Clinical trial NCT03860844
Conditions: Acute Lymphoblastic Leukemia Acute Myeloid Leukemia
Keywords: Anti-CD38 monoclonal antibody
Sponsor: Sanofi
Start date: 2019-08-06; Completion date: 2023-05-26
Enrollment: 67 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

Evaluate the anti-leukemic activity of isatuximab in combination with standard chemotherapies in pediatric participants of ages 28 days to less than 18 years with Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) or Acute Myeloid Leukemia (AML)

Secondary Objectives:

* Safety and tolerability assessments
* Assessment of infusion reactions (IRs)
* Pharmacokinetics (PK) of isatuximab
* Minimal residual disease
* Overall response rate
* Overall survival
* Event free survival
* Duration of response
* Relationship between clinical effects and CD38 receptor density and occupancy

Detailed description:
The study included:

* a screening period of up to (up to 3 weeks prior to the first study treatment administration);
* a study treatment period \[Day 1 to Day 57 for Acute Lymphoblastic Leukemia (ALL); Day 1 to Day 22 for Acute Myeloid Leukemia (AML)\];
* the period of aplasia followed by a recovery period;
* an end of treatment (EOT) visit \[within 30 days after hematological recovery;
* a follow-up period (until final analysis cut off date).

Arms: arm 1: This arm includes participants from 3 cohorts: AML, T-ALL and B-ALL.; AML: Weekly dosing of isatuximab with induction chemotherapy. The therapy may be repeated one more cycle; ALL: (Includes T-ALL and B-ALL) Weekly dosing of isatuximab with induction chemotherapy, then biweekly dosing of isatuximab with consolidation chemotherapy.
Interventions: intervention 1: Isatuximab intervention 2: Dexamethasone or equivalent intervention 3: Fludarabine intervention 4: Cytarabine intervention 5: Liposomal daunorubicin intervention 6: Daunorubicin (nonliposomal) intervention 7: Idarubicin intervention 8: Filgrastim or equivalent intervention 9: Mitoxantrone intervention 10: Doxorubicin intervention 11: Vincristine intervention 12: Pegaspargase (PEG) Asparaginase intervention 13: Cyclophosphamide intervention 14: Etoposide intervention 15: Methotrexate intervention 16: L - Asparginase intervention 17: Hydroxyurea intervention 18: L - Asparaginase (Erwinase)
Intervention descriptions: intervention 1: Pharmaceutical form: Concentrate for solution for intravenous infusion Route of administration: Intravenous intervention 2: Pharmaceutical form: Solution for injection or tablet Route of administration: Intravenous or oral intervention 3: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 4: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 5: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 6: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion intervention 7: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 8: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 9: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 10: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 11: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 12: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion intervention 13: Pharmaceutical form: Solution for injection Route of administration: Intravenous intervention 14: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion intervention 15: Pharmaceutical form: Solution for injection Route of administration: Intravenous infusion intervention 16: Pharmaceutical form: Solution for injection Route of administration: Intramuscular intervention 17: Pharmaceutical form: Solution for injection Route of administration: PO intervention 18: Pharmaceutical form: Solution for injection Route of administration: Intramuscular

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: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 05 
Protocol title: 
Open-label, Single-arm Trial to Evaluate Antitumor 
Activity, Safety, and Pharmacokinetics of Isatuximab 
Used in Combination With Chemotherapy in Pediatric 
Patients From 28 Days to Less Than 18 Years of Age 
With Relapsed/Refractory B or T Acute Lymphoblastic 
Leukemia or Acute Myeloid Leukemia In First or 
Second Relapse 
Protocol number: 
ACT15378 
Amendment number: 
05 
Compound number 
(INN/Trademark): 
SAR650984  
(isatuximab) 
Short title: 
Isatuximab in Combination with Chemotherapy in 
Pediatric Patients with Relapsed/Refractory Acute 
Lymphoblastic Leukemia or Acute Myeloid Leukemia 
(ISAKIDS) 
Sponsor name: 
Sanofi aventis recherche & développement 
Legal registered 
address: 
1 avenue Pierre Brossolette, 
91380 Chilly-Mazarin 
FRANCE 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifying number(s): 
EudraCT number: 
2018-002 697-45 
IND number: 
103217 
WHO number: 
U1111-1202-1096 
NCT number: 
NCT03860844 
Approval Date: 
14-Oct-2021
Total number of pages: 165 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 05 
All 
14 October 2021, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 04 
All 
24 November 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 
All 
30 July 2020, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 
All 
04 December 2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
11 March 2019, version 1 (electronic 1.0) 
Original Protocol 
 
21 September 2018, version 1 (electronic 1.0) 
Amended protocol 05 (14 October 2021) 
This amended protocol (amended protocol 05) is considered to be substantial based on the criteria 
set forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary driver for this amendment is to allow the enrollment of children <2 years old as after 
PK assessment, the dose of 20 mg/kg is confirmed in this young subpopulation.  
The main changes are:  
• Justification of the dose (20 mg/kg) for children <2 years old. 
• Definition of evaluable patient update. 
• Clarification on coagulation test frequency. 
• Adding possibility to perform a PET-MRI instead of PET-CT when needed. 
Protocol amendment summary of changes table  
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, and Section 
10.6.1.1 Response 
criteria 
Secondary endpoint regarding overall response rate is 
updated to “The overall response rate is defined as the 
proportion of participants with CR or CRi or PR for 
blood and bone marrow disease”.  
Clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
and Section 9.4 
Statistical Consideration 
“the last participant is treated “was updated to “the last 
participant is treated (last participant last dose)”. 
Clarification. 
Section 1.1 Synopsis 
The following statement was removed “Participant 
under 2 years of age can only be enrolled after the 
dose reassessment is completed on the first 
20 participants who are 2 to less than 18 years of age”. 
To allow the enrollment of participants 
<2 years old as after PK assessment the 
recommendation is to keep same dose 
(20 mg/kg). 
Section 1.1 Synopsis 
and Section 1.3 
Schedule of Activities 
(SoA) 
For AML, to be performed with BM aspiration samples 
at the time of hematological recovery or between 
Days 22 and 29, and/or at the time of each BM 
aspiration for disease assessment if CR or CRi is 
achieved. 
To clarify that MRD assessment is 
mandatory, only the day is flexible. 
Section 1.1 Synopsis 
and Section 9.3 
Populations for 
Analyses: Table 12 
The description of evaluable population was updated 
to: The evaluable population will include participants 
from the AT population who received at least 1 full 
dose of isatuximab in Cycle 1 and who had at least 
one valid response value that is evaluable. 
Patients should benefit even out of 1 full 
dose of the drug. 
Section 1.1 Synopsis 
and Section 9.4.1 
Efficacy analyses 
“Response to treatment that will be analyzed is the 
response after 1 full dose of isatuximab in Cycle 1 
(induction)” is added. 
Clarification. 
Section 1.1 Synopsis 
and Section 9.4 
Statistical Consideration 
“In case of stop of one of the cohorts after IA the actual 
date of the cut-off IA will be considered for the primary 
analysis of CR and other secondary endpoints” is 
added. 
To clarify the data to be collected if a 
cohort does not move to Stage 2. 
Section 1.2 Schema: 
Figure 1 
Hyperlink “a” for “Dexamethasone” is removed. 
Correction of a typo. 
Section 1.3 Schedule of 
Activities (SoA); Section 
10.2 Appendix 2: clinical 
laboratory tests  
Thyroid-stimulating hormone, free/total T3 and free T4 
may be used to determine thyroid status at screening. 
Clarification. 
Section 1.3 Schedule of 
Activities (SoA) 
Coagulation test will be done once a week until 
recovery and if clinically indicated, and country-
German specific coagulation test related requirement 
is mentioned in Section 10.8. 
To update according to current 
standards of treatment. 
Section 1.3 Schedule of 
Activities (SoA) and 
Section 8.1 Efficacy 
Assessments, Section 
10.9 Appendix 9: 
Contingency Measures 
for a regional or national 
emergency that is 
declared by a 
governmental agenecy 
For ALL and AMLcohorts, CT, PET-CT or PET-MRI 
scans are suggested to be performed. 
To allow PET-MRI and not only PET-CT 
imaging according to real practice in 
some countries. 
Section 1.3 Schedule of 
Activities (SoA) 
For ALL: Consolidation and Follow-up, 12-lead ECG 
and cardiac assessment should be performed during 
EOT visit. 
Correction of a typo. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
Footnote h) the text “AT-III substituted if necessary” 
was intended to read as “AT-III may be substituted if 
necessary”. 
Clarification. 
Section 1.3 Schedule of 
Activities (SoA) 
Footnote i) the text “in case of CRS occurrence…” was 
intended to read as “in case of CRS/TLS 
occurrence…”. 
Clarification. 
Section 1.3 Schedule of 
Activities (SoA) 
Vital signs monitoring in 2 hour after every isatuximab 
infusion and as clinically indicated mentioned already 
in section 8.2.2 was added in the footnote ‘k’ in SoA. 
Consistency. 
Section 1.3 Schedule of 
Activities (SoA) Table 1 
and 2 
12:00 AM was a typo, corrected to 12:00 PM. 
Correction of a typo. 
Section 1.3 Schedule of 
Activities (SoA): Table 1 
and 2 
PK and ADA predose samples must be collected just 
before administration of isatuximab and not in the 
3 days before start of infusion, new footnote ‘e’ is 
inserted in Table 1 and 2. 
Clarification. 
Section 2.1 Study 
Rationale 
“Among the patients who achieved a complete 
remission, 77% were MRD negative, the median 
relapse free survival (RFS) was 8.3 months, and the 
median OS was 5.7 months. Among patients reaching 
a complete remission, 42% were MRD negative, the 
median RFS was 5.6 months, and the median OS was 
4.3 months” is removed. 
Correction of a typo. 
Section 4.3 Justification 
for Dose 
Addition of the dose rationale for the youngest 
patients. Justification of the dose (20 mg/kg) for the 
cohort of children <2 years old, and figure 9 is inserted 
with reference to this change.  
To allow the enrollment of participants 
<2 years old as after PK assessment the 
recommendation is to keep same dose 
(20 mg/kg). 
Section 5.1 Inclusion 
criteria 
Inclusion criteria I 01 is updated, participants who are 
under 2 years old are included. 
To allow the enrollment of participants 
who are under 2 years old. 
Section 5.4 Screen 
Failures 
Rescreened participants should be assigned a new 
participant number. 
Correction according to company 
procedures. 
Section 6.1 Study 
intervention(s) 
administered 
The following statement was updated: “A mandatory 
monitoring of patients after every isatuximab infusion 
for 2 hours after the infusion should be set up.” 
Clarification. 
Section 6.1 Study 
intervention(s) 
administered 
“Patients should be monitored on site for at least 
2 hours after the first two infusions of isatuximab. 
Monitoring after subsequent infusions is 
recommended, but it is at the discretion of the 
investigator” is removed. 
Correction for consistency. 
Section 6.6.1 Guidelines 
for the management of 
potential infusion 
reactions 
The following statement in Section 6.6.1 was updated: 
“Participants with a Grade 3 or 4 IR must follow rules 
described in the Table 6 and appropriate supportive 
therapy should be administered.” 
Consistency. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.6.1 Guidelines 
for the management of 
potential infusion 
reactions: Table 6 
The following statement in Section 6.6.1-table 6 was 
updated: “If the same Grade 3 infusion-related AE 
occurs for a third time, treatment with isatuximab will 
be permanently discontinued for that patient.”. 
Clarification. 
Section 8.1 Efficacy 
assessments 
The following statement was updated: “If not done, 
PET-CT or PET-MRI scan is suggested to be 
performed at screening if lymphomatous involvement 
is present”. 
Consistency. 
Section 8.3 Adverse 
events and serious 
adverse events 
The following statement was added “AE will be 
reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant’s legally 
authorized representative”. 
Clarification. 
Section 8.11 Data 
collection after 
premature stop of the 
study in case of sponsor 
decision to stage 2 
criteria are not met for 
one of the cohorts 
New section was added. 
To clarify data collection after premature 
stop of the study in case of sponsor 
decision due to Stage 2 criteria are not 
met for one of the cohorts. 
Section 9.3 Populations 
for Analyses:Table 12 
The description of enrolled population was added: All 
participants who signed the ICF, regardless of whether 
the study intervention was received or not. 
The description of all-treated population was updated 
to: The AT population will include all participants who 
received at least 1 dose (even incomplete) of study 
intervention. 
Correction based on updated SAP dated 
on 16 Dec 2020. 
Section 10.3 Adverse 
events: definitions and 
procedures for recording, 
evaluating, follow-up, 
and reporting 
Bullet point “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” 
was added in Events NOT meeting the AE definition 
subsection. 
Clarification. 
Section 10.8 Appendix 8: 
Country-specific 
requirements 
The section was updated: “For German sites 
coagulation test will be done twice a week and if 
clinically indicated. For the rest of the world, it will 
remain once a week and if clinically indicated”. 
To update according to current 
standards of treatment. 
Section 10.11 Appendix 
11: Protocol amendment 
history 
Summary of changes to last version of protocol has 
been added. 
To provide summary of changes 
introduced in the last amended 
protocol 04. 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 05 .............................................................................................. 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 ........................................................................................................................................ 24 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 27 
2 
INTRODUCTION ............................................................................................................................ 38 
2.1 
STUDY RATIONALE...................................................................................................................... 38 
2.2 
BACKGROUND ............................................................................................................................. 43 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 46 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 49 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 50 
4 
STUDY DESIGN ............................................................................................................................ 51 
4.1 
OVERALL DESIGN ........................................................................................................................ 51 
4.1.1 
Study participants and cohorts ....................................................................................................... 51 
4.1.2 
Screening ....................................................................................................................................... 51 
4.1.3 
Study treatment period ................................................................................................................... 52 
4.1.4 
Post-study treatment period ........................................................................................................... 53 
4.1.5 
Study duration ................................................................................................................................ 53 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 54 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 54 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 57 
5 
STUDY POPULATION .................................................................................................................. 58 
5.1 
INCLUSION CRITERIA .................................................................................................................. 58 
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5.2 
EXCLUSION CRITERIA  ............................................................................................................... 59 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 61 
5.4 
SCREEN FAILURES...................................................................................................................... 62 
5.5 
CRITERIA FOR TEMPORARILY DELAYING OF ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 62 
6 
STUDY INTERVENTION ............................................................................................................... 63 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 63 
6.1.1 
Acute myeloid leukemia combination therapies ............................................................................. 69 
6.1.2 
T-ALL and B-ALL combination therapies ....................................................................................... 69 
6.1.3 
Mandatory evaluations on Day 1 prior to the first isatuximab administration ................................ 70 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 70 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 71 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 71 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 72 
6.5.1 
Rescue medicine ............................................................................................................................ 73 
6.6 
DOSE MODIFICATION .................................................................................................................. 74 
6.6.1 
Guidelines for the management of potential infusion reactions ..................................................... 75 
6.6.2 
Guidelines for the management of anaphylaxis ............................................................................. 77 
6.6.3 
Cytokine-release syndrome (CRS) ................................................................................................ 78 
6.6.4 
Guidelines for the management of tumor lysis syndrome ............................................................. 80 
6.6.5 
Guidance in case of hepatitis B reactivation occurring under study treatment .............................. 83 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 83 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 84 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 84 
7.1.1 
Definitive discontinuation ............................................................................................................... 84 
7.1.2 
Temporary intervention discontinuation ......................................................................................... 85 
7.1.3 
Rechallenge ................................................................................................................................... 85 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 85 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 86 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 87 
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8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 87 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 88 
8.2.1 
Physical examinations ................................................................................................................... 88 
8.2.2 
Vital signs ....................................................................................................................................... 89 
8.2.3 
Electrocardiograms ........................................................................................................................ 89 
8.2.4 
Cardiac assessment....................................................................................................................... 89 
8.2.5 
Chest X-ray .................................................................................................................................... 89 
8.2.6 
Clinical safety laboratory assessments .......................................................................................... 89 
8.2.6.1 
Blood type phenotyping/genotyping ............................................................................................... 90 
8.2.7 
Suicidal risk monitoring .................................................................................................................. 90 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 91 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 92 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 92 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 92 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 92 
8.3.5 
Pregnancy ...................................................................................................................................... 93 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 93 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 93 
8.5 
PHARMACOKINETICS .................................................................................................................. 94 
8.5.1 
Sampling time ................................................................................................................................ 94 
8.5.2 
Pharmacokinetic sample handling procedure ................................................................................ 94 
8.5.3 
Bioanalytical methods .................................................................................................................... 94 
8.5.4 
Pharmacokinetic parameters ......................................................................................................... 94 
8.5.4.1 
Population pharmacokinetic approach for isatuximab ................................................................... 94 
8.6 
PHARMACODYNAMICS ............................................................................................................... 95 
8.7 
GENETICS ..................................................................................................................................... 95 
8.8 
BIOMARKERS ............................................................................................................................... 95 
8.8.1 
CD38 expression, receptor density, and receptor occupancy ....................................................... 95 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 95 
8.10 
HEALTH ECONOMICS .................................................................................................................. 96 
8.11 
DATA COLLECTION AFTER PREMATURE STOP OF THE STUDY IN CASE OF 
SPONSOR DECISION DUE TO STAGE 2 CRITERIA ARE NOT MET FOR ONE OF THE 
COHORTS ..................................................................................................................................... 96 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 97 
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9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 97 
9.2 
SAMPLE SIZE DETERMINATION  ................................................................................................ 97 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 98 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 98 
9.4.1 
Efficacy analyses ........................................................................................................................... 99 
9.4.1.1 
Analysis of primary efficacy endpoint............................................................................................. 99 
9.4.1.2 
Analysis of secondary efficacy endpoints .................................................................................... 100 
9.4.2 
Safety analyses ............................................................................................................................ 100 
9.4.2.1 
Analyses of adverse events ......................................................................................................... 100 
9.4.2.2 
Deaths .......................................................................................................................................... 102 
9.4.2.3 
Clinical laboratory evaluations ..................................................................................................... 102 
9.4.2.4 
Vital signs ..................................................................................................................................... 102 
9.4.3 
Immunogenicity ............................................................................................................................ 102 
9.4.4 
Pharmacokinetic analysis ............................................................................................................ 103 
9.4.5 
Biomarkers analysis ..................................................................................................................... 104 
9.5 
INTERIM ANALYSES  ................................................................................................................. 104 
9.5.1 
Data monitoring committee .......................................................................................................... 104 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 105 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 105 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 105 
10.1.2 
Financial disclosure...................................................................................................................... 106 
10.1.3 
Informed consent process ............................................................................................................ 106 
10.1.4 
Data protection ............................................................................................................................. 106 
10.1.5 
Committees structure ................................................................................................................... 107 
10.1.6 
Dissemination of clinical study data ............................................................................................. 108 
10.1.7 
Data quality assurance ................................................................................................................ 108 
10.1.8 
Source documents ....................................................................................................................... 109 
10.1.9 
Study and site closure .................................................................................................................. 109 
10.1.10 Publication policy ......................................................................................................................... 109 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 110 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 111 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 116 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 119 
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10.6 
APPENDIX 6: OTHER ASSESSMENTS AND SAFETY ITEMS ................................................. 120 
10.6.1 
Response criteria ......................................................................................................................... 120 
10.6.1.1 Acute lymphoblastic leukemia ...................................................................................................... 120 
10.6.1.2 Acute myeloid leukemia ............................................................................................................... 121 
10.6.2 
Eastern cooperative oncology group performance status scale .................................................. 122 
10.6.3 
Lansky score scale....................................................................................................................... 123 
10.6.4 
Revised Schwartz equation to estimate GFR in children............................................................. 123 
10.6.5 
Types of infusion reactions and typically associated symptoms ................................................. 123 
10.6.6 
CD38 blood test interference guideline ........................................................................................ 124 
10.6.7 
Grading system and mitigation strategy for ICANS, based on 2019 ASTCT consensus 
guidelines ..................................................................................................................................... 128 
10.6.8 
Encephalopathy Assessment Tools for Grading of ICANS Immune Effector Cell-Associated 
Encephalopathy (ICE) score ........................................................................................................ 129 
10.6.9 
Encephalopathy assessment for children age <12 years using the CAPD score ....................... 129 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  ............................................. 130 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  ........................................................... 130 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 130 
10.10 
APPENDIX 10: ABBREVIATIONS ............................................................................................... 131 
10.11 
APPENDIX 11: PROTOCOL AMENDMENT HISTORY .............................................................. 134 
10.11.1 Amended protocol 04 (24 November 2020) ................................................................................. 134 
10.11.2 Amended protocol 03 (30 July 2020) ........................................................................................... 139 
10.11.3 Amended protocol 02 (04 December 2019) ................................................................................. 142 
10.11.4 Amended protocol 01 (11 March 2019) ....................................................................................... 151 
11 
REFERENCES ............................................................................................................................. 162 
 
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LIST OF TABLES  
Table 1 - PK and PD flowchart - AML cohort ................................................................................................ 36 
Table 2 - PK and PD flowchart ALL cohorts .................................................................................................. 37 
Table 3 - Objectives and endpoints ............................................................................................................... 49 
Table 4 - Overview of study interventions administered ............................................................................... 63 
Table 5 - Noninvestigational medicinal products ........................................................................................... 66 
Table 6 - Management of infusion reactions ................................................................................................. 76 
Table 7 - Clinical criteria for diagnosing anaphylaxis .................................................................................... 77 
Table 8 - Guidelines for the management of Cytokine Release Syndrome (CRS) ....................................... 79 
Table 9 - Recommendations on selection of hypouricemic agents ............................................................... 82 
Table 10 - Management of tumor lysis syndrome ......................................................................................... 83 
Table 11 - Bioanalytical methods for isatuximab pharmacokinetic analysis ................................................. 94 
Table 12 - Populations for analyses .............................................................................................................. 98 
Table 13 - Efficacy analyses ......................................................................................................................... 99 
Table 14 - Safety analyses .......................................................................................................................... 100 
Table 15 - Protocol-required safety laboratory assessments ...................................................................... 110 
Table 16 - Highly effective contraceptive methods ..................................................................................... 118 
 
LIST OF FIGURES  
Figure 1 - Graphical study design: AML cohort ............................................................................................. 24 
Figure 2 - Graphical study design: ALL cohorts - induction .......................................................................... 25 
Figure 3 - Graphical study design - ALL cohorts - consolidation................................................................... 26 
Figure 4 - CD38 expression (% of CD38 positive cells and receptor density) in cancer cells from patients 
with different hematological malignancies ..................................................................................................... 42 
Figure 5 - Disseminated T-ALL xenograft model of survival (isatuximab versus control vehicle) ................. 43 
Figure 6 - Disseminated syngeneic model of survival (isatuximab versus control vehicle) .......................... 43 
Figure 7 - Body weight normalized clearance versus age ............................................................................ 55 
Figure 8 - Body weight-based doses versus age .......................................................................................... 56 
Figure 9 - Boxplots of predicted and simulated AUCs for a 20 mg/kg isatuximab dose administered under 
ALL and AML design, by weight groups ........................................................................................................ 57 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and 
Pharmacokinetics of Isatuximab Used in Combination With Chemotherapy in Pediatric 
Patients From 28 Days to Less Than 18 Years of Age With Relapsed/Refractory B or T 
Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia In First or Second Relapse 
Short title: 
 
Isatuximab in Combination with Chemotherapy in Pediatric Patients with 
Relapsed/Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia 
(ISAKIDS) 
Rationale: 
More than 80% of children affected by acute leukemia are successfully treated; however, relapse 
remains a remarkable clinical concern, with 50% to 60% of relapsing patients facing a fatal 
outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens 
based on conventional drugs, and hematopoietic stem cells transplantation for patients with 
unfavorable features. Biological targeted drugs, in particular the monoclonal antibodies (mAbs), 
could be novel potential agents to be integrated in salvage acute leukemia therapy to further 
improve patients’ outcomes. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To evaluate the antileukemic activity of isatuximab in 
combination with chemotherapies in pediatric participants 
of 28 days to less than 18 years of age with R/R ALL or 
AML. 
CR rate is defined in this study as the proportion of participants 
with CR or CRi, in AML, B-ALL, and T-ALL cohorts. 
For AML:  
• 
CR: bone marrow blasts lower than 5%; No blasts with 
Auer rods or persistence of extramedullary disease; 
ANC higher than 1000/mm3, platelets higher than 
100 000/mm3; red blood cells transfusion 
independence. If the physician documents transfusion 
dependency related to study treatment and not to the 
patient's underlying disease, CRi can be reported. 
• 
CRi: same criteria as for CR, except neutrophils and/or 
platelets recovery 
For B-ALL and T-ALL:  
• 
CR: bone marrow blasts lower than 5%, no circulating 
blasts or lymphoblasts in CSF or extramedullary 
disease; ANC higher than 1000/mm3, platelets higher 
than 100 000/mm3; red blood cells transfusion 
independence. If the physician documents transfusion 
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Objectives 
Endpoints 
dependency related to study treatment and not to the 
patient’s underlying disease, CRi can be reported. 
• 
CRi: same criteria as for CR, except neutrophils and/or 
platelets recovery. 
• 
Extramedullary disease: complete resolution of 
lymphomatous enlargement by CT. For participants 
with a previous positive PET scan, a post-treatment 
residual mass of any size is considered a CR as long 
as it is PET negative. 
Secondary 
• 
Safety and tolerability assessments 
• 
Safety assessment, in terms of AEs/SAEs. In addition, 
laboratory data, vital signs, and physical examination 
will be assessed throughout the study. 
• 
Assessment of IRs 
• 
Incidence and severity of IRs. 
• 
PK of isatuximab 
• 
PK parameters of isatuximab calculated using a 
population PK approach including at least Cmax, Ctrough, 
and AUC. 
• 
Minimal residual disease 
• 
Estimation of minimal residual disease in participants 
achieving CR or CRi. 
• 
Overall response rate 
• 
The overall response rate is defined as the proportion 
of participants with CR or CRi or PR for blood and 
bone marrow disease.  
• 
Overall survival 
• 
Overall survival is defined as the time interval from the 
date of first study intervention administration to death 
from any cause. 
• 
Event free survival 
• 
Event free survival is defined as the time interval from 
the date of first study intervention administration to the 
date of the first of: completion or going off protocol 
induction/consolidation therapy without CR, relapse 
from CR, or death due to any cause.  
• 
Duration of response 
• 
Duration of response is defined as the time from the 
date of the first response to the date of first disease 
progression or death from any cause, whichever 
happens first.  
• 
Relationship between clinical effects and CD38 
receptor density and occupancy 
• 
CD38 receptor density will be assessed at baseline 
and CD38 receptor occupancy at Day 15 and 
correlated with clinical endpoints.  
AE = adverse event; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; ANC = absolute neutrophil count; AUC = area 
under the curve; B-ALL = B-cell acute lymphoblastic leukemia; Cmax = maximum serum concentration; CR = complete response; 
CRi = complete response with incomplete peripheral recovery; CSF = cerebrospinal fluid; CT = computed tomography; Ctrough = lowest serum 
concentration reached by a drug before the next dose is administered; IR = infusion reaction; NCCN = National Comprehensive Cancer 
Network; PET = positron emission tomography; PK = pharmacokinetics; PR = partial response; R/R = relapsed or refractory; SAE = serious 
adverse event; T-ALL = T-cell acute lymphoblastic leukemia. 
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Overall design: 
This is a Phase 2, single-arm, multicenter, open-label study evaluating the antitumor activity, 
safety, and pharmacokinetics (PK) of isatuximab in combination with standard salvage 
chemotherapies in pediatric participants with relapsed or refractory (R/R) acute lymphoblastic 
leukemia (ALL; including both T-cell [T]-ALL and B-cell [B]-ALL) and acute myeloid leukemia 
(AML) conducted in 3 separate cohorts. Male and female children from 28 days to less than 
18 years of age with R/R B-ALL or T-ALL or AML in first or second relapse will be eligible. 
Treatment periods 
Study treatment period: 
In all 3 disease cohorts, participants will receive 1 administration of single-agent isatuximab on 
Day 1. Starting on Day 8, combination chemotherapy will be added. Only if the clinical condition 
of the participant worsens after Day 1 of the first isatuximab infusion and the participant’s 
condition requires intensive therapy, chemotherapy can be started earlier, based on investigator’s 
decision. Isatuximab schedule of administration will not be changed for later infusions. 
A bone marrow (BM) aspiration will be performed as follows: 
• Acute myeloid leukemia: 
- 
Once at screening  
- 
Once from Days 8 and 15 (optional, between the second and third isatuximab 
infusions, during Cycle 1 only) 
- 
Once from Days 22 to 29 (MRD [minimal residual disease]) 
- 
Once during hematological recovery (including MRD; at least 48 hours after the last 
injection of granulocyte colony-stimulating factor [G-CSF], when neutrophils reach 
1 G/L and platelet count 100 G/L; this last sample is recommended but not mandatory 
if peripheral blood blasts are present) 
• Acute lymphoid leukemia: 
- 
Once at screening (including MRD baseline sample)  
- 
Once from Days 8 and 15 (optional, between the second and third isatuximab 
infusions)  
- 
Once from Days 36 to 43 
- 
Once during hematological recovery (at least 48 hours after the last injection of 
G-CSF, when neutrophils reach 1 G/L and platelet count 100 G/L; this last sample is 
recommended but not mandatory if peripheral blood blasts are present). 
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In case hematological recovery cannot be reached for any reason, in both AML and ALL 
participants, BM aspiration could be done at any time if investigator does not expect any more 
hematological change and/or urgent need for therapeutic strategy decision. Any additional BM 
aspirations will be performed at the Investigator's discretion and should be reported in the 
electronic case report form (eCRF). 
The mandatory cytoreductive chemotherapy drugs to be administered before isatuximab infusion 
in patient with high tumor burden (WBC counts higher than 20 x 109/L and below 50 x 109/L with 
or without pulmonary leukostasis or significant organ involvement as per Investigator’s 
judgement) at screening are cyclophosphamide (ALL), hydroxyurea (AML), or cytarabine (AML) 
and dexamethasone. Refer to Section 6.5.1 for details.  
In order to have rapid control of the tumor burden, the administration of cyclophosphamide 
200 mg/m² is allowed (optional for both AML and ALL cohorts). Dexamethasone 10 mg/m²/day 
(or equivalent) before the first study intervention administration (at least 3 times, on Days -3, -2, 
and -1) is mandatory for ALL cohorts as a part of study treatment and optional for AML cohort. 
Administration of dexamethasone on Day 1 is mandatory in both cohorts as part of isatuximab 
premedication.  
Intrathecal prophylaxis is mandatory for all cohorts; the drugs that will be used 
(methotrexate/aracytine/steroids) are per investigator discretion (only one drug, or two or all 
three). 
When dexamethasone is administered at 10 mg/m2 per os, it can be divided in two daily doses. 
This does not apply to dexamethasone administration as part of isatuximab premedication. 
AML combination therapies: 
In the AML cohort, up to 2 cycles will be given as defined below. Refer to Figure 1 and 
Section 1.3 for days of investigational medicinal product (IMP) administration. 
Cycle 1 (first induction): 
• Isatuximab 20 mg/kg IV 
• Dexamethasone or equivalent IV or oral administration (PO) 10 mg/m2  
• Fludarabine 30 mg/m² IV  
• Cytarabine 2 g/m² IV  
• Intrathecal prophylaxis as per site practice  
• G-CSF (filgrastim or equivalent) 200 μg/m²/day SC or IV (optional) 
• Anthracyclines (mandatory in Cycle 1 Day 8, optional in Cycle 1 Days 10 and 12 and in 
Cycle 2), after administration of fludarabine - either liposomal daunorubicin 60 mg/m2 IV, 
nonliposomal daunorubicin 60 mg/m2, or idarubicin 10 mg/m2. The choice of 
anthracyclines is at the Investigator’s discretion (either liposomal daunorubicin, 
nonliposomal daunorubicin, or idarubicin) and the same anthracycline should be used 
throughout the study.  
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Cycle 2 (second induction): 
If the BM aspiration performed 1 week after the end of induction treatment shows less than 
20% blasts, a second cycle of combination therapy can be administered if neutrophils of 
≥500/mm3 and platelets of ≥50 000/mm3, while keeping the same schedule and doses. 
Anthracyclines are optional in Cycle 2 and will be administered at the Investigator's discretion. 
T-ALL and B-ALL combination therapies:  
In the ALL cohorts, the treatment period will include 1 induction and 1 consolidation cycle.  
Induction cycle:  
• Isatuximab 20 mg/kg IV 
• Intrathecal chemotherapy (as per site’s practice) 
• Dexamethasone or equivalent IV or PO 10 mg/m2  
• Vincristine 1.5 mg/m² IV (should not exceed 2 mg per infusion in any patient) 
• pegaspargase 1000 IU/m² (or L-asparaginase [Erwinase] 25 000 IU/m² only in case of 
confirmed hypersensitivity reaction to pegaspargase prior or during the study or loss of 
asparaginase activity and/or country availability and regulations, IM or IV  
• Anthracyclines - either: doxorubicin 25 mg/m² IV or mitoxantrone 10 mg/m² IV 
Consolidation cycle:  
• Isatuximab 20 mg/kg 
• Intrathecal chemotherapy (as per site’s practice) 
• Dexamethasone or equivalent IV or PO 10 mg/m2 
• Vincristine 1.5 mg/m² IV (should not exceed 2 mg per infusion in any patient) 
• Methotrexate 1000 mg/m² IV 
• pegaspargase 1000 IU/m² (or L-asparaginase [Erwinase] 25000 IU/m² only in case of 
confirmed hypersensitivity reaction to pegaspargase prior or during the study or loss of 
asparaginase activity and/or country availability and regulations), IM or IV 
• Cyclophosphamide 440 mg/m² IV 
• Etoposide 100 mg/m² IV 
Before starting consolidation cycle, the patient must have neutrophils of ≥500/mm3 and platelets 
of ≥50 000/mm3. 
Poststudy treatment period: 
After completion of these treatment periods, participants will be treated following the 
Investigator’s and site’s standard of care. 
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Number of participants: 
Three cohorts of participants will be treated: T-ALL, B-ALL, and AML. Approximately 
128 participants will be screened (32, 48, and 48, respectively) to achieve 104 assigned to study 
intervention (approximately 26, 39, and 39, respectively) and 96 evaluable participants for an 
estimated total of 24, 36, and 36 evaluable participants per cohort, respectively. In addition, for 
each cohort, at least 5 participants should be recruited for each of the following age groups: 
28 days to 4 years, 5 to 11 years, and 12 to 18 years. 
Intervention groups and duration: 
Intervention groups and duration are described in the following section. 
Investigational medicinal products 
 
AML Cohort 
Investigational 
medicinal 
products 
Formulation 
Route of 
administration 
Dose regimen 
Isatuximab 
Isatuximab drug product will be 
presented as a concentrate for solution 
for infusion in vials containing 20 mg/mL 
(500 mg/25 mL and 100 mg/5 mL) of 
isatuximab in 20 mM histidine, 10% (w/v) 
sucrose, and 0.02% (w/v) polysorbate 
80 at pH 6.0. It is packed in 30 and 6 mL 
glass vials fitted with elastomeric 
closure. Each vial will contain a nominal 
content of 500 or 100 mg isatuximab. 
The fill volume has been established to 
ensure removal of 25 or 5 mL. 
IV 
20 mg/kg weekly on Days 1, 8, and 
15 (mandatory for Cycles 1 and 2). 
Dexamethasone or 
equivalent 
Please refer to the product approved 
leaflet for further information.  
IV or PO 
Dexamethasone, is part of isatuximab 
premedication in the AML cohort, and 
will be given as premedication for 
prevention of infusion associated 
reactions before each administration of 
isatuximab, at least 15 to 30 minutes 
(but no longer than 60 minutes) prior to 
infusion Dexamethasone 10 mg/m2 
(maximum 20 mg) IV or PO on Days 1, 
8, and 15 during the induction period 
(mandatory for Cycle 1 and before first 
isatuximab infusion Cycle 2). It could 
be optionally used for rapid control of 
tumor burden on Days -3, -2 and -1. 
When dexamethasone is administered 
at 10 mg/m2 per os, it can be divided in 
two daily doses. This does not apply to 
dexamethasone administration as part 
of isatuximab premedication. 
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AML Cohort 
Investigational 
medicinal 
products 
Formulation 
Route of 
administration 
Dose regimen 
Fludarabine 
Please refer to the product approved 
leaflet for further information. 
IV 
30 mg/m² on Days 8 to 12, inclusive 
(mandatory for Cycles 1 and 2). 
Cytarabine 
Please refer to the product approved 
leaflet for further information. 
IV 
2 g/m² on Days 8 to 12, inclusive 
(mandatory for Cycles 1 and 2). 
Liposomal 
daunorubicin  
Please refer to the package insert for 
further information. 
IV 
60 mg/m², mandatory for Cycle 1 
Day 8, optional for Cycle 1 Days 10 
and 12, and optional for Cycle 2. 
Nonliposomal 
daunorubicin  
Please refer to the product approved 
leaflet for further information. 
IV 
60 mg/m², mandatory for Cycle 1 
Day 8, optional for Cycle 1 Days 10 
and 12, and optional for Cycle 2. 
Idarubicin 
Please refer to the product approved 
leaflet for further information. 
IV 
10 mg/m², mandatory for Cycle 1 
Day 8, optional for Cycle 1 Days 10 
and 12, and optional for Cycle 2. 
Granulocyte 
colony-stimulating 
factor (Filgrastim 
or equivalent) 
Please refer to the product approved 
leaflet for further information. 
SC or IV 
200 µg/m²/day on Days 7 to 12, 
inclusive; can be continued until 
neutrophil recovery (optional for 
Cycles 1 and 2). 
AML = acute myeloid leukemia; EU = Europe; IV = intravenous(ly); PO = oral; SC = subcutaneous; w/v = weight per volume. 
 
ALL cohorts 
Investigational 
medicinal 
products 
Formulation 
Route of 
administration 
Dose regimen 
Isatuximab 
Isatuximab drug product will be 
presented as a concentrate for solution 
for infusion in vials containing 
20 mg/mL (500 mg/25 mL and 
100 mg/5 mL) of isatuximab in 20 mM 
histidine, 10% (w/v) sucrose, and 
0.02% (w/v) polysorbate 80 at pH 6.0. It 
is packed in 30 and 6 mL glass vials 
fitted with elastomeric closure. Each vial 
will contain a nominal content of 500 or 
100 mg isatuximab. The fill volume has 
been established to ensure removal of 
25 or 5 mL. 
IV 
20 mg/kg weekly Days 1, 8, 15, 22, 
29, 43, and 57. 
Dexamethasone or 
equivalent 
Please refer to the product approved 
leaflet for further information. 
IV or PO 
Dexamethasone, being part of both 
backbone treatment regimen and 
isatuximab premedication, before 
each administration of isatuximab, at 
least 15 to 30 minutes (but no longer 
than 60 minutes) prior to infusion, will 
be given as premedication for 
prevention of infusion associated 
reactions consisting of 
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ALL cohorts 
Investigational 
medicinal 
products 
Formulation 
Route of 
administration 
Dose regimen 
dexamethasone 10 mg/m² 
(maximum 20 mg) IV or PO on 
Days -3, -2, and -1 before isatuximab 
administration, Days 1, 8, 15 to 19, 
22, and 29 to 33 during the induction 
period, and on Days 43 to 47 and 
57 during the consolidation period. 
Mitoxantrone 
Please refer to the product approved 
leaflet for further information. 
IV 
10 mg/m² on Days 8 and 9 of the 
induction period. 
Doxorubicin 
Please refer to the product approved 
leaflet for further information. 
IV 
25 mg/m² on Days 10, 17, 24, and 
31 of the induction period. 
Vincristine 
Please refer to the product approved 
leaflet for further information. 
IV 
1.5 mg/m² on Days 10, 17, 24, and 
31 during the induction period (should 
not exceed 2 mg per infusion in any 
patient); on Day 38 during the 
consolidation period. 
Pegaspargase 
Please refer to the product approved 
leaflet for further information. 
IM or IV 
1000 IU/m² on Days 10 and 24 during 
the induction period; Day 44 during 
the consolidation period. 
L-asparaginase 
(Erwinase) 
Please refer to the product approved 
leaflet for further information. 
IM or IV 
25000 IU/m² on Days 8, 10, 12, 15, 
17, 19, 22, 24, 26, 29, 31, 33 during 
induction and days 43, 45, 47, 50, 52, 
54 during consolidation, only in case 
of confirmed hypersensitivity reaction 
to pegaspargase prior or during the 
study or loss of asparaginase activity 
and/or country availability and 
regulations. 
Cyclophosphamide 
Please refer to the product approved 
leaflet for further information. 
IV 
440 mg/m² on Days 50 to 54 inclusive, 
during the consolidation period. 
Etoposide 
Please refer to the product approved 
leaflet for further information. 
IV 
100 mg/m² on Days 50 to 54, 
inclusive, during the consolidation 
period. 
Methotrexate 
Please refer to the product approved 
leaflet for further information. 
IV 
1000 mg/m² on Day 43 during the 
consolidation period. 
ALL = acute lymphoblastic leukemia; IM = intramuscular(ly); IV = intravenous(ly); PO = oral; w/v = weight per volume. 
 
Noninvestigational Medicinal Products 
The recommended isatuximab premedication agents are: montelukast, diphenhydramine 
(or equivalent), methylprednisolone, and acetaminophen (paracetamol) PO. Taking into 
consideration the disease context and the frequent use of steroids in acute leukemia, 
methylprednisolone will be replaced by dexamethasone. 
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The mandatory cytoreductive chemotherapy drugs to be administered before isatuximab infusion 
in patient with high tumor burden at screening are cyclophosphamide (ALL), hydroxyurea 
(AML), or cytarabine (AML) and dexamethasone. Refer to Section 6.5.1 for details. 
 
Noninvestigational 
medicinal products 
Formulationa 
Route of 
administration 
Dose regimen 
Paracetamol 
(acetaminophen) 
 
PO 
Paracetamol (acetaminophen) will be given 15 to 
30 minutes (but no longer than 60 minutes) before 
isatuximab infusion and at dose per weight as follows: 
≤10 kg: 7.5 mg/kg, >10 to 50 kg: 15 mg/kg, and 
>50 kg: 1 g. 
Diphenhydramine or 
equivalent 
 
IV 
Diphenhydramine or equivalent will be given at a dose 
of 1 mg/kg, 15 to 30 minutes (but no longer than to 
60 minutes) before isatuximab infusion. 
Montelukast 
 
PO 
Montelukast should be given to a child under adult 
supervision, before isatuximab infusion. The 
recommended dosage for pediatric participants: 
• 
Montelukast is not recommended for 
participants less than 2 years of age 
• 
4 mg for participants 2 to 5 years of age 
• 
5 mg for participants of 6 to 14 years of age 
• 
10 mg for participants ≥15 years of age 
Folinic acid 
(Leucovorin®) 
 
PO, IM, or IV 
Folinic acid should be administered 48 hours after the 
start of methotrexate infusion at a dose of 30 mg/m2 
PO, IM, or IV and 15 mg/m2 at 54 hours. Folinate 
rescue can be modified at the Investigator’s discretion. 
Dexamethasone 
 
PO or IV 
Dexamethasone is part of isatuximab premedication in 
the AML cohort only, and will be given as 
premedication for prevention of infusion associated 
reactions before each administration of isatuximab, at 
least 15 to 30 minutes (but no longer than 60 minutes) 
prior to infusion. Dexamethasone 10 mg/m2 (maximum 
20 mg) IV or PO on Days 1, 8, and 15 during the 
induction period (mandatory for Cycle 1 and before 
first isatuximab infusion at Cycle 2). 
IM = intramuscularl(ly); IV = intravenous(ly); PO = oral. 
a Noninvestigational medicinal products will be locally sourced and the formulation may vary. 
 
Statistical considerations: 
Sample size determination: 
A 2-stage Simon’s Min/Max design was used for sample size calculations in 3 cohorts (T-ALL, 
B-ALL, and AML). 
T-ALL: a maximum of 24 evaluable participants will be enrolled in this cohort. This sample size 
will provide 80% power to reject the null hypothesis that the complete response (CR + CRi) rate 
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is ≤60% if the CR rate is ≥80%, based on a 1-sided exact binomial test at a significance level of 
0.1: 
• Stage 1: 11 evaluable participants. Proceed to Stage 2 if more than 6 responses are 
observed. 
• Stage 2: 24 evaluable participants (13 additional participants). If more than 17 responses 
are observed among the 24 participants evaluable for efficacy, the null hypothesis will be 
rejected. 
B-ALL cohort and AML cohort: a maximum of 36 evaluable participants will be enrolled in each 
cohort. This sample size will provide 80% power to reject the null hypothesis that the complete 
response (CR + CRi) rate is ≤70% if the CR rate is ≥85%, based on a 1-sided exact binomial test 
at a significance level of 0.1: 
• Stage 1: 23 evaluable participants. Proceed to Stage 2 if more than 17 responses are 
observed. 
• Stage 2: 36 evaluable participants (13 additional participants). If more than 28 responses 
are observed among the 36 participants evaluable for efficacy, the null hypothesis will be 
rejected. 
Interim analysis: for each cohort, an interim analysis of efficacy, safety, and other data (including 
PK) will be performed after the completion of enrollment in Stage 1. Enrollment may be 
interrupted at the end of Stage 1 until the interim analysis is performed, unless the required 
number of responses is reached before completion of enrollment. 
A subgroup PK analysis will be performed after the first 20 participants of 2 years of age or more 
(at least 5 participants in the age group of 2 to 10 years, including approximately 3 patients 
between 2- and 5-year-old) are exposed to isatuximab. The dosage for participants aged less than 
2 years will be reassessed based on the results.  
Close safety monitoring of each participant is planned, and an independent Data Monitoring 
Committee (DMC) will regularly monitor participant safety. A first safety review by the DMC is 
planned after the first 10 participants will have completed at least 1 induction cycle. 
Main analysis population: the all-treated (AT) population will include all participants who receive 
at least 1 dose (even incomplete) of study intervention. This population is the primary population 
for safety parameters. The evaluable population will include participants from the AT population 
who received at least 1 full dose of isatuximab in Cycle 1 and who had at least one valid response 
value that is evaluable (5 infusions for ALL cohorts and 3 infusions for AML cohort). The 
evaluable population will be the primary population for the analyses of efficacy parameters. The 
PK population will include all participants from the AT population with at least one available 
concentration post-baseline (whatever the cycle and even if dosing is incomplete) with adequate 
documentation of dosing and sampling dates and times. The antidrug antibody (ADA) evaluable 
population will include all participants from the AT population with at least 1 nonmissing ADA 
result during the on-study observation period. 
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Response to treatment that will be analyzed is the response after 1 full dose of isatuximab in 
Cycle 1 (induction). 
General statistical approach 
Unless otherwise specified, analyses will be descriptive and performed on the AT population 
except for the analyses of efficacy endpoints that will utilize the evaluable population. Tables and 
listings will be presented for each cohort separately. 
Continuous data will be summarized using the number of available observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical and ordinal data will be 
summarized using number and percentage of participants. 
Analysis of primary endpoint:  
The CR rate, defined as the proportion of participants with CR or CR with incomplete peripheral 
recovery (CRi), will be summarized with descriptive statistics on the evaluable population. 
Confidence intervals will be computed using the Clopper-Pearson method. 
Analysis of secondary endpoints: 
The duration of response (DOR), event free survival (EFS), and overall survival (OS) will be 
analyzed using the Kaplan-Meier method. Among participants who achieved CR or CRi, the 
number and percentage of participants by MRD status will be provided in the evaluable 
population.  
The overall response rate (ORR) will be summarized with descriptive statistics. Confidence 
intervals will be computed using the Clopper-Pearson method. 
Individual PK parameters for isatuximab will be summarized. 
Receptor density and occupancy data: The descriptive statistics of receptor density and receptor 
occupancy will be summarized by cohort and overall as well as for best overall response 
(responders versus non-responders) will be calculated.  
Analysis of safety endpoints: 
Number (%) of participants experiencing treatment-emergent adverse events (TEAEs) by primary 
system organ class and preferred term will be summarized by the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0 grade (all grades 
and Grade ≥3) for the AT population. Similar tables will be prepared for treatment-related 
TEAEs, AEs of special interest, TEAEs leading to treatment discontinuation, TEAEs leading to 
dose modification, serious TEAEs, TEAEs with fatal outcome, and adverse events (AEs)/serious 
AEs (SAEs) occurring during the post-treatment dosing period. For participants with multiple 
occurrences of the same preferred term, the most severe grade within the observation period 
analyzed will be used. 
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Number (%) of participants experiencing infusion reactions by primary system organ class and 
preferred term will be summarized by NCI-CTCAE Version 5.0 grade. 
All the laboratory abnormalities will be graded according to the NCI-CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and by 
grades) using the worst grade during the on-treatment period will be provided for the AT 
population. 
Analysis of tertiary/exploratory endpoints: 
The number and the percentage of participants with positive/negative ADA will be provided. 
Cut-off dates/Planned database lock date 
For each cohort, the cut-off date for interim analysis (Stage 1) will be approximately 2 months 
after the last participant is treated (last participant last dose) in Stage 1. In case of stop of one of 
the cohorts after IA the actual date of the cut-off IA will be considered for the primary analysis of 
CR and other secondary endpoints. 
For each cohort, the cut-off date for the primary analysis of CR and other secondary endpoints 
will be approximately 6 months after the last participant has had their first study intervention 
administration. Then, the final analysis cut-off date for the analysis of OS and other secondary 
endpoints will be approximately 12 months after the last participant has had their first study 
intervention administration. 
Data Monitoring Committee: Yes 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design: AML cohort  
 
AML = Acute Myeloid Leukemia; BMA = bone marrow aspiration; G-CSF = granulocyte colony-stimulating factor; IT = intrathecal; IV = intravenous; max = maximum; MRD = minimal residual disease; PO = oral; 
SC = subcutaneous. 
a Fludarabine is given as a 30-minute infusion after G-CSF administration, if any. 
b Cytarabine is given as a 4-hour infusion, beginning 4 hours after start of fludarabine. 
c Anthracycline (a choice of liposomal daunorubicin 60 mg/m2, nonliposomal daunorubicin 60 mg/m2, or idarubicin 10 mg/m2) is given after administration of fludarabine. 
d Anthracycline administration on Day 8 in Cycle 1 is mandatory. Administrations on Cycle 1 Days 10 and 12 and on Cycle 2 are at the Investigator’s discretion. 
e G-CSF is optional and can be continued until neutrophil recovery. 
 
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Figure 2 - Graphical study design: ALL cohorts - induction  
 
 
ALL = Acute Lymphoblastic Leukemia; BMA = bone marrow aspiration; IM = intramuscular; IT = intrathecal; IV = intravenous(ly); max = maximum; MRD = minimal residual disease; PO = oral. 
a Dexamethasone is a part of both backbone treatment regimen and isatuximab premedication. 
b Mitoxantrone and Doxorubicin are given IV over 15 minutes.  
c Only in case of intolerance to pegaspargase prior or during the study or loss of asparaginase activity if known and/or country availability and regulations. If patient will present intolerance to Pegaspargase at 
Day 10, L-asparaginase (Erwinase) should be started at Week 4, in order to avoid cumulative toxicities, unless Investigator’s judgement is that dose infused at Day 10 was not significant. In this case Erwinase can 
be started earlier. 
Agent
Dosage
Application
Dexamethasonea 10 mg/m2 (max: 20 mg)
IV or PO
Isatuximab
20 mg/kg
IV
Mitoxantroneb
10 mg/m2
IV
or
Doxorubicinb
25 mg/m2
IV
Vincristine
1.5 mg/m2
IV
Pegaspargase
1000 IU/m2
IM or IV
L-asparaginasec
25000 IU/m2
IM or IV
IT chemotherapy
As per site practice
IT
Day
-21 -3
-2
-1
1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
BMA + MRD
From Days 8 to 15: optional BMA
Screening:
Week 5
Screening
Week 1
Week 2
Week 3
Week 4
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Figure 3 - Graphical study design - ALL cohorts - consolidation  
 
 
 
ALL = Acute Lymphoblastic Leukemia; BMA = bone marrow aspiration; IM = intramuscular; IT = intrathecal; IV = intravenous; max = maximum; MRD = minimal residual disease; PO = oral. 
a Dexamethasone is a part of both backbone treatment regimen and isatuximab premedication. 
b Methotrexate is infused over 36 hours and calcium folinate rescue started 48 hours from start of infusion. 
c Cyclophosphamide is given as a 1-hour infusion. 
d Etoposide is given as a 2-hour infusion. 
e Only in case of intolerance to pegaspargase prior or during the study or loss of asparaginase (Erwinase) activity if known and/or country availability and regulations. If patient will present intolerance to 
Pegaspargase at Day 10, L-asparaginase (Erwinase) should be started at Week 4, in order to avoid cumulative toxicities, unless Investigator’s judgement is that dose infused at Day 10 was not significant. In this 
case Erwinase can be started earlier. 
 
Agent
Dosage
Application
Week 
9
Hematological 
recovery
Dexamethasonea
10 mg/m2 (max: 20 mg) IV or PO
Isatuximab
20 mg/kg
IV
Methotrexateb
1000 mg/m2
IV
Cyclophosphamidec
440 mg/m2
IV
Etoposided
100 mg/m2
IV
Vincristine
1.5 mg/m2
IV
Pegaspargase
1000 IU/m2
IM or IV
L-asparaginasee
25000 IU/m2
IM or IV
IT chemotherapy
As per site practice
IT
Day
36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56
57
From Days 36 to 43: BMA + MRD
BMA + MRD 
Week 7
Week 8
Week 6
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
AML cohort 
Procedures 
Screening 
Induction period 
FU 
 
-D21 to  
-D1 
-D3 -D2 -D1 
D1 
D2 
D3 
D7 
D8 
D9 
D10 
D11 
D12 
D15 
D22-29 
Hematological 
recovery 
EOT 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
Physical examination every day during hospitalization or at each visit until hematological recovery 
X 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past and current medical 
conditionsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CNS leukemia 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood type 
phenotyping/genotyping, 
screend 
X 
IAT to be tested once after Cycle 1 Day 1d 
 
 
Pregnancy test (WOCBP 
only)e 
X 
 
 
 
X 
Monthly during the treatment period 
X 
X 
HIV, hepatitis B and Cf 
X 
 
 
 
As clinically indicated 
 
 
Hematologyg 
X 
 
 
 
Every 2 days until recovery 
X 
 
Coagulationh 
X 
 
 
 
Once weekly until recovery and if clinically indicated 
X 
 
Biochemistryi 
X 
 
 
 
Twice weekly until recovery 
X 
 
TSH, free/total T3 and 
free T4 
X 
 
 
 
 
 
 
Ferritin, CRP 
X 
 
 
 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
 
 
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Procedures 
Screening 
Induction period 
FU 
 
-D21 to  
-D1 
-D3 -D2 -D1 
D1 
D2 
D3 
D7 
D8 
D9 
D10 
D11 
D12 
D15 
D22-29 
Hematological 
recovery 
EOT 
 
Cytokinest 
X 
 
 
 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
 
 
Urinalysisj 
X 
 
 
 
Once weekly until recovery 
X 
 
12-lead ECG 
X 
 
 
 
If clinically indicated  
X 
X 
 
Vital signsk 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Chest X-rayu 
X 
 
 
 
X 
If clinically indicated 
 
 
Cardiac assessmentl 
X 
 
 
 
If clinically indicated  
X 
X 
 
Bone marrow for disease 
assessmentm 
X 
 
 
 
 
 
 
 
Optional, during Cycle 1 only 
 
X  
X 
 
 
MRD assessmentn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
X 
 
 
Extramedullary disease 
assessmento 
X 
(Optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
(Optional) 
X 
(Optional) 
 
Lumbar puncture with IT 
chemotherapy 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Isatuximab 
administration 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Dexamethasone or 
equivalent administration 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
Anthracycline 
administrationp 
 
 
 
 
 
 
 
 
X 
 
X 
(Optional) 
 
X 
(Optional) 
 
 
 
 
 
Fludarabine 
administration 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
Cytarabine 
administration 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
G-CSF administration 
(Optional) 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
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Procedures 
Screening 
Induction period 
FU 
 
-D21 to  
-D1 
-D3 -D2 -D1 
D1 
D2 
D3 
D7 
D8 
D9 
D10 
D11 
D12 
D15 
D22-29 
Hematological 
recovery 
EOT 
 
AE/SAE reviewq 
X 
X 
X 
X 
Continuously 
X 
Concomitant medications 
X 
X 
X 
X 
Continuously 
 
PK 
 
 
 
 
See flowchart (Table 1) 
 
ADA 
 
 
 
 
See flowchart (Table 1) 
 
CD38 biomarker 
 
 
 
 
See flowchart (Table 1) 
 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
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ALL cohorts: Screening and Induction 
Procedures 
Screening 
Induction 
 
-D21 to  
-D1 
-D3 -D2 -D1 
D1 
D3 D8 D9 D10 D12 D15 D16 D17 D18 D19 D22 D24 D25 D26 D29 D30 D31 D32 D33 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographya 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationb 
X 
 
 
 
Physical examination every day during hospitalization or at each visit until hematological recovery 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Past and current medical conditionsc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CNS leukemia assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood type phenotyping/genotyping, screend 
X 
IAT to be tested once after Day 1d 
Pregnancy test (WOCBP only)e 
X  
 
 
 
X  
Monthly during the treatment period 
HIV, hepatitis B and Cf 
X 
 
 
 
As clinically indicated 
Hematologyg 
X 
 
 
 
Every 2 days until recovery 
Coagulationh 
X 
 
 
 
Once per week until recovery and if clinically indicated 
Biochemistryi 
X 
 
 
 
Twice weekly until recovery 
TSH, free/total T3, and free T4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ferritin, CRP 
X 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
Cytokinest 
X 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
Urinalysisj 
X 
 
 
 
Once per week until recovery 
12-lead ECG 
X 
 
 
 
If clinically indicated 
Vital signsk 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Chest X-rayu 
X 
 
 
 
X 
If clinically indicated 
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Procedures 
Screening 
Induction 
 
-D21 to  
-D1 
-D3 -D2 -D1 
D1 
D3 D8 D9 D10 D12 D15 D16 D17 D18 D19 D22 D24 D25 D26 D29 D30 D31 D32 D33 
Cardiac assessmentl 
X 
 
 
 
If clinically indicated 
Bone marrow for disease assessmentm 
X 
 
 
 
 
 
Optional 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRD assessmentn 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Extramedullary disease assessmento 
X 
(Optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture with IT chemotherapy 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab administration 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
Dexamethasone or equivalent administration 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
Mitoxantrone administration (if doxorubicin is not used) 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Doxorubicin administration (if mitoxantrone is not used) 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Vincristine administration 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Pegaspargase administrationq 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
L-asparaginase (Erwinase) administrationq 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
AE/SAE reviewr 
X  
X 
X 
X 
Continuously 
Concomitant medications 
X 
X 
X 
X 
Continuously 
PK 
 
 
 
 
See flowchart (Table 2) 
ADA 
 
 
 
 
See flowchart (Table 2) 
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ALL cohorts: Consolidation and Follow-up 
Procedures 
Consolidation 
FU 
 
D36 
D38 
D43 
D44 
D45 
D46 
D47 
D50 
D51 
D52 
D53 
D54 
D57 
Hematological 
recovery 
EOT 
 
Physical examinationb 
Physical examination every day during hospitalization or at each visit until hematological recovery 
X 
 
Hematologyg 
Every 2 days until recovery 
X 
 
Coagulationh 
Once per week until recovery and if clinically indicated 
X 
 
Biochemistryi 
Twice weekly until recovery 
X 
 
Ferritin, CRP 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
 
 
Cytokinest 
To be repeated in case of CRS occurrence of any grade, at 3 days and 1 week after CRS occurrence 
 
 
Urinalysisj 
Once per week until recovery 
X 
 
12-lead ECG 
If clinically indicated 
X 
X 
 
Vital signsk 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood type 
phenotyping/genotyping, 
screend 
IAT to be tested once after Day 1d 
 
 
Pregnancy test 
(WOCBP only)e 
Monthly during the treatment period 
X 
X 
HIV, hepatitis B and Cf 
As clinically indicated 
 
 
Chest X-rayu 
If clinically indicated 
 
 
Cardiac assessmentl 
If clinically indicated 
X 
X 
 
Bone marrow for disease 
assessmentm 
X (from Days 36 to 43) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
MRD assessmentn 
X (from Days 36 to 43) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Extramedullary disease 
assessmento 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
(Optional) 
X 
(Optional) 
 
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Procedures 
Consolidation 
FU 
 
D36 
D38 
D43 
D44 
D45 
D46 
D47 
D50 
D51 
D52 
D53 
D54 
D57 
Hematological 
recovery 
EOT 
 
Lumbar puncture with IT 
chemotherapy 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab administration 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Dexamethasone or equivalent 
administration 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Vincristine administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Methotrexate administration 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pegaspargase administrationq 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
L-asparaginase (Erwinase) 
administrationq 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
Cyclophosphamide 
administration  
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
Etoposide administration 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
AE/SAE reviewr 
Continuously 
X 
Concomitant medications 
Continuously 
 
PK 
See flowchart (Table 2) 
 
ADA 
See flowchart (Table 2) 
 
CD38 biomarker 
See flowchart (Table 2) 
 
Disease status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AABB = American Association of Blood Banks; ADA = antidrug antibody; AE = adverse event; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; aPTT = activated partial thromboplastin time; 
B = B-cell; BM = bone marrow; CNS = central nervous system; CR = complete response; CRi = complete response with incomplete peripheral recovery; CT = computed tomography; D = Day; DNA = deoxyribonucleic 
acid; DTT = dithiothreitol; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end of treatment; FU = follow-up; G-CSF = granulocyte 
colony-stimulating factor; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; IAT = indirect antiglobulin test; IMP = investigational medicinal product; INR = international normalized ratio; 
IT = intrathecal; IV = intravenous(ly); LBL = lymphoblastic lymphoma; LDH = lactic acid dehydrogenase; MRD = minimal residual disease; MUGA = multigated acquisition scan; PET = positron emission tomography; 
PK = pharmacokinetics; PT = prothrombin time; RNA = ribonucleic acid; SAE = serious adverse event; T = T-cell; WOCBP = women of childbearing potential.  
a Demography: date of birth (age derived), gender, and race (if local regulation allows). 
b Physical examination: Examination of major body systems including weight, neurological examination, digestive, skin/mucosae, mediastinal, testicular involvements, respiratory, hepatomegaly, splenomegaly, 
lymphadenopathy, and ECOG or Lansky score (this assessment will be collected during treatment if clinically relevant). Height will be measured only at screening. 
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c Past and current medical condition: date of initial diagnosis, type of disease (T-ALL/T-LBL, B-ALL, B-LBL, AML, immunophenotyping and cytogenetic, molecular profile), previous antileukemia treatment (reason 
for discontinuation, date of relapse, and best overall response to prior treatments), risk group as per site institutional practice (including clinical factors but also cytogenetic and molecular ones; as an example, but 
not limited to: MLL rearrangement/KMT2A rearrangement; Ph+ [BCR/ABL translocation]; Hypodiploidy; IKZF1 del; TCF3-HLF [t(17,19) ], Abnormalities chromosome 3, 5, 7; FLT3 mutated; 11q23 [KMT2A] 
rearrangement; T(6,9); TP53 mut). 
d Blood type phenotyping/genotyping: Blood typing and complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is recommended, if not available, the site’s standard will be followed) if not already done, and 
antibody screening (IAT) to be obtained prior to the start of the study treatment. After the start of the study treatment, a new IAT assessment will be performed once. If the second test is positive, a DTT test should 
be performed (in accordance with Section 10.6.6). Results of IAT (and DTT test, if applicable) will be recorded in the eCRF, including those performed prior to any transfusion during study intervention. 
Transfusions are to be recorded in the eCRF. The transfusion service should be made aware that the participant is receiving an antiCD38 treatment (isatuximab). During the study intervention, the transfusion 
service should follow the recommendations issued in the AABB bulletin in case a blood red cells transfusion is needed. The web link to the AABB bulletin will be indicated on the study participant card. Participants 
should keep their study participant card with their blood type card together throughout the duration of the study intervention. 
e Pregnancy testing should be carried out in WOCBP as follows: for ALL induction: within 2 weeks prior to first dose, Day 1 (predose), and Day 30 (predose). For ALL consolidation: on Day 57 (predose), end of 
treatment (30 days after last dose), and monthly during the follow-up period for 180 days (6 months) after the last dose of isatuximab, or 12 months after the last dose of cyclophosphamide. For AML: within 
2 weeks prior to first dose, Cycle 1 Day 1 (predose), Cycle 2 Day 1 (predose), end of treatment (30 days after last dose), and monthly during the follow-up period for 180 days (6 months) after the last dose of 
isatuximab, or 12 months after the last dose of cyclophosphamide. 
f 
Viral serologies: HIV serology will be collected in countries where required by local regulations. Screening with serological tests for hepatitis B and C should  be done prior to randomization/enrollment (HBsAg, 
anti-HBs, anti-HBc (total and IgM), anti-HCV, HCV RNA level) or at any time if not performed within 1 year. Patient not having been tested for HBV/HCV at screening that are still on treatment at the time of the 
amended protocol 4 will need to be tested additionally for HBsAg, anti HBs, anti-HBc (total and IgM), anti-HCV, HCV RNA level. Patients with anti-HBc positive (HBsAg positive patients being not eligible), HBV 
DNA testing by PCR will also be done at baseline. 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.  
g Hematology: Hemoglobin, hematocrit, white blood cell count with differential, percentage of blasts, platelet count (please see Table 15 for a complete list). Hematology sample collection is recommended every 
2 days, but mandatory at least weekly. Hematology test including WBC with differential is mandatory for all patients prior to the first isatuximab infusion on Day 1. Hematology test should be assessed prior to the 
first isatuximab infusion. In case of high tumor burden at screening requiring cytoreductive chemotherapy or occurrence of CRS event, WBC with differential count must be repeated every day. 
h Coagulation: D-dimer, fibrinogen, PT (and INR), and aPTT. In ALL patients on treatment with pegaspargase or L-asparaginase (Erwinia) weekly (Section 10.8) monitoring of INR, PTT, fibrinogen and AT-III must 
be performed and fibrinogen; AT-III may be substituted if necessary. 
i 
Biochemistry: glucose (fasting; if the participant has not fasted overnight, glucose should not be measured), albumin, total protein, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, 
bilirubin (total and direct), LDH, sodium, potassium, total calcium, corrected and ionized calcium (corrected calcium = total calcium level in milligrams per deciliter + 0.8 × [4 albumin in grams per deciliter]; ionized 
calcium level in milligrams per deciliter = total calcium level in milligrams per deciliter + 0.02*[40 - albumin in grams per deciliter]), phosphorus, uric acid, blood urea nitrogen, serum creatinine, amylase (please see 
Table 15 for a complete list). Prior to the first infusion on Day 1, potassium, phosphorus, uric acid, corrected calcium are to be assessed to rule out tumor lysis syndrome. If it is not possible to organize this test 
(potassium, phosphorus, uric acid, corrected calcium) to be done and assessed prior to infusion on Day 1, it can be done on Day -1 or Day -2, and only in case this is not possible – on Day -3.   In case of 
CRS/TLS occurrence, potassium, phosphorus, uric acid, corrected calcium, blood urea nitrogen, creatinine are to be repeated every day until resolution of the event. 
j 
Urinalysis: Dipstick only. If other analytes are collected based on clinical context, they must be reported in the eCRF  
k Vital signs: Blood pressure, heart rate, temperature, and respiration rate performed at screening and at preinfusion, 1 hour after starting the infusion, and at the end of isatuximab infusion, 2 hour after every 
isatuximab infusion and as clinically indicated. In case of high tumor burden at screening requiring cytoreductive chemotherapy or occurrence of CRS event, continuous monitoring of vital signs is required as per 
site clinical practice. 
l 
Cardiac assessment: Left ventricular ejection fraction measured by echocardiogram, cardiac scintigraphy, or MUGA. 
m Bone marrow for disease assessment: To be performed once at screening, once between Days 8 and 15 (optional), once at the end of induction for ALL (first week of consolidation), once between Days 22 and 
29 for AML, and once at the time of complete hematological recovery (at least 48 hours after the last injection of G-CSF, when neutrophils reach 1 G/L and platelet count 100 G/L). In case hematological recovery 
cannot be reached for any reason, in both AML and ALL participants, BM aspiration could be done at any time if investigator does not expect any more hematological change and/or urgent need for therapeutic 
strategy decision. No BM assessment is necessary if nonresponse or progressive disease can be diagnosed with peripheral blood evaluation, or if the BM assessment is considered noncontributory by the 
Investigator. Any additional BM aspirations will be performed at the Investigator’s discretion and should be reported in the eCRF. If BM aspirate fails, BM biopsy could be an option. 
n MRD assessment: For ALL, to be performed with BM aspiration at screening and with peripheral blood samples at the end of induction (between Days 36 and 43), at the time of hematological recovery, and/or at 
the time of each BM aspiration for disease assessment if CR or CRi is achieved. For AML, to be performed with BM aspiration samples at the time of hematological recovery or between Days 22 and 29, and/or at 
the time of each BM aspiration for disease assessment if CR or CRi is achieved.  
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o Extramedullary disease assessment: For ALL, CT, PET-CT or PET-MRI scans are suggested to be performed at screening and at hematological recovery or at EOT (if no hematological recovery) if 
lymphomatous involvement is suspected. If not done, PET-CT or PET-MRI scan is suggested to be performed at screening if lymphomatous involvement is present. If positive at screening, PET-CT or PET-MRI 
will be repeated at the time of CR in BM. For AML, physical examination may be used for specific locations when imaging is not appropriate (ex cutaneous location). CT, PET-CT or PET-MRI can be performed if 
clinically indicated. 
p Anthracycline: The choice of anthracycline (liposomal daunorubicin, nonliposomal daunorubicin, or idarubicin) is at the Investigator’s discretion and the same anthracycline should be used throughout the study. 
The administration of Day 8 in Cycle 1 is mandatory. Other administrations of anthracycline, including Day 8 in Cycle 2, are at the Investigator’s discretion. 
q Only in case of confirmed hypersensitivity to pegaspargase prior or during the study or loss of asparaginase and/or country availability and regulations L-asparaginase (Erwinase) may be used. Hypersensitivity to 
pegaspargase and/or loss of asparaginase activity should be documented in the eCRF. 
r 
AE/SAE: The period of safety observation extends from the date informed consent is signed, until the time of hematological recovery or a new anticancer therapy is started, whichever is first. Related AEs and any 
SAE ongoing at the end of treatment must be followed until resolution or stabilization. Any AE or SAE assessed as related to study intervention that are new during the follow-up period will be reported and followed 
until recovery or stabilization. 
s Concomitant treatments: All treatments being taken by the participant for up to 7 days prior to the first dose of study intervention and at any time during the treatment period and for up to hematological recovery 
are regarded as prior and concomitant treatments. Then, only further anticancer therapy will be reported. 
t 
Following cytokines will be collected at baseline – proinflammatory cytokine panel (including interleukin IL2, IL6, IL8, IL10, interferon (IFN) γ, tumor necrosis factor (TNF) alpha). In case of CRS occurrence, 
cytokines are to be repeated 3 days and 1 week after CRS occurrence. 
u Chest X-ray: Prior to the first infusion on Day 1, should be done and assessed. If it is not possible to organize on Day 1 prior it can be done on Day -1 or Day -2.  In case of high tumor burden at screening or 
occurrence of CRS event, chest X-ray must be repeated every day. CT-scan can also be used based on site’s clinical practice. 
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PK and PD flowcharts 
Table 1 - PK and PD flowchart - AML cohort  
 
 
Study period 
Procedure 
 
Induction 
 
FUP 
Day within cycle 
 
D1 
D4 
D8 
D15 
30 days after last 
isatuximab 
admininistration 
 (±5 days)  
90 days after last 
isatuximab 
administration 
(±5 days) 
Time (decimal hours) 
 
SOI 
EOI 
EOI +4 h 
72 h 
SOI 
SOI 
EOI 
EOI +1 h 
 
 
Indicative clock time 
 
8:00 AM 
12:00 PM 
4:00 PM 
8:00 AM 
8:00 AM 
8:00 AM 
12:00 PM 
1:00 PM 
 
 
Time window 
 
-120 min, SOI 
±10 min 
±30 min 
±5 h 
-10 min, SOI -10 min, SOI ±10 min 
±10 min 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab (IV infusion) 
 
X------------------X 
 
 
X 
X--------------------X 
 
 
 
Pharmacokineticsa 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab 
 
P00e 
P01c 
P02 
P03 
P04e 
P05e 
P06c 
P07 
PF0 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
Antidrug antibodyd 
 
AB00e 
 
 
 
 
AB01e 
 
 
ABF0 
ABF1 
Pharmacodynamics 
CD38 Receptor density 
and occupancy in blood 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
 AB = antibody; ABF = antibody at end of treatment or follow-up; ADA = antidrug antibody; D = Day; EOI = end of infusion; FUP = follow-up period (post-treatment safety); h = hour; ID = identification; 
IV = intravenous; min = minute; P = plasma; PF = plasma at end of treatment or follow-up; PK = pharmacokinetic; SOI = start of infusion. 
Note: In case a Cycle 2 (second induction) is administered, PK samples must be taken only at predose on Days 1 and 15. 
a Refer to the Laboratory Manual for sample collection, processing, and shipping procedures. 
b Sample should be collected just before isatuximab administration or up to 3 days prior to it. 
c Sample collected just before actual end of infusion. 
d If the ABF1 ADA result is positive or inconclusive, no additional ADA are required. 
e PK and ADA predose samples must be collected just before administration of isatuximab. 
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Table 2 - PK and PD flowchart ALL cohorts  
 
 
Study period 
Procedure 
 
Induction 
Consolidation 
 
FUP 
Day within cycle 
 
D1 
D4 
D8 
D15 
D22 
D29 
D43 
D57 
30 days after 
last isatuximab 
administration 
(±5 days)  
90 days after 
last isatuximab 
administration 
(±5 days) 
Time (decimal hours) 
 
SOI 
EOI 
EOI 
+4 h 
72 h 
SOI 
SOI 
SOI 
SOI 
EOI 
EOI  
+1 h 
SOI 
SOI 
 
 
Indicative clock time 
 
8:00 AM 12:00 PM 4:00 PM 8:00 AM 8:00 AM 8:00 AM 8:00 AM 8:00 AM 12:00 PM 1:00 PM 8:00 AM 8:00 AM 
 
 
Time window 
 
-120 min, 
SOI 
±10 min ±30 min 
± 5 h -10 min, 
SOI 
-10 min, 
SOI 
-10 min, 
SOI 
-10 min, 
SOI 
±10 min ±10 min -10 min, 
SOI 
-10 min, 
SOI 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Isatuximab (IV infusion) 
 
X-------------X 
 
 
X 
X 
X 
X 
 
 
X 
X 
 
 
Pharmacokineticsa 
 
Isatuximab 
 
P00e 
P01c 
P02 
P03 
P04e 
P05e 
P06e 
P07e 
P08c 
P09 
P10e 
P11e 
PF0 
 
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antidrug antibodyd 
 
AB00e 
 
 
 
 
AB02e 
 
AB03e 
 
 
AB04e 
AB05e 
ABF0 
ABF1 
Pharmacodynamics 
CD38 Receptor density 
and occupancy in blood 
 
Xb 
 
 
 
 
Xb 
 
 
 
 
 
 
 
 
 AB = antibody; ABF = antibody at end of treatment or follow-up; ADA = antidrug antibody; D = Day; EOI = end of infusion; FUP = follow-up period (post-treatment safety); h = hour; ID = identification; 
IV = intravenous; min = minute; P = plasma; PF = plasma at end of treatment or follow-up; PK = pharmacokinetic; SOI = start of infusion. 
a Refer to the Laboratory Manual for sample collection, processing, and shipping procedures. 
b Sample should be collected just before isatuximab administration or up to 3 days prior to it. 
c Sample collected just before actual end of infusion. 
d If the ABF1 ADA result is positive or inconclusive, no additional ADA are required. 
e PK and ADA predose samples must be collected just before administration of isatuximab. 
 
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2 
INTRODUCTION  
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer, 
including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), has been 
slowly increasing since 1975 (1).  
Acute lymphoblastic leukemia is the most common cancer diagnosed in children and represents 
approximately 25% of cancer diagnoses among children younger than 15 years of age (2, 3). 
A sharp peak in ALL incidence is observed among children 2 to 3 years of age (>90 cases per 
1 million per year), with rates decreasing to fewer than 30 cases per 1 million by 8 years of age 
(2, 3). The incidence of ALL among children 2 to 3 years of age is approximately 4-fold greater 
than that for infants and is likewise 4- to 5-fold greater than that for children 10 years of age and 
older (2, 3). 
Approximately 20% of childhood leukemias are of myeloid origin, and they represent a spectrum 
of hematopoietic malignancies (4). The majority of myeloid leukemias are acute. 
Dramatic improvements in survival have been achieved in children and adolescents with cancer 
(1). Between 1975 and 2010, childhood cancer mortality decreased by more than 50% (1, 2, 3). 
For ALL, the 5-year survival rate has increased over the same time from 60% to approximately 
90% for children younger than 15 years of age and from 28% to more than 75% for adolescents 
aged 15 to 19 years (5). For AML, the 5-year survival rate increased over the same time from less 
than 20% to 68% for children younger than 15 years of age and from less than 20% to 57% for 
adolescents aged 15 to 19 years (1). 
2.1 
STUDY RATIONALE  
Acute Lymphoblastic Leukemia 
In case of relapsed or refractory (R/R) acute leukemia, the outcome after first salvage therapy 
including transplantation is poor, whatever the treatment prescribed, and a number of new agents 
are currently being studied in this setting. Leukemia relapse represents the outgrowth of a clonal 
cell population not completely eliminated by treatment. 
For patients with R/R disease after an initial complete response (CR), the approach to second-line 
treatment may depend on duration of the initial response. For late relapses (ie, ≥36 months from 
initial diagnosis), re-treatment with the same induction regimen may be a reasonable option. 
Participation in a clinical study is preferred, but in absence of a clinical study, the patient may be 
considered for second-line therapy with induction regimens not previously used. 
Standard salvage regimens for relapsed ALL are still mostly based on different combinations of 
the same agents used in frontline therapy in various doses and schedules (6, 7). Many groups 
adopt treatment strategies consisting of risk-adapted, alternating short-course multiagent systemic 
and intrathecal (IT) chemotherapy, in some cases together with cranial/craniospinal irradiation, 
and conventional maintenance therapy.  
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Overall, remission can be achieved in >70% of early relapses and in up to 96% of late bone 
marrow (BM) relapses. Response rates cluster approximately 40% in second and subsequent 
relapse, although only 19 of 235 survivors (8%) have been reported among patients achieving a 
third remission after a second BM relapse (6, 7). 
A United Kingdom-based randomized study of ALL patients in first relapse compared reinduction 
with a 4-drug combination using idarubicin versus mitoxantrone (8). There was no difference in 
second CR rates or end-reinduction minimal residual disease (MRD) levels between the 2 study 
arms. A significant improvement in overall survival (OS) in the mitoxantrone arm (69% versus 
45%, p=.004) due to decreased relapse after transplantation was reported. 
Of the children and adolescents diagnosed with precursor B-cell (B)-ALL each year (based on 
2009 Surveillance, Epidemiology, and End Results Program data), approximately 25% will 
experience relapse or fail to achieve remission. The majority (85%) of those in first relapse will 
achieve a second remission (9). Response to chemotherapy decreases with each successive 
relapse. Approximately 44% of pediatric patients with a second marrow relapse of ALL and 
27% of those with a third marrow relapse achieve a subsequent complete remission. Five-year 
disease-free survival (DFS) rates in patients with a second and third remission are reported to be 
27% and 15%, respectively (9). 
Two percent of children with ALL who do not achieve a remission are classified as having 
refractory disease (10) and suffer a worse prognosis compared with patients with relapsed ALL. 
Patients with relapsed T-cell (T)-ALL have much lower rates of achieving a second CR with 
standard reinduction regimens than patients with precursor B-cell phenotype (7). 
Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be 
successful and lead to survival after hematopoietic stem cell transplantation (HSCT). Approaches 
have traditionally included the use of drug combinations distinct from the first attempt at 
treatment; these regimens often contain newer agents under investigation in clinical studies. 
Although survival is progressively less likely after each attempt, 2 to 4 additional attempts are 
often pursued, with diminishing levels of success measured after each attempt (9). 
For patients with T-cell ALL (T-ALL) who achieved remission after BM relapse, outcomes with 
postreinduction chemotherapy alone have generally been poor (11), and these patients are usually 
treated with allogeneic HSCT in a second CR, regardless of time to relapse. At 3 years after 
allogeneic transplant, OS for T-ALL in a second remission was reported to be 48% and DFS was 
46% (12).  
Treatment Options for Second and Subsequent Bone Marrow ALL Relapse 
Although there are no studies directly comparing chemotherapy with HSCT for patients in a third 
or subsequent CR, because cure with chemotherapy alone is rare, transplant is generally 
considered a reasonable approach for those achieving remission. Long-term survival for all 
patients after a second relapse is particularly poor, in the range of less than 10% to 20% (13). 
One of the main reasons for this is failure to obtain a third remission. Numerous attempts at novel 
combination approaches have resulted in only about 40% of children in a second relapse 
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achieving remission (14). However, 2 studies that added bortezomib to standard reinduction 
agents in multiple relapsed refractory patients have resulted in 70% to 80% complete remission 
rates (15, 16). If these patients achieve CR, HSCT has been shown to cure 20% to 35%, with 
failures occurring due to high rates of relapse and transplant-related mortality (17, 18, 19, 20, 21). 
Central Nervous System-Directed Therapy for Childhood ALL 
Because the central nervous system (CNS) is a sanctuary site (ie, an anatomic space that is poorly 
penetrated by many of the systemically administered chemotherapy agents typically used to treat 
ALL), specific CNS-directed therapies must be instituted early in treatment to eliminate clinically 
evident CNS disease at diagnosis and to prevent CNS relapse in all patients. Historically, survival 
rates for children with ALL improved dramatically after CNS-directed therapies were added to 
treatment regimens. 
Acute Myeloid Leukemia 
Despite second remission induction in over half of children with AML treated with drugs similar 
to drugs used in initial induction therapy, the prognosis for a child with recurrent or progressive 
AML is generally poor (22, 23). 
Approximately 50% to 60% of relapses occur within the first year after diagnosis, with most 
relapses occurring by 4 years from diagnosis (22). The vast majority of relapses occur in the bone 
marrow, and CNS relapse is very uncommon (22). 
Treatment options for children with recurrent AML may include chemotherapy and HSCT. 
Regimens that have been successfully used to induce remission in children with recurrent AML 
have commonly included high-dose cytarabine given in combination with the following agents: 
• Mitoxantrone (23) 
• Fludarabine and idarubicin (24, 25, 26) 
• L-asparaginase (Erwinase) (27) 
• Etoposide 
• Liposomal daunorubicin. A study by the International Berlin Frankfurt Munster Group 
compared fludarabine, cytarabine, and granulocyte colony-stimulating factor (G-CSF) 
with fludarabine, aracytine, G-CSF (FLAG) plus liposomal daunorubicin. Four-year 
OS was 38%, with no difference in survival for the total group; however, the addition of 
liposomal daunorubicin increased the likelihood of obtaining a remission and led to 
significant improvement in OS in patients with core-binding factor mutations (82%, FLAG 
plus liposomal daunorubicin versus 58%, FLAG; p=.04) (28). Regimens built upon 
clofarabine have also been used as have regimens of 2-chloroadenosine (29). The COG 
AAML0523 (NCT00372619) study evaluated the combination of clofarabine plus 
high-dose cytarabine in patients with relapsed AML; the response rate was 48% and the 
OS rate, with 21 of 23 responders undergoing HSCT, was 46%. Minimal residual disease 
before HSCT was a strong predictor of survival (30) 
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Central Nervous System Prophylaxis for AML 
Therapy with either radiation or IT chemotherapy has been used to treat CNS leukemia present at 
diagnosis and to prevent later development of CNS leukemia. The use of radiation has essentially 
been abandoned as a means of prophylaxis because of the lack of documented benefit and 
long-term sequelae. The Children’s Oncology Group has used single-agent cytarabine for both 
CNS prophylaxis and therapy (31). Other groups have attempted to prevent CNS relapse by using 
additional IT agents (32). 
Unmet Medical Need 
The population targeted by this pediatric study includes R/R ALL in a first and second bone 
marrow relapse, including relapse after allogeneic HSCT. This population has a poor prognosis 
and few effective standard treatment options. Existing treatment regimens for this disease rely 
heavily on high-intensity chemotherapy that consists of combinations of a few classes of drugs, 
eg, antimetabolites, anthracyclines, and alkylating agents. For patients who are refractory after 
such treatment, or who relapse, there is a higher probability of cross-resistance to available 
chemotherapeutic agents. Patients who undergo an allogeneic HSCT usually have received very 
intensive multidrug treatment regimens for induction/reinduction, consolidation, and additional 
conditioning followed by allogeneic HSCT, a procedure that is also associated with severe 
adverse reactions.  
Acute leukemia is a heterogeneous disease, and there is a clear need for increased efficacy within 
several poorer-prognosis subgroups, particularly patients with treatment-refractory or relapsed 
disease, including infants and adolescents. Novel agents are needed that provide a higher response 
rate or better quality of response than conventional drugs in order to contribute substantially to 
cure, without adding toxicities. 
Currently, acute leukemia therapy relies essentially on agents displaying only cytotoxic 
properties. Although cytotoxic drugs have proved their efficacy, the use of many of these 
compounds is limited due to: 
• A lack of selectivity, which can result in severe damage to healthy tissues, especially to 
hematopoietic cells and gastrointestinal mucosa (tissues with high cell proliferation rates). 
• Drug resistance, which can be either intrinsic or readily developed (acquired), mainly 
because the genetic mutations and the heterogeneity of the tumor cells allow the tumor to 
have a great adaptability to stress. 
Therefore, there is a need to find new systemic treatment for cancer and new approaches are now 
being tested: compounds targeting specific protein/components of the tumor cells, which do not 
exist on normal cells or are over-expressed in cancer cells. An effective biologic agent could 
represent a valuable treatment option for these patients. 
This approach was provided by blinatumomab, a genetically modified antibody that contains 
fragments that recognize both CD19 and CD3 (which is present on all T-cells) and therefore 
brings T-cells into direct contact with B-cell ALL (B-ALL) cells, allowing the cytotoxic T-cells to 
kill them (33). The Food and Drug Administration (FDA) has granted an accelerated approval to 
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blinatumomab (Blincyto) for the treatment of pediatric and adolescent patients with Philadelphia 
chromosome (Ph)-negative R/R B-cell precursor acute ALL. The approval of the anti-CD19 
immunotherapy in this setting was based on data from a single-arm Phase 1/2 study, known as 
Study 205, which met its primary Phase 2 endpoint of complete remission within the first 2 cycles 
of blinatumomab. In previously published data from Phase 1 of Study 205, the complete remission 
rate was approximately 32% among 41 patients with R/R ALL (34).  
Pharmacological rationale 
Preclinical rationale 
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2.2 
BACKGROUND  
Isatuximab (SAR650984) is an immunoglobulin G1 class naked monoclonal antibody (mAb) 
binding selectively the human CD38 membrane protein, which is expressed in a number of 
hematological malignancies from B-lymphocyte, T-lymphocyte, and myeloid origin. 
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Isatuximab has the capacity to kill CD38 positive tumor cells by a combination of 4 distinct 
biological mechanisms: 
• Antibody-dependent cell mediated cytotoxicity 
• Antibody-dependent cellular phagocytosis 
• Complement-dependent cytotoxicity 
• Pro-apoptotic activity 
Isatuximab demonstrated in vivo antitumor activity as a single agent and in combination with 
reference treatments on several CD38-positive tumor models. In addition, isatuximab 
demonstrated antitumor activity against primary patient cells ex vivo supporting its clinical 
evaluation in CD38+ multiple myeloma (MM), non-Hodgkin’s lymphoma, and leukemia patients 
including ALL of both B- and T-cell origin and AML. 
Isatuximab is being developed for the treatment of a number of hematological malignancies 
expressing the CD38 antigen, particularly MM in adults.  
For more details on clinical studies, please refer to the IB. 
In general, isatuximab is well tolerated clinically with a manageable safety profile. The most 
common adverse reactions are infusion reactions (IRs) which are clinically manageable. The IRs 
are not dose dependent and tend to occur most frequently during the first infusion. Participants 
who experience Grade 2 IRs may subsequently resume isatuximab treatment after receiving 
supportive care as needed. Both the mandatory prophylaxis against IRs and the additional 
medication in participants in whom the infusion of isatuximab was temporarily interrupted 
because of such reactions limit the risk of recurrence and have allowed participants to continue 
their therapy without sequelae.  
Overall, the most current findings from the clinical experience acquired from multiple clinical 
studies with isatuximab have not identified any potential safety risks or concerns in addition to 
those described in the IB of isatuximab. 
When given in combination with other anticancer agents, the overall safety profile of the 
combinations appears consistent with the safety profile of each drug individually. 
Together with efficacy and pharmacokinetic (PK)/pharmacodynamic (PD) analyses, 20 mg/kg 
given every week for the first 28-day cycle, and every other week after Cycle 1 is the selected 
dose for the single-agent study in the MM indication. 
For information regarding clinical studies in MM, please refer to the IB. 
Preliminary clinical PK data in adult participants with MM 
A preliminary analysis of the PK characteristics of isatuximab in participants with MM shows a 
nonlinear PK behavior with dose increase. 
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Isatuximab PK was best described by a 2-compartment model with parallel linear and nonlinear 
elimination from the central compartment, reflecting Michaelis-Menten approximation of 
target-mediated drug disposition. To account for the time-dependent phenomenon (ie, change of 
isatuximab PK over time influenced by the reduction of the CD38 target on tumor cells and by the 
change of pathophysiological status of the participant during the course of treatment), the time 
dependency of isatuximab linear clearance was further evaluated: the linear clearance was 
modeled as the sum of time-dependent clearance with associated decay coefficient, and 
time-independent clearance (CLinf). 
In the once every 2 weeks (Q2W) dosing schedule, the exposure, area under the curve from time 
0 to the last measurable concentration (AUClast) after first administration appeared to increase 
more than proportionally with the dose from 0.03 to 20 mg/kg, suggesting the presence of 
target-mediated clearance. However, based on AUC1week, no major deviation to the dose 
proportionality was observed between the 2 highest doses tested (10 and 20 mg/kg once a week 
(QW) × 4, Studies TCD11863 and TCD14079). 
Additionally, 4 doses of 20 mg/kg each week showed that total clearance (sum of nonlinear and 
linear clearances) approached linear clearance (CL) (indicating target saturation) after which the 
20 mg Q2W schedule appeared to maintain the total clearance close to the CL. Repeated dosing 
resulted in an accumulation of 2.2 and 3.3 at Cycle 2, respectively, for maximum serum 
concentration reached by the drug after a dose (Cmax ) and lowest serum concentration reached by 
a drug before the next dose is administered (Ctrough) for the 20 mg/kg QW/Q2W schedule of 
administration. Accumulation ratios were similar at Cycle 6, showing that the steady state was 
reached from Cycle 2 for this administration schedule. 
Using both time-independent and time-dependent clearance models, the population estimated for 
CL (0.0071 to 0.0077 L/h, monotherapy) or for CLinf (0.00723 L/h, pooled analysis 
[monotherapy-combination lenalidomide]) were very close to the clearance of nonspecific 
endogenous IgG and the volume of distribution of central compartment approached the blood 
volume (4.83 to 4.96 L). The half-life associated to the linear elimination was 28 days. 
Because isatuximab is an antibody, it is expected to be eliminated by proteolytic catabolism. 
Preliminary population PK analyses indicated that the central volume of distribution and 
isatuximab CL increase with increasing body weight (allometric exponents of 0.692 and 0.946, 
respectively), supporting the body weight-based dosing regimen. In addition, participants with 
higher CL values were also associated with higher M-protein. 
Since isatuximab appeared to be well tolerated, the exposure-response analyses focused on the 
efficacy endpoint. The preliminary PK/PD analyses to evaluate the relationship between overall 
response rate (ORR) and PK parameters were performed using an Emax model with pooled 
monotherapy TED10893 Phase 1 and Phase 2 (Stage 1) data. 
Briefly, the exposure-response analyses showed that Ctrough at 4 weeks is a significant predictor of 
ORR and the probability of response to treatment increases as Ctrough at 4 weeks increases up to a 
plateau. The dose of 20 mg/kg would maximize the number of patients close to the plateau (high 
interpatient variability) with the highest probability of success to reach a response rate ≥30%. 
Additional PK/PD modeling and simulations using M-protein concentration-time profiles to 
assess the benefit of changing dosing regimens over time showed a deeper response in terms of 
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decreases in M-protein levels at Weeks 8 and 12 using 20 mg/kg QW for 4 weeks followed by 
20 mg/kg Q2W. Thus, based on clinical efficacy, safety, PK simulations, and PK/PD analyses, 
20 mg/kg QW for 4 weeks followed by 20 mg/kg Q2W was chosen for dose and schedule for 
further monotherapy studies. 
Trial simulations of ORR and serum M-protein simulations using isatuximab/lenalidomide 
combination data showed a clear dose response with higher predicted ORR, and a deeper 
reduction in serum M-protein at 8 and 12 weeks from baseline at doses ≥10 mg/kg for 
lenalidomide combination was observed. Furthermore, the models predict minimal increased 
efficacy when increasing the isatuximab dose from 10 to 20 mg/kg QW × 4, Q2W. Therefore, 
based on clinical efficacy, safety, PK simulations, and PK/PD analyses, 10 mg/kg QW for 
4 weeks followed by 10 mg/kg Q2W was chosen for dose and schedule for further combination 
studies in MM. 
Matching PK exposure between pediatric and adult patients can be performed in case of same 
indication, similar disease pathophysiology and same outcome of therapy (eg, efficacy end-point) 
in children and adults.  
Therefore, preliminary PK in adults with ALL was developed using a population PK model and 
data from 14 patients with ALL treated with isatuximab at 20 mg/kg QW/Q2W. The PK in adult 
patients with ALL were comparable with those obtained in adults with MM with a typical CL 
value of 0.00882 L/h.  
2.3 
BENEFIT/RISK ASSESSMENT  
At the cut-off date of 05 January 2019, the clinical development program with isatuximab 
consisted of Phase 1/2/3 studies of isatuximab as a single agent or in various therapeutic 
combinations with other agents. A total of 1301 patients have been exposed to isatuximab thus far 
in the completed studies. During the dose-escalation phase (Phase 1) of the TED10893 study 
(monotherapy in R/R MM and other hematological malignancies), dose-limiting toxicities (DLTs) 
consistent with IRs (which were initially included in the definition of DLTs), occurred at Cycle 1 
in 2 participants with MM. After the occurrence of these 2 adverse events (AEs), the definition of 
DLTs has been corrected to not include IRs because these reactions are not dose dependent. 
The IRs associated with isatuximab in participants who are administered appropriate primary 
prophylaxis are most common with the first administration of the drug, are not dose dependent, 
are most frequently Grade 1 to Grade 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 in most cases, 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. 
Infusion reactions may involve immunogenicity mechanisms (human antihuman antigen) and 
hypersensitivity reactions and are well known to occur in association with other therapeutic mAb 
proteins. These adverse reactions, whether acute or delayed, may be serious and systemic 
(eg, anaphylactic reaction). 
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Overall, the safety profiles of backbone chemotherapies used in this study for ALL and AML are 
reported as well characterized and manageable. The adverse reactions possibly associated with 
isatuximab in combination with these backbone chemotherapies, however, cannot be predicted. 
Close safety monitoring of each participant is planned, and an independent DMC will regularly 
monitor participant safety. A first safety review by the DMC is planned after the first 
10 participants have completed at least 1 induction cycle. 
Study ACT14596 (isatuximab as a single agent in R/R adults T-ALL) was terminated 
prematurely, after no clinical response was reported in the first 14 participants treated with 
isatuximab as a single-agent. On that basis, sanofi has decided not to continue with the 
development of isatuximab as a single agent in adult participants with R/R T-ALL or T-cell 
lymphoblastic lymphoma (T-LBL).  
Based on the efficacy results from a pooled analysis of completed monotherapy studies 
TED10893 (Phase 1 and Phase 2 Stage 1) and TED14154 (monotherapy in R/R MM, Part A) 
(N = 212), overall response rate was 19.8%. Clinical benefit response (≥ minimal response) was 
28.3% and best response was stable disease in 39.2% of the treated participants.  
Administration of isatuximab in combination with lenalidomide and dexamethasone was 
evaluated for participants with R/R MM in the TCD11863 study. The first part of the trial 
evaluated 3 doses of isatuximab 3, 5, and 10 mg/kg using the Q2W schedule of administration; 
among the participants treated at 10 mg/kg (n = 24), the ORR was 62.5% with a PR rate of 20.8%, 
very good PR rate of 33.3%, and stringent CR rate of 8.3%. Administration of isatuximab in 
combination with standard therapy shows greater efficacy for participants with R/R MM. 
In addition to isatuximab, all participants treated in all cohorts in this ACT15378 study will 
receive combination chemotherapies that are part of established standard treatment options for 
participants with ALL or AML. 
Despite the result of isatuximab monotherapy for adult participants with T-ALL in the ACT14596 
study, administration of isatuximab with combination chemotherapies could provide additional 
benefit to the pediatric participants with R/R ALL or AML. 
A risk of hepatitis reactivation has been identified in the IB edition 11 (30-Apr-2020). Therefore, 
screening with serological tests for hepatitis B and hepatitis C must be done prior to enrollment. 
In case of viral reactivation during study treatment, the treatment will be held, and specialist 
consulted for initiation of anti-viral treatment and monitoring of the participant. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of isatuximab may be found in Section 2.1 and in the IB of isatuximab. 
In conclusion, the overall anticipated benefit/risk ratio appears favorable and supports the 
evaluation of the combination of isatuximab with chemotherapy in pediatric participants with R/R 
AML and ALL. 
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Benefit/risk assessment added in amended protocol 04   
The study DMC has evaluated on 01 Oct 2020 the adverse events recorded in the first 9 treated 
pediatric patients including the first fatal case (primarily pulmonary in nature which may have 
been secondary to CRS). DMC recommended the continuation of study with amendment to the 
protocol to include their recommendations with immediate need to restrict the treated population 
to those with a WBC <20 x 109/L.  
• Benefit Assessment: The 2-year survival rate for patients with relapsed post-transplant 
AML, who are eligible for the current study, is reported at less than 20%. Isatuximab is 
therefore being used as additive therapy where participants treated in all cohorts in the 
ACT15378 study receive combination chemotherapies that are part of established standard 
treatment options for participants with ALL or AML. It is known that patients with 
ALL/AML have elevated expression of CD-38 on leukemic blasts. Given its mechanism 
of action and established clinical efficacy in other hematologic malignancies, isatuximab 
when combined with chemotherapy may have the potential to improve the remission rate 
for children with relapsed/refractory AML. Only 9 patients have been enrolled to date, 
including 6 patients with AML; of the 4 evaluable patients for efficacy in AML cohort, 
two have achieved CRi. It is still too early to know whether isatuximab has efficacy in this 
population.  
• Risk assessment: There is an acceptable benefit risk profile within the isatuximab labelled 
indication for multiple myeloma. In the pediatric leukemic population there could be a 
change in the risk profile especially in the pediatric patients with WBC >100 000/mm3 
who are at higher risk for disease related treatment complications; thus restricting the 
treated population to those with a WBC <20 x 109/L should allow an appropriate benefit-
risk in this population with limited therapeutic choices. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To evaluate the antileukemic activity of 
isatuximab in combination with chemotherapies in 
pediatric participants of 28 days to less than 
18 years of age with R/R ALL or AML. 
CR rate is defined in this study as the proportion of participants 
with CR or CRi, in AML, B-ALL, and T-ALL cohorts. 
For AML:  
• 
CR: bone marrow blasts lower than 5%; No blasts 
with Auer rods or persistence of extramedullary 
disease; ANC higher than 1000/mm3, platelets higher 
than 100 000/mm3; red blood cells transfusion 
independence. If the physician documents 
transfusion dependency related to study treatment 
and not to the patient's underlying disease, CRi can 
be reported. 
• 
CRi: same criteria as for CR, except neutrophils 
and/or platelets recovery 
For B-ALL and T-ALL:  
• 
CR: bone marrow blasts lower than 5%, no circulating 
blasts or lymphoblasts in CSF or extramedullary 
disease; ANC higher than 1000/mm3, platelets higher 
than 100 000/mm3; red blood cells transfusion 
independence. If the physician documents 
transfusion dependency related to study treatment 
and not to the patient’s underlying disease, CRi can 
be reported. 
• 
CRi: same criteria as for CR, except neutrophils 
and/or platelets recovery. 
• 
Extramedullary disease: complete resolution of 
lymphomatous enlargement by CT. For participants 
with a previous positive PET scan, a post-treatment 
residual mass of any size is considered a CR as long 
as it is PET negative. 
Secondary 
• 
Safety and tolerability assessments 
• 
Safety assessment, in terms of AEs/SAEs. In 
addition, laboratory data, vital signs, and physical 
examination will be assessed throughout the study. 
• 
Assessment of IRs 
• 
Incidence and severity of IRs. 
• 
PK of isatuximab 
• 
PK parameters of isatuximab calculated using a 
population PK approach including at least Cmax, 
Ctrough, and AUC. 
• 
Minimal residual disease 
• 
Estimation of minimal residual disease in participants 
achieving CR or CRi. 
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Objectives 
Endpoints 
• 
Overall response rate 
• 
The overall response rate is defined as the proportion 
of participants with CR or CRi or PR for blood and 
bone marrow disease.  
• 
Overall survival 
• 
Overall survival is defined as the time interval from 
the date of first study intervention administration to 
death from any cause. 
• 
Event free survival 
• 
Event free survival is defined as the time interval from 
the date of first study intervention administration to 
the date of the first of: completion or going off 
protocol induction/consolidation therapy without CR, 
relapse from CR, or death due to any cause.  
• 
Duration of response 
• 
Duration of response is defined as the time from the 
date of the first response to the date of first disease 
progression or death from any cause, whichever 
happens first.  
• 
Relationship between clinical effects and CD38 
receptor density and occupancy 
• 
CD38 receptor density will be assessed at baseline 
and CD38 receptor occupancy at Day 15 and 
correlated with clinical endpoints.  
Tertiary/exploratory 
• 
Immunogenicity of isatuximab 
• 
Immunogenicity of isatuximab assessed throughout 
the study by detecting the presence of antidrug 
antibodies. 
• 
PK/PD relationships with regards to safety and 
efficacy endpoints. 
• 
PK/PD parameters estimated as prognostic factors 
for clinical outcomes including safety and efficacy 
endpoints, if possible 
AE = adverse event; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; ANC = absolute neutrophil count; AUC = area 
under the curve; B-ALL = B-cell acute lymphoblastic leukemia; Cmax = maximum serum concentration; CR = complete response; 
CRi = complete response with incomplete peripheral recovery; CSF = cerebrospinal fluid; CT = computed tomography; Ctrough = lowest serum 
concentration reached by a drug before the next dose is administered; IR = infusion reaction; NCCN = National Comprehensive Cancer 
Network; PD = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; PR = partial response; R/R = relapsed or 
refractory; SAE = serious adverse event; T-ALL = T-cell acute lymphoblastic leukemia. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the efficacy and safety assessments chosen for use in this study are considered well 
established and relevant in a hemato-oncology setting, and suitable steps have been built into each 
of these assessments to ensure their reliability and accuracy. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 2, single-arm, multicenter, open-label study evaluating the antitumor activity, 
safety, and PK of isatuximab in combination with standard salvage chemotherapies in pediatric 
participants with R/R ALL (including both T-ALL and B-ALL) and AML conducted in 3 separate 
cohorts. Male and female children from 28 days to less than 18 years of age with R/R T-ALL, 
B-ALL, or AML in first or second relapse will be eligible. Participants under 2 years of age can 
only be enrolled after the dose reassessment is completed on the first 20 participants who are 2 to 
less than 18 years of age (Section 4.3 and Section 9.5). 
4.1.1 Study participants and cohorts  
Three cohorts of study participants will be treated:  
• B-ALL 
• T-ALL 
• AML 
Approximately 128 participants will be screened (32, 48, and 48 participants for the T-ALL, 
B-ALL, and AML cohorts, respectively) to achieve 104 participants assigned to study intervention 
(approximately 26, 39, and 39 participants in the T-ALL, B-ALL, and AML cohorts, respectively) 
and 96 evaluable participants for an estimated total of 24, 36, and 36 evaluable participants in the 
T-ALL, B-ALL, and AML cohorts, respectively.  
For an assessment of the dose for children younger than 2 years of age, 20 participants of 2 years 
of age or more (at least 5 participants in the age group of 2 to 10 years, including approximately 
3 patients between 2 and 5 year-old) will be enrolled first to check the isatuximab exposure 
(see Section 4.3). 
In addition, for each cohort, at least 5 participants should be recruited for each of the following 
age groups: 28 days to 4 years of age, 5 to 11 years of age, and 12 to 18 years of age by the end of 
the trial.  
4.1.2 Screening  
The screening assessments are to be performed within 3 weeks prior to the first study intervention 
administration (Day 1), unless indicated otherwise. The screening assessment data obtained prior 
to the informed consent may be accepted if performed within 1 month prior to Day 1. 
All of the inclusion criteria (and none of the exclusion criteria) must be met, and informed consent 
must be signed by the legally acceptable representative (LAR) of the participant before any study-
specific procedure is performed. 
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Screening procedures are to be performed/assessed in accordance with the Schedule of Activities 
(SOA) in Section 1.3. 
In patients with high tumor burden (WBC count higher than 20 x 109/L (and <50 x 109/L) at 
screening with or without pulmonary leukostasis, or significant organ involvement as per 
Investigator’s judgement), a rescue cytoreductive chemotherapy should be started as 
recommended in order to decrease their WBC count <20 x 109/L by Day 1. For patients with 
WBC count <20 x 109/L at screening, but higher than 20 x 109/L on Day 1, a cytoreductive 
chemotherapy should be started as recommended in order to decrease their WBC count and the 
screening period will be extended without a deviation. Please refer to Section 6.5.1 for more 
details. Patients with >20 x 109/L on Day 1 cannot receive isatuximab on Day 1 and should be 
registered as screen failed. 
During this period of cytoreductive therapy, all patients should have a close monitoring (at least 
three times a day) of clinical and biological parameters and a rapid fast institution of life 
sustaining therapy, if required, as per site clinical practice. WBC count, biochemistry (potassium, 
phosphorus, uric acid, corrected calcium, blood urea nitrogen, creatinine) as well as chest X-ray 
should be performed daily, to monitor potential tumor lysis syndrome (TLS) and pulmonary 
leukostasis.  
For management of CRS and TLS syndromes please see Section 6.6.3 and Section 6.6.4. 
Dexamethasone 10 mg/m²/day (or equivalent) before the first study intervention administration (at 
least 3 times, on Days -3, -2, and -1) is mandatory for ALL cohorts as a part of study treatment 
and optional for AML cohort. Administration of dexamethasone on Day 1 is mandatory in both 
cohorts as part of isatuximab premedication. 
Intrathecal prophylaxis is mandatory for all cohorts; the drugs that will be used 
(methotrexate/aracytine/steroids) are per investigator discretion (only one drug, or two or all 
three). 
When dexamethasone is administered at 10 mg/m2 per os, it can be divided in two daily doses. 
This does not apply to dexamethasone administration as part of isatuximab premedication. 
4.1.3 Study treatment period  
In all 3 disease cohorts, participants will receive 1 administration of single-agent isatuximab on 
Day 1.  
On Day 1, before initiation of the first infusion of isatuximab, a chest X-ray, a hematology test 
including WBC with differential to rule out leukocyte elevation, and a biochemistry panel 
(including potassium, phosphorus, uric acid, corrected and ionized calcium (corrected calcium 
= total calcium level in milligrams per deciliter + 0.8 × [4 albumin in grams per deciliter]; ionized 
calcium level in milligrams per deciliter = total calcium level in milligrams per deciliter 
+ 0.02*[40 – albumin in grams per deciliter]) should be performed and results assessed by an 
investigator. If it is not possible to organize chest X-ray on Day 1 prior it can be done on Day -1 
or Day -2. If it is not possible to assess potassium, phosphorus, uric acid, corrected and ionized 
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calcium prior to the infusion on Day 1, it can be done on Day -1 or Day -2, and only in case this is 
not possible – on Day -3. Additional evaluations such as blood cultures would be performed if 
infection is suspected.  Please see Section 1.3 for more details. 
Starting on Day 8, combination chemotherapy will be added. Only if the clinical condition of the 
participant worsens after Day 1 of the first isatuximab infusion and the participant’s condition 
requires intensive therapy, chemotherapy can be started earlier, based on investigator's decision. 
Isatuximab schedule of administration will not be changed for later infusions. The details of the 
combination chemotherapies are in Section 6.1. 
Bone marrow aspirations will be performed in accordance with the SOA (Section 1.3). Any 
additional BM aspirations will be performed at the Investigator's discretion and should be reported 
in the electronic case report form (eCRF). Minimal residual disease assessments will be done at 
screening and at the end of induction for ALL only, at the time of hematological recovery and/or 
at the time of each BM aspiration for disease assessment if CR or CR with incomplete peripheral 
recovery (CRi) is achieved for both ALL and AML. 
In case hematological recovery cannot be reached for any reason, in both AML and ALL 
participants, BM aspiration could be done at any time if investigator does not expect any more 
hematological change and/or urgent need for therapeutic strategy decision. 
Patient not having been tested for HBV/HCV at screening that are still on treatment at the time of 
the amended protocol 4 will need to be tested additionally for HBsAg, anti HBs, anti-HBc (total 
and IgM), anti-HCV, HCV RNA level. 
4.1.4 Post-study treatment period  
After completion of these treatment periods, participants will be treated following Investigator’s 
and site’s standard of care. 
4.1.5 Study duration  
The duration of the study for an individual participant will include: 
• the screening period of up to 3 weeks prior to the first study intervention administration; 
• the treatment period as described above (see Section 4.1.3); 
• the period of aplasia followed by recovery period; 
• an EOT visit within 30 days after hematological recovery; 
• follow-up period. 
In case hematological recovery cannot be reached for any reason, in both AML and ALL 
participants, BM aspiration could be done at any time if investigator does not expect any more 
hematological change and/or urgent need for therapeutic strategy decision. 
Participants with documented disease progression at the EOT visit will be followed for survival 
every 4 months until death or final analysis cut-off date, whichever comes first. 
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Participants without documented disease progression at the EOT visit and who have not yet 
started treatment with another anticancer therapy will receive follow-up visits every 2 months 
until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off 
date, whichever comes first. After disease progression or initiation of a new anticancer treatment, 
participants will be followed every 4 months for survival until death or the cut-off date. 
Also, during the follow-up period, women of childbearing potential will perform pregnancy 
assessments every month, until 6 months after the last dose of isatuximab, or 12 months after the 
last dose of cyclophosphamide. 
In case the participant or the LAR withdraws consent for any reason or following the 
Investigator’s opinion that the participant will not follow the planned treatment, no follow-up will 
be done after these decision dates. 
The final analysis cut-off date will be approximately 12 months after the first study intervention 
administration in the last participant enrolled in the study. After the final analysis cut-off date, 
only new related AEs (serious or not), all ongoing SAEs (related or not) and all ongoing related 
nonserious AEs and related concomitant medications will continue to be collected. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
More than 80% of children affected by acute leukemia are successfully treated; however, relapse 
remains a remarkable clinical concern, with 50% to 60% of relapsing patients facing a fatal 
outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens 
based on conventional drugs and hematopoietic stem cells transplantation for patients with 
unfavorable features. Biological targeted drugs, in particular the mAbs, could be novel potential 
agents to be integrated in salvage acute leukemia therapy to further improve patients’ outcomes. 
Isatuximab is being developed for the treatment of a number of hematological malignancies 
expressing the CD38 antigen. In general, isatuximab is well tolerated clinically with a manageable 
safety profile. This study will further evaluate the safety, efficacy, and PK parameters in children 
with ALL or AML. 
Please refer to Section 2.1 for further details on the study design rationale. 
4.3 
JUSTIFICATION FOR DOSE  
Taking into account the higher tumor burden in acute leukemia compared with MM, and based on 
PK data indicating a saturation of the target at 20 mg/kg in MM (see Section 2.2), the dose 
selected for acute leukemia indication is 20 mg/kg, even for combination studies. 
Weekly infusions will be administered during the induction period of administration of backbone 
chemotherapy and every 2 weeks during the consolidation period for ALL. Compared with MM 
studies, after the end of the chemotherapy administration, isatuximab will not be administered 
because of the potential risk of treatment-related BM depression. At present, however, there is no 
evidence to suggest the risk of increased hematological abnormalities with isatuximab infusions. 
If future data from the first randomized, controlled study in MM confirms the lack of 
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hematological effects, the isatuximab administration after the end of backbone chemotherapy 
could be reconsidered. 
The dose in pediatric participants was selected by matching the exposure between pediatric 
participants and adults with ALL, assuming that same exposure (area under the curve [AUC]) in 
pediatric participants as the exposure in adults will lead to the same efficacy in pediatric 
participants. The target exposure for this study is the one estimated in adults with ALL of 
15 000 µg•h/mL that was observed following a dose of 20 mg/kg. 
At first, the CL in pediatric participants was extrapolated from the adult exposure using allometric 
scaling on weight. As there is no consensus on the use of allometric methods for mAbs, 
2 allometric exponents were used: 
• 0.75: a commonly used allometric exponent for pediatric extrapolation. 
• 0.85: a classical allometric exponent used for translation from animal to human for mAbs. 
As depicted in Figure 7 and Figure 8, the body weight normalized CL increase in participants 
younger than 2 years of age, leading to a higher predicted dose for these participants. A dose of 
20 mg/kg could lead to an under-exposure of up to 0.50-fold for participants <2 years of age. 
Therefore, 20 participants of 2 years of age or more (at least 5 participants in the age groups of 
2 to 10 years, including approximately 3 patients between 2 and 5 year-old) will be enrolled first 
to check the exposure. Based on these results, a reassessment of the dose will be done with the 
possibility to increase the dose to 25 or 30 mg/kg in children younger than 2 years of age. 
Figure 7 - Body weight normalized clearance versus age  
 
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Figure 8 - Body weight-based doses versus age  
 
A reassessment of the dose was done at the time of the interim analysis (ie among 20 participants 
treated and 18 evaluable for PK assessment, among them 6 participant 2 to 5 years old) and 
confirm the dose of 20 mg/kg in children younger than 2 years of age. 
A population PK model was developed with pooled data from 14 adults with T-ALL, aged 16 to 
74 years and weighing 46 to 93 kg coming from ACT14596 study and from the 18 pediatric 
patients with ALL or AML aged from 2 to 17 and weighting from 11to 65 kg to estimate the PK 
and derived exposure in pediatrics (≥2 years) and to predict the exposure in patient <2 years old. 
The pharmacokinetics of isatuximab were described by a two-compartment structural kinetic 
model with linear elimination from the central compartment, a proportional error model and 
interindividual variability on all parameters. Body weight allometric coefficients fixed to 0.85 for 
clearances (CL and Q) and 1 for volumes of distribution enable to well describe the observed data.  
No additional age effect was observed when body weight is included into the model. 
Since the steady-state may not be achieved given the short period of treatment, different 
cumulated AUCs matching with different treatment durations were simulated: 
• Cumulated AUC at week 5 (AUC_W5) and cumulated at week 10 (AUC_W10) for ALL 
design 
• Cumulated AUC at week 3 (AUC_W3) and cumulated at week 8 (AUC_W8) for AML 
design. 
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As shown in Figure 9, less than 20% median decrease is predicted in the youngest patients 
(4-12 kg, corresponding to 1 to 24 months) versus the reference group patients (51-100 kg).  
In addition, there is no evidence of a trend between PK exposure and efficacy (ORR).  
Therefore, taking all together, there is no need to change the dose (20 mg/kg) in patients younger 
than 2 years. 
Figure 9 - Boxplots of predicted and simulated AUCs for a 20 mg/kg isatuximab dose administered 
under ALL and AML design, by weight groups  
 
Figures within boxplots are median percent change compared with 51-100 kg considered as the reference adult. Figures outside 
boxplots are the percent of patients outside the 95% Prediction Interval of the reference. Circles are the individual predicted 
values. 
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 scheduled procedure shown in the SOA (Section 1.3). 
The end of the study is defined as the date of the last visit of the last participant in the study or last 
scheduled procedure shown in the SOA for the last participant in the study globally. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
I 01. Age 
Participant must be 28 days to less than 18 years of age at the time of the signing of the 
informed consent (including participants who are under 2 years old). (see Section 4.3 and 
Section 9.5). 
I 02. Type of participant and disease characteristics 
Participants must have a confirmed diagnosis of relapsed ALL of T- or B-cell origin 
including lymphoblastic lymphoma (LBL, or relapsed AML (excluding M3 type: acute 
promyelocytic leukemia) including participants with history of myelodysplasia (MDS).  
Participants must be previously treated for their disease and have relapsed or are refractory 
to most recent treatment. Participants in first or second relapse will be eligible regardless 
of the remission duration.  
Participants with no more than 1 prior salvage therapy. 
I 03. Sex 
Male or Female 
A) Male participants: A male participant with a female partner of childbearing potential must 
agree to use contraception as detailed in Appendix 4 (Section 10.4) of this protocol during 
the treatment period and for at least 6 months after the last dose of isatuximab, 12 months 
after the last dose of cyclophosphamide, and at least 6 months after other IMPs 
discontinuation (vincristine, pegaspargase, L-asparaginase (Erwinase), methotrexate, 
etoposide, doxorubicin, mitoxantrone, fludarabine, cytarabine), whatever occurs last and 
with the longest recommended period of contraception, and refrain from donating sperm 
during this period. 
B) Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 4 [Section 10.4]), not breastfeeding, and at least one of the following 
conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
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- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the treatment period and for at least 6 months after the last dose 
of isatuximab, 12 months after the last dose of cyclophosphamide, and at least 
6 months after other IMPs discontinuation (vincristine, pegaspargase, L-asparaginase 
(Erwinase), methotrexate, etoposide, doxorubicin, mitoxantrone, fludarabine, 
cytarabine), whatever occurs last and with the longest recommended period of 
contraception. 
I 04. Informed Consent 
The participant who has reached legal age of majority as defined by local regulation or the 
parent(s)/legal guardian(s) must provide signed informed consent prior to any study-related 
procedures being performed. If the participant is legally a minor per local regulations, 
assent shall be obtained from the participant, if applicable.  
I 05. Criterion added in amended protocol 04 
WBC counts below 20 x 109/L on Day 1 before isatuximab administration. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Evidence of ongoing infection or seropositivity for human immunodeficiency virus (HIV), 
or uncontrolled or active HBV infection (defined as either positive hepatitis B surface 
[HBs] antigen or positive HBV deoxyribonucleic acid [DNA] test above the lower limit of 
detection of the assay), or HCV infection (defined as positive HCV ribonucleic acid 
(RNA) and negative anti-HCV. 
Note: Patient can be eligible if anti-HBc immunoglobulin G (IgG) 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. 
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.  
E 02. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ 
carcinoma, unless they are successfully treated with curative intent for more than 3 years 
before entering the study. 
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E 03. Cardiomyopathy with ejection fraction <55%. 
E 04. History of thrombophilic disease. 
E 05. Eastern Cooperative Oncology Group (ECOG) performance status >2 or Lansky score 
<70 (see Section 10.6.2 and Section 10.6.3). 
E 06. Total bilirubin >2.5 × upper limit of normal (ULN) unless the participant has 
Gilbert’s syndrome or elevation related to acute leukemia. 
E 07. Alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase >5 × ULN, 
unless considered due to the disease. 
E 08. Serum creatinine >2 × ULN and/or estimated glomerular filtration rate (eGFR) 
<30 mL/min/1.73 m2 (by revised Schwartz equation, Section 10.6.4). 
E 09. Any serious active disease or comorbid condition (eg, infection or life threatening tumor 
lysis syndrome) if present at study entry or during the screening period that, in the opinion 
of the Investigator, may interfere with the safety of the study intervention or the 
compliance with the study protocol. 
Prior/concomitant therapy 
E 10. Participants must have been off prior treatment with immunotherapy/investigational agents 
and chemotherapy for >2 weeks and must have recovered from acute toxicity (ie, to 
Grade 1 or less except alopecia or peripheral neuropathy Grade ≤2 without pain) before the 
first study intervention administration. Exceptions are participants who need to receive 
cytoreductive chemotherapy in order to decrease tumor burden (the study treatment may 
start earlier if necessitated by the participant's medical condition [eg, rapidly progressive 
disease] following discussion with the Sponsor). 
E 11. Prior stem cell transplant within 3 months and/or evidence of active systemic Graft versus 
Host Disease (GVHD) and/or immunosuppressive therapy for GVHD within 1 week 
before the first study intervention administration. 
Prior/concurrent clinical study experience 
E 12. Intolerance or contraindication to treatment with mAb or any other drug part of the study 
intervention. 
Diagnostic assessments 
E 13. Participants with LBL with BM blasts <5%. 
E 14. Participants with Burkitt-type ALL. 
E 15. Acute leukemia with testicular or CNS involvement alone. 
E 16. Participants who have developed therapy-related acute leukemia. 
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Other exclusions 
E 17. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 18. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 (Section 10.8). 
E 19. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 20. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation Good Clinical Practice (ICH GCP 
Ordinance E6). 
E 21. Participants are employees of the clinical site or other individuals directly involved in the 
conduct of the study, or immediate family members of such individuals. 
E 22. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 23. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
Criteria added in amended protocol 
E 24. Live vaccine(s) within 30 days prior to the first IMP administration or plans to receive 
such vaccines during the study until 90 days after the last IMP administration. 
E 25. Participants who are expected to have a superior benefit if treated with alternative 
established standard therapies (eg, blinatumomab or TKI-based regimes). 
Criteria added as per amended protocol 04 
E 26. Participants with white blood cell count >50 x109/L at the time of screening visit. 
E 27. Participants who have been exposed to anti-CD38 therapies within 6 months prior to 
Day -1. 
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 treated. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened for as long as enrollment is open. Rescreened participants should be assigned a new 
participant number as for the initial screening. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING OF ENROLLMENT/ADMINISTRATION OF 
STUDY INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures proposed in 
Section 10.9: Contingency Measures for a regional or national emergency that is declared by a 
governmental agency should be considered for screening/enrollment/administration of study 
intervention. 
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6 
STUDY INTERVENTION  
Study intervention is defined as isatuximab and salvage chemotherapy intended to be 
administered to a study participant according to the study protocol. For chemotherapy, the body 
surface area used for dose determination is capped at 2 m2. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 4 - Overview of study interventions administered  
 
Study intervention name 
Cytarabine 
Liposomal daunorubicin 
Dosage formulation 
Dependent on country sourcing. 
Dependent on country sourcing 
Unit dose strength(s)/Dosage 
level(s) 
Please refer to the product approved leaflet for 
further information. 
Please refer to the package insert 
for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion 
Dosing instructions 
AML cohort only: 2 g/m², Days 8 to 
12 inclusive (mandatory for Cycles 1 and 2). 
AML cohort only: 60 mg/m², 
mandatory for Cycle 1 Day 8, 
optional for Cycle 1 Days 10 and 12, 
and optional for Cycle 2.  
Packaging and labeling 
Each container will be labeled as required per 
country requirement. 
Each container will be labeled as 
required per country requirement. 
 
Study intervention name 
Isatuximab 
Fludarabine 
Dosage formulation 
Concentrate for solution for intravenous infusion 
Dependent on country sourcing 
Unit dose strength(s)/Dosage 
level(s) 
20 mg/mL (500 mg/25 mL and 100 mg/5 mL) of 
isatuximab in 20 mM histidine, 10% (w/v) 
sucrose, and 0.02% (w/v) polysorbate 80 at 
pH 6.0. Each vial will contain a nominal content 
of 500 or 100 mg isatuximab. The fill volume 
has been established to ensure removal of 25 or 
5 mL. 
Please refer to the product approved 
leaflet for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion 
Dosing instructions 
AML cohort: 20 mg/kg weekly (this could be 
modified based on modeling and PK 
assessment on the first 20 participants) Days 1, 
8, and 15 (mandatory for Cycles 1 and 2). 
ALL cohorts: 20 mg/kg weekly (this could be 
modified based on modeling and PK 
assessment on the first 20 participants) Days 1, 
8, 15, 22, 29, 43, and 57. 
AML cohort only: 30 mg/m², 
Days 8 to 12, inclusive (mandatory 
for Cycles 1 and 2). 
Packaging and labeling 
Each glass vial will be labeled as required per 
country requirement. 
Each container will be labeled as 
required per country requirement. 
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Study intervention name 
Idarubicin 
Dexamethasone or equivalent  
Dosage formulation 
Dependent on country sourcing 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved 
leaflet for further information 
Please refer to the product approved leaflet 
for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion or Per os 
Dosing instructions 
AML cohort only: 10 mg/m², 
mandatory for Cycle 1 Day 8, optional 
for Cycle 1 Days 10 and 12, and 
optional for Cycle 2. 
Dexamethasone, being part of both 
backbone treatment regimen and 
isatuximab premedication in ALL cohorts, 
before each administration of isatuximab, at 
least 15 to 30 minutes (but no longer than 
60 minutes) prior to infusion, will be given 
as premedication for prevention of infusion 
associated reactions. 
When dexamethasone is administered at 
10 mg/m2 per os, it can be divided in 
two daily doses. This does not apply to 
dexamethasone administration as part of 
isatuximab premedication. 
AML cohort: Dexamethasone 10 mg/m2 
(maximum 20 mg) IV or PO optional on 
Days -3, -2, -1; premedication before 
isatuximab administration, on Days 1, 8, 
and 15 during the induction period 
(mandatory at Cycle 1 and before first 
isatuximab infusion at Cycle 2). 
ALL cohorts: Dexamethasone 10 mg/m2 
(maximum 20 mg) IV or PO on Days -3, -2, 
-1 before isatuximab administration, 1, 8, 
15 to 19, 22, and 29 to 33 for the induction 
period and Days 43 to 47, and 57 during 
the consolidation period. 
Packaging and labeling 
Each container will be labeled as 
required per country requirement. 
Each product will be labeled as required per 
country requirement. 
 
Study intervention name 
Doxorubicin 
Mitoxantrone 
Dosage formulation 
Dependent on country sourcing 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved 
leaflet for further information. 
Please refer to the product approved leaflet 
for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion 
Dosing instructions 
ALL cohorts only: 25 mg/m² Days 10, 
17, 24, and 31 of the induction period. 
ALL cohorts only: 10 mg/m² Days 8 and 
9 of the induction period. 
Packaging and labeling 
Each container will be labeled as 
required per country requirement  
Each container will be labeled as required 
per country requirement. 
 
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Study intervention name 
Vincristine 
Pegaspargase  
or L-asparaginase (Erwinase) 
Dosage formulation 
Dependent on country sourcing 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved 
leaflet for further information. 
Please refer to the product approved leaflet 
for further information. 
Route of administration 
Intravenous infusion 
Intramuscular injection or intravenous 
infusion 
Dosing instructions 
ALL cohorts only: 1.5 mg/m² on 
Days 10, 17, 24, and 31 during the 
induction period (should not exceed 
2 mg per infusion in any patient); 
Day 38 during the consolidation 
period. 
Vincristine should be given 3 to 
24 hours before administration of 
pegaspargase in order to minimize the 
toxicity. 
ALL cohorts only:  
Pegaspargase: 1000 IU/m² Days 10 and 
24 during the induction period, Day 44 
during the consolidation period. 
L-asparaginase (Erwinase): 25000 IU/m² on 
Days 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 
31, 33 during induction and days 43, 45, 
47, 50, 52, 54 during consolidation, only in 
case of confirmed hypersensitivity reaction 
to pegaspargase prior or during the study 
or loss of asparaginase and/or country 
availability and regulations. Hypersensitivity 
to pegaspargase and/or loss of 
asparaginase activity should be 
documented in the eCRF. 
Packaging and labeling 
Each container will be labeled as 
required per country requirement. 
Each container will be labeled as required 
per country requirement. 
 
Study intervention name 
Cyclophosphamide 
Etoposide 
Dosage formulation 
Dependent on country sourcing 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved 
leaflet for further information. 
Please refer to the product approved leaflet 
for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion 
Dosing instructions 
ALL cohorts only: 440 mg/m² on 
Days 50 to 54 inclusive, during the 
consolidation period. 
ALL cohorts only: 100 mg/m² Days 50 to 
54 inclusive, during the consolidation 
period. 
Packaging and labeling 
Each container will be labeled as 
required per country requirement. 
Each container will be labeled as required 
per country requirement. 
Study intervention name 
Methotrexate 
Daunorubicin (nonliposomal) 
Dosage formulation 
Dependent on country sourcing 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved 
leaflet for further information. 
Please refer to the product approved leaflet 
for further information. 
Route of administration 
Intravenous infusion 
Intravenous infusion 
Dosing instructions 
ALL cohorts only: 1000 mg/m² 
Day 43 during the consolidation 
period. 
AML cohorts only: 60 mg/m2, mandatory 
for Cycle 1 Day 8, optional for Cycle 1 Days 
10 and 12, and optional for Cycle 2. 
Packaging and labeling 
Each container will be labeled as 
required per country requirement. 
Each container will be labeled as required 
per country requirement. 
 
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Study intervention name 
Filgrastim or equivalent (G-CSF) 
Dosage formulation 
Dependent on country sourcing 
Unit dose strength(s)/Dosage level(s) 
Please refer to the product approved leaflet for further information. 
Route of administration 
Subcutaneous or intravenous injection 
Dosing instructions 
AML cohort only: 200 g/m² Days 7 to 12. G-CSF is optional for Cycles 1 
and 2 and can be continued until neutrophil recovery. 
Packaging and labeling 
Each container will be labeled as required per country requirement. 
AML = acute myeloid leukemia; ALL = acute lymphoblastic leukemia; EU = European Union; G-CSG = granulocyte colony stimulating factor; 
IV = intravenous(ly); PK = pharmacokinetic; PO = oral; ROW = rest of world; US = United States; w/v = water/volume. 
INVESTIGATIONAL MEDICINAL PRODUCTS 
Investigational medicinal products (IMPs) (except isatuximab) from available commercial 
supplies will be used for this study where applicable otherwise it will be relabeled by the Sponsor 
according to Good Manufacturing Practice (GMP) guidelines before supplies are provided to the 
sites. 
On days when isatuximab is administered, the order of administration is recommended to be 
dexamethasone first, isatuximab second, and chemotherapy third. 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
Table 5 - Noninvestigational medicinal products  
Noninvestigational 
medicinal 
products 
Formulationa 
Route of 
administration 
Dose regimen 
Paracetamol 
(acetaminophen) 
 
PO 
Paracetamol (acetaminophen) will be given 15 to 
30 minutes (but no longer than 60 minutes) before 
isatuximab infusion and at dose per weight as follows: 
≤10 kg: 7.5 mg/kg, >10 to 50 kg: 15 mg/kg, and >50 kg: 
1 g. 
Diphenhydramine or 
equivalent 
 
IV 
Diphenhydramine or equivalent will be given at a dose of 
1 mg/kg, 15 to 30 minutes (but no longer than to 
60 minutes) before isatuximab infusion. 
Montelukast 
 
PO 
Montelukast should be given to a child under adult 
supervision, before isatuximab infusion. The 
recommended dosage for pediatric participants: 
• 
Montelukast is not recommended for 
participants less than 2 years of age 
• 
4 mg for participants 2 to 5 years of age 
• 
5 mg for participants of 6 to 14 years of age 
• 
10 mg for participants ≥15 years of age. 
Folinic acid 
(Leucovorin®) 
 
PO, IM, or IV 
Folinic acid should be administered 48 hours after the 
start of methotrexate infusion at a dose of 30 mg/m2 PO, 
IM, or IV and 15 mg/m2 at 54 hours. Folinate rescue can 
be extended at the Investigator’s discretion. 
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Noninvestigational 
medicinal 
products 
Formulationa 
Route of 
administration 
Dose regimen 
Dexamethasone 
 
PO or IV 
Dexamethasone is part of isatuximab premedication in 
the AML cohort only, and will be given as premedication 
for prevention of infusion associated reactions before 
each administration of isatuximab, at least 15 to 
30 minutes (but no longer than 60 minutes) prior to 
infusion. Dexamethasone 10 mg/m2 (maximum 20 mg) 
IV or PO on Days 1, 8, and 15 during the induction period 
(mandatory for Cycle 1 and before first isatuximab 
infusion at Cycle 2). 
Cyclophosphamide 
 
PO or IV 
Cyclophosphamide is a part of rescue cytoreductive 
chemotherapy up to 1 g/m² PO or IV for 1 day before first 
isatuximab treatment recommended for ALL 
Hydroxyurea  
 
PO  
Hydroxyurea is a part of rescue cytoreductive 
chemotherapy 50-75 mg/kg/day PO for 4-5 days with or 
without steroids before first isatuximab treatment 
recommended for AML 
Cytarabine  
 
IV 
Cytarabine is a part of rescue cytoreductive 
chemotherapy up to 1 g/m² IV every 12 hours for up to 
2-3 days before Isatuximab administration recommended 
for AML 
IM = intramuscular(ly); IV = intravenous(ly); PO = oral. 
a Noninvestigational medicinal products will be locally sourced and the formulation may vary. 
Noninvestigational medicinal products (NIMPs) from available commercial supplies will be used 
for this study where applicable otherwise it will be relabeled by the Sponsor according to GMP 
guidelines before supplies are provided to the sites. 
For isatuximab, the rate of infusion should be initiated at 2.5 mg/kg/hour (maximum 
175 mg/hour): 
• First infusion: initiate infusion at 2.5 mg/kg/hour (maximum 175 mg/hour). In the absence 
of IRs after 1 hour of infusion, increase the infusion rate by 0.5 mg/kg/hour increments 
every 30 minutes, to a maximum of 5.5 mg/kg/hour (maximum 400 mg/hour). 
• Subsequent infusions: initiate infusion at 2.5 mg/kg/hour (maximum 175 mg/hour). In the 
absence of IR after 1 hour of infusion, increase the infusion rate by 1.0 mg/kg/hour 
increments every 30 minutes, to a maximum of 5.5 mg/kg/hour (maximum 400 mg/hour). 
A mandatory monitoring of patients after every isatuximab infusion for 2 hours after the infusion 
should be set up. Please see Section 8.2.2. 
In case of the presence of IR, please see Section 6.6.1 for guidelines for the management of 
potential IRs. 
Other IMPs should be prepared and administrated per the site’s clinical practice unless otherwise 
indicated in the protocol. 
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In all 3 disease cohorts, participants will receive 1 administration of single-agent isatuximab on 
Day 1. Starting on Day 8, combination chemotherapy will be added. 
All participants will receive the following premedication to prevent or reduce incidence or 
severity of IRs at least 15 to 30 minutes (but no longer than 60 minutes except for Montelukast 
that should be 2 hours) prior to the isatuximab infusion. For participants who do not experience an 
IR during the first 4 administrations of isatuximab, the need for premedication at the subsequent 
infusions may be reconsidered at the Investigator’s discretion in consultation with the Sponsor, 
with the exception of dexamethasone administered as a part of study treatment in ALL cohorts 
(Days -3 to -1, 15 to 19, 29 to 33 and 43 to 47) that should be administered as planned, unless 
there are dose modifications related to toxicities.  
The recommended isatuximab premedication agents are: montelukast, diphenhydramine 
(or equivalent), methylprednisolone, and acetaminophen (paracetamol) PO. Taking into 
consideration the disease context and the frequent use of steroids in acute leukemia, 
methylprednisolone will be replaced by dexamethasone. 
Prophylaxis for tumor lysis syndrome and CNS relapse may be administered at the discretion of 
the treating physician during the treatment period. In case of CNS involvement, participant will be 
treated in parallel with IT chemotherapy as per the site’s clinical practice. IT prophylaxis is 
mandatory for all cohorts; the drugs that will be used (methotrexate/aracytine/steroids) are per 
investigator discretion (only one drug, or two or all three). 
In patients with high tumor burden (WBC counts higher than 20 x 109/L with or without 
pulmonary leukostasis, or significant organ involvement as per Investigator’s judgement), a 
rescue cytoreductive chemotherapy before study treatment start is mandatory. In order to have 
rapid control of the tumor burden, in addition to dexamethasone pre-dose mandatory in ALL 
cohorts, the administration of following cytoreductive therapies are proposed (these are 
examples): 
• cyclophosphamide up to 1 g/m² PO or IV for 1 day before first isatuximab treatment for 
ALL 
• hydroxyurea 50-75 mg/kg/day PO for 4-5 days with or without steroids before first 
isatuximab treatment for AML 
• cytarabine up to 1 g/m² IV every 12 hours for up to 2-3 days before first isatuximab 
treatment for AML 
Dexamethasone 10 mg/m²/day (or equivalent) before the first study intervention administration 
(at least 3 times, on Days -3, -2, and -1) is optional for AML cohort. Administration of 
dexamethasone on Day 1 is mandatory in both cohorts as part of isatuximab premedication. 
The dexamethasone in oral form may be supplied at the site or from the PI/site/Sponsor to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
agreed upon by the participant. 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
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Section 10.9: Contingency Measures for a regional or national emergency that is declared by a 
governmental agency. 
6.1.1 Acute myeloid leukemia combination therapies  
AML combination therapies: 
In the AML cohort, up to 2 cycles of induction will be given as defined in the SOA (Section 1.3). 
Dosing instructions and premedication are described in Section 6.1.  
Cycle 2 (second induction): 
If the BM aspiration performed 1 week after the end of induction treatment shows less than 
20% blasts, a second cycle of combination therapy can be administered if neutrophils of 
≥500/mm3 and platelets of ≥50 000/mm3, while keeping the same schedule and doses. 
Anthracyclines are optional in Cycle 2 (as well as Cycle 1 Days 10 and 12) and will be 
administered at the Investigator’s discretion. The choice of anthracyclines is at the Investigator’s 
discretion (either liposomal daunorubicin, nonliposomal daunorubicin, or idarubicin) and the same 
anthracycline should be used throughout the study. 
6.1.2 T-ALL and B-ALL combination therapies  
In the ALL cohorts, the treatment period will include 1 induction and 1 consolidation cycle. 
Dosing scheduled is defined in the SOA (Section 1.3). Dosing instructions and premedication are 
described in Section 6.1 (Table 4).  
The choice of anthracyclines is at the Investigator’s discretion (either doxorubicin or 
mitoxantrone) and the same anthracycline should be used throughout the study. 
Prophylaxis for tumor lysis syndrome and CNS relapse may be administered at the discretion of 
the treating physician during the treatment period. In case of CNS involvement, the participant 
will be treated in parallel with IT chemotherapy as per the site’s clinical practice. 
Folinic acid (Leucovorin®) should be administered 48 hours after the start of methotrexate 
infusion at a dose of 30 mg/m2 PO, IM, or IV and 15 mg/m2 at 54 hours. Folinate rescue can be 
modified at the Investigator’s discretion. 
Before starting consolidation cycle, the patient must have neutrophils of ≥500/mm3 and platelets 
of ≥50 000/mm3. 
In ALL patients treated with pegaspargase or L-asparaginase (Erwinase) daily monitoring of INR, 
PTT, fibrinogen and AT-III must be performed and fibrinogen and AT-III substituted, 
if necessary. 
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6.1.3 Mandatory evaluations on Day 1 prior to the first isatuximab administration  
In order to thoroughly evaluate the patient’s status on Day 1, before initiation of the first infusion 
of isatuximab, a chest X-ray, a hematology test including WBC with differential to rule out 
leukocyte elevation, and a biochemistry panel (including potassium, phosphorus, uric acid, 
corrected and ionized calcium) to exclude TLS should be performed and results assessed by an 
Investigator. If it is not possible to organize chest X-ray on Day 1 prior it can be done on Day -1 
or Day -2. If it is not possible to assess potassium, phosphorus, uric acid, corrected and ionized 
calcium prior to the infusion on Day 1, it can be done on Day -1 or Day -2, and only in case this is 
not possible – on Day -3. Additional evaluations such as blood cultures would be performed if 
infection is suspected.  Please see Section 1.3. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Isatuximab concentrate for solution for infusion will be diluted in an infusion bag with 
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. 
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. If 
the participant’s weight on the day of the dose preparation is not available, the most recent 
participant’s weight may be used, assuming it was assessed in a reasonable time frame and the 
participant did not have any events leading to significant weight loss (more than 10%) according 
to Investigator assessment. In such cases, the participant’s weight should still be assessed on the 
day of administration to ensure the accuracy of the dose preparation.  
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. 
For other IMPs, please refer to the product approved leaflet for further information. 
The following conditions for drug storage and accountability apply:  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
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in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual. 
Any quality issue noticed with the receipt or use of isatuximab (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure 
(see Section 8.3.6). 
A potential defect in the quality of isatuximab 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 isatuximab and eliminate potential hazards. 
Under no circumstances will the Investigator supply isatuximab to a third party, allow isatuximab 
to be used other than as directed by this clinical trial protocol, or dispose of isatuximab in any 
other manner. 
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 isatuximab 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 is to be 
protected from light. All containers 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. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
This is a nonrandomized and noncontrolled study. No blinding or randomization will be used for 
this study. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Administration of the IMPs will be supervised by the Investigator or sub-Investigator. 
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The person responsible for drug dispensing is required to maintain adequate records of the IMPs. 
These records include the date IMPs are received from the Sponsor, dispensed to the participant, 
and destroyed or returned to the Sponsor. The packaging batch number and the treatment number 
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. 
Deviation(s) from the prescribed dosage regimen should be recorded in the eCRF. 
6.5 
CONCOMITANT THERAPY  
Participants should receive full supportive care, including transfusions of blood and blood 
products, antibiotics, antiemetics, allopurinol, etc, when appropriate. Prophylaxis and treatment 
for tumor lysis syndrome are recommended (see Section 6.6.4). 
The mandatory cytoreductive chemotherapy drugs should be administered before isatuximab 
infusion in patient with high tumor burden at screening are cyclophosphamide (ALL), 
hydroxyurea (AML), or cytarabine (AML) and dexamethasone. Refer to Section 6.5.1 for details. 
Treatment with hormones or other chemotherapeutic agents must not be administered except for 
steroids given for adrenal failure; and hormones administered for nondisease-related conditions 
(eg, insulin for diabetes).  
Steroids may be used to treat and/or prevent hypersensitivity reactions or transfusion reactions. 
Brief use of corticosteroids as antiemetics is permitted but not recommended in these 
immunocompromised participants. Their use must be reported in participant records.  
In the ALL cohorts, myeloid growth factors should not be used routinely or prophylactically but 
are permitted as indicated by the American Society of Clinical Oncology guidelines for 
neutropenic participants with prognostic factors that are predictive of clinical deterioration such as 
pneumonia, hypotension, multi-organ dysfunction (sepsis syndrome) or fungal infection. The use 
of G-CSF (filgrastim, polyethylene glycol [PEG]-filgrastim, etc) must be documented and 
reported in the participant’s records. 
In the ALL cohorts, folinic acid is to be administered after methotrexate infusion in the 
consolidation period, at 48 and 54 hours. Folinate rescue can be modified at the Investigator’s 
discretion. 
The use of epoetin or darbepoetin in this protocol is permissible but not recommended. 
Pneumocystis prophylaxis should be provided as per the site’s clinical practice. 
Antimicrobial prophylaxis (bacterial, viral, and fungal) as per the National Comprehensive Cancer 
Network (NCCN) guidelines or site’s clinical practice is recommended. 
Prophylactic heparin therapy is recommended for participants receiving pegaspargase, as well as 
use of anti-allergy premedication as per site clinical practice in order to decrease the risk of 
allergic reactions. 
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Effect of coadministered drugs on isatuximab: Isatuximab is a mAb and is likely to be eliminated 
by proteolytic degradation. Thus, drugs that impact cytochrome P450 (CYP) or transporter 
expressions are not anticipated to alter the PK of isatuximab. 
Effect of isatuximab on other drugs: Direct drug-drug interactions (DDI) via CYP enzymes or 
transporters is not expected because isatuximab is a therapeutic mAb. However, potential risks of 
DDI caused by isatuximab due to the alteration of cytokine levels were taken into consideration. 
The activity of drug metabolizing enzymes, such as CYPs, can be modified during altered 
immunological states (eg, inflammation), and modulators of proinflammatory cytokines have been 
shown to affect both CYP expression and enzyme activity. However, based on a physiologically 
based PK (PBPK) model, transient elevation of cytokines, such as interlukin-6 and interferon-γ, is 
predicted to have only a limited effect on CYP activities with low potential for DDIs. 
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 1-2 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 DDI 
with the drug associated with isatuximab. 
Patient not having been tested for HBV/HCV at screening that are still on treatment at the time of 
the amended protocol 4 will need to be tested additionally for HBsAg, anti HBs, anti-HBc (total 
and IgM), anti-HCV, HCV RNA level. 
In case of viral reactivation during study treatment (greater than 1 log10 IU/mL increase in HBV 
DNA or reappearance of HBsAg or detection of HBV DNA in patients with resolved infection*), 
(*defined as previous known history of acute or chronic hepatitis B or the presence of total anti 
HBc Ab with/without anti-HBs Ab; HBsAg negative; undetectable serum HBV DNA; and normal 
ALT levels) study treatment will be held, and specialist consulted for initiation of anti-viral 
treatment and monitoring of the patient. Restart of study treatment should be agreed between the 
Sponsor, the Investigator and specialist (hepatologist) if infection is controlled. ALT and AST 
will be closely monitored every month up to study treatment discontinuation. HBV DNA to be 
done as per specialist advice. 
Administration of any live vaccine from 30 days before the first IMP administration until 90 days 
after the last IMP administration is forbidden. 
6.5.1 Rescue medicine  
In patients with high tumor burden (WBC count higher than 20 x 109/L or significant organ 
involvement as per Investigator’s judgement), a rescue cytoreductive chemotherapy before study 
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treatment start is mandatory. In order to have rapid control of the tumor burden, in addition to 
dexamethasone pre-dose mandatory in ALL cohorts, the administration of following 
cytoreductive therapies are proposed (these are examples): 
• cyclophosphamide up to 1g/m² PO or IV for 1 day before isatuximab treatment for ALL  
• hydroxyurea 50-75 mg/kg/day PO for 4-5 days before isatuximab treatment for AML 
• cytarabine up to 1g/m² IV every 12 hours for up to 2-3 days before isatuximab treatment 
for AML 
Dexamethasone 10 mg/m²/day (or equivalent IV or PO) before the first study intervention 
administration (at least 3 times, on Days -3, -2, and -1) is optional for AML cohort. 
Administration of dexamethasone on Day 1 is mandatory in both cohorts as part of isatuximab 
premedication. 
In case of Grade 2 or higher CRS event, anti-IL6 therapy (for example, tocilizumab) may be 
started as a rescue therapy. For more details, see Section 6.6.3 (guidelines for CRS management). 
6.6 
DOSE MODIFICATION  
Dose modifications different from those stated in the protocol should only be made in consultation 
with the Sponsor unless required for immediate participant safety.  
Isatuximab: within a cycle (induction or consolidation), an isatuximab administration can be 
delayed for up to 1 day in case of weekly administration or 2 days for every 2 weeks 
administration. If the dose cannot be administered within 3 days, the isatuximab dose will be 
omitted. Only 1 omission per cycle is permitted. Further omissions must be discussed on a 
case-by-case basis with the Sponsor. 
Administration of other IMPs in the study intervention will be discontinued/modified in the event 
of a treatment-emergent AE (TEAE) that persists despite appropriate dose modifications or any 
other AE that, in the opinion of the Investigator, warrants discontinuation or dose modification. 
If there is a suspicion of anaphylaxis of any degree, every effort should be made to distinguish it 
from other IRs. If the suspicion of anaphylaxis persists or is confirmed, isatuximab (or any other 
product causally responsible for anaphylaxis) should be permanently disontinued. 
The final decision will be per Investigator’s judgment for the best interest of the participant. 
In case of Grade 3 or 4 neurotoxicity or autoimmune events under fludarabine, no rechallenge 
with fludarabine is allowed. 
In case of eGFR between 30 and 70 mL/min/1.73 m2, the fludarabine dose will be reduced to 
20 mg/m2. 
In case of hypersensitivity, allergy or non-allergic reaction to pegaspargase monitoring and 
treatment will be administered as per the site’s clinical practice or NCCN guidelines. 
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Pegaspargase IV infusion should last at least 2 hours, infusion of normal saline and use of anti-
allergy premedication (such as montelukast, hydrocortisone, diphenhydramine, paracetamol) 
should be administered, in order to reduce the incidence and severity of adverse events and the 
need for substitution with L-asparaginase (Erwinase). 
For further information, please refer to the products’ product approved leaflet. 
The term IR indicates only a specific temporal relationship with the infusion and does not specify 
a particular mechanism underlying the signs or symptoms. Note that an IR is different from the 
diagnostic terms ‘anaphylactic reaction’ ‘anaphylactoid reaction’ or ‘cytokine release syndrome 
(CRS), which does imply a specific pathophysiologic mechanism, and may or may not be an IR 
(see Section 6.6.2 for anaphylaxis and see Section 6.6.3 for CRS). 
This study has specific instructions for IRs, CRS, and anaphylactic reaction.   
6.6.1 Guidelines for the management of potential infusion reactions   
Participants should routinely receive premedication prior to isatuximab infusion as detailed in 
Section 6.1 to reduce the risk and severity of IRs commonly observed with mAbs. Infusion 
reactions are defined as AEs related to isatuximab with onset within 24 hours from the start of the 
infusion and assessed as related to an IMP (National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE] Version 5.0 term “allergic/hypersensitivity reactions” 
or “cytokine release syndrome/acute infusion reaction”). For the NCI Consensus Guideline for 
cytokine release syndrome is in Section 6.6.3. 
Please refer to the current edition of the IB for IR manifestations reported in participants treated 
with isatuximab. 
In case of an IR while receiving or after isatuximab administration, additional medication can be 
provided for symptom treatment as per the Investigator’s judgment including epinephrine, 
diphenhydramine 1 mg/kg IV (or equivalent; maximum of 25 mg) and methylprednisolone 
2 mg/kg IV (maximum of 100 mg), IV fluids, vasopressors, oxygen, bronchodilators, and 
acetaminophen (paracetamol). These participants must be informed of the potential risk of 
recurrent IRs. 
Further treatment with isatuximab (subsequent infusions) is to be started at 2.5 mg/kg/hour and 
follow the same rule in case of an IR.  
Once a Grade 2 IR leading to interruption has improved to Grade ≤1, the infusion may be 
restarted at one-half (1.25 mg/kg/hour) of the initial infusion rate. If symptoms do not recur after 
30 minutes, the infusion rate may be increased in 0.50 mg/kg/hour increments every 30 minutes, 
to a maximum of 5.5 mg/kg/hour (maximum of 400 mg/hour). 
Participants with a Grade 3 or 4 IR must follow rules described in the Table 6 and appropriate 
supportive therapy should be administered. 
Grade 1 IRs lasting more than 24 hours and Grade 2 or higher IRs, regardless of duration, must be 
reported as AEs of special interest (AESIs) (see Section 8.3).  
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Recommendations for management of IRs are described in Table 6.  
If there is a suspicion of anaphylaxis of any degree, every effort should be made to distinguish it 
from other IRs. If the suspicion of anaphylaxis persists or is confirmed, isatuximab (or any other 
product causally responsible for anaphylaxis) will be permanently discontinued. 
The final decision will be per Investigator’s judgment for the best interest of the participant. 
Table 6 - Management of infusion reactions  
NCI-CTCAE Version 5 criteria 
definition 
Intervention recommendation 
Mild (Grade 1) 
Infusion interruption or intervention not indicated 
Continuation of isatuximab infusion per the judgment of the Investigator 
following close direct monitoring of the participant’s clinical status. 
Isatuximab infusion may be stopped at any time if deemed necessary. 
If stopped, the IR will be classified as Grade 2 as per NCI-CTCAE 
Version 5.0.  
Grade 1 IRs lasting more than 24 hours must be reported as AESIs. 
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 isatuximab infusion. Give additional premedication with 
diphenhydramine 1 mg/kg IV (or equivalent; maximum of 25 mg) and/or 
methylprednisolone 2 mg/kg IV (maximum of 100 mg) as needed. 
Isatuximab may be resumed only after participant recovery, with a slower 
infusion rate and with close monitoring.  
All Grade 2 IRs must be reported as AESIs. 
Severe Grade 3 
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 
If a Grade 3 infusion-related AE occurs, the isatuximab infusion must be 
interrupted, and the patient observed carefully and treated as needed until 
the AE either resolves or improves to Grade 1. Then, at the investigator’s 
discretion, the infusion may be restarted at half the infusion rate before the 
interruption. The infusion rate may be increased subsequently, at the 
investigator’s discretion. Please refer to Section 6.6.2.  
If after restarting the infusion, the severity of an infusion-related AE 
returns to Grade 3, the infusion can be interrupted and restarted again 
(as described above) at the investigator’s discretion. If the same Grade 3 
infusion-related AE occurs for a third time, treatment with isatuximab will 
be permanently discontinued for that patient. 
All Grade 3 IRs must be reported as AESIs. 
Severe or life-threatening (Grade 4) 
Grade 4: life-threatening consequences; urgent 
intervention indicated 
Stop isatuximab infusion. Give additional premedication with 
diphenhydramine 1 mg/kg IV (or equivalent; maximum of 25 mg), and/or 
methylprednisolone 2 mg/kg IV (maximum of 100 mg), and/or epinephrine 
as needed. Definitive treatment discontinuation. For signs or symptoms of 
anaphylaxis, please refer to Section 6.6.2.  
All Grade 4 IRs must be reported as AESIs. 
AE = adverse event; AESI = adverse event of special interest; IAR = infusion associated reaction; IR = infusion reaction; IV = intravenous; 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSAIDs = nonsteroidal antiinflammatory drugs. 
Infusion should be completed within 16 hours from the end of infusion preparation or a new infusion should be prepared with the remaining 
dose to be administered the same day. 
In case of allergic reactions to pegaspargase, or L-asparaginase (Erwinase), either these NCCN 
guidelines or the site’s clinical practice should be followed. 
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6.6.2 Guidelines for the management of anaphylaxis  
Evidence-based guidelines for the diagnosis and management anaphylaxis has been published by 
the National Institute of Allergy and Infectious Disease (36). Analogous guidelines for the 
diagnosis and management of anaphylaxis have been published by the European Academy of 
Allergy and Immunology and the European Society for Oncology (37). 
Anaphylaxis is a severe, potentially life-threatening systemic hypersensitivity reaction, only 
Grade 3 and Grade 4 are defined in the NCI-CTCAE v 5.0 (38) as a disorder characterized by an 
acute inflammatory reaction resulting from the release of histamine and histamine-like substances 
from mast cells, causing a hypersensitivity immune response. Clinically, it presents with breathing 
difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. It is 
characterized by being rapid in onset with life-threatening airway, breathing, or circulatory 
problems and is usually, although not always associated with skin and mucosal skin changes. 
Please see Table 7 below for the clinical criteria for diagnosing anaphylaxis (36). 
Table 7 - Clinical criteria for diagnosing anaphylaxis  
Anaphylaxis is highly likely when anyone of the following criteria is fulfilled: 
1. 
Acute onset during or after treatment exposure of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips–tongue–uvula AND AT LEAST ONE 
OF THE FOLLOWING 
a) 
Respiratory compromise (eg, dyspnea, wheeze–bronchospasm, stridor, reduced PEF, hypoxemia) 
b) 
Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia [collapse], syncope, 
incontinence) 
2. 
Two or more of the following that occur rapidly after treatment exposure: 
a) 
Involvement of the skin–mucosal tissue (eg, generalized hives, itch-flush, swollen lips–tongue–uvula 
b) 
Respiratory compromise (eg, dyspnea, wheeze–bronchospasm, stridor, reduced PEF, hypoxemia) 
c) 
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence) 
d) 
Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
Notes: PEF, peak expiratory flow; BP, blood pressure. 
*Low systolic blood pressure for children is defined as<70 mmHg from 1 month to 1 year, less than (70 mmHg+[2*age]) from 1 to10 years 
and<90 mmHg from 11 to 17 years. 
Anaphylaxis should lead to immediate interruption of ongoing infusion, and to permanent 
discontinuation of isatuximab and any chemotherapy suspected of inducing the anaphylactic 
reaction. 
Management should be prompt and may include but is not limited to administration of 
epinephrine, IV fluids, antihistamines, oxygen, vasopressors, corticosteroids, as well as increased 
monitoring of vital signs as medically indicated, until the participant recovers. 
Note that these guidelines place epinephrine as the first intervention for anaphylaxis. It is 
stated that there is no absolute contraindication to treatment with epinephrine in a patient 
experiencing anaphylaxis (37). 
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6.6.3 Cytokine-release syndrome (CRS)  
CRS should be suspected in a participant with fever, which may be accompanied by tachypnea, 
tachycardia, hypotension, hypoxia or other findings. The diagnosis of CRS requires fever 
(≥38.0°C), with or without hypotension, hypoxia, and/or organ dysfunction that can start within 
hours or days after IMP treatment. CRS may also occur within minutes of or after the infusion 
start and therefore may overlap with an anaphylactic reaction, an infusion reaction of unknown 
mechanism, TLS, infections, sepsis. Other causes that could mimic CRS should be excluded. The 
Investigator should use his clinical judgement for making the correct diagnosis. 
Early signs of cytokine release syndrome should also prompt a thorough clinical assessment to 
identify the involvement of a specific organ system, including neurological system to identify 
potential immune effector cell-associated neurotoxicity syndrome (ICANS) see Section 10.6.7. 
Laboratory tests are not required to diagnose CRS, however, since CRP and ferritin levels are 
usually elevated in patients with CRS, they will be collected to distinguish CRS from other 
conditions. Cytokine levels will be assessed as part of safety markers and investigations to 
exclude infection. Potassium, corrected calcium, phosphorus, uric acid, blood urea nitrogen, and 
serum creatinine should be evaluated to differentiate from TLS and repeated daily. Grade 1 CRS 
with flu-like symptoms can also be reported as Grade 1 or Grade 2 flu-like symptoms depending 
on severity of the symptoms as per NCI-CTCAE v 5.0 (38). Flu-like symptoms are similar to 
those observed in patients with the flu influenza and includes fever, chills, body aches, malaise, 
loss of appetite and dry cough. 
Since these recommendations concern CRS induced by therapeutics other than chimeric antigen 
receptor T (CAR-T) cells, NCI-CTCAE v 5.0 grading will be used. While fever is absolutely 
required, it must not be attributable to any other cause. In participants who develop CRS and 
receive antipyretic and anti-cytokine therapy, fever is no longer required to grade CRS toxicity 
and grading is driven by hypotension and/or hypoxia (39). 
Although there is limited data tocilizumab us in the management of CRS induced by therapeutics 
other than CAR-T cell therapy, it appears that it may be less effective than steroids in these 
settings (39). 
Observation in intensive care unit (ICU) is required in case a participant develops hemodynamic 
or respiratory compromise and ICU should be staffed by a critical care physician who has 
experience in treating CRS. 
In case a CRS event occurs, chest X-ray and WBC counts must be repeated daily. Please refer to 
Section 1.3 for other biological parameters. 
Guidelines for management CRS events according to severity grading are provided in Table 8.  
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Table 8 - Guidelines for the management of Cytokine Release Syndrome (CRS)  
Event severity (NCI-CTCAE v 5.0 
criteria) 
Recommended IMP  
dose modification and supportive care guidelines 
Mild 
Grade 1 
Fever, with or without constitutional symptoms 
Continuation of an IMP infusion is as per the judgment of the Investigator 
under close monitoring of the participant’s clinical status. IMP infusion 
may be stopped at any time if deemed necessary. If stopped, IMP may be 
resumed only after participant’s recovery, with a slower infusion rate and 
with close monitoring. 
Appropriate symptomatic treatment may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, nonsteroidal anti-inflammatory drugs 
(NSAID) and acetaminophen.  
Close direct monitoring of the patient’s clinical status. Clinical and 
laboratory monitoring should initially be performed daily, then less 
frequently as the participant improves. 
A blood sample should be collected to measures cytokines. 
Moderate 
Grade 2 Hypotension responding to fluids. 
Hypoxia responding to <40 percent FiO2  
Temporarily interrupt IMPs, if the events occur during the infusion. 
If an event of CRS of Grade 2, isatuximab will be permanently 
discontinued. 
Additional appropriate medical therapy may include but is not limited to 
IV fluids (care should be taken to not excessively hydrate if evidence of 
vascular leak), antihistamines, NSAIDs and acetaminophen. 
Monitoring of vital signs, cardiac and other organ functions closely as 
medically indicated should be increased until the participant recovers. 
Transfer to ICU may be required. 
For patients with comorbidities, older age, or with oxygen requirement, 
hypotension, or patients in whom symptoms (eg, high grade fever) that do 
not respond to antipyretics within 72 hours treatment with corticosteroids 
and/or tocilizumab may be considered. 
IMP (except isatuximab) may be resumed when clinical symptoms have 
resolved or improved to Grade 1 and corticosteroid taper. No dose 
modification is required but decreasing to half the infusion rate can be 
considered. 
A blood sample should be collected to measures cytokines. 
Severe or Life-threatening 
Grade 3 
Hypotension managed with one vasopressor. 
And/or hypoxia responding to ≥40 percent FiO2 
 
 
 
 
 
 
 
 
 
 
If CRS Grade 3, isatuximab should be permanently discontinued. 
Temporarily interrupt other IMPs, if the events occur during the infusion. 
The participant can continue treatment with other IMPs without dose 
modification. 
IV corticosteroids should be initiated, and tocilizumab may be considered, 
and/or epinephrine or another vasopressor should be administered as 
needed. Participants with severe CRS may require management in 
intensive care setting, with monitoring of clinical status and laboratory 
tests performed at least daily. 
As the participant improves, the intensity of the monitoring and setting can 
be decreased, but the participant should not be discharged from the 
hospital until clinically stable. Corticosteroids can then be administered IV 
or orally every 8 hours for up to 3 days, then tapered over 4 days. In 
general, tapering of steroids can start when vasopressors and high-flow 
oxygen are no longer needed.  
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Event severity (NCI-CTCAE v 5.0 
criteria) 
Recommended IMP  
dose modification and supportive care guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 4 
Life-threatening consequences; urgent 
intervention indicated 
CRS is considered resolved when there is a sustained resolution of fever 
and there is no longer a need for oxygen supplementation to relieve 
hypoxia nor vasopressors to maintain blood pressure; however, 
normalization of temperature alone does not define resolution of CRS. 
If no clinical improvement in oxygenation, hypotension, fever, and other 
CRS manifestations is observed within 24 to 72 hours, management for 
persistent or worsening CRS should be initiated. Re-evaluation of other 
contributing conditions should be done, such as infection, cardiac, 
thromboembolic and other complications. Intravenous Tocilizumab at 
8 mg/kg (for patients weighing ≥30 kg) or 12 mg/kg (for patients weighing 
<30 kg) should be considered, and steroids should be administered 
concurrently. If still no improvement in oxygenation, hypotension, fever 
and other manifestations is observed after the first dose of tocilizumab, it 
may be repeated after an interval of at least 8 hours and should not 
exceed 4 doses in total.  
A blood sample should be collected to measures cytokines. 
 
 
If CRS Grade 4, all IMPs should be permanently discontinued. 
 
In addition to recommendations listed for Grade 3 for participants with 
severe CRS who fail to improve after repetitive treatment with both 
tocilizumab and steroids, alternative options should be discussed with 
clinical site specialists. 
 A blood sample should be collected to measures cytokines. 
6.6.4 Guidelines for the management of tumor lysis syndrome  
Tumor lysis syndrome may occur and is a life-threatening event. Hydration is recommended for 
all participants prior to Cycle 1 infusions and is left to Investigator judgment for further cycles.  
The participants at greatest risk of tumor lysis syndrome (TLS) are, as an example, those with 
high tumor burden prior to treatment, elevated uric acid level, receiving intensive cytoreductive 
therapy, poor hydration or tumor infiltration of the kidney. 
These participants should be monitored closely, and appropriate precautions should be taken (such 
as systematic use of prophylactic uric acid lowering agents [eg, allopurinol or rasburicase], 
regular measurement of electrolytes).  
Prophylaxis against TLS may be required depending on the participant’s risk for TLS, as 
described below. 
Low risk is defined as: 
• Participants with low tumor burden (WBC ≤50 × 109/L and normal lactic acid 
dehydrogenase [LDH] level) 
• Participants receiving low intensity cytoreductive therapy 
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• Normal preexisting uric acid  
• Adequate hydration 
• No tumor infiltration in the kidney 
High risk is defined as: 
• Hematological malignancies with high proliferative rate 
• High tumor burden (WBC >50 × 109/L and high LDH level) 
• Elevated uric acid level 
• Participants receiving intensive cytoreductive therapy 
• Poor hydration 
• Leukemia infiltration of the kidney 
Recommendations for IV hydration during isatuximab treatment in participants at high risk for 
TLS include the following: 
• Normal saline solution 3 L/m2/d, unless no symptoms of acute renal dysfunction and 
oliguria 
• Maintain urine output >100 mL/m2/h 
• Diuretics may be required to maintain urine output at >100 mL/m2/h: mannitol 0.5 mg/kg 
or furosemide 0.5 to 1.0 mg/kg 
For high-risk participants, prophylactic treatment with allopurinol should begin 2 to 3 days before 
the start of antineoplastic therapy and continue for 10 to 14 days, as described: 
• Allopurinol: 
- 
100 mg/m2/dose q8 hour (10 mg/kg/d divided q8 hour) oral (maximum 800 mg/d) or 
200 to 400 mg/m2/d in 1 to 3 divided doses IV (maximum 600 mg/d) 
- 
Reduce dose by 50% or more in renal failure 
- 
Adjust doses of drugs metabolized by P450 hepatic microsomal enzymes with 
concomitant allopurinol 
• Rasburicase: 
- 
Avoid in glucose-6-phosphate dehydrogenase deficient participants 
- 
Immediate and permanent stop of treatment if methemoglobinemia is result 
- 
0.05 to 0.20 mg/kg IV over 30 minutes 
- 
To measure uric acid levels, place blood sample immediately on ice to avoid continual 
pharmacological ex vivo enzymatic degradation 
- 
10% incidence of antibody formation 
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Rasburicase is indicated for participants with the following features: 
• High risk of TLS development 
• Urgent need to initiate therapy in a participant with a high bulk of malignant disease 
• In a situation where adequate hydration may be difficult or impossible 
• Acute renal failure 
Recommendations regarding the selection of allopurinol and/or rasburicase are summarized in 
Table 9. 
Table 9 - Recommendations on selection of hypouricemic agents  
 
Allopurinol 
Rasburicase 
Uric acid level 
Normal 
Elevated 
Tumor type 
Nonhematological  
Hodgkin’s lymphoma,  
Chronic myeloid leukemia 
Burkitt’s lymphoma,  
lymphoblastic 
lymphoma, ALL, AML 
Tumor burden 
WBC count 
≤50 × 109/L 
>50 × 109/L 
Lactic acid dehydrogenase 
≤2 × normal 
>2 × normal 
Cytoreductive  
intensity 
Mild 
Aggressive 
Kidney tumor  
infiltration 
Absent 
Present 
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; WBC = white blood cell 
Tumor lysis syndrome has to be managed according to the site’s usual practice. Table 10 provides 
some parameters to be checked in case of TLS suspicion and high-level recommendations for TLS 
management. Abnormalities listed in Table 10 do not exclusively support TLS diagnosis and any 
differential diagnosis also needs to be assessed, if appropriate.  
After recovery, study intervention can be re-administered as planned at the same dose. 
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Table 10 - Management of tumor lysis syndrome  
TLS diagnosis 
Recommended action 
Laboratory TLS: ≥2 simultaneous abnormalities within 3 days 
prior to and up to 7 days after treatment start: 
• 
Uric acid >8 mg/dL (>475.8 µmol/L) 
• 
Potassium >6.0 mmol/L 
• 
Phosphorus >4.5 mg/dL (>1.5 mmol/L) 
• 
Corrected calcium <7.0 mg/dL (<1.75 mmol/L), ionized 
calcium <1.12 mg/dL (<0.3 mmol/L)a. 
Omit study intervention until all serum chemistries have 
resolved.  
Ensure normal hydration, correct laboratory 
abnormalities, fluid overload, electrolyte, or acid-base 
deviation. 
Monitor TLS complications including renal functions. 
Reinstitute study intervention at full dose after resolution. 
Clinical TLS: laboratory TLS in addition to 1 of the following 
complications: 
• 
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. 
TLS = tumor lysis syndrome. 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 × (4-albumin in grams per 
deciliter). The ionized calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter (total calcium) 
+ 0.02*(40 – albumin in grams per deciliter). 
 
6.6.5 Guidance in case of hepatitis B reactivation occurring under study treatment  
In case of viral reactivation during study treatment (greater than 1 log10 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. Resolved infection means previous known history of acute or chronic 
hepatitis B or the presence of total anti-HBc Ab with/without anti-HBs Ab; HBsAg negative; 
undetectable serum HBV DNA; and normal ALT levels. Restart of study treatment should be 
agreed between the Sponsor, the Investigator and specialist (hepatologist) if infection is 
controlled. ALT and AST will be closely monitored every month up to study treatment 
discontinuation. HBV DNA to be done as per specialist advice. 
6.7 
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 the last IMP will be at the discretion of the 
treating physician.  
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
      
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The study intervention should be continued whenever possible.  
In case the IMP is stopped, it should be determined whether the interruption is temporary; 
definitive IMP discontinuation should be a last resort. 
For the details of dose modification in the study intervention, please refer to Section 6.6. 
Any IMP discontinuation must be fully documented in the eCRF. In any case, the participant 
should remain in the study as long as possible. 
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.      
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 (Section 1.3). 
Withdrawal from the intervention with IMPs may occur if, in the Investigator’s opinion, 
continuation of the study intervention would be detrimental to the participant’s well-being, such 
as: 
• Disease progression 
• Unacceptable AE 
• Poor compliance to the study protocol 
• Pregnancy (see Section 10.4) 
• Any other reason such as intercurrent illness that prevents further administration of study 
intervention (will be specified) 
• Participant is lost to follow-up 
Any abnormal laboratory value or electrocardiogram (ECG) parameter will be immediately 
rechecked for confirmation before making a decision of definitive discontinuation of the IMP for 
the concerned participant. 
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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 
PK sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator or 
designee in the appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary intervention discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 10.9: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. 
For dose modifications or dose delays, please refer to Section 6.6. 
7.1.3 Rechallenge  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency. 
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned adverse event 
was unlikely and if the selection criteria for the study are still met (refer to Section 5). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
Participants (or the LAR to the participants) may withdraw or discontinue the study for the 
following reasons:  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
• 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. 
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• 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 the SOA (Section 1.3) 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 the participants the 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 nonparticipant contact follow-up, eg, medical 
record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-enrolled in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
Please refer to the SOA (Section 1.3). 
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 site.  
The following actions must be taken if a participant fails to return to the site for a required study 
visit: 
• The site must attempt to contact the participant or the LAR to 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  
The following apply to all study assessments and procedures:  
• Study procedures and their timing are summarized in the SOA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SOA 
(Section 1.3), 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, BM 
assessment) and obtained before signing of the Informed Consent Form (ICF) may be 
utilized for screening or baseline purposes provided the procedures met the 
protocol-specified criteria and were performed within 1 month before Day 1 (Section 1.3). 
• For a regional or national emergency declared by a governmental agency, contingency 
measures are included in Section 10.9: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency.  
8.1 
EFFICACY ASSESSMENTS   
To assess response, BM aspiration (or biopsy if clinically indicated), computed tomography (CT) 
of chest with IV contrast or positron emission tomography (PET)-CT or PET-MRI scans will be 
performed for extramedullary disease assessment, and peripheral blood sampling at the time 
points indicated in the flowchart (Section 1.2) and as summarized hereafter. 
Bone marrow aspiration will be performed in accordance with the SOA (Section 1.3). In case 
hematological recovery cannot be reached for any reason, in both AML and ALL participants, 
BM aspiration could be done at any time if investigator does not expect any more hematological 
change and/or urgent need for therapeutic strategy decision. Any additional BM aspirations will 
be performed at the Investigator’s discretion and should be reported in the eCRF. In case BM 
aspiration fails, BM biopsy could be an option. No BM assessment is necessary if nonresponse or 
progressive disease can be diagnosed with peripheral blood evaluation, or if a WBC <300/mm3, or 
if the BM assessment is considered noncontributory by the Investigator. The BM assessment will 
be performed locally. 
Extramedullary assessments are optional. For the extramedullary assessment of ALL, CT, 
PET-CT or PET-MRI scan are suggested to be performed as defined in the SOA (Section 1.3) 
if lymphomatous involvement is suspected. If not done, PET-CT or PET-MRI scan is suggested to 
be performed at screening if lymphomatous involvement is present. If positive at screening, the 
PET-CT or PET-MRI scan will be repeated at the time of CR in BM. 
Extramedullary assessment of AML will be performed by physical examination if radiology 
assessment cannot be performed. A CT or PET-CT or PET-MRI scan can be performed if 
clinically indicated for the AML cohort. 
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Assessment of extramedullary disease will be performed locally. 
Lumbar puncture with IT chemotherapy will be performed at time points indicated in the SOA 
(Section 1.3) and when clinically indicated. The assessment of CNS involvement by the lumbar 
puncture will be performed locally. 
For ALL, MRD assessments are to be performed with BM aspiration at screening and with 
peripheral blood samples at the end of induction, at the time of hematological recovery, and/or at 
the time of each BM aspiration for disease assessment if CR or CRi is achieved. For AML, MRD 
assessments are to be performed with BM aspiration samples at the time of hematological 
recovery, and/or at the time of each BM aspiration for disease assessment if CR or CRi is 
achieved. Minimal residual disease assessments will be performed by central laboratories. 
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SOA (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. 
Treatment-emergent AEs 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 lower level term (LLT), preferred term (PT), high level term 
(HLT), high group level term, and associated primary system organ class (SOC) using the 
Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be summarized 
with respect to the type, frequency, severity, seriousness, and relatedness. 
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  
The following should be assessed during physical examinations:  
• Examination of major body systems will include neurological examination, digestive, 
skin/mucosae, mediastinal, testicular involvements, respiratory, hepatomegaly, 
splenomegaly, and lymphadenopathy. Body weight and ECOG or Lansky score will also 
be measured and recorded. Height will be recorded only at screening. 
• Testicular involvement should be assessed for male participants with ALL. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Any new finding or worsening of a previous finding should be reported as a new AE. 
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8.2.2 Vital signs  
Temperature, heart rate, respiratory rate, and blood pressure will be assessed at screening and 
preinfusion, to be measured just before starting infusion of isatuximab, 1 hour after starting the 
infusion, at the end of infusion, in 2 hours after every isatuximab infusion and as clinically 
indicated. 
In case of high tumor burden at screening requiring cytoreductive chemotherapy or occurrence of 
CRS event, continuous monitoring of vital signs is required as per site clinical practice. 
8.2.3 Electrocardiograms  
A 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 heart rate, QRS, QT, and QTc intervals. 
Clinically significant abnormalities should be reported as an 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 Cardiac assessment  
Left ventricular ejection fraction measurement will be performed by echocardiogram, cardiac 
scintigraphy, or multigated acquisition scan at baseline, as clinically indicated during the study 
treatment period, and at the end of Cycle 2 (second induction for AML or consolidation for ALL). 
8.2.5 Chest X-ray  
Chest X-ray should be done at screening and as well mandatory done and assessed prior to the 
first infusion on Day 1. If it is not possible to organize on Day 1 prior it can be done on Day -1 or 
Day -2. In case of high tumor burden at screening requiring cytoreductive chemotherapy or 
occurrence of CRS event, chest X-ray must be repeated every day until the event is improved to 
Grade 1. CT-scan can also be used based on site’s clinical practice. 
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 (Section 1.3) for the timing and frequency. 
Hematology test is mandatory for all patients prior to the first isatuximab infusion on Day 1. 
Hematology test including WBC counts with differential should be assessed prior to the first 
isatuximab infusion. In case of high tumor burden at screening requiring cytoreductive 
chemotherapy or occurrence of CRS event, white blood cell count with differential must be 
repeated every day. 
Please refer to sections Section 6.2 and Section 6.6.3 for CRS and for Section 6.6.4 for TLS 
guidance. 
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Where possible, blood volume sampling for each visit will be minimized to less than 
approximately 1% of total blood volume and less than approximately 3% of total blood volume 
over a 4-week period. If necessary, blood sampling related to patient safety and the primary 
endpoint of the study should be prioritized. Additional blood samples may be collected at the 
Investigator’s discretion for participant safety monitoring. 
• 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. A vital sign or ECG 
abnormality or laboratory value is reported as an AE if it meets the definition of AE. 
See Appendix 3 (Section 10.3) 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 14 days the last dose of study intervention should be 
repeated until the values return to normal or baseline or stabilized or are no longer 
considered clinically significant by the Investigator or medical monitor 
- 
The etiology should be identified by the Investigator 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 
(Section 1.3).  
- 
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 eCRF.  
8.2.6.1 Blood type phenotyping/genotyping  
Blood typing and complete blood phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is recommended, 
if not available, the site’s standard will be followed) and indirect antiglobulin test (IAT) will be 
assessed in accordance with the SOA (Section 1.3). After the start of the study treatment, a new 
IAT assessment will be performed once. If the second test is positive, a dithiothreitol (DTT) test 
should be performed only if transfusions are required (in accordance with Section 10.6.6). Results 
of IAT (and DTT test, if applicable) will be recorded in the eCRF, including those performed 
prior to any transfusion during study intervention.  
Transfusions are to be recorded in the eCRF. The transfusion service should be made aware that 
the participant is receiving an antiCD38 treatment (isatuximab). During the study intervention, the 
transfusion service should follow the recommendations issued in the AABB bulletin in case a 
blood red cells transfusion is needed. The web link to the AABB bulletin will be indicated on the 
study participant card. Participants should keep their study participant card with their blood type 
card together throughout the duration of the study intervention. 
8.2.7 Suicidal risk monitoring  
Not applicable. 
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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
isatuximab program, for which ongoing monitoring and immediate notification by the Investigator 
to the Sponsor within 24 hours is required. Such AESIs 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 a protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the study or in a female partner 
of a male participant entered in the study. 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, 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 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with the IMP/NIMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based, for example, on 
systematic pills count) and defined as: 
- 
Infusion: increase of at least 30% of the dose to be administered in the specified 
duration or if the dose is administered in less than half the recommended duration 
of administration. 
- 
Oral: increase of at least 30% of the dose to be taken. 
- 
An overdose of the IMP or NIMP that meets the definition of an SAE. 
• Of note, asymptomatic overdose should be reported as a standard AE. 
• Infusion reaction: an IR is an AE related to isatuximab typically with onset within 
24 hours from the start of the isatuximab infusion: 
- 
Infusion reaction of Grade 1 lasting more than 24 hours 
- 
Infusion reaction of Grade 2 or higher, regardless of duration. 
• Seizures equal or greater than Grade 3 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative. The Investigator and any qualified designees are 
responsible for detecting, documenting, and recording events that meet the definition of an AE or 
SAE and remain responsible for following up AEs that are serious, considered related to the study 
intervention or study procedures, or that caused the participant to discontinue the study 
intervention (see Section 7).  
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8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the last follow-up visit at the 
time points specified in the SOA (Section 1.3). 
All SAEs, AESIs, and updated SAE data will be recorded and reported to the Sponsor or designee 
immediately and under no circumstance should this exceed 24 hours of the data being available, 
as indicated in Appendix 3 (Section 10.3). 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigators are required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs, and 
nonserious AESIs (as defined in Section 8.3), will be followed until resolution, stabilization, or 
the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
The following apply to the reporting of SAEs: 
• Prompt notification by the Investigator to the Sponsor of any SAE is essential so that 
regulatory obligations and ethical responsibilities towards the safety of participants and the 
safe use 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. 
• Expected serious adverse reactions are specified in the Reference Safety Information 
(Section 8 of the isatuximab IB). 
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• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows (Note: A serious adverse reaction is 
considered “unexpected,” if it is not listed in the Investigator Brochure in the section on 
Reference Safety Information): 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days. 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor. 
• An Investigator who receives a safety report describing an SAE, SUSAR, or any other 
specific safety-related information (eg, summary or listing of SAEs), from the Sponsor 
will review and file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
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 until 6 months after the last 
dose of isatuximab, or 12 months after the last dose of cyclophosphamide or start of another 
anticancer therapy. 
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 4 (Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
8.3.6 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 the 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  
Symptomatic overdose (serious or nonserious) of study intervention: an overdose (accidental or 
intentional) with the study intervention is an event suspected by the Investigator or spontaneously 
notified by the participant and defined as an increase of at least 30% of the dose to be 
administered in the specified duration or if the dose is administered in less than half the 
recommended duration of administration.  
Symptomatic overdose must be reported as an AESI.  
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8.5 
PHARMACOKINETICS  
8.5.1 Sampling time  
The following blood collection time points are defined to measure isatuximab concentrations and 
conduct the PK analysis: 
• The sampling times for blood collection can be found in the PK and immunogenicity 
flowchart (Section 1.3). 
• It is of utmost importance to collect all blood samples at the specified times and according 
to the specifications. 
• Samples missed or lost for any reason should be recorded. Actual dates and times of blood 
collection should be recorded in the eCRF. Actual dates and times of drug administration 
should also be precisely recorded. 
8.5.2 Pharmacokinetic sample handling procedure  
Detailed instructions for collection, sample preparation, storage, and shipment will be provided to 
the sites in a separate Laboratory Manual. 
8.5.3 Bioanalytical methods  
Bioanalytical methods are summarized in Table 11. 
Table 11 - Bioanalytical methods for isatuximab pharmacokinetic analysis  
Analyte 
Isatuximab 
Matrix: 
Plasma 
Analytical technique: 
ELISA 
Assay volume: 
100 µL 
Lower limit of quantification: 
0.500 ng/mL 
Site of bioanalysis: 
Refer to PK Manual 
ELISA = enzyme-linked immunosorbent assay; PK = pharmacokinetic. 
8.5.4 Pharmacokinetic parameters  
8.5.4.1 Population pharmacokinetic approach for isatuximab  
Plasma concentrations of isatuximab will be used for population PK analysis by nonlinear mixed 
effects modeling. Additional details of the analysis plan and the results will be provided in a 
separate document. This analysis will involve an estimation of population PK parameters and 
interparticipant PK variability. Empirical Bayesian estimation of individual parameters and of 
individual exposure (AUCs, Cmax, and Ctrough) will also be performed. The PK estimates will then 
be investigated as prognostic factors for clinical outcome, including safety and efficacy endpoints, 
if possible.  
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8.6 
PHARMACODYNAMICS  
Pharmacokinetic and pharmacodynamics (PK/PD) parameters will be investigated as prognostic 
factors for clinical outcomes including safety and efficacy endpoints, if possible. 
8.7 
GENETICS  
Not applicable. 
8.8 
BIOMARKERS  
8.8.1 CD38 expression, receptor density, and receptor occupancy  
CD38 expression, receptor density (RD) and receptor occupancy (RO) will be assessed and 
correlated with clinical response. Blood samples will be collected once on Day 1 predose and 
once on Day 15 predose. The testing will be limited to European countries and North America. 
8.9 
IMMUNOGENICITY ASSESSMENTS  
Human antidrug antibody (ADA) to isatuximab will be assessed throughout the study. The 
sampling times for blood collection will be according to the schema and flowcharts in Section 1.2 
and Section 1.3. 
It is of utmost importance to collect all blood samples at the specified times and according to the 
specifications. 
Samples not collected, missed, or lost for any reason should be documented. Actual dates and 
times of blood collection should be recorded in the eCRF. The dates and the times of study 
intervention administration should also be precisely recorded.  
Detailed instructions for collection, sample preparation, storage, and shipment will be provided to 
the sites in a separate Laboratory Manual. 
The ADA results will be communicated to the sites on an ongoing basis. 
The observation period for ADAs will be divided into 2 periods: 
• The ADA pretreatment period will be defined as the time that informed consent is signed 
until the first study intervention administration. 
• The ADA on-study observation period will be defined as the time from the first study 
intervention administration until the end of the study. 
• Once a participant is off treatment, ADA samples will be collected 30 and 90 days after 
the last isatuximab administration. No additional ADA samples will be collected, 
regardless of the result of these samples (negative, positive or inconclusive). 
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Participants with at least 1 evaluable ADA result during the ADA pretreatment period will be 
considered as evaluable at baseline. Participants with at least 1 evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period.  
8.10 
HEALTH ECONOMICS  
Not applicable. 
8.11 
DATA COLLECTION AFTER PREMATURE STOP OF THE STUDY IN CASE OF 
SPONSOR DECISION DUE TO STAGE 2 CRITERIA ARE NOT MET FOR ONE OF THE 
COHORTS  
If the IA criteria are not met to move to Stage 2 and one of the cohorts is stopped only ongoing 
related AE/SAE data will be collected. Patients will be followed by phone for survival until final 
cut-off. 
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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
T-ALL:  
• Null hypothesis: complete response (CR + CRi) rate ≤60%  
• Alternative hypothesis: CR rate ≥80% 
B-ALL and AML: 
• Null hypothesis: complete response (CR + CRi) rate ≤70%  
• Alternative hypothesis: CR rate ≥85% 
9.2 
SAMPLE SIZE DETERMINATION   
A 2-stage Simon’s Min/Max design was used for sample size calculations in 3 cohorts (T-ALL, 
B-ALL, and AML). 
T-ALL cohort: a maximum of 24 evaluable participants will be enrolled in this cohort. This 
sample size will provide 80% power to reject the null hypothesis that the complete response 
(CR + CRi) rate is ≤60% if the CR rate is ≥80%, based on a 1-sided exact binomial test at a 
significance level of 0.1: 
• Stage 1: 11 evaluable participants. Proceed to Stage 2 if more than 6 responses are 
observed 
• Stage 2: 24 evaluable participants (13 additional participants). If more than 17 responses 
are observed among the 24 participants evaluable for efficacy, the null hypothesis will be 
rejected 
B-ALL cohort and AML cohort: a maximum of 36 evaluable participants will be enrolled in each 
cohort. This sample size will provide 80% power to reject the null hypothesis that the complete 
response (CR + CRi) rate is ≤70% if the CR rate is ≥85%, based on a 1-sided exact binomial test 
at a significance level of 0.1: 
• Stage 1: 23 evaluable participants. Proceed to Stage 2 if more than 17 responses are 
observed 
• Stage 2: 36 evaluable participants (13 additional participants). If more than 28 responses 
are observed among the 36 participants evaluable for efficacy, the null hypothesis will be 
rejected 
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 12): 
Table 12 - Populations for analyses  
Population 
Description 
Enrolled 
All participants who signed the ICF, regardless of whether the study intervention 
was received or not. 
All-treated 
The AT population will include all participants who received at least 1 dose (even 
incomplete) of study intervention. This population is the primary population for the 
analyses of safety parameters. 
Evaluable  
The evaluable population will include participants from the AT population who 
received at least 1 full dose of isatuximab in Cycle 1 and who had at least one valid 
response value that is evaluable. This population is the primary population for the 
analyses of efficacy parameters. 
PK 
The PK population will include all participants from the AT population with at least 
one available concentration post-baseline (whatever the cycle and even if dosing is 
incomplete) with adequate documentation of dosing and sampling dates and times. 
ADA evaluable 
The ADA evaluable population will include all participants from the AT population 
with at least 1 nonmissing ADA result during the on-study observation period. 
ADA = antidrug antibody; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AT = all-treated; PK = pharmacokinetic. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.9: Contingency Measures for a regional or national emergency that is 
declared by a governmental agency.  
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan 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 primary, secondary, and other endpoints. 
General statistical approach 
Data from participants enrolled in 3 cohorts (T-ALL, B-ALL, and AML) will be analyzed 
separately. 
Unless otherwise specified, analyses will be descriptive and performed on the AT population, 
except for the analyses of efficacy endpoints that will utilize the evaluable population. The 
baseline for a given parameter is defined as the last assessment for this parameter before the 
first study intervention administration.  
Continuous data will be summarized using the number of available observations, mean, SD, 
median, minimum, and maximum by cohort and overall (where applicable). Categorical and 
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ordinal data will be summarized using the number and percentage of participants by cohort and 
overall (where applicable).  
Planned date for analysis cut-off: 
For each cohort, the cut-off date for interim analysis (Stage 1) will be approximately 2 months 
after the last participant is treated (last participant last dose) in Stage 1. In case of stop of one of 
the cohorts after IA the actual date of the cut-off IA will be considered for the primary analysis of 
CR and other secondary endpoints. 
For each cohort, the cut-off date for the primary analysis of CR and other secondary endpoints 
will be approximately 6 months after the last participant has had their first study intervention 
administration. The final analysis cut-off date for the analysis of OS and other secondary 
endpoints will be approximately 12 months after the last participant has had their first study 
intervention administration. 
9.4.1 Efficacy analyses  
All efficacy analyses (summarized in Table 13) will be performed based on the evaluable 
population for each ALL and AML cohort.  
Response to treatment that will be analyzed is the response after 1 full dose of isatuximab in 
Cycle 1 (induction). 
Table 13 - Efficacy analyses  
Endpoint 
Statistical analysis methods 
Primary 
Complete response rate (CR + CRi) 
 
Descriptive statistics and Clopper-Pearson method 
Secondary 
DOR, EFS and OS 
MRD status 
ORR 
 
Kaplan-Meier method 
Descriptive statistics 
Descriptive statistics and Clopper-Pearson method 
CR = complete response: CRi = complete response with incomplete peripheral recovery; DOR = duration of response; EFS = event free 
survival; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival. 
9.4.1.1 Analysis of primary efficacy endpoint  
The primary efficacy endpoint is the CR rate, defined in this study as the proportion of 
participants with CR or CRi. 
The CR rate will be summarized with descriptive statistics on all evaluable population. An 80% 
confidence interval will be computed using the Clopper-Pearson method. 
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9.4.1.2 Analysis of secondary efficacy endpoints  
The following secondary efficacy endpoints will be analyzed: 
• Duration of response (DOR), event free survival (EFS), and OS will be analyzed using the 
Kaplan-Meier method. The Kaplan-Meier estimates of the 25th, 50th, and 75th percentiles 
and the 95% confidence intervals of median will also be computed. The Kaplan-Meier 
curves will be plotted.  
• Minimal residual disease: Among participants who achieved CR or CRi, the number and 
percentage of participants by MRD status (negative and positive) will be provided in the 
evaluable population. 
• Overall response rate, defined as the proportion of participants with a CR, CRi, or PR, will 
be summarized with descriptive statistics. An 80% confidence interval will be computed 
using Clopper-Pearson method. 
9.4.2 Safety analyses  
All safety analyses (Table 14) will be performed on the AT population for each ALL and AML 
cohort, and overall. 
Table 14 - Safety analyses  
Endpoint 
Statistical analysis methods 
Secondary 
AEs/SAEs 
Laboratory parameters, vital signs, and physical examination 
Incidence and severity of IRs 
 
Descriptive statistics 
Descriptive statistics 
Descriptive statistics 
Tertiary/Exploratory  
ADA against isatuximab 
 
Descriptive statistics 
If needed, other tertiary/exploratory analyses will be described 
in the statistical analysis plan finalized before database lock 
ADA = antidrug antibody; AE = adverse event; IR = infusion reaction; SAE = serious adverse event. 
9.4.2.1 Analyses of adverse events  
The observation period will be divided into 3 segments: screening, on-treatment, and 
post-treatment: 
• The screening period is defined as the time from when informed consent is signed until the 
first IMP administration. 
• The on-treatment period is defined as from the time of the first IMP administration until 
the time of hematological recovery or new anticancer therapy is started or 30 days after the 
last IMP, whichever is first.  
• The post-treatment period is defined as the time following the on-treatment period. 
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Pretreatment AEs are defined as any AE during the screening period. Treatment-emergent AEs 
are defined as AEs that develop, worsen (according to the Investigator opinion) or become serious 
during the on-treatment period. The primary focus of AE reporting will be on TEAEs. 
Post-treatment AEs are defined as AEs that are reported during the post-treatment period. Related 
AEs and any SAE ongoing at the end of treatment must be followed until resolution or 
stabilization. Any AEs or SAEs assessed as related to IMP that are new during the follow-up 
period will be reported and followed until recovery or stabilization. 
The TEAEs will be coded according to the MedDRA dictionary. Adverse events will be graded 
according to the NCI-CTCAE Version 5.0. The grade will be taken into account in the summary. 
For participants with multiple occurrences of the same PT within an observation period, the 
maximum grade will be used. 
An overall summary of TEAEs will be provided. The number and percentage of participants who 
experience any of the following will be provided: 
• Treatment-emergent AEs 
• Treatment-emergent adverse events of Grade ≥3 
• Treatment-related TEAEs 
• Serious TEAEs 
• Serious treatment-related TEAEs 
• Treatment-emergent AEs with a fatal outcome 
• Treatment-emergent AEs leading to permanent treatment discontinuation 
• Infusion reactions and other AESIs 
The number and percentage of participants experiencing TEAEs by primary SOC and PT will be 
summarized by NCI-CTCAE grade (all grades and Grade ≥3). Similar tables will be prepared for 
treatment-related TEAEs, AESIs, TEAEs leading to permanent or premature discontinuation, 
TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, and AEs/SAEs 
occurring during the post-treatment dosing period. 
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (screening, on-treatment, and post-treatment). For that purpose, the table of all 
TEAEs will be presented by SOC and PT sorted by internationally agreed order unless otherwise 
specified. 
Infusion reactions will be analyzed using both Investigator reporting and treatment-related TEAEs 
occurring within 24 hours after treatment administration. 
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9.4.2.2 Deaths  
A summary of the number and proportion of participants who died by study period (screening, 
on-treatment period, and post-treatment) and cause will be generated. A listing of deaths will be 
provided. 
9.4.2.3 Clinical laboratory evaluations  
All laboratory abnormalities will be graded according to NCI-CTCAE Version 5.0, when 
applicable. Number (%) of participants with laboratory abnormalities (ie, all grades and by grade) 
using the worst grade during the on-treatment period will be provided for the AT population. 
9.4.2.4 Vital signs  
The incidence of a potentially clinically significant abnormality (PCSA) at any time during the 
on-treatment period will be summarized whatever the baseline level and according to the 
following baseline status categories:  
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
The PCSA criteria will determine which participants had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, including 
nonscheduled or repeated evaluations. 
A listing of participants with at least 1 PSCA will be provided. 
9.4.3 Immunogenicity  
The observation period for ADA will be divided into 2 periods: pretreatment and on-study 
observation period: 
• The ADA pretreatment period will be defined as the time from informed consent signature 
until the first isatuximab administration. 
• The ADA on-study observation period will be defined as the time from the first isatuximab 
administration until the end of the study. 
Participants with at least 1 evaluable ADA result during the ADA pretreatment period will be 
considered as evaluable at baseline. Participants with at least 1 evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period. 
The following notions will be derived:  
• Preexisting ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
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• Treatment-induced ADA, defined as ADA that developed at any time during the ADA 
on-study observation period in participants without preexisting ADA (including 
participants without pretreatment samples). 
• Transient ADA response: 
- 
Treatment-induced ADA detected only at 1 sampling time point during the treatment 
or follow-up observation period (excluding the last sampling time point) OR 
- 
Treatment-induced ADA detected at 2 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 participant’s last sampling time point is ADA negative. 
• Persistent ADA response: treatment induced detected at 2 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 
at least 16 weeks. 
• Indeterminate ADA response: 
- 
Only the last sampling time point is positive OR 
- 
The last 2 samples, separated by a period less than 16 weeks, are positive. 
• Treatment-boosted ADA, defined as preexisting ADA with a significant increase in the 
ADA titer during ADA on-study observation period compared with the baseline titer. 
• ADA-positive participants, defined as participants with at least 1 treatment-induced or 
treatment-boosted ADA positive sample at any time following the first isatuximab 
administration. 
• ADA prevalence, defined as the sum of the number of participants with preexisting ADA 
and the number of participants with treatment-induced ADAs, divided by the number of 
evaluable participants. 
• ADA incidence, defined as the number of ADA-positive participants divided by the 
number of evaluable participants. 
The immunogenicity for isatuximab will be assessed by summarizing the number (%) of 
participants with preexisting ADAs and negative ADAs at baseline, and by summarizing the 
number (%) of ADA-positive participants (including treatment-induced ADAs and 
treatment-boosted ADAs) during the on-study observation period. 
9.4.4 Pharmacokinetic analysis  
The population PK analyses will be described in the population PK analysis plan provided by 
Pharmacokinetics and Drug Metabolism Modeling and Simulation group. 
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9.4.5 Biomarkers analysis  
The PD and biomarker analyses will be described in the statistical analysis plan finalized before 
database lock. 
CD38 receptor density (RD) and occupancy (RO) data will be presented in summary statistics by 
cohort. The data by groups of responders versus non-responders in best overall response will also 
be summarized.  
9.5 
INTERIM ANALYSES   
For each cohort, an interim analysis of efficacy, safety, and other data (including PK) will be 
performed after the completion of enrollment in Stage 1. Enrollment may be interrupted at the end 
of Stage 1 until the interim analysis is performed, unless the required number of responses is 
reached before completion of enrollment. 
A subgroup PK analysis will be performed after the first 20 participants of 2 years of age or more 
(at least 5 participants in the age group of 2 to 10 years, including approximately 3 patients 
between 2 and 5 year-old) are exposed to isatuximab. The dosage for participants aged less than 
2 years will be reassessed based on the results. 
The statistical analysis plan will describe the planned interim analyses in greater detail 
(see Section 10.1.5 for the committee structure). 
9.5.1 Data monitoring committee  
Close safety monitoring of each participant is planned, and an independent DMC will regularly 
monitor participant safety. A first safety review by the DMC is planned after the first 
10 participants have completed at least 1 induction cycle. See Section 10.1.5 for details of the 
DMC. 
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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 GCP Guidelines 
- 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated  
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants  
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
• The Sponsor will be responsible for the following: 
- 
Submitting to the regulatory authorities for notification and approval any change(s) of 
the protocol that are deemed as “substantial” (ie, changes which are likely to have a 
significant impact on the safety or physical or mental integrity of the clinical trial 
participants or on the scientific value of the trial) 
- 
Notifying IRBs/IECs and competent authorities of the Member States the reason for, 
and the content of, any substantial amendments 
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10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
For informed consent: 
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her LAR and answer all questions regarding the study  
• Participants and LAR must be informed that their participation is voluntary. The LAR 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 
requirements, where applicable, and the IRB/IEC or site. Participants are encouraged to 
sign an assent form, if possible 
• 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 
• Legally acceptable representatives or participants who reach the legal age of majority as 
defined by local regulation during the course of the study must be reconsented 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 LAR  
• Participants who are rescreened are required to have their LAR sign a new ICF 
• The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional oncohematology exploratory research. 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 Section 10.9: Contingency Measures for a regional or national 
emergency that is declared by a governmental agency. 
10.1.4 Data protection  
All personal data collected 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 Global Data Protection Regulation.  
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Data collected must be adequate, relevant, and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because these data are required by 
regulatory agencies (eg, on Afro American population for the Food and Drug Administration or 
on Japanese population for the Pharmaceuticals and Medical Devices Agency in Japan). 
• 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. 
• 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  
An independent DMC, consisting of external independent experts, not associated with the conduct 
of the study, will meet regularly to: 
• Review the progress of the trial. 
• Review the safety data. 
• Advise the Sponsor on potential modifications or communications that may be necessary 
to ensure the participant safety or protect the scientific integrity of the trial. The Sponsor 
will make the final decision(s). 
The first meeting will be set up to review early safety results (eg, after approximately 
10 participants have completed at least one induction period), and then periodically. Ad hoc DMC 
meetings may also be held if a significant safety issue or issue deemed important for discussion 
arises on this or any other isatuximab studies. After each meeting, the DMC will advise the 
Sponsor’s representatives on recommendations regarding the continued safety of treating ongoing 
and future study participants, as well as the course of action regarding the conduct of the trial. 
One interim analysis is planned, and, after review of the results by cohort, the DMC will make 
recommendations on continuation of the study or not. 
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10.1.6 Dissemination of clinical study data  
Sanofi shares information about clinical studies and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical study disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical studies 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. 
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 studies. 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  
For data quality insurance: 
• 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 eCRF.  
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
• 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 assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• 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 eCRF 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.  
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• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.8 Source documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data 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. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the site or terminate the study at any time for 
any reason at the sole discretion of the Sponsor. Sites will be closed upon study completion. A site 
is considered closed when all required documents and study supplies have been collected and a 
site closure visit has been performed. 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the sponsor, as well as reasons for the early closure of a site by 
the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines. 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
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.  
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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 15 will be performed by the local laboratories with the exceptions of 
PK, ADA, RO/RD, MRD analyses, pro-inflammatory cytokine panel (including IL2, IL6, IL8, 
IL10, IFN γ, TNF alpha) which will be performed at the central laboratory. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5 
of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by the 
Investigator or required by local regulations. 
Table 15 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Blasts 
Clinical chemistrya 
Blood urea 
nitrogen 
Potassium 
Aspartate 
aminotransferase(AST)/Serum 
glutamic-oxaloacetic transaminase 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine aminotransferase 
(ALT)/Serum glutamic-pyruvic 
transaminase 
Total protein 
 
Glucose (fasting) 
Total 
Calcium 
Amylase 
Albumin 
 
Uric acid  
Phosphorus 
Lactic acid dehydrogenase 
Alkaline 
phosphatase 
 
Free T4 
Free/total 
T3 
Thyroid-stimulating hormone 
 
 
Ferritin 
CRP 
 
 
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Laboratory 
assessments 
Parameters 
Coagulationa 
D-dimers 
AT-III 
Fibrinogen 
Prothrombin time and international 
normalized ratio 
Partial 
thromboplastin time 
Routine urinalysis 
• 
pH, glucose, protein, blood, ketones, by dipstick 
Other screening tests 
• 
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential)b  
• 
Serology (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)c 
• 
All study-required laboratory assessments will be performed by a local laboratory, with the 
exception of PK, ADA, RO/RD and MRD. 
The results of each test must be entered into the eCRF 
ADA = antidrug antibody; eCRF = electronic case report form; DNA = deoxyribonucleic acid; HIV = human immunodeficiency virus; 
IEC = Independent Ethics Committee; INR = international normalized ratio; IRB = Institutional Review Board; ISI = international sensitivity 
index; MRD = minimal residual disease; PK = pharmacokinetics; PTnormal = normal prothrombin time; PTtest = prothrombin time in the 
participant; RD = receptor density; RNA = ribonucleic acid; RO = receptor occupancy; SAE = serious adverse event; ULN = upper limit of 
normal. 
NOTES : 
a 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 (possible Hy’s Law) must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
INR = (PTtest /PTnormal)^(ISI value) 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
c For patients with positive anti-HBc and negative HBsAg and undetectable HBV DNA at study entry (past resolved infection, resolving 
acute infection or receiving antiviral treatment with controlled infection), close monitoring of viral reactivation (greater than 1 log10 IU/mL 
increase in HBV DNA or reappearance of HBsAg or HBV DNA in resolved infection) throughout and following the end of study treatment 
should be proposed (ALT, AST, and HBV DNA 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 1 log10 IU/mL increase in HBV DNA or reappearance 
of HBsAg or detection of HBV DNA in patients with resolved infection [see definition in Section 6.5]), close monitoring of ALT and 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. 
In ALL patients on treatment with pegaspargase or L-asparaginase (Erwinase) daily monitoring of international normalized ratio (INR), partial 
thromboplastin time (PTT), fibrinogen and antithrombin III (AT-III) must be performed and fibrinogen and AT-III substituted if necessary. 
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 participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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Events meeting the AE definition 
• Any abnormal laboratory results which impact the study treatment, leads to treatment 
discontinuation, or fulfill the definition of an SAE. 
• Any safety assessments (eg, ECG, radiological scans, or vital sign measurements) 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator. 
• Exacerbation of a chronic or intermittent preexisting 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 DDI. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
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 preexisting 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 
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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. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised 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 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 eCRF. 
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• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Monitoring Team in lieu of completion of the AE/SAE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Monitoring Team. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to the Monitoring Team. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the severity categories as defined by the NCI-CTCAE Version 5.0. 
An AE 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. 
Assessment of causality 
• The Investigator is obligated to assess the causal relationship between study intervention 
and each occurrence of each AE/SAE, as a YES or NO evaluation. 
• A “reasonable possibility” of a causal 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 causal 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 IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the 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. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
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Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 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 sanofi with a copy of any postmortem findings including 
histopathology. 
• New or updated information will be recorded in the originally completed eCRF. 
• The Investigator will submit any updated SAE data to the Monitoring Team within 
24 hours of receipt of the information. 
• All AEs/SAEs will be followed until resolution, stabilization, or the participant is lost to 
follow-up. 
REPORTING OF SAES 
SAE reporting to the Monitoring Team via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Monitoring Team will be the 
electronic data collection tool. 
• 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 telephone. 
• Contacts for SAE reporting will be informed by the Monitoring Team. 
SAE reporting to the Monitoring Team via paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Monitoring Team. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting will be informed by the Monitoring Team. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
• Premenarchal 
• Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
CONTRACEPTION GUIDANCE 
Participants who receive cyclophosphamide should use a highly effective method of contraception 
for 1 year after the last dose of cyclophosphamide. 
Male participants 
• Male participants with female partners of childbearing potential are eligible to participate 
if they agree to 1 of the following during the protocol-defined time frame in Section 5.1: 
- 
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 16 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 the last dose of isatuximab, 12 months after the last dose of 
cyclophosphamide, and at least 6 months after other IMPs discontinuation (vincristine, 
pegaspargase, L-asparaginase (Erwinase), methotrexate, etoposide, doxorubicin, 
mitoxantrone, fludarabine, cytarabine), whatever occurs last and with the longest 
recommended period of contraception. 
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• 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 for the duration of the study and for 6 months after the last dose of isatuximab, 
12 months after the last dose of cyclophosphamide, and at least 6 months after other IMPs 
discontinuation (vincristine, pegaspargase, L-asparaginase (Erwinase), methotrexate, 
etoposide, doxorubicin, mitoxantrone, fludarabine, cytarabine), whatever occurs last and 
with the longest recommended period of contraception.  
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception as described in Table 16, consistently and correctly from 
2 weeks prior to the first dose and 6 months after the last dose of isatuximab, 12 months after the 
last dose of cyclophosphamide, and at least 6 months after other IMPs discontinuation 
(vincristine, pegaspargase, L-asparaginase (Erwinase), methotrexate, etoposide, doxorubicin, 
mitoxantrone, fludarabine, cytarabine), whatever occurs last and with the longest recommended 
period of contraception. 
Since an indirect interaction between components of the oral contraception and asparaginase 
cannot be ruled out, oral contraceptives are not considered sufficiently safe in such clinical 
situation. A method other than oral contraceptives should be used in women of childbearing 
potential using pegaspargase or L-asparaginase (Erwinase). 
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Table 16 - 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. Participants 
taking hormonal contraception should take only progesterone while being treated with polyethylene glycol-asparaginase. 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
Highly effective methods that are user independenta 
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb. 
• 
Intrauterine device. 
• 
Intrauterine hormone-releasing system. 
• 
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. 
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, 2 highly effective methods of contraception should be utilized during the treatment period and for at least 6 months 
after the last dose of isatuximab or 12 months after the last dose of cyclophosphamide. 
PREGNANCY TESTING: 
• Women of childbearing potential should only be included after a confirmed menstrual 
period and a negative highly sensitive urine or serum pregnancy test 2 weeks prior to the 
first dose of study intervention. 
• Additional pregnancy testing is required monthly during the treatment period on Day 1 of 
each cycle prior to the dose, and up to 6 months after the last dose of isatuximab, or 
12 months after the last dose of cyclophosphamide and as required locally 
(see the corresponding protocol-defined time frame in the SOA [Section 1.3]).  
• Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
Note: For adolescent participants of childbearing potential, specific contraceptive counseling is 
recommended to ensure understanding of these requirements. 
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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 poststudy 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 of the protocol. 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 be 
withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
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10.6 
APPENDIX 6: OTHER ASSESSMENTS AND SAFETY ITEMS  
10.6.1 Response criteria  
The following response criteria are from the NCCN Guidelines Version 1.2018. 
10.6.1.1 Acute lymphoblastic leukemia  
Response Criteria for Blood and BM: 
• Complete response: 
- 
No circulating blasts or extramedullary disease. 
- 
No lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central 
nervous system involvement. 
- 
Trilineage hematopoiesis and <5% blasts. 
- 
Absolute neutrophil count (ANC) >1000/μL. 
- 
Platelets >100 000/μL. 
- 
RBC transfusion independence: If the physician documents transfusion dependency 
related to study treatment and not to the patient’s underlying disease, CRi can be 
reported. 
• Complete response with incomplete blood count recovery: 
- 
Meet all criteria for CR except platelet count and/or ANC. 
• Overall response rate (ORR = CR + CRi+PR). 
• Refractory disease: 
- 
Failure to achieve CR at the end of induction. 
• Progressive disease: 
- 
Increase of at least 25% in the absolute number of circulating or bone marrow blasts or 
development of extramedullary disease. 
• Relapsed disease: 
- 
Reappearance of blasts in blood or bone marrow (>5%) or in any extramedullary site 
after a CR. 
Response Criteria for Mediastinal Disease (CT of chest with IV contrast and PET imaging should 
be performed to assess): 
• Complete response: 
- 
Complete resolution of mediastinal enlargement by CT. For participants with a 
previous positive PET scan, a post-treatment residual mass of any size is considered a 
CR as long as it is PET negative. 
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• Partial response: 
- 
>50% decrease in the sum of the product of the greatest perpendicular diameters (SPD) 
of the mediastinal enlargement. 
- 
For participants with a previous positive PET scan, a post-treatment PET must be 
positive in at least 1 previously involved site. 
• Progressive disease: 
- 
>25% increase in the SPD of the mediastinal enlargement. 
- 
For participants with a previous positive PET scan, a post-treatment PET must be 
positive in at least 1 previously involved site. 
• No response: 
- 
Failure to qualify for PR or progressive disease. 
• Relapse: 
- 
Recurrence of mediastinal enlargement after achieving CR. For participants with a 
previous positive PET scan, a post-treatment PET must be positive in at least 
1 previously involved site. 
Response criteria for CNS disease: 
• Central nervous system remission: 
- 
Achievement of CNS-1 status in a patient with CNS-2 or CNS-3 at diagnosis 
(see Table below). 
• Central nervous system relapse: 
- 
New development of CNS-3 status or clinical signs of CNS leukemia without other 
explanation. New development of CNS-2 status on 2 consecutive lumbar punctures 
(between 2 to 4 weeks apart). 
Definition of CNS Disease 
Criteria 
NS 1 
No blasts seen on cytocentrifuge (CNS negative) 
NS 2 
Total Nucleated Cell Count <5 x 106/L, but blasts seen on cytocentrifuge 
NS 3 
Total Nucleated Cell Count ≥ 5 x 106/L with blasts on cytocentrifuge and/or 
signs of CNS leukemia (eg, cranial nerve palsy) 
10.6.1.2 Acute myeloid leukemia  
For AML, a morphologic leukemia-free state is defined as: 
• <5% blasts in a BM aspirate with spicules. 
• No blasts with Auer rods or persistence of extramedullary disease. 
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A CR is defined as: 
• Morphologic CR - participant independent of transfusions 
- 
<5% blasts in a BM aspirate with spicules 
- 
No blasts with Auer rods or persistence of extramedullary disease  
- 
ANC ≥1000/μL 
- 
Platelets ≥100 000/μL 
- 
No residual evidence of extramedullary disease 
- 
Red blood cell transfusion independence; If the physician documents transfusion 
dependency related to study treatment and not to the patient’s underlying disease, CRi 
can be reported 
A CRi is defined as: 
• Same criteria as for CR, except neutrophils and/or platelets recovery (ANC <1000/L or 
platelets <100 000/L) 
A partial remission is defined as a decrease of at least 50% in the percentage of blasts to between 
5% to 25% in the BM aspirate and the normalization of blood counts as defined for CR. 
A relapse is defined as, following a CR, the reappearance of leukemic blasts in the peripheral 
blood or the finding of more than 5% blasts in the BM, not attributable to another cause (eg, BM 
regeneration after consolidation therapy) or extramedullary relapse. 
As induction failure is defined as the failure to attain CR following exposure to at least 2 courses 
of intensive induction therapy. 
10.6.2 Eastern cooperative oncology group performance status scale  
ECOG PS (40) 
0 – Fully active, able to carry on all predisease performance without restriction 
1 – Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (eg, light housework, office work) 
2 – Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 – Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 – Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 – Death 
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10.6.3 Lansky score scale  
Lansky scores (41): 
• 100 – fully active, normal 
• 90 – minor restrictions in strenuous physical activity 
• 80 – active, but tires more quickly 
• 70 – both greater restriction and less time spent in active play 
• 60 – up and around, but minimal active play; keeps busy with quieter activities 
• 50 – gets dressed, but lies around much of the day; no active play; able to participate in all 
quiet play and activities 
• 40 – mostly in bed; participates in quiet activities 
• 30 – in bed; needs assistance even for quiet play 
• 20 – often sleeping; play entirely limited to very passive activities 
• 10 – no play; does not get out of bed 
• 0 – unresponsive 
10.6.4 Revised Schwartz equation to estimate GFR in children  
eGFR* (mL/min/1.73 m2) = 0.413 × Height(cm) / Serum Creatinine (mg/dL) (42). 
*eGFR: estimated glomerular filtration rate. 
10.6.5 Types of infusion reactions and typically associated symptoms  
Please refer to the IB of isatuximab for the list of infusion reactions and typically associated 
symptoms. Common symptoms and infusion reactions from Study TED10893 are detailed below. 
TED10893 (Phases 1 and 2 - Stage 1): Most frequent symptoms (≥5%) of infusion associated 
reaction in participants exposed to isatuximab 
 
Isatuximab 
(N=186) 
Preferred term 
All grades, n (%) 
Grade ≥3, n (%) 
Any event 
93 (50.0) 
13 (7.0) 
Infusion related reaction 
87 (46.8) 
4 (2.2) 
Chills 
25 (13.4) 
0 
Dyspnoea 
22 (11.8) 
1 (0.5) 
Nausea 
22 (11.8) 
0 
Chest discomfort 
17 (19.1) 
0 
Flushing 
11 (5.9) 
0 
Headache 
10 (5.4) 
0 
Only rows with frequency of at least 5% in isatuximab in the all grades column are shown. 
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10.6.6 CD38 blood test interference guideline  
The AABB issued the following bulletin (Association Bulletin #16-02, Dated 15 January 2016) to 
mitigate the anti-CD38 interference with serologic testing. 
https://www.aabb.org/programs/publications/bulletins/Documents/ab16-02.pdf 
Association Bulletin #16-02  
Date: 15 January 2016 
To: AABB Members 
From: 
President 
—Chief Executive Officer 
Re: Mitigating the Anti-CD38 Interference with Serologic Testing 
Summary 
A new class of therapeutic agents for multiple myeloma, CD38 mAbs, can result in interference 
with blood bank serologic tests and thereby cause delays in issuing red blood cell (RBC) units to 
participants receiving these agents. To minimize these delays, hospitals should set up procedures 
to inform the transfusion service when participants 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 mAbs 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 mAb 
therapies. In November 2015, the first therapeutic CD38 mAb (daratumumab [Darzalex, Janssen 
Biotech, Horsham, PA]) was approved by the Food and Drug Administration1. Other CD38 mAbs 
are under development. 
CD38 mAbs 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 participants consistently cause 
positive reactions in IATs, antibody detection (screening) tests, antibody identification panels, and 
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antihuman globulin (AHG) crossmatches. Agglutination due to anti-CD38 may occur in all media 
(eg, saline, low ionic strength saline, and polyethylene glycol), and with all IAT methods (eg, gel, 
tube, and solid phase). Agglutination reactions caused by antiCD38 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 auto controls. 
• Some rare Lu(a–b–) cells are not reactive in the presence of anti-CD38, potentially giving 
the false impression that the participant has a Lutheran-related antibody.4, 5  
• Positive IATs can be observed for up to 6 months after anti-CD38 is discontinued.1, 3 
• Anti-CD38 may cause a small decrease in hemoglobin in vivo (approximately 1 g/dL), but 
severe hemolysis has not been observed among treated participants.3, 6  
Anti-CD38 interference can cause delays in issuing RBCs 
If the transfusion service is unaware that a participant has received anti-CD38, the following 
scenario may occur when the participant’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 (auto control 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 participant. In some cases, the anti-CD38 interference 
could mask the presence of a clinically significant alloantibody. 
Recommendations 
To avoid problems with transfusions, hospitals should set up procedures to inform the transfusion 
service whenever any participant is scheduled to begin taking anti-CD38. 
BEFORE a participant begins taking anti-CD38: 
• A baseline type and screen should be performed. 
• In addition, a baseline phenotype or genotype is recommended. 
AFTER a participant begins taking anti-CD38: 
• ABO/RhD typing can be performed normally. 
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• For antibody detection (screening) and identification, 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 participant 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; however, such antibodies are encountered infrequently. 
Crossmatch 
• For participants 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 participants with known alloantibodies, phenotypically or genotypically matched RBC 
units may be provided.6, 8 
- 
As some typing antisera require the use of AHG, phenotyping should be performed 
before the participant receives anti-CD38. 
- 
Genotyping can be performed either before or after the participant 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 antibody.2, 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 cells.9  
References for Section 10.6.6 
1. Darzalex package insert. Horsham, PA: Janssen Biotech, 2015. [Online]. [cited 2016 Jan 
07]. Available from:URL: http://www.darzalex.com/shared/product/darzalex/darzalex-
prescribing-information.pdf  
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(6 pt 2):1545-54. 
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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(6 pt 2):1555-62. 
4. Velliquette RW, Shakarian G, Jhang J, Rodriguez M, Morrison M, Adamy 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, Do J, Rodberg K, Aldridge L, 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. (2015, December) 
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, AuBuchon JP, Cohn CS, Delaney M, 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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10.6.7 Grading system and mitigation strategy for ICANS, based on 2019 ASTCT 
consensus guidelines  
 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Impact, Confidence, 
and Ease (ICE) score 
for children age 
≥12 years* 
7-9 
3-6 
0-2 
0 (patient is unarousable 
and unable to perform ICE) 
Cornell Assessment of 
Pediatric Delirium 
(CAPD) score for 
children age <12 years 
1-8 
1-8 
≥9 
Unable to perform CAPD 
Depressed level of 
consciousness† 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to tactile 
stimulus 
Unarousable or requires 
vigorous or repetitive tactile 
stimuli to arouse; stupor or 
coma 
Seizure (any age) 
N/A 
N/A 
Any clinical seizure focal 
or generalized that 
resolves rapidly or 
nonconvulsive seizures 
on EEG that resolve with 
intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between 
Motor weakness 
(any age)‡ 
N/A 
N/A 
N/A 
Deep focal motor weakness, 
such as hemiparesis or 
paraparesis 
Elevated ICP/ cerebral 
edema (any age) 
N/A 
N/A 
Focal/local edema on 
neuroimaging§ 
Decerebrate or decorticate 
posturing, cranial nerve 
VI palsy, papilledema, 
Cushing's triad, or signs of 
diffuse cerebral edema on 
neuroimaging 
ICANS grade is determined by the most severe event (ICE or CAPD score, level of consciousness, seizure, motor findings, raised intracranial 
pressure (ICP)/cerebral edema) not attributable to any other cause. Baseline CAPD score should be considered before attributing to ICANS. 
*  A patient with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a patient with an ICE score of 0 may be 
classified as grade 4 ICANS if unarousable. 
† Depressed level of consciousness should be attributable to no other cause (eg, no sedating medication). 
‡ Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they do not influence 
ICANS grading. 
§ Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from ICANS grading. It 
may be graded according to CTCAE v5.0 
Data source: Lee et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector 
Cells Biol Blood Marrow Transplant 25 (2019) 625-638 (43) 
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10.6.8 Encephalopathy Assessment Tools for Grading of ICANS Immune Effector Cell-
Associated Encephalopathy (ICE) score  
10.6.9  Encephalopathy assessment for children age <12 years using the CAPD score  
 
 
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10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING   
Not applicable.  
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS   
For German sites coagulation test will be done twice a week and if clinically indicated. For the 
rest of the world, it will remain once a week and if clinically indicated.  
10.9 
APPENDIX 9: 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 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/enrollment/administration of study intervention may be temporarily delayed. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible. In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.  
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. Possibility of visit extension must 
be discussed on a case by case basis with the Sponsor considering first subject’s safety and 
best interests.   
If onsite visits are possible and there is a need to reduce the time spent on site to a minimum, the 
focus should be on IMP infusion/administration, collection of safety information (vital signs, 
adverse events) and safety blood collection (mainly biochemistry, hematology and ADA, if 
planned for the visit). However, all efforts should be made to perform the measurements of key 
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parameters for efficacy endpoints. These would include bone marrow aspirations and optional 
extramedullary disease assessments: CT, PET-CT or PET-MRI for this study. 
For ongoing patients unable to come to the study site, administration of isatuximab and other 
study drugs (dexamethasone, fludarabine, cytarabine, anthracycline, IT chemotherapy for AML; 
dexamethasone, mitoxantrone or doxorubicin, vincristine, pegaspargase, L-asparagase, IT 
chemotherapy for ALL induction; dexamethasone, methotrexate, cyclophosphamide, etoposide, 
vincristine, pegaspargase, L-asparagase, IT chemotherapy for ALL consolidation cycle) requiring 
IV infusion need to occur in investigator site hospital, consequently these infusions will be 
delayed until the moment when regular study visits will be conducted again at the study site. 
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
can only occur once the Investigator has determined, according to his/her best judgement, that the 
contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was unlikely. 
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained) to make clinical supplies available to the participant for the 
duration of the emergency:  
The dexamethasone in oral form may be supplied at the site or from the PI/site/Sponsor to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
agreed upon by the participant. 
Contingencies implemented due to emergency will be documented. 
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, use of 
local labs).  
The impact of the regional or national emergency if any declared by a governmental agency on 
study conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of 
the intervention due to the emergency). Any additional analyses and methods required to evaluate 
the impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the 
SAP. 
10.10 APPENDIX 10: ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AE: 
adverse event 
AESI: 
adverse events of special interest  
AHG: 
antihuman globulin 
ALL: 
acute lymphoblastic leukemia 
AML: 
acute myeloid leukemia 
ANC: 
absolute neutrophil count  
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AT: 
all-treated 
AT-III: 
antithrombin III  
AUC: 
area under the curve 
AUClast: 
area under the curve from time 0 to the last measurable concentration 
B: 
B-cell 
B-ALL: 
B-cell acute lymphoblastic leukemia 
BM: 
bone marrow 
CAPD: 
Cornell Assessment of Pediatric Delirium 
CAR-T: 
chimeric antigen receptor T cells 
CFR: 
Code of Federal Regulations 
CIOMS: 
Council for International Organizations of Medical Sciences 
CL: 
linear clearance 
CLinf: 
time-independent clearance 
Cmax: 
maximum serum concentration reached by the drug after a dose 
CNS: 
central nervous system 
CONSORT: 
Consolidated Standards of Reporting Trials 
CR: 
complete response 
CRi: 
complete response with incomplete peripheral recovery 
CRP: 
C-reactive protein 
CRS: 
cytokine release syndrome  
CT: 
computed tomography 
Ctrough: 
lowest serum concentration reached by a drug before the next dose is 
administered 
CYP: 
cytochrome P450 
D: 
day 
DAT: 
direct antiglobulin test 
DDI: 
drug-drug interactions 
DFS: 
disease-free survival 
DLT: 
dose-limiting toxicity 
DMC: 
data monitoring committee  
DNA: 
deoxyribonucleic acid 
DOR: 
duration of response 
DTT: 
dithiothreitol 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EFS: 
event free survival 
eGFR: 
estimated glomerular filtration rate 
FDA: 
Food and Drug Administration 
FLAG: 
Fludarabine, Aracytine, G-CSF 
GCP: 
Good Clinical Practice 
G-CSF: 
granulocyte colony-stimulating factor 
GMP: 
Good Manufacturing Practice 
GVHD: 
Graft versus Host Disease 
HBs: 
hepatitis B surface 
HBsAg: 
hepatitis B surface antigen 
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HBV: 
hepatitis C virus 
HCV: 
hepatitis C virus 
HIV: 
human immunodeficiency virus 
HLT: 
high level term 
HSCT: 
hematopoietic stem cell transplantation 
IAT: 
indirect antiglobulin test 
IB: 
Investigator's Brochure 
ICE: 
Impact, Confidence, and Ease 
ICF: 
Informed Consent Form 
ICH: 
International Council for Harmonisation 
ICP: 
intracranial pressure 
ICU: 
intensive care unit 
IEC: 
Independent Ethics Committee 
IFN: 
interferon  
IgG: 
immunoglobulin G 
IgM: 
immunoglobulin M 
IL: 
interleukin  
IMP: 
investigational medicinal product 
INR: 
 international normalized ratio 
IR: 
infusion reaction 
IRB: 
Institutional Review Board 
IT: 
intrathecal 
IV: 
intravenous(ly) 
LAR: 
legally acceptable representative 
LBL: 
lymphoblastic lymphoma 
LDH: 
lactic acid dehydrogenase 
LLT: 
lower level term 
mAb: 
monoclonal antibody 
MDS: 
myelodysplasia 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MM: 
multiple myeloma 
MRD: 
minimal residual disease 
NCCN: 
National Comprehensive Cancer Network 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIMP: 
noninvestigational medicinal product 
NSAID: 
nonsteroidal anti-inflammatory drugs 
ORR: 
overall response rate 
OS: 
overall survival 
PBPK: 
physiologically based pharmacokinetic 
PCR: 
polymerase chain reaction 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics(s) 
PEG: 
polyethylene glycol 
PET: 
positron emission tomography 
Ph: 
Philadelphia chromosome 
PK: 
pharmacokinetic(s) 
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PO: 
oral administration 
PT: 
preferred term 
PTT: 
partial thromboplastin time 
Q2W: 
once every 2 weeks 
QW: 
once a week 
R/R: 
relapsed or refractory 
RBC: 
red blood cell 
RD: 
receptor density 
RNA: 
ribonucleic acid 
RO: 
receptor occupancy 
SAE: 
serious adverse event 
SD: 
standard deviation 
SOA: 
Schedule of Activities 
SOC: 
system organ class 
SPD: 
sum of the product of the greatest perpendicular diameters 
SUSAR: 
suspected unexpected serious adverse reactions 
T: 
T-cell 
T-ALL: 
T-cell acute lymphoblastic leukemia 
TEAE: 
treatment-emergent adverse event 
T-LBL: 
T-cell lymphoblastic lymphoma 
TLS: 
tumor lysis syndrome 
TLS: 
tumor lysis syndrome  
TNF: 
tumor necrosis factor 
TSH: 
thyroid-stimulating hormone 
ULN: 
upper limit of normal 
WBC: 
white blood cell  
WOCBP: 
woman of childbearing potential 
 
10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).  
10.11.1 
Amended protocol 04 (24 November 2020)  
This amended protocol (Amendment 04) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary driver for this amendment is to implement DMC recommendations following the 
occurrence of first fatal case as an outcome of a Cytokine Release Syndrome (CRS) event. 
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On 01 October 2020, due to the occurrence of first fatal CRS event, the study data monitoring 
committee (DMC) has evaluated the safety profile of the first 9 treated patients and recommended 
the continuation of the study with changes to be implemented in an amendment to the protocol.  
The main changes are:  
• White blood cell (WBC) counts should be below 20 x 109/L before isatuximab 
administration.  
• Patients with high WBC counts between 20 and 50 x 109/L at screening and with high 
tumor burden in relation to extramedullary disease should receive a rescue cytoreductive 
therapy with a short half-life in order to potentially reach the 20 x 109/L WBC threshold 
before first isatuximab administration.  
• As consequence the list of cytoreductive drugs with suggested doses are proposed in this 
amendment in order to have less heterogeneity in the participants’ cytoreductive therapy 
management across participating sites.  
• Guidance is added to clarify the CRS events with inclusion of a specific section and table 
describing criteria for diagnosis, grading, as well as management of these events. 
Prospective determinations of CRS biomarkers at different time points are included. 
• Cytokines panel, ferritin, and C-reactive protein (CRP) are added at baseline and at 
different time points in order to better assess events like CRS, hemophagocytic 
lymphohistiocytosis (HLH), infections, etc. Moreover, specific guidance for hematology, 
vital signs, radiology are added in case of high tumor burden or CRS events. 
• Anti-IL6 as concomitant or rescue medication in case of CRS Grade 2 or above is added. 
• Seizures ≥ Grade 3 should be reported as adverse events of special interest (AESI). 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1, Section 
4.1.2, Section 5.1, 5.2, 
Section 6.1, Section 6.5, 
Section 6.5.1, Section 
8.2.2 and Section 8.2.6 
For patients with high tumor burden, cytoreductive 
chemotherapy should become mandatory, before the 
study treatment start. Threshold for tumor burden and 
types of chemotherapy are provided. 
Inclusion criterion 05 was added to reflect these 
changes.  
Clarification on cytoreductive 
chemotherapy and modification of 
inclusion and exclusion criteria to 
address DMC recommendations. 
Section 4.1.2 
For patients with WBC count <20 x 109/L at screening, 
but higher than 20 x 109/L on Day 1, a cytoreductive 
chemotherapy should be started as recommended in 
order to decrease their WBC count and the screening 
period will be extended without a deviation. 
Clarification on cytoreductive 
chemotherapy for with WBC count 
<20 x 109/L at screening.   
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Section # and 
Name 
Description of Change 
Brief Rationale 
Sections 1.1, Section 1.2, 
Section 1.3, Section 6.1, 
Section 6.1.2 
Erwinase is the treatment of choice that should be 
used to replace PEG-Asparaginase in case of 
hypersensitivity or loss of activity and/or country 
availability and regulations; infusion should last at 
least 2 hours.  
Instructions were added for daily monitoring of INR, 
PTT, and related to fibrinogen and AT-III parameters 
for ALL patients treated with pegaspargase or 
L-asparginase. 
Clarification on L-asparaginase 
(Erwinase) use conditions and treatment 
procedures. 
Section 1.2  
Patients may experience intolerance to 
PEG-asparaginase during study treatment period. 
They may switch to Erwinase, the rules on the switch 
process are provided. 
Clarification on the use of 
L-Asparaginase (Erwinase) and switch 
from PEG-Asparaginase during 
treatment to all cohorts. 
Section 2.3 
Instructions for screening with serological tests was 
modified 
Serological tests during screening are 
now mandatory 
Section 1.3, 
Section 10.2 (appendix 2) 
Cytokines panel, ferritin, CRP are added at baseline 
and at different time points in case of CRS. Moreover, 
specific guidance for hematology, vital signs, radiology 
was added in case of high tumor burden or CRS 
events.  
Addition of some clinical, radiological 
and biological parameters needed for 
specific events assessments.  
Section 5.2 
As cytoreductive therapy is requested for some 
participants, the exclusion criterion E10 is updated in 
order to allow these prior treatments. 
To update according to DMC 
recommendations the exclusion criteria 
E10.  
Sections 1.1, Section 6.1, 
Section 6.5.1, 
Section 4.1.2 
Cytoreductive chemotherapy is non-IMP, added as a 
rescue therapy for patients with high tumor burden at 
screening.  
To add according to DMC 
recommendations the possibility of 
cytoreductive chemotherapy and clarify 
these are non-IMP products.  
Section 6.5.1  
Added anti-IL6 as concomitant or rescue medication in 
case of CRS event of Grade 2 or above as a rescue 
therapy. 
CRS risk has been identified for this 
study, consequently treatment and 
guidance are provided. 
Section 8.3  
Added seizures ≥ Grade 3 as AESI. 
Two cases of Grade 3 seizures have 
been identified among the first 9 treated 
patients. DMC recommended to add 
these events as AESI. 
Section 5.2 
An exclusion criterion E09 has been modified to clarify 
that patients with infection or life-threatening tumor 
lysis syndrome if present at study entry or during the 
screening period cannot participate in the study. 
The exclusion criteria E09 has been 
modified to exclude patients with 
infections and life-threatening tumor 
lysis syndrome if present at study entry 
or during the screening period to prevent 
avoidable risks for participants. 
Section 5.2 
Additional exclusion criterion was added as regard to 
WBC count threshold. Participants with white blood 
cell count > 50x109/L at the time of screening visit are 
not allowed. 
An additional exclusion criterion E26 to 
define the WBC count threshold at 
screening visit. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.2 
Additional exclusion criterion was added to exclude 
participants who have been exposed to anti-CD38 
therapies within 6 months prior to Day 1. 
An additional exclusion criterion E27 to 
exclude prior treatment with anti-CD38 
therapies as prior exposure may 
decrease CD38 expression within 
6 months. 
Section 6.6.1 
Definition of IR has been added, 
Table 6 - Management of infusion reactions have been 
updated. 
To prevent avoidable risks for 
participants. 
Added Section 6.6.2 
Guidance for Anaphylaxis management is provided. In 
case of anaphylaxis of any grade isatuximab (or other 
product) will be permanently discontinued. 
To prevent avoidable risks for 
participants. 
Added Section 6.6.3 
Guidance for CRS management are provided. In case 
of any event of CRS of Grade 2 or higher isatuximab 
will be permanently discontinued. 
CRS risk has been identified for this trial, 
consequently treatment and guidance are 
provided. 
Section 8.2.1 
Guidance for physical exam in case of CRS with 
potential occurrence of ICANS was added. 
CRS may complicate with neurological 
symptoms that need specific grading 
and guidance. 
Section 1.3, Section 8.2.2 
Vital signs monitoring after every isatuximab infusion 
in case of high tumor burden or CRS event added. 
Vital signs need intensive monitoring 
after every isatuximab infusion in case of 
CRS for subjects’ safety follow up. 
Section 1.3, and, added 
Section 8.2.5 
Guidance on pulmonary imaging was added in case of 
high tumor burden or CRS event. 
Risk of leukostasis is high in case these 
events occur, consequently, more 
intensive chest X-ray monitoring was 
added. 
Section 8.2.6  
Safety laboratory section updated. 
To be consistent with different protocol 
sections. 
Section 9.3 
Definition of all treated and evaluation patients were 
modified. 
To add more clarification.  
Section 9.4.2.1 
Definition of On-treatment period was modified. 
To add more clarification. 
Section 10.6.7 
The 2014 CRS grading is replaced with 2019 ASTCT 
ICANS grading. Encephalopathy Assessment Tools for 
Grading of ICANS Immune Effector Cell-Associated 
Encephalopathy (ICE) score and Encephalopathy 
Assessment for Children Age <12 Years Using the 
CAPD score were added. 
As CRS grading is already added into 
the protocol as a specific section, 
appendix will include these neurological 
events ASTCT ICANS grading and its 
assessments tolls. 
Section 1.3 
Cardiac assessment and ECG has been added to 
hematological recovery visit and at "EOT visit" also to 
AML cohort. 
Correction of an inconsistency. 
Section 1.3 
Instructions were added to assess Potassium, 
phosphorus, uric acid, corrected and ionized calcium.  
To rule out tumor lysis syndrome. 
Table 1 and Table 2 in 
Section 1.3 
Sample for CD38 RO/RD test should be collected just 
before isatuximab administration or up to 3 days prior 
to it. 
Some flexibility to CD38 RO/RD test 
collection has been added.  
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3, 
Section 4.1.3, Section 6.5 
HBV/HCV serological tests are mandatory for all 
patients at study entry. Patient not having been tested 
for HBV/HCV at screening that are still on treatment at 
the time of the amended protocol 4 will need to be 
tested additionally for HBsAg, anti HBs, anti-HBc (total 
and IgM), anti-HCV, HCV RNA level.   
Clarification. 
Section 6.6.1, 
Section 6.6.2 
If there is a suspicion of anaphylaxis of any degree, 
every effort should be made to distinguish it from other 
IRs. If the suspicion of anaphylaxis persists or is 
confirmed, isatuximab (or any other product causally 
responsible for anaphylaxis) should be permanently 
discontinued. 
Clarification that repeated IMP 
administration regardless of the grade of 
anaphylaxis must be prevented. 
Section 10.4 
Since an indirect interaction between components of 
the oral contraception and asparaginase (Erwinase) 
cannot be ruled out, oral contraceptives are not 
considered sufficiently safe in such clinical situation. 
A method other than oral contraceptives should be 
used in women of childbearing potential using 
pegaspargase or L-asparaginase (Erwinase). 
Clarification on contraception for 
WOCBP receiving pegaspargase or 
L-asparaginase (Erwinase). 
Section 1.3, Section 10.2, 
Section 6.1.2 
In ALL patients on treatment with pegaspargase or 
L-asparaginase (Erwinase) daily monitoring of 
international normalized ratio (INR), partial 
thromboplastin time (PTT), fibrinogen and 
antithrombin III (AT-III) must be performed and 
fibrinogen and AT-III substituted if necessary. 
Pegaspargase IV infusion should last at least 2 hours. 
To improve surveillance of participants 
receiving pegaspargase or 
L-asparaginase (Erwinase). 
Added Section 6.1.3, 
Section 1.3, 
Section 4.1.3, 
Section 8.2.5, 
Section 8.2.6 
Mandatory evaluations (hematology test including 
WBC with differential, Chest X-ray, potassium, 
phosphorus, uric acid, albumin, and calcium must be 
repeated every day) on Day 1 (or on schedule of 
evaluations provided) prior to the first isatuximab 
administration have been added. 
To prevent avoidable risks in 
participants. 
Section 6.1 
Mandatory monitoring of patients after every 
isatuximab infusion is set up for 2 hours. 
To prevent avoidable risks in 
participants. 
Section 10.11 
Summary of changes to last version of protocol has 
been added. 
To provide summary of changes 
introduced in the last amended 
protocol v3. 
 
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10.11.2 
Amended protocol 03 (30 July 2020)  
This amended protocol (Amendment 03) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary driver for this amendment is to implement changes following health Authorities 
comments and to mitigate the risk of hepatitis reactivation identified in the SAR650984 
Investigator’s Brochure edition 11 (30-Apr-2020). 
Protocol amendment summary of changes table  
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
(SoA); 2.3 Benefit/Risk 
Assessment; 
10.2 Appendix 2: Clinical 
laboratory tests 
Additional hepatitis-related serology tests to be 
performed at screening. 
A risk of hepatitis reactivation has been 
identified. 
1.3 Schedule of Activities 
(SoA); 10.2 Appendix 2: 
Clinical laboratory tests 
Hepatitis viral serology to be performed during 
treatment period as clinically indicated. 
A risk of hepatitis reactivation has been 
identified. 
5.2 Exclusion criteria 
Hepatitis-related exclusion criteria clarified. 
A risk of hepatitis reactivation has been 
identified. 
5.2 Exclusion criteria; 
6.5 Concomitant therapy 
Exclusion of live vaccines from 30 days before 
first IMP administration until 90 days after last IMP 
administration. 
To prevent potential safety risks. 
6.5 Concomitant therapy; 
10.2 Appendix 2: Clinical 
laboratory tests 
Procedure for HBV vaccination and antiviral therapy 
defined. 
A risk of hepatitis reactivation has been 
identified. 
6.5 Concomitant therapy; 
6.6.3 Guidance in case 
of hepatitis B reactivation 
occurring under study 
treatment; 
10.2 Appendix 2: 
Clinical laboratory tests 
Description of monitoring of alanine aminotransferase 
(ALT) and aspartate aminotransferase (AST) in case of 
viral reactivation. 
A risk of hepatitis reactivation has been 
identified. 
2.3 Benefit/Risk 
Assessment; 
6.5 Concomitant therapy; 
6.6.3 Guidance in case 
of hepatitis B reactivation 
occurring under study 
treatment; 
10.2 Appendix 2: 
Clinical laboratory tests 
Description of study treatment discontinuation and 
restart procedure in case of viral reactivation. 
A risk of hepatitis reactivation has been 
identified. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.5 Criteria for 
temporarily delaying of 
enrollment/administration 
of study intervention; 
6.1 Study intervention(s) 
administered; 
7.1.2 Temporary 
intervention 
discontinuation; 
7.1.3 Rechallenge; 
8 Study assessments 
and procedures; 
9.3 Populations for 
analyses; 
10.1.3 Informed consent 
process; 
10.9 Appendix 9: 
Contingency Measures 
for a regional or national 
emergency that is 
declared by a 
governmental agency 
The specific contingency measures in case of regional 
or national emergency that is declared by a 
governmental agency (eg, remote visits, use of local 
laboratory, temporary treatment discontinuation) have 
been added. 
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. 
1.1 Synopsis; 3 Objectives 
and Endpoints 
Secondary endpoints: CD38 receptor density will be 
assessed at baseline and CD38 receptor occupancy 
on Day 15. 
Clarification. 
1.1 Synopsis; 
4.1.3 Study treatment 
period 
Earlier initiation of chemotherapy is allowed if required. 
During pre-phase with isatuximab alone, 
some patients may aggravate their 
clinical condition in absence of intensive 
associated treatment; only for these 
patients, chemotherapy may be started 
earlier than Day 8, without change in 
isatuximab infusions. 
1.1 Synopsis; 
1.3 Schedule of Activities 
(SoA); 4.1.3 Study 
treatment period; 
4.1.5 Study duration; 
8.1 Efficacy Assessments 
Flexibility is added to bone marrow aspiration at the 
time of hematological recovery. 
For medical reasons, some patients 
cannot reach hematological recovery. 
1.1 Synopsis; 
1.2 Schema; 
1.3 Schedule of Activities 
(SoA); 5.2 Exclusion 
criteria; 6.1 Study 
intervention(s) 
administered; 6.6 Dose 
modification 
L-asparaginase (Erwinase) can be used in case of 
intolerance to pegaspargase prior or during the study 
as per local clinical practice. 
Many patients may have experienced or 
will present during the trial intolerance to 
pegaspargase; excluding this option may 
significantly decrease recruitment and 
does not provide any option for 
participants who will experience this 
issue during the trial. 
1.1 Synopsis; 6.1 Study 
intervention(s) 
administered 
Dose of vincristine should not exceed 2 mg per 
infusion in any patient. 
Clarification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
(SoA); 4.1.2 Screening; 
6.1 Study intervention(s) 
administered 
IT prophylaxis is mandatory for all cohorts; the drugs 
that will be used (methotrexate/aracytine/steroids) are 
per investigator discretion. 
Clarification. 
5.2 Exclusion criteria 
Exclusion for cardiomyopathy is defined as ejection 
fraction <55%. 
New York Heart Association Grade 3 and 
4 does not apply to pediatric population. 
6.1 Study intervention(s) 
administered 
Mandatory monitoring of first infusions of isatuximab. 
To prevent and treat infusion reactions. 
6.1 Study intervention(s) 
administered 
Timing of premedication with montelukast was 
changed. 
Montelukast activity is observed after 
2 hours. 
1.1 Synopsis; 
4.1.2 Screening; 
6.1 Study intervention(s) 
administered 
When dexamethasone is administered at 10 mg/m2 
per os, it can be divided in two daily doses, except for 
administration as part of isatuximab premedication. 
Clarification. 
1.1 Synopsis; 6.1 Study 
intervention(s) 
administered 
Ranitidine or equivalent are deleted from 
premedication list. 
According to Investigator’s Brochure 
edition 11. 
5.1 Inclusion criteria; 
10.4 Appendix 4: 
Contraceptive guidance 
and collection of 
pregnancy information 
Change in duration of contraception depending on the 
last treatment discontinued and considering the 
longest recommended duration of contraception. 
To cover recommended duration of 
contraception for all study treatments. 
7.1.1 Definitive 
discontinuation 
Mention that pregnancy will result in treatment 
discontinuation. 
Consistency. 
1.3 Schedule of Activities 
(SoA); 8.2.4 Cardiac 
assessment 
ECG and cardiac assessment to be performed at the 
end of Cycle 2. 
It is not possible to rule out a relationship 
between isatuximab concentration and 
heart rate. 
8.8.1 CD38 expression, 
receptor density, and 
receptor occupancy 
CD38 testing will be limited to European countries and 
North America. 
Clarification. 
1.3 Schedule of Activities 
(SoA); 10.2 Appendix 2: 
Clinical laboratory tests 
Addition of thyroid panel to the clinical chemistry tests. 
To prevent potential safety risks. 
1.3 Schedule of Activities 
(SoA); 10.2 Appendix 2: 
Clinical laboratory tests 
Addition of alkaline phosphatase to the clinical 
chemistry tests. 
Correction of an inconsistency. 
1.3 Schedule of Activities 
(SoA) 
Risk groups were clarified 
To provide examples of what will be 
consider as risk factor for final analysis. 
1.1 Synopsis; 
6.1.1 Acute myeloid 
leukemia combination 
therapies; 6.1.2 T ALL 
and B ALL combination 
therapies 
Conditions for second induction include neutrophils of 
≥500/mm3 and platelets of ≥50,000/mm3. 
Typo. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
5.2 Exclusion criteria 
Participants who are expected to have a superior 
benefit if treated with alternative established standard 
therapies are excluded. 
In the interest of the patient. 
1.1 Synopsis; 
9.1 Statistical 
hypotheses; 9.2 Sample 
size determination 
Complete response (CR) rate in statistical analysis 
defined as CR + complete response with incomplete 
peripheral recovery (CRi) rate. 
Consistency with primary endpoint. 
1.1 Synopsis; 
9.3 Populations for 
analyses 
Definition of pharmacokinetic population was clarified. 
Clarification. 
9.4.5 Biomarkers 
analysis 
The analysis of CD38 receptor density and occupancy 
was clarified. 
Clarification. 
10.1.3 Informed consent 
process 
Consent process for optional onco-hematology 
research is described. 
Clarification. 
Whole document 
Correction of typos and minor inconsistencies. 
 
10.11.3 
Amended protocol 02 (04 December 2019)  
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The objectives of this amendment were: 
• To bring clarifications on the definition of complete response, in order to avoid patients 
being ‘not evaluable’ if still dependent on red blood cell transfusions. 
• To include dexamethasone as an IMP for ALL cohort as part of study treatment. To further 
clarify the difference that for AML cohort dexamethasone is optional, except as 
premedication for isatuximab. 
• To update the duration for contraception.  
• To add Montelukast as a systematic premedication, the objective being to decrease the 
incidence and severity of IRs; it should not be at Investigator's discretion. 
• To add hematological criteria for ALL patients before starting the consolidation period. 
• To simplify some procedures in order to be closer to clinical practice. 
• To add recommendations in case of pegaspargase hypersensitivity. 
• To add analysis of CD38 receptor density and occupancy, in order to better understand the 
response profile at the end of the trial. 
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• To bring more clarification on the first interim analysis that will be performed on first 
20 patients. 
• To perform administrative and editorial updates and corrections to the protocol. 
Protocol amendment summary of changes table  
Section # and 
Name 
Description of Change 
Brief Rationale 
Short title 
The short title of the study has been updated to include 
the following name of the study: 
Isatuximab in Combination with Chemotherapy in 
Pediatric Patients with Relapsed/Refractory Acute 
Lymphoblastic Leukemia or Acute Myeloid Leukemia 
(ISAKIDS). 
To include the new approved short title. 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, Section 4.1.2 
Screening 
The following primary endpoint has been updated in 
Section 1.1 and Section 3: 
For AML: 
CR: bone marrow blasts lower than 5%; No blasts with 
Auer rods or persistence of extramedullary disease; 
absolute ANC higher than 1000/mm3, platelets higher 
than 100 000/mm3; red blood cells transfusion 
independence. If the physician documents 
transfusion dependency related to study treatment 
and not to the patient’s underlying disease, CRi can 
be reported.  
For B-ALL and T-ALL: 
CR: bone marrow blasts lower than 5%, no circulating 
blasts or lymphoblasts in CSF or extramedullary 
disease; ANC higher than 1000/mm3, platelets higher 
than 100 000/mm3; red blood cells transfusion 
independence. If the physician documents 
transfusion dependency related to study treatment 
and not to the patient’s underlying disease, CRi can 
be reported.  
Avoid having patients recruited and not 
evaluated in case they still require red 
blood cell transfusions. 
The following secondary endpoint has been updated in 
Section 1.1 and Section 3: 
The overall response rate is defined as the proportion of 
participants with CR or CRi for blood and bone marrow 
disease; PR based on the NCCN guideline will be 
considered in case of lymphomatus extramedullary 
disease for participants with T-ALL. 
PR as response doesn’t apply only for 
T-ALL, also for AML assessment. 
A new secondary objective/endpoint has been added to 
Section 1.1 and Section 3:  
Relationship between clinical effects and CD38 
receptor density and occupancy: CD38 receptor 
density and occupancy will be assessed at baseline 
and at Day 15 and correlated with clinical endpoints. 
Relationship between clinical effects 
and CD38 receptor density and 
occupancy will be evaluated to better 
understand the response profile at the 
end of the trial. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
The following text has been updated in synopsis and 
Section 4.1.2: 
In order to have rapid control of the tumor burden, the 
administration of cyclophosphamide 200 mg/m² is 
allowed (optional for both AML and ALL 
cohorts).and/or Dexamethasone 10 mg/m²/day 
(or equivalent) before the first study intervention 
administration (at least 3 times, on Days -3, -2, and -1) is 
(mandatory for ALL in all cohorts as a part of study 
treatment and optional for AML cohort). 
Administration of dexamethasone on Day 1 is 
mandatory in both cohorts as part of isatuximab 
premedication.  
Based on clinical practice, 
dexamethasone will be mandatory and 
consequently IMP only in ALL cohort; 
in both cohorts it will replace 
methylprednisolone as isatuximab 
premedication. 
Section 1.1 Synopsis, 
Section 6.1.1 AML 
combination therapies, 
Section 6.1.2 T-ALL and 
B-ALL combination 
therapies 
The following text has been added in AML combination 
therapies in synopsis: 
Refer to Figure 1 and Section 1.3 for days of 
investigational medicinal product (IMP) 
administration. 
Cycle 2 (second induction) text has been modified in 
synopsis and Section 6.1.1: 
If the BM aspiration performed 1 week after the end of 
induction treatment shows less than 20% blasts, a 
second cycle of combination therapy can be 
administered if neutrophils of ≥ 0.5/mm3 and platelets 
of ≥ 50/mm3after complete hematological recovery (ie, 
absolute neutrophil count >1000/µL and platelets 100 
000/ µL), while keeping the same schedule and doses.  
The following text has been added after the 
consolidation cycle for TALL and B-ALL combination 
therapies in the synopsis and Section 6.1.2: 
Before starting consolidation cycle, the patient must 
have neutrophils of ≥0.5/mm3 and platelets of 
≥50/mm3.  
Inconsistency corrected as presence of 
< 20% bone marrow blasts cannot 
correspond with complete 
hematological recovery. 
Minimal hematological function 
recovery is needed before starting a 
second induction treatment in AML. 
Section 1.1 Synopsis, 
Section 4.1.1 Study 
participants and cohorts, 
Section 4.3 Justification 
of dose, Section 6.1 
Study interventions 
administered, Section 
9.5 Interim analyses 
The dose regimen for dexamethasone or equivalent 
Investigational medicinal product for the AML cohort has 
been updated in the synopsis table and Section 6.1 
(Table 4): 
Dexamethasone being is part of both backbone 
treatment regimen and isatuximub premedication in the 
AML cohort only, and will be given as premedication 
for prevention of infusion associated reactions 
before each administration of isatuximab, at least 15 to 
30 minutes (but no longer than 60 minutes) prior to 
infusion, will be given as premedication for prevention of 
infusion associated reactions. Dexamethasone 
10 mg/m2 (maximum 20 mg) IV or PO on Days -3, -2, 
and -1 before isatuximab administration, and Days 1, 8, 
and 15 during the induction period (mandatory for 
Cycle 1 and before first isatuximab infusion Cycle 2). 
It could be optionally used for rapid control of tumor 
burden on Days -3, -2 and -1.  
Based on clinical practice, 
dexamethasone will be mandatory and 
consequently IMP only in ALL cohort; 
in both cohorts it will replace 
methylprednisolone as isatuximab 
premedication. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Noninvestigational Medicinal Products: 
The following text has been added in the synopsis and 
Section 6.1: 
The recommended isatuximab premedication agents 
are: montelukast, diphenhydramine (or equivalent), 
methylprednisolone, ranitidine (or equivalent), and 
acetaminophen (paracetamol) PO. Taking into 
consideration the disease context and the frequent 
use of steroids in acute leukemia, methylprednisolone 
will be replaced by dexamethasone.  
The following text has been modified in the synopsis and 
Section 6.1 (Table 5): 
Montelukast is to be given to a child under adult 
supervision, before isatuximab infusion, upon the 
Investigator’s decision.  
Dexamethasone has been added to the noninvestigational 
products table in the synopsis and Section 6.1 (Table 5): 
Route of administration: PO or IV 
Dose regimen: Dexamethasone is part of isatuximab 
premedication only in the AML cohort only, and will be 
given as premedication for prevention of infusion 
associated reactions before each administration of 
isatuximab, at least 15 to 30 minutes (but no longer 
than 60 minutes) prior to infusion. Dexamethasone 
10 mg/m2 (maximum 20 mg) IV or PO on Days 1, 8, and 
15 during the induction period (mandatory for Cycle 1 
and before first isatuximab infusion at Cycle 2).  
 
 
The following subgroup PK analysis age group has been 
modified in the synopsis, Section 4.1.1, Section 4.3, and 
Section 9.5: 
at least 5 participants in the age groups of 2 to 
4-10 years, 5 to 11 years and 12 to 18 years including 
approximately 3 patients between 2 and 5 year-old.  
Based on PK simulations, the threshold 
of 2 year-old has been identified as a 
potential risk for dose adaptation, and 
the population of interest for this 
analysis would focus on patients 
younger than 10 years; consequently, 
for interim analysis purposes, at least 
5 patients would be needed between 
2 and 10 year-old and no further 
stratification is needed. The current 
version is not consistent, as it requests 
the same minimal sample size by age 
subgroup as for the whole population at 
the end. This change is also in relation 
with the important challenges in 
patients’ recruitment, due to the 
epidemiology of the diseases 
Section 1.1 Synopsis 
and Section 9.4.5 
Biomarkers analysis 
The following text was added to synopsis and 
Section 9.4.5: 
Receptor density and occupancy data: 
The descriptive statistics of receptor density and 
receptor occupancy will be summarized by cohort and 
overall as well as for best overall response (responders 
versus non-responders) will be calculated.  
Relationship between clinical effects 
and CD38 receptor density and 
occupancy will be evaluated to better 
understand the response profile at the 
end of the trial. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SOA), 
Section 4.1.5 Study 
duration, Section 5.1 
Inclusion criteria, Section 
8.3.5 Pregnancy, 
Section 10.4 
(Appendix 4) 
Contraceptive guidance 
and collection of 
pregnancy information 
Physical examination has been added to the EOT visit 
for the AML cohort.  
CD38 biomarker added to the AML and ALL cohorts; 
consolidation and follow-up.  
Duration updated for bone marrow for disease 
assessment and MRD assessment (from Days 367 to 
43) for ALL cohorts consolidation and follow-up. 
The following footnotes were updated in Section 1.3: 
c-Past and current medical condition: date of initial 
diagnosis, type of disease (T-ALL/T-LBL, B-ALL, B-LBL, 
AML, immunophenotyping and cytogenetic, molecular 
profile), previous antileukemia treatment (reason for 
discontinuation, date of relapse, and best overall 
response to prior treatments), risk group as per site 
institutional practice, and prior transplant. 
e-Pregnancy testing should be carried out in WOCBP as 
follows: for ALL induction: within 2 weeks prior to first 
dose, Day 1 (predose), and Day 30 (predose). For ALL 
consolidation: on Day 57 (predose), end of treatment 
(30 days after last dose), and monthly during the follow 
up period for 180 days (6 months) after the last dose of 
isatuximab, or 12 months after the last dose of 
cyclophosphamide. For AML: within 2 weeks prior to 
first dose, Cycle 1 Day 1 (predose), Cycle 2 Day 1 
(predose), end of treatment (30 days after last dose), 
and monthly during the follow up period for 180 days 
(6 months) after the last dose of isatuximab, or 
12 months after the last dose of cyclophosphamide. 
This text is also updated in Section 4.1.5, Section 5.1 
(I 03), Section 8.3.5, and Section 10.4 (Appendix 4). 
g-Hematology: Hemoglobin, hematocrit, white blood cell 
count with differential, percentage of blasts, platelet 
count (please see Table 13 for a complete list). 
Hematology sample collection is recommended 
every 2 days, but mandatory at least weekly. 
j- Urinalysis: Dipstick only. If other analytes are 
collected based on clinical context, they must be 
reported in the eCRF. 
m-Bone marrow for disease assessment: No BM 
assessment is necessary if nonresponse or progressive 
disease can be diagnosed with peripheral blood 
evaluation, or, if a white blood cell count <300/mm3, or if 
the BM assessment is considered noncontributory by the 
Investigator. Any additional BM aspirations will be 
performed at the Investigator’s discretion and should be 
reported in the eCRF. If BM aspirate fails, BM biopsy 
could be an option. 
o-Extramedullary disease assessment: For ALL, CT or 
PET-CT (preferred) scans are suggested to be 
performed at screening and at hematological recovery or 
Clarifications and simplifications on 
some procedures and visits were 
needed in order to be more compatible 
with clinical practice. 
Pregnancy testing is updated based on 
the use of cyclophosphamide. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
at EOT (if no hematological recovery) if lymphomatous 
involvement is suspected. If not done, PET-CT scan is 
suggested to be performed at screening if 
lymphomatous involvement is present. If positive at 
screening, PET-CT will be repeated at the time of CR in 
BM. For AML, by physical examination may be used for 
specific locations when imaging is not appropriate 
(ex cutaneous location).  
 
The following procedure has been added to PK 
flowcharts: 
Pharmacodynamics: CD38 receptor density and 
occupancy in blood. 
 
Section 2.2 Background 
The following text has been updated: 
The half-life associated to the linear elimination was 18.6 
28 days 
Half-life for Isatuximab has been 
corrected. 
Section 2.3 Benefit/risk 
assessment 
The following text has been modified: 
At the cut-off date of 05 January 2019, the clinical 
development program with isatuximab consisted of 
Phase 1/2/3 studies of isatuximab as a single agent 
or in various therapeutic combinations with other 
agents. A total of 1301 patients have been exposed 
to isatuximab thus far in the completed studiesAs of 
05 January 2018, the clinical development program with 
isatuximab consists of Phase 1, Phase 2, and Phase 3 
studies of isatuximab as a single agent or in various 
therapeutic combinations with other agents. A total of 
675 participants have been exposed to isatuximab so far 
in company sponsored trials. During the dose escalation 
phase (Phase 1) of the TED10893 study (monotherapy 
in relapsed-refractory multiple myeloma [R/R MM] 
and other hematological malignancies), dose-limiting 
toxicities (DLTs) consistent with IRs (which were initially 
included in the definition of DLTs), occurred at Cycle 1 in 
2 participants with MM. 
Based on the efficacy results from a pooled analysis 
of completed monotherapy studies TED10893 
(Phase 1 and Phase 2 Stage 1) and TED14154 
(monotherapy in RRMM, Part A) (N = 212)From June 
2010 to August 2016, a total of 89 participants with 
CD38+ hematological malignancies were treated with 
isatuximab monotherapy in the TED10893 study. , 
Ooverall response rate (≥ partial response [PR]) 
according to Investigator assessment by the European 
Society for Blood and Marrow Transplantation criteria 
among the 84 MM treated participants was 19.820.2% (1 
CR, 16 PRs). Clinical benefit response (≥ minimal 
response) was 26.228.3% and best response was stable 
disease in 42.939.2% of the MM treated participants. 
To be consistent with the latest version 
of IB (edition 10). 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 4.1.2 Screening 
The following text has been modified: 
The screening assessment data obtained prior to the 
informed consent may be accepted if performed within 3 
weeks 1 month prior to Day 1. 
More flexibility for screening testings. 
Section 5.1 Inclusion 
criteria and Section 5.2 
Exclusion criteria 
Numbering of the eligibility criteria has been corrected.  
Minor formatting error corrections. 
Section 5.2 Exclusion 
criteria 
The following text has been added to E01: 
Human immunodeficiency virus, hepatitis B, and 
hepatitis C virus serology testing to be performed 
and collected in database only in countries where 
requested by local regulations.  
The E 12 has been clarified: 
Intolerance or contraindication to treatment with mAb 
or any other drug part of the study intervention. 
To anticipate specific regulatory 
requests in some countries. 
 
 
Clarification on exclusion criteria 
related to prior drug administrations. 
Section 5.2 Exclusion 
criteria 
The Exclusion criterion 13 has been clarified: 
E 13 - Participants with LBL with BM blasts <205%.  
Clarification on exclusion criteria: typo 
has been corrected. 
Section 6.1 Study 
interventions 
administered 
Dosing instructions for Vincristine have been updated to 
include the following text: 
Vincristine should be given 3 to 24 hours before 
administration of Asparaginasepegaspargase in 
order to minimize the toxicity. 
The following text has been updated: 
For participants who do not experience an IR during the 
first 4 administrations of isatuximab, the need for 
premedication at the subsequent infusions may be 
reconsidered at the Investigator’s discretion in 
consultation with the Sponsor, with the exception of 
dexamethasone administered as a part of study 
treatment in ALL cohorts (Days -3 to -1, 15 to 19, 29 
to 33 and 43 to 47) that should be administered as 
planned, unless there are dose modifications related 
to toxicities. 
Clarification on IMP administration. 
Section 6.5 Concomitant 
therapy 
The following text has been updated: 
Pneumocystis prophylaxis can should be provided as 
per the site’s clinical practice. 
Prophylactic heparin therapy is recommended for 
participants receiving PEG asparaginasepegaspargase, 
as well as use of anti-allergy premedication as per 
site clinical practice in order to decrease the risk of 
allergic reactions. 
Supportive care was updated in order 
to be compliant with clinical practice 
and international guidelines. 
Section 6.6 Dose 
modification 
The following texts have been updated: 
Administration of other IMPs in the study intervention will 
be discontinued/modified in the event of a treatment 
emergent AE (TEAE) that persists despite appropriate 
dose modifications or any other AE that, in the opinion of 
the Investigator, warrants discontinuation or dose 
modification. 
Clarification on IMP dose modification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
In case of Grade 3 or 4 hypersensitivity, allergy or 
non-allergic reaction to pegaspargasePEG 
asparaginase, no rechallenge with this drug is allowed. 
Mmonitoring and treatment will be administered as per 
the site’s clinical practice or NCCN guidelines. Slowing 
infusion to ≥2 hours, infusion of normal saline and 
use of anti-allergy premedication (such as 
hydrocortisone, diphenhydramine) can reduce the 
incidence and severity of these reactions and the 
need for substitution with Erwinia. 
Provide guidelines for asparaginase 
administration in order to avoid 
substitution with other equivalents that 
are less effective. 
Section 6.6.1 Guidelines 
for the management of 
potential infusion 
reaction 
Severe Grade 3 NCI CTCAE version 5 criteria definition 
has been modified with the following intervention 
recommendation: 
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 - If a Grade 3 infusion-related AE occurs, 
the isatuximab infusion must be interrupted, and the 
patient observed carefully and treated as needed 
until the AE either resolves or improves to Grade 1. 
Then, at the investigator’s discretion, the infusion 
may be restarted at half the infusion rate before the 
interruption. The infusion rate may be increased 
subsequently, at the investigator’s discretion. If after 
restarting the infusion, the severity of an infusion-
related AE returns to Grade 3, the infusion can be 
interrupted and restarted again (as described above) 
at the investigator’s discretion. If a Grade 3 infusion-
related AE occurs for a third time, treatment with 
isatuximab will be permanently discontinued for that 
patient. All Grade 3 IRs must be reported as AESIs. 
Modification of guidelines in case of 
isatuximab Grade 3 IRs, in order to 
avoid early discontinuation of the drug. 
8.1 Efficacy 
assessments 
The following text has been modified: 
Extramedullary assessment of AML will be performed by 
physical examination if radiology assessment cannot 
be performed. A CT or PET CT scan can be performed 
if clinically indicated for the AML cohort. 
Analysis Assessment of extramedullary assessment 
disease will be performed locally. 
Editorial update. 
 
The following sentence has been added:  
Minimal residual disease assessments will be 
performed by central laboratories. 
 
8.2.5.1 
Blood type 
phenotyping/genotyping 
After the start of the study treatment, a new IAT 
assessment will be performed once. If the second test is 
positive, a dithiothreitol (DTT) test should be performed 
only if transfusions are required (in accordance with 
Section 10.6.6). 
Clarification on dithiothreitol (DTT) test. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
New Section 8.8.1 CD38 
expression, receptor 
density, and receptor 
occupancy added 
The following text has been added: 
CD38 expression, receptor density (RD) and 
receptor occupancy (RO) will be assessed and 
correlated with clinical response. Blood samples will 
be collected once on Day 1 predose and once on 
Day 15 predose. 
Addition of RO and RD analysis in 
order to identify subgroups of patients 
who may benefit from treatment. 
Section 8.9 
Immunogenicity 
assessments 
Immunogenicity assessment has been updated as a 
separate heading. 
Updated formatting. 
New Section 9.4.4 
Pharmacokinetic 
analysis added 
The following text has been added to the new section 
9.4.4 pharmacokinetic analysis: 
The population PK analyses will be described in the 
Population PK analysis plan provided by 
Pharmacokinetics and Drug Metabolism Modeling 
and Simulation group. 
Clarification on PK analysis. 
Section 9.4.5 
Biomarkers analyses 
The section heading and the text has been updated: 
Other Biomarkers analysies: 
The PK, PD and biomarker exploratory analyses will be 
described in the statistical analysis plan finalized before 
database lock, if applicable. The population PK analysis 
and PD analyses and biomarker will be presented 
separately from the main clinical study report. 
 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
The following heading and text has been updated: 
Flowchart Appendix 2: Clinical laboratory tests. 
The tests detailed in Table 13 will be performed by the 
local laboratories with the exceptions of PK, ADA, 
RO/RD and MRD analyses, which will be performed at 
the central laboratory. 
Clarification on central and local 
laboratory tests. 
Section 10.6.1.1 Acute 
lymphoblastic leukemia 
Response criteria have been added for blood and BM: 
RBC transfusion independence: If the physician 
documents transfusion dependency related to study 
treatment and not to the patient’s underlying 
disease, CRi can be reported. 
Response criteria for CNS disease have been added: 
• 
Central nervous system remission: 
Achievement of CNS-1 status in a patient with 
CNS-2 or CNS-3 at diagnosis (see Table below) 
• 
Central nervous system relapse: New 
development of CNS-3 status or clinical signs of 
CNS leukemia without other explanation. New 
development of CNS-2 status on 2 consecutive 
lumbar punctures (between 2 to 4 weeks apart). 
Definition of CNS Disease Criteria 
CNS 1-No blasts seen on cytocentrifuge (CNS 
negative) 
CNS disease assessment have been 
added to be in line with international 
guidance. 
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Section # and 
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CNS 2-Total Nucleated Cell Count < 5 x 106/L, but 
blasts seen on cytocentrifuge 
CNS 3-Total Nucleated Cell Count ≥ 5 x 106/L with 
blasts on cytocentrifuge and/or signs of CNS 
leukemia (eg, cranial nerve palsy). 
Section 10.6.1.2 Acute 
myeloid leukemia 
Definition of CR has been updated to add the following 
points: 
• 
<5% blasts in a BM aspirate with spicules 
• 
No blasts with Auer rods or persistence of 
extramedullary disease 
• 
Red blood cell transfusion independence: If the 
physician documents transfusion dependency 
related to study treatment and not to the 
patient’s underlying disease, CRi can be 
reported.  
The following text has been modified: 
ANC ≥>1000/μL 
CRi definition has been updated as follows: 
• 
Same criteria as for CR, except neutrophils 
and/or platelets recovery (ANC <1000/L or 
platelets <100 000/L) 
Clarification to be in line with 
international guidance and clinical 
practice. 
 
•<5% BM blasts 
•Either ANC <1000/ L or platelets <100 000/ L 
•Transfusion independence but with persistence of 
cytopenia (usually thrombocytopenia) 
 
Throughout 
Generic drug name pegaspargase updated to replace 
Polyethylene glycol (PEG) asparaginase and product 
approved leaflet updated to replace package insert. 
Clarifications in order to allow available 
generics and be more compatible with 
clinical practice. 
Throughout 
Editorial changes and/or typographical errors. 
To improve text clarity, consistency, 
and readability and address 
typographical errors. 
10.11.4 
Amended protocol 01 (11 March 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 objectives of this amendment were: 
• To clarify suspected unexpected serious adverse reactions and sponsor responsibilities to 
submit any change(s) considered substantial to the regulatory authorities for notification 
and approval. 
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• To clarify contraception and pregnancy testing for females and males of childbearing 
potential, as well as clarification of the criteria for discontinuation of the study by the 
Sponsor. 
• To update the pharmacokinetic follow-up assessment from 60 to 90 days after last 
isatuximab administration to align with other isatuximab studies. 
• To improve the feasibility of the study procedures. 
• To perform administrative and editorial updates and corrections to the protocol. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Throughout 
Editorial changes and/or typographical errors. 
To improve text clarity, consistency, 
and readability and address 
typographical errors. 
Section 1.1 (Synopsis), 
Section 4.1.1 (Study 
participants and cohorts); 
Section 4.3 (Justification for 
dose); Section 9.5 (Interim 
analyses) 
Subgroup pharmacokinetic analysis re-stratified by 
age group. The following change has been made in 
Section 1.1, and performed with the same intent for 
Sections 4.1.1, 4.3, and 9.5: 
“A subgroup PK analysis will be performed after the 
first 20 participants (approximately 10 participants in 
each ALL and AML cohorts) of 2 years of age or more 
(at least 5 participants in the age groups of 2 to 
4 years, 5 to 11 years and 12 to 18 years) are 
exposed to isatuximab. The dosage for younger age 
participants aged less than 2 years will be 
reassessed based on the results. ” 
To include more patients in the lower 
age range. The inclusion of younger 
patients improves the possibility of 
supporting dosing in children below 
2 years of age. 
Section 1.1 (Synopsis); 
Section 1.3 (Schedule of 
activities); Section 6.1 
(Study intervention[s] 
administered) 
Granulocyte colony-stimulating factor administration 
updated to be optional during the study. 
To add flexibility to the product 
administration, in accordance with the 
Investigator’s discretion and 
participant’s clinical status and history. 
Clinical standards for granulocyte 
colony-stimulating factor 
administration vary between countries. 
Section 1.2 (Schema) 
Figures re-designed.  
Figures have been re-designed to 
improve clarity and consistency with 
the remaining updates.  
Section 1.3 (Schedule of 
activities); Section 8.1 
(Efficacy assessments) 
The following updates have been made to Section 1.3, 
footnote n: 
Specimen collection and time of 
collection have been updated for 
minimal residual disease assessment, 
to be consistent with the specifications 
of the assays used to assess minimal 
residual disease.  
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Brief Rationale 
“Bone marrow for MRD assessment: To For ALL, to be 
performed with BM aspiration samples at screening, 
and with peripheral blood samples at the end of 
induction for ALL (between Days 36 and 43), at the 
time of hematological recovery, and/or at the time of 
each BM aspirate aspiration for disease assessment if 
CR or CRi is achieved. For ALL only, if BM aspirates are 
not available (biopsy not allowed), peripheral blood 
samples could be used for these assessments except 
for the screening period. For AML, to be performed 
with BM aspiration samples at the time of 
hematological recovery between Days 22 and 29 
(optional), and/or at the time of each BM aspiration 
for disease assessment if CR or CRi is achieved”.  
Also in Section 1.3, the minimal residual disease 
assessments schedule was updated to include the first 
week of the consolidation phase “from Days 37 to 43”.
Section 8.1 has also been updated to reflect these 
changes. 
Section 1.3 (Schedule of 
activities); Section 6.1 
(Study intervention[s] 
administered) 
The following updates have been made regarding 
anthracycline administration in the AML cohort. 
In Section 1.3, footnote p:  
“Anthracycline: The choice of anthracycline 
(DaunoXome,liposomal daunorubicin, 
nonliposomal daunorubicin, or idarubicin) is at the 
Investigator’s discretion and the same anthracycline 
should be used throughout the study. The 
administration of Day 8 in Cycle 1 is mandatory. 
Other administrations of anthracycline, including 
Day 8 in Cycle 2, are at the Investigator’s 
discretion”. 
In Section 6.1, Table 4, dosing instructions for 
liposomal daunorubicin, nonliposomal daunorubicin, 
or idarubicin were updated so that doses would be 
mandatory for Cycle 1 Day 8, optional for Cycle 1 
Days 10 and 12, and optional for Cycle 2. 
To add flexibility to the product 
administration, in accordance with the 
Investigator’s discretion and 
participant’s clinical status and history. 
Anthracycline administration will 
depend on previous participant’s 
exposure and history of transplant. 
Section 1.3 (Schedule of 
activities) 
Contraception and pregnancy testing updated to 
include the period 2 weeks prior to treatment, and on 
a monthly basis during treatment and 6 months after 
treatment. 
To ensure compliance with the 
European Medicines Agency Clinical 
Trial Facilitation Group 
Recommendations related to 
contraception and pregnancy testing in 
clinical trials. 
Section 1.1 (Synopsis), 
Section 6.1 (Study 
intervention[s] administered) 
Polyethylene glycol-asparaginase updated to include 
intravenous mode of administration. 
To add flexibility to the product 
administration, in accordance with the 
approved package insert and 
Investigator’s discretion. Intravenous 
route was also included to account for 
the increased risk of thrombocytopenia 
in these participants, which does not 
allow for subcutaneous administration. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 (Synopsis), 
Section 6.1 (Study 
intervention[s] administered) 
Formulation, packaging, and labeling information for 
all investigational medicinal products (except for 
isatuximab) has been removed. In its place, the 
approved package inserts of these products have 
been referred. 
This information may be dependent on 
country sourcing and respective 
instructions should be performed in 
accordance with the approved 
package insert. 
Section 1.3 (Schedule of 
activities) 
Lumbar puncture and intrathecal chemotherapy in the 
acute lymphoblastic leukemia induction changed from 
Days 1 to 8. 
The original text was incorrect.  
Section 1.3 (Schedule of 
activities) 
Day 37 moved from the acute lymphoblastic leukemia 
induction schedule to the consolidation schedule.  
Day 37 is part of treatment Week 6, 
outside of the induction period 
(5 weekly isatuximab infusions for the 
acute lymphoblastic leukemia cohort). 
Section 1.3 (Schedule of 
activities); Section 8.1 
(Efficacy assessments) 
It has been clarified that extramedullary assessments 
are optional. In addition, it has been added that 
computed tomography (CT) or positron emission 
tomography (PET)-CT scans should be performed if 
lymphomatous involvement is suspected, whereas if 
lymphomatous involvement is present, PET-CT scan 
should be performed. In Section 1.3 footnote o, the 
following updates have been made: 
“Extramedullary disease assessment: For ALL, A CT 
of neck/chest/abdomen/pelvis with IV contrast at 
baseline;CT or PET-CT scans are suggested to be 
performed at screening and at hematological 
recovery or at EOT (if no hematological recovery) 
if lymphomatous involvement is suspected. 
PET-CT scan should is suggested to be performed 
at screening if lymphomatous involvement suspected 
is present. If positive at screening, to be PET-CT 
will be repeated at the time of CR in BM. For AML, 
by physical examination. CT or PET-CT can be 
performed if clinically indicated”. 
In Section 8.1, the following updates have been 
made: 
“Extramedullary assessments are optional. For the 
extramedullary assessment of ALL, CT or PET-CT 
scan should scans are suggested to be performed 
at screening and at hematological recovery or at EOT 
(if no hematological recovery). A CT of 
neck/chest/abdomen/pelvis with IV contrast will be 
performed at screening. In case of as defined in the 
SOA (Section 1.3) if lymphomatous involvement is 
suspected. If lymphomatous involvement is 
present at screening, a PET-CT scan should is 
suggested to be performed, instead. If positive at 
screening, the PET-CT scan will be repeated at the 
time of CR in BM”. 
To clarify the extramedullary 
assessment procedures for this study 
and to decrease the participant’s 
exposure to radiations, as systematic 
PET-CT is not standard in European 
countries. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 (synopsis), 
Section 1.3 (Schedule of 
activities); Section 4.1.3 
(study treatment period) 
For the acute myeloid leukemia cohort, it has been 
clarified that bone marrow aspirations (with optional 
minimal residual disease assessment) were to be 
performed once between Days 22 and 29. 
The following updates have been made to Section 1.3 
footnote m, and updates in accordance have been 
made to, Section 1.1, and Section 4.1.3: 
“Bone marrow for disease assessment: To be 
performed once at baseline screening, once 
between Days 8 and 15 (optional), once at the end of 
induction for ALL (first week of consolidation 
± 1 week), once between Days 8 and 15 
(optional), once between Days 22 and 29 for AML, 
and once at the time of complete hematological 
recovery in case bone marrow aspirate failed, bone 
marrow biopsy could be an option. If recovery from 
aplasia (at least 48 hours after the last injection of 
G-CSF, when neutrophils reach 1 G/L and platelet 
count 100 G/L). No BM assessment is necessary 
if nonresponse or progressive disease can be 
diagnosed with peripheral blood evaluation, or, if 
a white blood cell count <300/mm3, or if the BM 
assessment is considered noncontributory by the 
Investigator. Any additional BM aspirations will 
show persistence of peripheral leukemic blasts, bone 
marrow aspirate is not mandatory be performed at 
the Investigator’s discretion and should be 
reported in the eCRF”. 
Also in Section 1.3, the bone marrow assessments 
schedule was updated to include the first week of the 
consolidation phase “from Days 37 to 43”. 
To clarify the bone marrow aspiration 
requirement for the acute myeloid 
leukemia cohort. 
 
Section 1.3 (Schedule of 
activities) 
Blood type phenotyping/genotyping text updated as 
follows: “Blood typing and complete blood 
phenotyping (C,c; E,e; Kell. Kidd; Duffy; S,s is 
recommended, if not available, the site’s standard 
will be followed) if not already done, and antibody 
screening (IAT) to be obtained prior to the start of 
the study treatment. After the start of the study 
treatment, a new IAT assessment will be 
performed once. If the second test is positive, a 
DTT test should be performed (in accordance with 
Section 10.6.6). Results of IAT (and DTT test, if 
applicable) will be recorded in the eCRF, 
including those performed prior to any 
transfusion during study intervention. 
Transfusions are to be recorded in the eCRF. If not 
previously performed, blood type phenotyping (or 
genotyping) and screen to be done after enrollment in 
the study and prior to first study treatment 
intervention administration” 
To clarify AABB guidance on 
managing antiCD38 interference with 
blood bank serologic testing. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 (Schedule of 
activities) 
For glucose assessments, fasting is necessary. When 
the participant has not fasted overnight, glucose 
should not be measured. The following changes have 
been made in Section 1.3 footnote i 
“Biochemistry: “glucose (fasting; if the participant 
has not fasted overnight, glucose should not be 
measured)”. 
To clarify that participants must fast 
overnight for glucose to be measured. 
Section 1.3 (Schedule of 
activities) – PK flowchart for 
AML cohort 
Immunogenicity follow-up assessment ABF1 changed 
from 60 to 90 days after last isatuximab 
administration (±5 days). 
Half-life of endogenous 
immunoglobulin G (IgG) is 21 to 
25 days. Therefore, an IgG transient 
response is expected to be eliminated 
at the end of 5 times the half-life 
(approximately 16 weeks). 
Section 1.3 (Schedule of 
activities) – PK flowchart for 
ALL cohorts 
Immunogenicity follow-up assessment ABF1 changed 
from 60 to 90 days after last isatuximab 
administration (±5 days). 
Half-life of endogenous IgG is 21 to 
25 days. Therefore, an IgG transient 
response is expected to be eliminated 
at the end of 5 times the half-life 
(approximately 16 weeks). 
Section 1.3 (Schedule of 
activities) – PK flowchart for 
ALL cohorts 
Footnote d of Table 1 has been updated as follows: 
“At EOT, if participant If the ABF1 ADA result is 
positive or inconclusive for ADA, no additional ADA 
are required every visit until sample is negative 
(sample ID: ABF2, ABF3, etc)”. 
Follow-up immunogenicity 
assessments will not be required after 
ABF1 to reduce the participants’ 
burden. 
Section 1.3 (Schedule of 
activities) – PK flowchart for 
AML cohort 
The following footnote has been added to Table 1: 
“Note: In case a Cycle 2 (second induction) is 
administered, PK samples must be taken only at 
predose on Days 1 and 15.” 
In case of second induction, 
pharmacokinetic sampling times are 
not the same as during Cycle 1. 
Section 1.3 (Schedule of 
activities) – PK flowchart for 
AML cohorts 
Footnote d of Table 1 has been updated as follows: 
“At EOT, if participant If the ABF1 ADA result is 
positive or inconclusive for ADA, no additional ADA 
are required every visit until sample is negative 
(sample ID: ABF2, ABF3, etc)”. 
Follow-up immunogenicity 
assessments will not be required after 
ABF1 to reduce the participants’ 
burden. 
Section 4.1.2 (Screening) 
The following text has been added “The screening 
assessment data obtained prior to the informed 
consent may be accepted if performed within 
3 weeks prior to Day 1”. 
To clarify that data obtained prior to 
the informed consent can be 
accepted, as long as within the 
3-week period prior to Day 1. 
Section 5.1 (Inclusion 
criteria) 
Changes described below have been made to I 05: 
“A) Male participants: A male participant with a female 
partner of childbearing potential must agree to use 
contraception as detailed in Appendix 4 
(Section 10.4) of this protocol during the intervention 
treatment period and for at least 3 6 months after the 
last dose of study intervention and refrain from 
donating sperm during this period (…) A WOCBP who 
agrees to follow the contraceptive guidance in 
Appendix 4 (Section 10.4) during the intervention 
treatment period and for at least 3 6 months after the 
last dose of study intervention.” 
Participants must follow the 
contraceptive guidance for at least 
6 months after the last dose of study 
intervention. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 (Study 
intervention[s] administered) 
Manufacturer row has been removed from Table 4 
(Overview of study interventions administered). 
Removed, as the product sourcing can 
change during the course of the study. 
Section 6.1.1 (AML 
combination therapies) 
Text listing the assessments to be performed on 
Cycle 1 has been removed. Instead, all assessments 
have been referred to the schedule of activities. 
To reduce repetition of information. 
Section 6.1.1 (AML 
combination therapies) 
The following text has been added “The choice of 
anthracyclines is at the Investigator’s discretion 
(either liposomal daunorubicin, nonliposomal 
daunorubicin, or idarubicin) and the same 
anthracycline should be used throughout the 
study”. 
To clarify that only 1 anthracycline 
compound is allowed per participant. 
Section 6.1.2 (T-ALL and 
B-ALL combination 
therapies) 
Text listing the assessments to be performed has 
been removed. Instead, all assessments have been 
referred to the schedule of activities. 
To reduce repetition of information. 
Section 6.1.2 (T-ALL and 
B-ALL combination 
therapies) 
The following text has been added: “The choice of 
anthracyclines is at the Investigator’s discretion 
(either doxorubicin or mitoxantrone) and the 
same anthracycline should be used throughout 
the study”. 
To clarify that only 1 anthracycline 
compound is allowed per participant. 
Section 6.2 
(Preparation/handling/ 
storage/accountability) 
The following text has been added: “If the 
participant’s weight on the day of the dose 
preparation is not available, the most recent 
participant’s weight may be used, assuming it 
was assessed in a reasonable time frame and the 
participant did not have any events leading to 
significant weight loss according to Investigator 
assessment. In such cases, the participant’s 
weight should still be assessed on the day of 
administration to ensure the accuracy of the dose 
preparation”.  
Word added to add flexibility on the 
determination of participant weight on 
dosing days. 
Section 8 (Study 
assessments and 
procedures) 
The following text has been removed: “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”. 
Any discontinuation is left to the 
Principal Investigator’s medical 
judgment. 
Section 8 (Study 
assessments and 
procedures) 
The following text has been updated: “Procedures 
conducted as part of the participant’s routine clinical 
management (eg, blood count BM assessment) and 
obtained before signing of the Informed Consent 
Form (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 1 month before 
Day 1 (Section 1.3)”. 
To reduce the participants’ burden, by 
decreasing the need to repeat routine 
clinical examinations. 
Section 8.2.1 (Physical 
examinations) 
The following text has been removed: “A complete 
physical examination will include, at a minimum, 
assessments of the cardiovascular, respiratory, 
gastrointestinal and neurological systems”. 
To reflect the correct procedures and 
keep consistency with the schedule of 
activities. 
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Section # and Name 
Description of Change 
Brief Rationale 
The following text has been added: “Examination of 
major body systems will include neurological 
examination, digestive, skin/mucosae, 
mediastinal, testicular involvements, respiratory, 
hepatomegaly, splenomegaly, and 
lymphadenopathy”. 
Section 8.2.2 (Vital signs) 
Text corrected to reflect that vital signs are to be 
taken just before starting infusion of isatuximab, 
1 hour after starting the infusion, at the end of 
infusion, and as clinically indicated. 
In addition, the following sentence has been removed 
“The measurements will also be performed at the 
EOT visit and post treatment follow up visits”. 
To reflect the correct procedures and 
keep consistency with the schedule of 
activities. 
Section 8.2.5 (Clinical safety 
laboratory assessments) 
The following text has been added: “Where possible, 
blood volume for sampling for each visit will be 
minimized to less than approximately 1% of total 
blood volume and less than approximately 3% of 
total blood volume over a 4-week period. If 
necessary, blood sampling related to patient 
safety and the primary endpoint of the study 
should be prioritized. Additional blood samples 
may be collected at the Investigator’s discretion 
for participant safety monitoring”. 
Text added to clarify the desirable 
amount of blood to be collected from 
each participant clarify which 
procedures requiring blood sampling 
should be prioritized. 
Section 8.2.5 (Clinical safety 
laboratory assessments) 
Details on vital signs, electrocardiogram abnormalities 
or laboratory values meeting the definition of adverse 
event have been removed from this section and 
referred to Section 10.3. Changes are shown below: 
“A vital sign or ECG abnormality or laboratory value is 
reported as an AE if it meets the definition of AE. 
See Appendix 3 (Section 10.3).: 
- 
Is associated with a sign or symptom 
- 
Requires treatment 
- 
Leads to treatment discontinuation 
- 
Leads to dose modification 
- 
Fulfills a seriousness criterion 
- 
Is defined as an AESI”. 
To clarify and centralize the definition 
of vital signs, electrocardiogram 
abnormalities or laboratory values 
meeting the definition of adverse 
event, to avoid redundancy and 
inconsistencies. 
Section 8.2.5.1 (Blood type 
phenotyping/genotyping) 
New section added, describing the blood 
phenotyping/genotyping and indirect antiglobulin tests 
to be performed in this study, in alignment with the 
Schedule of Activities. 
Section added to better clarify these 
assessments. 
Section 8.3.4 (Regulatory 
reporting requirements for 
SAEs) 
The deadlines for unexpected serious adverse events 
(SUSARs) reporting by the Sponsor to the authorities 
have been included in the protocol, as below: 
• 
For SUSARs that are life-threatening or 
result in death: 7 days after first knowledge, 
with follow-up information reported within an 
additional 8 days. 
• 
For other SUSARs: 15 days after first 
knowledge. 
Details provided for compliance with 
Directive 2001/20/EC. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.5 (Pregnancy) 
The following change has been made “Details of 
pregnancies in female participants and, if indicated, 
female partners of male participants will be collected 
after the start of study intervention and until 3 6 months 
after the last administration…”. 
Pregnancy data collection limit 
changed from 3 months after last 
administration to 6 months. 
Section 8.4 (Treatment of 
overdose) 
The following sentence has been removed: 
“Asymptomatic overdose should be reported as 
standard AE (See Section 8.3)”. 
Text deleted as it is not aligned with 
the electronic case report form 
completion guide (overdose electronic 
case report form page will be used). 
Section 8.8.1 
(Immunogenicity 
assessments)  
The following sentence has been removed: “At 30 
days after the last study treatment administration, if a 
participant is positive or inconclusive for ADA, 
additional ADAs are required to be collected and 
assessed at every follow-up visit until the sample is 
negative”. 
The following sentence has also been added: 
“Once a participant is off treatment, ADA samples 
will be collected 30 and 90 days after the last 
isatuximab administration. No additional ADA 
samples will be collected, regardless of the result 
of these samples (negative, positive or 
inconclusive)”. 
Follow-up immunogenicity 
assessments will not be required after 
ABF1 to reduce the participants’ 
burden. 
Section 10.1.1 (Regulatory 
and ethical considerations) 
Text included to clarify that the Sponsor will submit 
any change(s) considered substantial to the 
regulatory authorities for notification and approval: 
• 
“The Sponsor will be responsible for the 
following: 
- 
Submitting to the regulatory authorities 
for notification and approval any 
change(s) of the protocol that are 
deemed as “substantial” (ie, changes 
which are likely to have a significant 
impact on the safety or physical or 
mental integrity of the clinical trial 
participants or on the scientific value of 
the trial). 
- 
Notifying IRBs/IECs and competent 
authorities of the Member States the 
reason for, and the content of, any 
substantial amendments.” 
To clarify the Sponsor responsibilities 
on the notification of substantial 
amendments. 
Section 10.1.3 (Informed 
consent process) 
The following sentence has been removed: “A 
participant who reaches the legal age of majority as 
defined by local regulation during the course of the 
study must sign a new ICF”. 
This sentence has been removed for 
redundancy, as it is already reflected 
in the following text “Legally 
acceptable representatives or 
participants who reach the legal age of 
majority as defined by local regulation 
during the course of the study must be 
reconsented to the most current 
version of the ICF(s) during their 
participation in the study”. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.4 (Data 
protection) 
The following text has been added: “Participant race 
and ethnicity will be collected in this study 
because these data are required by regulatory 
agencies (eg, on afro American population for the 
Food and Drug Administration or on Japanese 
population for the Pharmaceuticals and Medical 
Devices Agency in Japan)”. 
Text added to clarify the reason for 
collecting race and ethnicity 
information. 
Section 10.1.7 (Data quality 
assurance) 
The following bullets have been added: 
• 
“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 assumes accountability for 
actions delegated to other individuals 
(eg, Contract Research Organizations)”. 
To clarify monitoring strategies and 
accountabilities for this study. 
Section 10.1.9 (Study and 
site closure) 
Text changed as follows: 
“Reasons for study termination by the Sponsor, as 
well as reasons for the early closure of a study site 
by the sponsor or Investigator may include but are not 
limited to: 
• 
For study termination:  
- 
Information on the product leads to 
doubt as to the benefit/risk ratio 
- 
Discontinuation of further study 
intervention development 
• 
For site termination:  
- 
Failure of the investigator to comply 
with the protocol, the requirements of 
the IRB/IEC or local health authorities, 
the sponsor's procedures, or GCP 
guidelines 
- 
Inadequate or no recruitment 
(evaluated after a reasonable 
amount of time) of participants by the 
Investigator 
- 
Total number of participants included 
earlier than expected”. 
To further clarify the criteria for study 
and site closure 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.4 (Contraceptive 
guidance and collection of 
pregnancy information) 
The following text has been added to the definition of 
women of childbearing potential: “If fertility is 
unclear (eg, amenorrhea in adolescents or 
athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, 
additional evaluation should be considered”. 
The following text has been added to the definition of 
women not considered of childbearing potential: “For 
individuals with permanent infertility due to an 
alternate medical cause other than the above 
(eg, mullerian agenesis, androgen insensitivity), 
Investigator discretion should be applied to 
determining study entry”. 
Text added to further clarify the 
definition of women of childbearing 
potential. 
Section 10.4 (Contraceptive 
guidance and collection of 
pregnancy information) 
The following changes have been made to the text: 
“In addition, male participants must refrain from 
donating sperm for 3 6 months after the last dose of 
study completion 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 for the duration 
of the study and for 6 months after the last dose 
of study treatment (during the protocol-defined time 
frame).” 
“Female participants of childbearing potential are 
eligible to participate if they agree to use a highly 
effective method of contraception as described in 
Table 14, consistently and correctly as described in 
.from 2 weeks prior to the first dose and 
6 months after the last dose of study treatment.” 
 
Section 10.6.1.1 (Acute 
lymphoblastic leukemia) 
In the response criteria for blood and bone marrow, 
“no recurrence for 4 weeks” has been removed from 
the complete response criteria. 
Criterion removed because it is not 
practical in clinical trials. 
 
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11 
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Page 1 
AMENDED STATISTICAL ANALYSIS PLAN 01 
Protocol title: 
Open-label, Single-arm Trial to Evaluate Antitumor 
Activity, Safety, and Pharmacokinetics of Isatuximab 
Used in Combination With Chemotherapy in 
Pediatric Patients From 28 Days to Less Than 
18 Years of Age With Relapsed/Refractory B or T 
Acute Lymphoblastic Leukemia or Acute Myeloid 
Leukemia In First or Second Relapse 
Protocol number: 
ACT15378 
Compound number 
(INN/Trademark): 
SAR650984 
Isatuximab 
Study phase: 
2 
Short title: 
Isatuximab in Combination with Chemotherapy in 
Pediatric Patients with Relapsed/Refractory Acute 
Lymphoblastic Leukemia or Acute Myeloid Leukemia 
(ISAKIDS) 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
02-May-2022
Regulatory agency identifier number(s): 
EudraCT number: 
2018-002 697-45 
IND number: 
103217 
WHO number: 
U1111-1202-1096 
NCT number: 
NCT03860844 
Total number of pages: 40 
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TABLE OF CONTENTS 
AMENDED STATISTICAL ANALYSIS PLAN 01 ........................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
VERSION HISTORY ....................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.1.1 
Study participants and cohorts ......................................................................................................... 7 
1.1.1.1 
Screening ......................................................................................................................................... 7 
1.1.2 
Study treatment period ..................................................................................................................... 8 
1.1.3 
Post-study treatment period ............................................................................................................. 8 
1.1.4 
Study duration .................................................................................................................................. 8 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 9 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 11 
3 
ANALYSIS POPULATIONS .......................................................................................................... 12 
4 
STATISTICAL ANALYSES ........................................................................................................... 13 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 13 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 13 
4.3 
PRIMARY EFFICACY ENDPOINT(S) ANALYSIS ......................................................................... 14 
4.3.1 
Definition of primary efficacy endpoint ........................................................................................... 14 
4.3.2 
Main analytical approach ............................................................................................................... 14 
4.3.3 
Sensitivity analysis ......................................................................................................................... 15 
4.3.4 
Supplementary analyses ................................................................................................................ 15 
4.3.5 
Subgroup analyses ........................................................................................................................ 15 
4.4 
SECONDARY EFFICACY ENDPOINT(S) ANALYSIS .................................................................. 15 
4.4.1 
Definition of secondary endpoints .................................................................................................. 15 
4.4.1.1 
Minimal residual disease (MRD) .................................................................................................... 16 
4.4.1.2 
Overall response rate (ORR) ......................................................................................................... 16 
4.4.1.3 
Overall survival (OS) ...................................................................................................................... 16 
4.4.1.4 
Event free survival (EFS) ............................................................................................................... 16 
4.4.1.5 
Duration of response ...................................................................................................................... 16 
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4.4.1.6 
CD38 Receptor density and occupancy......................................................................................... 16 
4.4.2 
Main analytical approach ............................................................................................................... 16 
4.4.3 
Subgroup anaslysis for selected secondary efficacy endpoints .................................................... 17 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 17 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 17 
4.7 
SAFETY ANALYSES ..................................................................................................................... 17 
4.7.1 
Extent of exposure ......................................................................................................................... 18 
4.7.1.1 
Extent of investigational medicinal product exposure .................................................................... 18 
4.7.1.2 
Isatuximab or other study treatment exposure .............................................................................. 18 
4.7.2 
Analysis of adverse events ............................................................................................................ 20 
4.7.2.1 
Adverse events .............................................................................................................................. 20 
4.7.2.2 
Analysis of adverse events ............................................................................................................ 20 
4.7.3 
Analysis of infusion reactions (IRs) ................................................................................................ 22 
4.7.3.1 
Infusion reactions ........................................................................................................................... 22 
4.7.3.2 
Analysis of infusion reaction .......................................................................................................... 22 
4.7.4 
Analysis of deaths .......................................................................................................................... 23 
4.7.4.1 
Deaths ............................................................................................................................................ 23 
4.7.4.2 
Analysis of deaths .......................................................................................................................... 23 
4.7.5 
Analysis of adverse events of special interest (AESIs) .................................................................. 24 
4.7.6 
Analysis of laboratory variables ..................................................................................................... 24 
4.7.6.1 
Laboratory variables....................................................................................................................... 24 
4.7.6.2 
Analyses of laboratory variables .................................................................................................... 25 
4.7.7 
Analysis of vital signs ..................................................................................................................... 26 
4.7.7.1 
Vital signs variables ....................................................................................................................... 26 
4.7.7.2 
Analysis of vital signs ..................................................................................................................... 26 
4.7.8 
Analysis of electrocardiograms (ECGs) ......................................................................................... 26 
4.7.8.1 
Electrocardiogram variables .......................................................................................................... 26 
4.7.8.2 
Analyses of electrocardiogram variables ....................................................................................... 26 
4.8 
OTHER ANALYSES....................................................................................................................... 27 
4.8.1 
Analyses of pharmacokinetic variables .......................................................................................... 27 
4.8.1.1 
Over treatment concentrations: Ctrough and Ceoi ............................................................................. 27 
4.8.1.2 
Population PK analysis .................................................................................................................. 27 
4.8.1.3 
Immunogenicity impact on PK ....................................................................................................... 27 
4.8.2 
Immunogenicity analyses ............................................................................................................... 27 
4.8.3 
Analyses of biomarker variables .................................................................................................... 29 
4.8.4 
Analyses of quality of life/health economics variables ................................................................... 29 
4.9 
INTERIM ANALYSES (IA) ............................................................................................................. 29 
4.9.1 
Data Monitoring Committee ........................................................................................................... 29 
4.9.2 
Cut-off date .................................................................................................................................... 30 
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5 
SUPPORTING DOCUMENTATION .............................................................................................. 31 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 31 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 32 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 32 
5.3.1 
Demographic and baseline characteristics .................................................................................... 32 
5.3.2 
Prior, concomitant or post medications (other than anticancer therapies) .................................... 34 
5.3.3 
Anticancer therapies ...................................................................................................................... 35 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 35 
5.4.1 
General conventions ...................................................................................................................... 35 
5.4.2 
Missing data ................................................................................................................................... 35 
5.4.3 
Windows for time points ................................................................................................................. 38 
5.4.4 
Unscheduled visits ......................................................................................................................... 38 
5.4.5 
Pooling of centers for statistical analyses ...................................................................................... 39 
5.4.6 
Statistical technical issues ............................................................................................................. 39 
6 
REFERENCES ............................................................................................................................... 40 
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LIST OF TABLES 
Table 1 - Major changes in statistical analysis plan ........................................................................................ 6 
Table 2 - Objectives and endpoints ................................................................................................................. 9 
Table 3 - Populations for analyses ................................................................................................................ 12 
Table 4 - List of variables for subgroup analyses .......................................................................................... 15 
Table 5 - Safety analyses .............................................................................................................................. 18 
Table 6 - Sorting of AE tables ....................................................................................................................... 21 
Table 7 - Protocol required safety laboratory assessment ............................................................................ 25 
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VERSION HISTORY 
This statistical analysis plan (SAP) for study ACT15378 is based on the protocol amendment 
V5.0 dated 14-Oct-2021.   
Table 1 - Major changes in statistical analysis plan 
Document 
Approval Date 
Changes 
Rationale 
Original SAP 
07-Dec-2020
Not Applicable 
Original version 
Amended SAP 01 
02-May-2022
Section 3 Analysis population: 
The evaluation population has been 
changed to: 
The evaluable population will include 
participants from the AT population 
who received at least 1 full dose of 
isatuximab in Cycle 1 and who had at 
least one valid response value that is 
evaluable. 
Updated according to Amended 
Protocol 05 
Section 4.3.5: Subgroup analyses 
Add one more column to provide 
derivation algorithms for those that 
are not retrieved directly for CRF 
data. 
To provide derivation algorithms. 
Section 4.3.5: Subgroup analyses 
1, Removed MRD 
2, Added 4 more subgroup 
categories: Immunophenotyping, 
Prior lines, Prior cell therapy, and 
Prior transplant. 
1, This becomes redundancy 
because it is actually the secondary 
efficacy endpoint.  
2, To provide more supplemental 
subgroup analyses on primary 
efficacy endpoint.  
Section 4.7.6.2 Analyses of 
laboratory variables: 
Add modified baseline for lab results 
as: 
Baseline for laboratory analysis is 
defined as the last assessment prior 
to the first administration of 
isatuximab 
For clarification. 
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1 
INTRODUCTION 
1.1 
STUDY DESIGN 
This is a Phase 2 single arm, multicenter, open-label study evaluating the antitumor activity, 
safety, and pharmacokinetic (PK) of isatuximab in combination with standard salvage 
chemotherapies in participants with Relapsed/Refractory Acute Lymphoblastic Leukemia 
(R/R ALL) (including both T- and B-ALL) and Acute Myeloid Leukemia (AML) conducted in 
3 separate cohorts. Male and female children from 28 days to less than 18 years of age with 
R/R B- or T-ALL or AML in first or second relapse will be eligible. 
1.1.1 Study participants and cohorts  
Three cohorts of study participants will be treated: 
•
B-ALL
•
T-ALL
•
AML
Approximately 128 participants will be screened (32, 48, and 48 for the T-ALL, B-ALL, and 
AML cohorts, respectively) to achieve 104 participants assigned to study treatment 
(approximately 26, 39, and 39 in the T-ALL, B-ALL, and AML cohorts, respectively) and 
96 evaluable participants for an estimated total of 24, 36, and 36 evaluable participants in the 
T-ALL, B-ALL, and AML cohorts, respectively.
For an assessment of the dose for children younger than 2 years of age, 20 participants of 2 years 
of age or more (at least 5 participants in the age group of 2 to 10 years, including approximately 
3 patients between 2 and 5 years old) will be enrolled first to check the isatuximab exposure. 
In addition, for each cohort, at the end of the trial, at least 5 participants should be recruited for 
each of the following age groups: 28 days to 4 years of age, 5 to 11 years of age, and 12 to 
18 years of age. 
1.1.1.1 Screening 
The screening assessments are to be performed within 3 weeks prior to the first study intervention 
administration (Day 1), unless indicated otherwise. The screening assessment data obtained prior 
to the informed consent may be accepted if performed within 1 month prior to Day 1. 
All of the inclusion criteria (and none of the exclusion criteria) must be met, and informed consent 
must be signed by the legally acceptable representative of the participant before any study-
specific procedure is performed. 
Screening procedures are to be performed/assessed in accordance with the Schedule of Activities 
(SOA) in the protocol. 
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In order to have rapid control of the tumor burden, in addition to dexamethasone pre-dose 
mandatory in ALL cohorts, the administration of following cytoreductive therapies are proposed 
(these are examples): 
•
cyclophosphamide up to 1g/m² PO or IV for 1 day before isatuximab treatment for ALL
•
hydroxyurea 50-75 mg/kg/day PO for 4-5 days before isatuximab treatment for AML
•
cytarabine up to 1g/m² IV every 12 hours for up to 2-3 days before isatuximab treatment
for AML
Dexamethasone 10 mg/m²/day (or equivalent) before the first study intervention administration (at 
least 3 times, on Days -3, -2, and -1) is (mandatory for ALL cohorts as a part of study treatment 
and optional for AML cohort). Administration of dexamethasone on Day 1 is mandatory in both 
cohorts as part of isatuximab premedication. 
1.1.2  Study treatment period 
In all 3 disease cohorts, participants will receive 1 administration of single agent isatuximab on 
Day 1. Starting on Day 8, combination chemotherapy will be added. In case of rapid degradation 
of patient’s status during this week, chemotherapy could be started earlier than Day 8. 
A bone marrow (BM) aspiration will be performed at screening (including minimal residual 
disease [MRD] screening sample, only for ALL cohorts), between Days 8 and 15 (optional; 
between second and third isatuximab infusion), between 36 and 43 days for the ALL cohorts, for 
the AML cohort either between Days 22 and 29 or at the time of hematological recovery (at least 
48 hours after last injection of G-CSF, when neutrophils will reach 1 G/L and platelet count 
100 G/L); this last sample is recommended but not mandatory if peripheral blood blasts are 
present. The MRD will be done at the time of hematological recovery and/or at the time of each 
BM aspirate for disease assessment if complete response (CR) or complete response with 
incomplete peripheral recovery (CRi) is achieved. 
1.1.3 Post-study treatment period 
After completion of these treatment periods, participants will be treated following Investigator’s 
and site’s standard of care. 
1.1.4 Study duration  
The duration of the study for an individual participant will include: 
•
The screening period of up to 3 weeks prior to the first study treatment administration
•
The on-treatment period
•
The period of aplasia followed by recovery period
•
An EOT visit within 30 days after hematological recovery
•
Follow-up period.
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Participants with documented disease progression at the EOT visit will be followed for survival 
every 4 months until death or final analysis cut-off date, whichever comes first. 
Participants without documented disease progression at the EOT visit and who have not yet 
started treatment with another anticancer therapy will receive follow-up visits every 2 months 
until initiation of another anticancer therapy, disease progression, death or final analysis cut-off 
date, whichever comes first. After disease progression or initiation of a new anticancer treatment, 
participants will be followed every 4 months for survival until death or the cut-off date. 
Also, during the follow-up period, women of childbearing potential will perform pregnancy 
assessments every month, until 6 months after the last dose of isatuximab, or 12 months after the 
last dose of cyclophosphamide and at least 6 months after other IMPs discontinuation (vincristine, 
pegaspargase, L-asparaginase (Erwinase), methotrexate, etoposide, doxorubicin, mitoxantrone, 
fludarabine, cytarabine), whatever occurs last and with the longest recommended period of 
contraception. 
In case the participant or the LAR withdraws consent for any reason or following the 
Investigator’s opinion that the participant will not follow the planned treatment, no follow-up will 
be done after these decision dates. 
The final analysis cut-off date will be approximately 12 months after first study treatment 
administration in the last participant enrolled in the study. After the final analysis cut-off date, 
only new related AEs (serious or not), all ongoing SAE (related or not) and all ongoing related 
non-serious AEs and related concomitant medications will continue to be collected. 
1.2 
OBJECTIVE AND ENDPOINTS 
The objectives and their corresponding endpoints are presented in the table below. 
Table 2 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
To evaluate the anti-leukemic activity of isatuximab in 
combination with chemotherapies in pediatric participants 
of ages 28 days to 18 years with R/R ALL or AML as 
measured by CR + CRi 
Morphological CR rate defined as the proportion of participants 
with CR+CRi, in each cohort. 
For AML: 
•
CR: bone marrow blasts lower than 5%; No blasts with
Auer rods or persistence of extramedullary disease;
absolute ANC higher than 1000/mm3, platelets higher
than 100 000/mm3; transfusion independence.
•
CRi: same criteria as for CR, except neutrophils and/or
platelets recovery.
For ALL: 
•
CR: bone marrow blasts lower than 5%, no circulating
blasts or lymphoblasts in CSF or extramedullary
disease; ANC higher than 1000/mm3, platelets higher
than 100 000/mm3.
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Objectives 
Endpoints 
•
CRi: same criteria as for CR, except neutrophils and/or
platelets recovery.
•
Extramedullary disease: complete resolution of
lymphomatous enlargement by computed CT. For
participants with a previous positive PET scan, a post-
treatment residual mass of any size is considered a CR
as long as it is PET negative.
Secondary 
•
Safety and tolerability assessments
•
Safety assessment, in terms of AEs/SAEs, laboratory
parameters, vital signs, and physical examination.
•
Assessment of IRs
•
Incidence and severity of IRs.
•
PK of isatuximab
•
PK parameters of isatuximab calculated using a
population PK approach including at least Cmax, Ctrough,
and AUC.
•
Minimal residual disease
•
Estimation of minimal residual disease in participants
achieving CR or CRi.
•
Overall response rate
•
The overall response rate is defined as the proportion
of participants with CR or CRi for blood and bone
marrow disease; PR based on the NCCN guideline will
be considered
•
Overall survival
•
Overall survival is defined as the time interval from the
date of first study treatment administration to death
from any cause.
•
Event free survival
•
Event free survival is defined as the time interval from
the date of first study treatment administration to the
date of the first of: completion or going off protocol
induction/consolidation therapy without CR, relapse
from CR, or death due to any cause.
•
Duration of response
•
Duration of reponse is defined as the time from the
date of the first response to the date of first disease
progression or death from any cause, whichever
happens first.
•
Relationship between clinical effects and CD38
receptor density and occupancy
•
CD38 receptor density will be assessed at baseline and
CD38 receptor occupancy at Day 15 and correlated
with clinical endpoints.
Tertiary/exploratory 
•
Immunogenicity of isatuximab
•
Immunogenicity of isatuximab assessed throughout the
study by detecting the presence of antidrug antibodies.
•
PK/ PD relationships with regards to safety and
efficacy endpoints.
•
PK/PD parameters estimated as prognostic factors for
clinical outcomes including safety and efficacy
endpoints, if possible
AE = adverse event; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; ANC = absolute neutrophil count; AUC = area 
under the curve; B-ALL = B-cell acute lymphoblastic leukemia; Cmax = maximum serum concentration; CR = complete response; CRi = 
complete response with incomplete peripheral recovery; CSF = cerebrospinal fluid; CT = computed tomography; Ctrough = lowest serum 
concentration reached by a drug before the next dose is administered; IR = infusion reaction; NCCN = National Comprehensive Cancer 
Network; PD = pharmacodynamics; PET = positron emission tomography; PK = pharmacokinetics; PR = partial response; R/R = relapsed or 
refractory; SAE = serious adverse event; T-ALL = T-cell acute lymphoblastic leukemia. 
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2 
SAMPLE SIZE DETERMINATION 
A 2 stage Simon’s Min/Max design was used for sample size calculations in 3 cohorts (T-ALL, 
B-ALL, and AML).
T-ALL cohort: a maximum of 24 evaluable participants will be enrolled in this cohort. This
sample size will provide 80% power to reject the null hypothesis that the CR rate is ≤60% if the
complete response (CR + CRi) rate is ≥80%, based on a 1-sided exact binomial test at a
significance level of 0.1:
•
Stage 1: 11 evaluable participants. Proceed to Stage 2 if more than 6 responses are
observed
•
Stage 2: 24 evaluable participants (13 additional participants). If more than 17 responses
are observed among the 24 participants evaluable for efficacy, the null hypothesis will be
rejected.
B-ALL cohort and AML cohort: a maximum of 36 evaluable participants will be enrolled in each
cohort. This sample size will provide 80% power to reject the null hypothesis that the CR rate is
≤70% if the complete response (CR + CRi) rate is ≥85%, based on a 1-sided exact binomial test at
a significance level of 0.1:
•
Stage 1: 23 evaluable participants. Proceed to Stage 2 if more than 17 responses are
observed
•
Stage 2: 36 evaluable participants (13 additional participants). If more than 28 responses
are observed among the 36 participants evaluable for efficacy, the null hypothesis will be
rejected.
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3 
ANALYSIS POPULATIONS 
The following populations for analyses are defined: 
Table 3 - Populations for analyses 
Population 
Description 
All-treated 
The AT population will include all participants who received at least 1 dose (even 
incomplete) of study intervention. This population is the primary population for the 
analyses of safety parameters. 
Evaluable population 
The evaluable population will include evaluable participants from the AT population 
who received at least 1 full dose of isatuximab in Cycle 1 and who had at least one 
valid response value that is evaluable. This population is the primary population for 
the analyses of efficacy parameters. 
PK 
The PK population will include all participants from the AT population with at least 
1 PK parameter available. 
ADA evaluable 
The ADA evaluable population will include all participants from the AT population 
with at least 1 non-missing ADA result during the on-study observation period. 
ADA = antidrug antibody; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; AT = all-treated; PK = pharmacokinetic. 
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4 
STATISTICAL ANALYSES 
4.1 
GENERAL CONSIDERATIONS  
The following are general considerations for statistical analysis. 
•
Data from participants enrolled in 3 cohorts (T-ALL, B-ALL, and AML) will be analyzed
separately.
•
Unless otherwise specified, analyses will be descriptive and performed on the AT
population, except for the analyses of efficacy endpoints that will utilize the evaluable
population.
•
The baseline for a given parameter is defined as the last assessment for this parameter
before the first study intervention administration unless otherwise specified.
•
Continuous data will be summarized using the number of available observations, mean,
SD, median, minimum, and maximum by cohort and overall (where applicable).
•
Categorical and ordinal data will be summarized using the number and percentage of
participants by cohort and overall (where applicable).
•
All efficacy analysis will be performed using the evaluable population for each ALL and
AML cohort.
•
The database will be locked when clinical review of the database has been completed and
all critical queries have been resolved.
•
All summaries and statistical analyses will be generated using SAS® version 9.4 or higher.
Planned date for analysis cut-off 
For each cohort, the cut-off date for interim analysis (Stage 1) will be approximately 2 months 
after the last participant is treated in Stage 1. 
For each cohort, the cut-off date for the primary analysis of complete response (CR + CRi) and 
other secondary endpoints will be approximately 6 months after the last participant has had their 
first study intervention administration. The final analysis cut-off date for the analysis of OS and 
other secondary endpoints will be approximately 12 months after the last participant has had their 
first study intervention administration. 
4.2 
PARTICIPANT DISPOSITIONS 
Participant disposition will be summarized by cohort based on the analysis populations defined in 
Section 3.  
For participant study status, the total number of participants 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
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•
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 participants in analysis populations (defined in Section 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 participants treated by country and center will be summarized using the 
all-treated population (defined in Section 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. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the all-treated 
population. 
4.3 
PRIMARY EFFICACY ENDPOINT(S) ANALYSIS 
4.3.1 Definition of primary efficacy endpoint 
The primary efficacy endpoint of the study is the complete response rate (CR + CRi), which is 
defined as the proportion of participants achieving complete response (CR + CRi) assessed by the 
investigator per NCCN Guidelines version 1.2018 criteria, relative to the total number of patients 
in the analysis population. 
4.3.2 Main analytical approach 
The complete response (CR + CRi) rate will be summarized with descriptive statistics on the all 
evaluable population. An 80% confidence interval will be computed using the Clopper Pearson 
method. 
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4.3.3 Sensitivity analysis  
There is no sensitivity analysis planned to perform on the primary efficacy endpoint. 
4.3.4 Supplementary analyses 
Analysis will be performed based on the all-treated participants with valid response assessment 
for the primary efficacy endpoint as supplementary analysis. 
4.3.5 Subgroup analyses 
Subgroup analyses will be performed as supplemental to support the primary efficacy.  The 
subgroup categories are specified in Table 4 below. 
Additional subgroup analysis may be produced as appropriate upon the study team’s request. 
Table 4 - List of variables for subgroup analyses 
Subgroup Category 
Description 
Derivation if applicable 
Extramedullary 
Yes vs No 
Derived upon ‘Disease Involvement Location’ 
in Leukemia / Lymphoma Diagnosis.  ‘Yes’ if 
any location is checked except bone marrow. 
‘No’ otherwise.  
Refractory to prior treatment 
Yes vs No 
Hyperleucocytosis prior to Isatuximab 
Yes vs No 
‘Yes’ if WBC >20 prior to isatuximab 
administration. ‘No’ otherwise. 
Selected observed cytogenetics 
negative vs positive 
Select the following: 11q23, t(12;21),   
t(9;22), and under ‘Other’ - IAMP21,  T(1;19) 
Selected immunophenotyping 
negative vs positive 
Select the following: CD19, CD22 for B-ALL; 
CD33 for AML. 
Number of prior lines 
1 vs 2 vs >2 
Prior cell therapy 
Yes vs No 
‘Yes’ if any therapy of Blinatumomab, 
Gemtuzumab, or CAR T cell received. ‘No’ 
otherwise. 
Prior allogeneic transplant 
Yes vs No 
Age  
28 days to 4, 5 to 11, and equal 
or greater than 12 years old   
Subgroup analyses will be conducted when at least 10 patients are included in a subgroup. 
4.4 
SECONDARY EFFICACY ENDPOINT(S) ANALYSIS 
4.4.1 Definition of secondary endpoints  
The secondary efficacy endpoints are specified in the subsequent sections. 
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4.4.1.1 Minimal residual disease (MRD)  
Proportion of participants with CR or CRi who have achieved negative MRD will be analyzed. 
4.4.1.2 Overall response rate (ORR)  
ORR is defined as the proportion of participants with CR, CRi, or PR. 
4.4.1.3 Overall survival (OS) 
OS is defined as the time interval from the date of first study treatment administration to death 
from any cause. 
If patient did not die prior to the analysis cut-off date or the study completion date, OS will be 
censored at the last date the patient was known to be alive or the cut-off date, whichever comes 
first. 
4.4.1.4 Event free survival (EFS) 
EFS is defined as the time interval from the date of first study treatment administration to the date 
of the first of: completion or going off protocol induction/consolidation therapy without complete 
response, relapse from complete response or death due to any cause. 
In absence of the above events, EFS will be censored at the cutoff date or the last date the patient 
was known to be alive, whichever comes first. 
4.4.1.5 Duration of response 
The DOR is defined as the time from the date of the first response to the date of first disease 
progression or death from any cause, whichever happens first.  In absence of disease progression 
or death before the cutoff date or the date of the last valid response assessment, DOR will be 
censored at the date of the last valid response assessment not showing disease progression or the 
analysis cut-off date, whichever is earlier. DOR will not be calculated for patients who do not 
achieve a response.  
4.4.1.6 CD38 Receptor density and occupancy 
CD38 receptor density (RD) at baseline and receptor occupancy (RO) at Day 15 in blood will be 
assessed. 
4.4.2 Main analytical approach  
The analyses of secondary efficacy endpoints will be performed as described: 
•
Minimal residual disease: The number and percentage of participants by MRD status
(negative and positive) will be provided.
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•
Overall response rate: ORR will be summarized with descriptive statistics. A 80%
confidence interval will be computed using Clopper-Pearson method.
•
Overall survival (OS) will be analyzed using the Kaplan-Meier method. The Kaplan-Meier
estimates of the 25th, 50th and 75th percentiles and the 95% confidence intervals of median
will also be computed. The Kaplan-Meier curves will be plotted.
•
Event free survival (EFS) will be analyzed using the Kaplan-Meier method. The analyses
will be provided by for patient with bridging to transplant vs patients without bridging to
transplant. The Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and the 95%
confidence intervals of median will also be computed. The Kaplan-Meier curves will be
plotted. The analyses will be provided by patients with bridging to transplant vs patients
without bridging to transplant.
•
Duration of response (DOR) will be analyzed using the Kaplan-Meier method. The
Kaplan-Meier estimates of the 25th, 50th and 75th percentiles and the 95% confidence
intervals of median will also be computed. The Kaplan-Meier curves will be plotted.
•
CD38 receptor density (RD) at baseline and receptor occupancy (RO) at Day 15 will be
summarized with descriptive statistics across the efficacy responses.
4.4.3 Subgroup anaslysis for selected secondary efficacy endpoints 
A subgroup analysis for selected secondary efficacy endpoints (eg, DOR, EFS and OS) may be 
performed using subgroups specified in Table 4 if considered necessary. 
4.5 
 TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS   
Additional exploratory endpoints can be added if considered appropriate. 
Exploratory analysis will be descriptive unless otherwise specified. 
4.6 
MULTIPLICITY ISSUES 
There is no formal statistical test to be performed for this study.  Multiplicity is not an applicable 
issue. 
4.7 
 SAFETY ANALYSES 
All safety analyses will be performed based on the AT population (Section 3) for each ALL and 
AML cohort, and overall, unless otherwise specified. 
The analysis of the safety variables will be essentially descriptive, and no testing is planned. 
Table 5 provides a brief list of safety endpoints and their corresponding analysis methodology. 
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Table 5 - Safety analyses 
Endpoint 
Statistical Analysis Methods 
Secondary 
AEs/SAEs 
Laboratory parameters, vital signs, and physical examination 
Incidence and severity of IRs 
Incidence of seizures graded >=3 as AESI 
Descriptive statistics 
Descriptive statistics 
Descriptive statistics 
Descriptive statistics 
Tertiary/Exploratory  
ADA against isatuximab 
Descriptive statistics 
If needed, other tertiary/exploratory analyses will be 
described in the statistical analysis plan finalized before 
database lock 
ADA = antidrug antibody; AE = adverse event; IR = infusion reaction; SAE = serious adverse event. 
4.7.1 Extent of exposure 
The extent of study treatment exposure will be assessed and summarized on the all-treated 
population. 
4.7.1.1 Extent of investigational medicinal product exposure 
The overall extent of exposure will be assessed as: 
•
Overall number of cycles started
•
Duration of overall exposure (weeks): defined as Min[(last day of last cycle, date of death)
– 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 of the
following:
-
Day of the last dose of isatuximab +7 days
-
Day of the last dose of any other IMPs.
Total number of cycles started, number of cycles started by patient by category (ie, number [%] of 
patients receiving 1 cycle or 2 cycles), duration of overall exposure will be summarized using 
descriptive statistics. 
4.7.1.2 Isatuximab or other study treatment exposure 
The following variable will be described to summarize each IMP exposure (ie, isatuximab, 
Dexamethasone, Fludarabine, Cytarabine Anthracycline, G-CSF, Mitoxantrone and Doxorubicin 
etc): 
•
Total number of cycles started
•
Number of cycles started by patient by category (C1, C2)
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•
Duration of exposure (weeks) is defined as
-
For isatuximab:
-
Min[(Date of the last dose of isatuximab + 7 days, date of death) – date of the first
dose of isatuximab]/7 if the frequency of infusion is QW
-
Min[(Date of the last dose of isatuximab + 14 days, date of death) – date of the
first dose of isatuximab]/7 if the frequency of infusion is Q2W (only in
consolidation period for ALL cohorts).
-
For others:
-
Min[(Date of last dose of other, date of death) - first dose of other + 1 day]/7.
•
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, %):
100 ×
ADI (mg/kg/week) 
Planned Dose Intensity (mg/kg/week).
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 and divided by the
theoretical cycle duration (weeks).
•
The total number of cycles started, number of cycles started by patients by category
(ie, number [%] of patients receiving at least 1 cycle, at least 2 cycles), duration of
isatuximab exposure, cumulative dose, ADI and RDI will be summarized by descriptive
statistics.
The following variables will be derived to describe dose modification: 
•
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 at the planned dates.
Dose 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
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-
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.).
4.7.2 Analysis of adverse events 
4.7.2.1 Adverse events  
The observation periods, screening period, treatment-emergent AE period, and post-treatment 
period, are defined as follows: 
•
The screening period is defined as the time informed consent is signed until the first IMP
administration.
•
The treatment-emergent adverse event (TEAE) period is defined as from the time of the
first IMP administration until the time of hematological recovery or new anticancer
therapy is started or 30 days after the last IMP, whichever is first.
•
The post-treatment period is defined as the period from the end of the treatment-emergent
period.
Pre-treatment AEs are defined as any AE during the screening period. Treatment-emergent AEs 
(TEAEs) are defined as AEs that develop, worsen (according to the Investigator opinion) or 
become serious during the treatment-emergent AE period. Post-treatment AEs are defined as AEs 
that are reported during the post-treatment period. The primary focus of AE reporting will be on 
TEAEs. 
The TEAEs will be coded according to the MedDRA dictionary. AEs will be graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
version 5.0. The grade will be taken into account in the summary. For participants with multiple 
occurrences of the same PT within an observation period, the maximum grade will be used. 
4.7.2.2 Analysis 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. 
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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 5.4. 
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 5.4. 
The AE tables will be sorted as indicated in Table 6. 
Table 6 - Sorting of AE tables 
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs. 
SOC, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLTs and PTs. 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the overall incidence. 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, 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
•
Treatment emergent SAE
•
Treatment-related TEAEs (any grade)
•
Treatment-related TEAEs of ≥ Grade 3
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•
Serious treatment related TEAEs
•
TEAE leading to definitive study treatment discontinuation
•
TEAE leading to premature discontinuation of Isatuximab
•
AESI
•
Infusion reactions (IR)
•
Cytokine-release syndrome (CRS).
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. 
4.7.3 Analysis of infusion reactions (IRs)  
4.7.3.1 Infusion reactions  
IRs typically occur within 24 hours from the start of each isatuximab 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. 
4.7.3.2 Analysis of infusion reaction  
IR analysis will include all adverse events regardless of relationship to isatuximab. 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
•
Number (%) of patients experiencing anaphylaxis according to investigator
•
Description of the IR diagnoses (using the diagnosis reported and excluding symptoms)
-
Number (%) of patients with 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
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-
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)
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.
4.7.4 Analysis of deaths  
4.7.4.1 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
the TEAE period (defined in Section 4.7.2.1).
•
Deaths in post-treatment period: includes all deaths occurring after the end of TEAE
period up to study closure.
4.7.4.2 Analysis of 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), and
TEAEs with fatal outcome during the post-treatment period summarized by SOC and PT
-
In context of disease progression (death within 30 days from last study intervention
administration and the cause of death is disease progression),
-
In context other than disease progression (death within 30 days from last study
intervention administration and for whom cause of death is not disease progression or
the death occurred more than 30 days from last study intervention administration and
the cause of death is AE).
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4.7.5 Analysis of adverse events of special interest (AESIs) 
Adverse events of special interest may be added, modified, or removed during a study by a 
protocol amendment.  The following are specified as AESI for the study: 
•
Pregnancy: a female participant entered in a study as well as pregnancy occurring in a
female partner of a male participant entered in a study with IMP/NIMP.
•
Symptomatic overdose (serious or nonserious) with the IMP/NIMP reported.
•
Infusion reaction of Grade 1 lasting more than 24 hours.
•
Infusion reaction of Grade 2 or higher, regardless of duration.
•
Seizures graded ≥3
Number (%) of participants experiencing at least one AESI will be provided for each category 
event of interest.  
A listing of patients with at least one AESI will be provided. 
4.7.6 Analysis of laboratory variables  
4.7.6.1 Laboratory variables  
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 before the first isatuximab administration 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 end of treatment (EOT) visit. 
Blood and urine samples for clinical laboratories parameters will be taken as defined in the study 
flow charts and as clinically indicated.  
The safety laboratory assessments required by protocol are listed in the table below. 
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Table 7 - Protocol required safety laboratory assessment 
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count  
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Blasts 
Clinical chemistrya 
Blood urea nitrogen 
Potassium 
Aspartate 
aminotransferase(AST)/Serum 
glutamic-oxaloacetic transaminase 
Total and direct 
bilirubin 
Creatinine 
Sodium 
Alanine aminotransferase 
(ALT)/Serum glutamic-pyruvic 
transaminase 
Total protein 
Glucose (fasting) 
Total Calcium 
Amylase 
Albumin 
Uric acid  
Phosphorus 
Lactic acid dehydrogenase 
Alkaline phosphatase 
Free T4 
Free T3 
Thyroid-stimulating hormone 
Ferritin 
CRP 
Coagulationa 
D-dimers
AT-III 
Fibrinogen 
Prothrombin time and international 
normalized ratio 
Partial thromboplastin 
time 
Routine urinalysis 
pH, glucose, protein, blood, ketones, by dipstick 
a 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 (possible Hy’s Law) must be reported as an SAE (excluding studies of hepatic impairment or cirrhosis). 
INR = (PTtest /PTnormal)^(ISI value) 
4.7.6.2 Analyses of laboratory variables 
Each laboratory test result will be graded by CTCAE criteria, 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 the parameters in 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.  
Change from baseline to each post-baseline visit will be summarized for each parameter. 
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Baseline for laboratory analysis is defined as the last assessment prior to the first administration of 
isatuximab. 
4.7.7 Analysis of vital signs 
4.7.7.1 Vital signs variables 
Vital signs include temperature, pulse rate, respiratory rate, and blood pressure will be 
summarized. 
Parameters measured before the first isatuximab administration will be considered as part of the 
baseline measurements. 
4.7.7.2 Analysis of vital signs 
Descriptive statistics at each visit and change from baseline to each post-baseline visit will be 
provided for all vital signs. 
The incidence of a potentially clinically significant abnormality (PCSA) at any time during the 
on-treatment period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
•
Normal/missing
•
Abnormal according to PCSA criterion or criteria
The PCSA criteria will determine which participants had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, including 
nonscheduled or repeated evaluations. 
A listing of participants with at least 1 PSCA will be provided. 
4.7.8 Analysis of electrocardiograms (ECGs)  
4.7.8.1 Electrocardiogram variables  
12-lead ECG assessments will be described as normal or abnormal.
4.7.8.2 Analyses of electrocardiogram variables 
For ECG, the incidence of participants with at least one abnormal ECG during the treatment-
emergent period will be summarized regardless of the baseline level and according to the 
following baseline status categories:  
•
Normal/missing
•
Abnormal
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A listing of patients with ECG results will be provided 
4.8 
OTHER ANALYSES  
4.8.1 Analyses of pharmacokinetic variables  
4.8.1.1 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, in a time window of 12 to 16 days after the previous 
infusion for the Q2W 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 flowcharts 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 PK flowcharts 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 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). 
Mean (±SE) of Ctrough will be plotted over treatment phase. 
For ALL cohort, individual Ctrough ratio (D29 vs D8, D43 vs D8, and D57 vs D8) and Ceoi ratio 
(D29 vs D1) will be listed and summarized by descriptive statistics as described above. 
For AML cohort, individual Ctrough ratio (D15 vs D8) and Ceoi ratio (D15 vs D1) will be listed and 
summarized by descriptive statistics as described above. 
4.8.1.2 Population PK analysis 
The population PK analyses will be described in the population PK analysis plan provided by 
Modeling and Simulation unit, Pharmacokinetics and Drug Metabolism (PKDM), Translational 
Medicine and Early Development (TMED) department. 
4.8.1.3 Immunogenicity impact on PK 
4.8.2 Immunogenicity analyses  
Participant’s ADA status, response variable (see definitions below) will be summarized on the 
ADA population. A summary table with the number of evaluable participants, number (%) of 
pre-existing ADA and negative participants at baseline, number (%) of boosted and induced 
participants (either transient, persistent or indeterminate) will be reported, along with descriptive 
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statistics of titer. Prevalence and incidence will also be presented. Kinetics of ADA responses will 
be described for participants with treatment-induced ADA and for participants with 
treatment-boosted ADA, separately. 
In addition, for positive ADA participants, 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 
applicabledate 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 positive and 
inconclusive ADA participants. 
The impact of positive immune response on efficacy, PK and safety variables may be further 
explored, depending on ADA incidence. 
Participant’s ADA status 
•
Participants with pre-existing ADAs correspond to participants with ADAs present in
samples drawn before first administration of intervention. Participants with missing ADA
sample at baseline will be considered as without pre-existing ADA.
•
Participants with treatment-emergent ADA correspond to participants with at least one
treatment-induced/boosted ADA.
-
Participants with treatment-induced ADAs correspond to participants with ADAs
that developed during the treatment-emergent (TE) period and without pre-existing
ADA (including participants without pre-treatment samples).
-
Participants with treatment-boosted ADAs correspond to participants with pre-
existing ADAs that are boosted during the TE period to a significant higher titer than
the baseline. A 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.
•
Participants without treatment-emergent ADA correspond to participants without
treatment-induced/boosted ADA and without any inconclusive sample during the TE
period.
•
Participants with inconclusive ADA are defined as participants which cannot irrefutably
be classified as with or without treatment-emergent ADA.
•
Participants with cross-reactivity with endogenous protein(s) and/or cross-neutralization of
endogenous protein(s)
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ADA response variable: 
ADA incidence is defined as the proportion of participants found to have seroconverted 
(treatment-induced ADAs) or boosted their pre-existing ADA response (treatment-boosted ADAs) 
at any time point during the TE period. 
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. 
4.8.3 Analyses of biomarker variables 
CD38 receptor density (RD) and occupancy (RO) data will be presented in summary statistics by 
cohort, including changes from baseline to post-baseline visits.  
The data by groups of responders versus non-responders in best overall response will also be 
summarized.  
4.8.4  Analyses of quality of life/health economics variables 
Not planned for this study. 
4.9 
INTERIM ANALYSES (IA) 
For each cohort, an interim analysis of efficacy, safety, and other data will be performed after the 
completion of enrollment in Stage 1 (Section 2). Enrollment may be interrupted at the end of 
Stage 1 until the interim analysis is performed, unless the required number of responses is reached 
before completion of enrollment. 
A subgroup PK analysis will be performed after the first 20 participants of 2 years of age or more 
(at least 5 participants in the age group of 2 to 10 years, including approximately 3 patients 
between 2 and 5 years old) are exposed to isatuximab. The dosage for participants aged less than 
2 years will be reassessed based on the results. 
The analysis will include the following parameters/analyses (defined in Section 4 and 
Section 5.3): demographics and baseline characteristics, prior or concomitant medication, AEs 
(TEAE, death, SAE, TEAE leading to discontinuation, IR, AESI), efficacy (primary and selected 
secondary), and PK. 
4.9.1 Data Monitoring Committee 
Close safety monitoring of each participant is planned, and an independent DMC will regularly 
monitor participant safety. The first meeting will be set up to review early safety results (eg, after 
approximately 10 participants have completed at least one induction period), and then 
periodically. 
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Ad hoc DMC meetings may also be held if a significant safety issue or issue deemed important 
for discussion arises on this or any other isatuximab studies. After each meeting, the DMC will 
advise the Sponsor’s representatives on recommendations regarding the continued safety of 
treating ongoing and future study participants, as well as the course of action regarding the 
conduct of the trial. 
4.9.2 Cut-off date 
For each cohort, the cut-off date for interim analysis (Stage 1) will be approximately 2 months 
after the last participant is treated in Stage 1. In case of stop of one of the cohorts after IA the 
actual date of the cut-off IA will be considered for the primary analysis of CR and other 
secondary endpoints. 
For each cohort, the cut-off date for the primary analysis of CR and other secondary endpoints 
will be approximately 6 months after the last participant has had their first study intervention 
administration. The final analysis cut-off date for the analysis of OS and other secondary 
endpoints will be approximately 12 months after the last participant has had their first study 
intervention administration. 
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5 
SUPPORTING DOCUMENTATION 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
CD38: 
cluster of differentiation 38 
CR: 
complete response 
CRS: 
cytokine-release syndrome 
CTCAE: 
Common Terminology Criteria for Adverse Events 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
EOT: 
end of treatment 
IRs: 
infusion reactions 
IMP: 
investigational medicinal product 
INR: 
international normalized ratio 
IV: 
intravenous 
MedDRA: 
Medical Dictionary for Regulatory Activities 
ORR: 
objective response rate 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PD: 
progressive disease 
PK: 
pharmacokinetics 
PK/PD: 
pharmacokinetics/pharmacodynamics 
PR: 
partial response 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SD: 
stable disease 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
WBC: 
whole blood cell 
WHO-DD: 
World Health Organization-Drug Dictionary 
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5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES 
There are no changes from the protocol-planned analyses. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics and baseline characteristics will be summarized on the all-treated population. 
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 summarized. 
5.3.1 Demographic and baseline characteristics  
The baseline value is defined as the last assessment for this parameter before first administration 
of study treatment (ie, isatuximab). 
Demographics characteristics 
Demographic variables include age in years and/or months, sex, ethnicity (Hispanic or Latino, Not 
Hispanic or Latino, Not reported, Unknown),  race (American Indian or Alaska Native, Asian, 
Black or African American, Native Hawaiian or Other Pacific Islander, White, Not reported, 
Unknown), weight (kg), height (cm) and eastern cooperative oncology group (ECOG) 
performance status at baseline. 
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at diagnosis 
The following disease characteristics at initial diagnosis will be described: 
•
French-American-British (FAB) classification of Diagnosis
•
Disease Involvement Location (Bone Marrow, Central Nervous System, Mediastinal
Lymph Node, Lymph Node, Testis, Other, If Other, Specify)
•
Leukemia / Lymphoma Diagnosis, Cytogenetic abnormality by category as collected
-
AML (inv(16), t(16;16), t(8;21), t(15;17), t(9;11), 11q23, t(9;22) Other )
-
B-ALL (Hyperdiploidy, Hypodiploidy, t(12;21), t(4;11), 14q23, t(9;22), Other)
-
T-ALL (Hyperdiploidy, Hypodiploidy, 1p32, t(11;14), t(10;11), Other
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Disease characteristics at study entry/baseline  
The following disease characteristics at study entry will be described: 
•
Type of disease (as collected in eCRF)
-
Acute Myeloid Leukaemia
-
B-cell Acute Lymphoblastic Leukemia/Lymphoma
-
T-cell Acute Lymphoblastic  Leukemia/Lymphoma
•
Disease status
-
Refractory
-
Relapsed
•
Blasts
-
0 - 20
-
21 - 50
-
≥ 50
•
WBC counts (x109/L)
-
0 to 5
-
6 to 10
-
11 to 20
-
20 to 50
-
> 50
•
Extramedullary disease
•
CNS impairment
-
Normal
-
Abnormal
•
Selected cytogenetics
-
11q23,
-
t(12;21)
-
t(9;22)
-
‘Other’: IAMP21, T(1;19)
•
Selected Immunophenotyping
-
CD19, CD22 for B-ALL
-
CD33 for AML
•
Time from initial diagnosis to first study treatment administration (in years),
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Prior anti-leukemia/lymphoma therapies 
Prior anti-leukemia/lymphoma treatments are collected by regimen in the eCRF. The following 
variables will be summarized: 
•
Time from last Relapse/Progression to first study treatment administration (in years)
•
Best response at last regimen
•
Number of prior regimens (quantitatively and by category: 1, 2, …7 and ≥8)
•
Number of prior lines (quantitatively and by category: 1 or 2)
-
A prior line of therapy is defined as all treatment received by the participant up to the
occurrence of relapse or progressive disease.
-
A line may be represented by one or multiple regiments.
•
Prior radiation therapies
•
Prior cell therapies
•
Prior transplant received
Prior radiation therapy was collected and will also be summarized in number (%) of patients with 
any prior radiotherapy. 
5.3.2 Prior, concomitant or post 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 up to 7 days prior to the first treatment to the last administration +
30 days.
•
Post-treatment medications are those the patient took in the period running from the day
after the last study treatment administration +30 days up to the end of the study.
Infusion reaction (IR) medications 
Participants should routinely receive premedication prior to isatuximab infusion as detailed in 
Section 6.1 of the study protocol to reduce the risk and severity of IRs commonly observed with 
mAbs. Infusion reactions (National Cancer Institute Common Terminology Criteria for Adverse 
Events [NCI CTCAE] version 5.0 term “allergic/hypersensitivity reactions” or “cytokine release 
syndrome/acute infusion reaction”) are defined as AEs related to isatuximab with onset within 
24 hours from the start of the infusion. 
Any technical details related to imputation for missing dates are described in Section 5.4. 
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5.3.3 Anticancer therapies 
Prior anti-cancer treatments will be summarized for the all-treated population. Number (%) of 
patients with the anti-cancer treatments will be summarized as described in Section 5.3. 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
5.4.1 General conventions  
The following formulas will be used for computation of the lab parameters. 
Creatinine clearance (eGRF) using the equation of MDRD formula: 
with serum creatinine in mg/dL and age in year. 
Corrected calcium formula: 
Corrected Calcium (mmol/L) = Serum Calcium (in mmol/L) + 0.8 (4 - serum albumin [in g/dL] x 
0.1)) x 0.25 
5.4.2 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 were found in the eCRF, attempts were 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 or time 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. 
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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;
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. 
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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 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.
•
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 
If the grade is missing for one of the treatment emergent occurrences of an AE, the maximal 
severity on the remaining occurrences will be considered. If the severity is missing for all the 
occurrences, no imputation will be done, and missing grades will be summarized in the “all 
grades” category. 
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 NMIP. 
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Handling of parameters expressed as inequality or approximation 
For some parameters (such as laboratory parameters), if the value is expressed as “< xx”, “≤xx, 
half of the numeric portion of the entry or limit of quantification will be used in calculations. 
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. 
5.4.3 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 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.  
5.4.4 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 
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administration will be also used for computation of baseline except if they are not collected on the 
day of first administration. 
5.4.5 Pooling of centers for statistical analyses  
Data from all sites will be pooled together for analyses. 
5.4.6 Statistical technical issues  
There are no expected statistical technical issues. 
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6 
REFERENCES 
Not applicable. 
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