patient was last known to be alive is partial or missing, no imputation for missing or 
partial death date will be performed. The last date the patient was known to be alive is the last of: 
date of last dose, date of last visit performed (when the patient is known to be alive according to 
subject vital status), date of last laboratory assessment, and date of last vital signs. 
Handling of AEs with missing grade 
No imputation of AE grade will be done. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to the regimen is missing, then the relationship to the regimen 
has to be assumed and the adverse event considered as such in the frequency tables of possibly 
related adverse events, but no imputation should be done at the data level. No imputation will be 
done for relationship to NIMP. 
Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), the following imputation rule will be 
implemented. 
 
Handling of missing date/time in duration of infusion calculation 
When both cemiplimab and isatuximab are given to a patient on the same visit: 
 Missing cemiplimab end date/time will be imputed by isatuximab start date/time 
(if available). 
 Missing isatuximab start date/time will be imputed by cemiplimab end date/time 
(if available). 
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Other types of missing date/time will not be imputed, and data will be excluded from the analysis 
of duration of infusion.  
Handling of other missing dates 
Incomplete date of cancer diagnosis:  
 If the day of the cancer diagnosis is missing, the date will be imputed to the first day of the 
month. 
 If day and month of the cancer diagnosis are missing, no imputation will be done. 
Incomplete date of progression for the last prior regimen:  
 If the day of the progression for the last prior regimen is missing, the date will be imputed 
to the end day of the month. 
 If day and month of the progression for the last prior regimen are missing, no imputation 
will be done. 
Incomplete date of prior surgery:  
 If the day of the last prior surgery is missing, the date will be imputed to the end day of the 
month. 
 If day and month of the last prior surgery are missing, no imputation will be done. 
Incomplete date of prior radiotherapy: 
 If the day of the last prior radiotherapy is missing, the date will be imputed to the end day 
of the month. 
 If day and month of the last prior radiotherapy are missing, no imputation will be done. 
2.5.4 Windows for time points  
Laboratory data 
A protocol planned laboratory test is considered to have occurred during a cycle if the date of 
sampling is after (>) the first day of the cycle, but prior to or equal (≤) to the first day of the next 
cycle. For unscheduled tests, a lab test is not required per protocol, a test is considered to have 
occurred during a cycle if the date of sampling is equal to or after (≥) the first day of the cycle, but 
prior (<) to the first day of the next cycle. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs and ECG will be used for 
computation of worst values and/or grades on treatment. Unscheduled visits prior to first 
administration will be also be used for computation of baseline except if they are not collected on 
the day of first administration. 
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2.5.6 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
2.5.7 Statistical technical issues  
Not applicable. 
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3 
INTERIM ANALYSIS  
An interim analysis will be performed for cHL PD-1/PD-L1 naïve cohort A1, cHL PD-1/PD-L1 
progressors cohort A2, DLBCL, and PTCL cohorts when approximately the first 17, 12, 18 and 
10 participants, respectively, in Phase 2 have been treated and followed-up for 24 weeks. The 
analysis will include the following parameters/analyses (defined in Section 2.1): CR for patients 
with cHL PD-1/PD-L1 naïve, or ORR for patients with cHL PD-1/PD-L1 progressor, DLBCL, and 
PTCL. Demographics and baseline characteristics, prior or concomitant medication, AEs (TEAE, 
death, SAE, TEAE leading to discontinuation, IR, AESI), and laboratory variables (abnormality of 
hematological and chemistry test).  If needed, more data will be analyzed to inform the futility 
decision including additional efficacy, PK, and biomarker.   
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4 
DATABASE LOCK  
The database will be locked when clinical review of the database has been completed and all 
critical queries have been resolved. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS® Version 9.4 or higher. 
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6 
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. Kratz A, Ferraro M, Sluss PM, Lewandrowski KB. Case records of the Massachusetts General 
Hospital. Laboratory reference values. N Engl J Med. 2004;351:1548-63. 
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7 
LIST OF APPENDICES  
 
Appendix A 
Generic ranges for hematological and biochemistry parameters 
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Appendix A 
Generic ranges for hematological and biochemistry parameters  
Table 6 - Generic ranges for hematological parameters  
Test 
Gender 
Unit 
Lower/Upper limit of normal 
Hemoglobin 
F 
g/L 
120 - 160 
Hemoglobin 
M 
g/L 
135 - 175 
Lymphocytes 
109/L 
1 - 2 
Neutrophils 
109/L 
1.8 - 3.15 
Platelets 
109/L 
150 - 350 
Leukocytes 
 
109/L 
4.5 - 11 
Eosinophils 
109/L 
0 - 0.4 
Basophils 
109/L 
0 - 0.15 
Monocytes 
109/L 
0.18 - 0.5 
Hematocrit 
M 
Ratio 
0.41 -0.53 
Hematocrit 
F 
Ratio 
0.36 - 0.46 
Erythrocytes 
F 
1012/L 
4 - 5.2 
Erythrocytes 
M 
1012/L 
4.5 -5.9 
INR 
 
ratio 
0.8 -1.2 
Based on Kratz et al (2). 
Table 7 - Generic ranges for biochemistry parameters  
Test 
Unit 
Lower - Upper limit of normal 
Albumin 
g/L 
35 - 55 
BUN 
mmol/L 
3.6 - 7.1 
Calcium 
mmol/L 
2.2 - 2.6 
Chloride 
mmol/L 
80 - 115 
Corrected calcium 
mmol/L 
2.2 - 2.6 
Glucose 
mmol/L 
3.9 - 7 
Bicarbonate (HCO3) 
mmol/L 
22 - 29 
Carbon dioxide 
mmol/L 
21 - 30 
Potassium 
mmol/L 
3.5 - 5 
Magnesium 
mmol/L 
0.8 - 1.2 
Sodium 
mmol/L 
136 - 145 
Phosphate 
mmol/L 
1 - 1.4 
Protein 
g/L 
55 - 80 
Urea 
mmol/L 
3.6 - 7.1 
 
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