Clinical trial NCT02999633
Conditions: T-cell Type Acute Leukemia-Precursor T-lymphoblastic Lymphoma/Leukaemia
Sponsor: Sanofi
Start date: 2017-03-08; Completion date: 2017-11-14
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To evaluate the efficacy of isatuximab.

Secondary Objectives:

* To evaluate the safety profile of isatuximab.
* To evaluate the duration of response (DOR).
* To evaluate progression free survival (PFS) and overall survival (OS).
* To evaluate the pharmacokinetics (PK) of isatuximab in participants with T-ALL or T-LBL.
* To evaluate immunogenicity of isatuximab in participants with T-ALL or T-LBL.
* To assess minimal residual disease (MRD) and correlate it with clinical outcome.

Detailed description:
The study duration per participant included a 3-week screening period, an approximately 1 year of treatment period or until disease progression or discontinuation for any other reason, and a follow-up period of at least 30 days after the last investigational medicinal product administration.

Arms: arm 1: Participants received intravenous administration of isatuximab at a dose of 20 milligrams/kilogram (mg/kg) at Day 1, 8, 15 and 22 of each Cycle (up to 2 treatment cycles, each cycle 28 days).
Interventions: intervention 1: Isatuximab SAR650984 intervention 2: dexamethasone intervention 3: dexamethasone intervention 4: acetaminophen intervention 5: ranitidine intervention 6: diphenhydramine
Intervention descriptions: intervention 1: Pharmaceutical form:solution Route of administration: intravenous intervention 2: Pharmaceutical form:pills Route of administration: oral intervention 3: Pharmaceutical form:solution Route of administration: intravenous intervention 4: Pharmaceutical form:pills Route of administration: oral intervention 5: Pharmaceutical form:solution Route of administration: intravenous intervention 6: Pharmaceutical form:solution Route of administration: intravenous

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016)
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 
COMPOUND: SAR650984 (isatuximab) 
Phase 2, safety and efficacy study of isatuximab, an anti-CD38 monoclonal 
antibody, administered by intravenous infusion in patients with relapsed or 
refractory T-acute lymphoblastic leukemia or T-lymphoblastic lymphoma 
STUDY NUMBER: ACT14596 
STUDY NAME: ISLAY 
VERSION DATE / STATUS: Approval date (27-Feb-2017) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 27-Feb-2017 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 01-Jul-2016 
EudraCT
2016-002739-14
IND Number(s) 
103217 
Version Number: 
1 
WHO universal trial number: 
Not applicable 
Date: 
27-Feb-2017 
Total number of pages: 
106 
(electronic 2.0)
NCT Number: NCT02999633


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
  
 
 
 
 
 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
Company: 
Address: 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
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CLINICAL TRIAL SUMMARY 
COMPOUND: isatuximab 
(SAR650984) 
STUDY No.: ACT14596  
 
TITLE 
Phase 2, safety and efficacy study of isatuximab, an anti-CD38 monoclonal 
antibody, administered by intravenous (IV) infusion in patients with relapsed or 
refractory T-acute lymphoblastic leukemia (-ALL) or T-lymphoblastic 
lymphoma (-LBL). 
INVESTIGATOR/TRIAL LOCATION 
International. 
PHASE OF DEVELOPMENT 
Phase 2. 
STUDY OBJECTIVES 
 
Primary objectives: 
To evaluate the efficacy of isatuximab in patients with relapsed or refractory 
T-ALL or T-LBL as measured by overall response rate (ORR) (as per National 
Comprehensive Cancer Network [NCCN] guidelines). 
Secondary objectives: 
• 
To evaluate the safety profile of isatuximab. 
• 
To evaluate the duration of response (DOR). 
• 
To evaluate progression free survival (PFS) and overall survival 
(OS). 
• 
To evaluate the pharmacokinetics (PK) of isatuximab in patients with 
T-ALL or T-LBL. 
• 
To evaluate immunogenicity of isatuximab in patients with T-ALL or 
T-LBL. 
• 
To assess minimal residual disease (MRD) and correlate it with 
clinical outcome. 
Exploratory objectives: 
• 
To explore the relationship between CD38 expression and clinical 
response. 
• 
To explore the relationship between CD38 receptor occupancy and 
CD38 receptor density on blast cells (peripheral blood and bone 
marrow) and clinical response. 
• 
To explore the relationship between acute leukemia tumor molecular 
alterations and clinical response. 
• 
To explore the relationship of soluble CD38, the PK of isatuximab 
and clinical response. 
• 
To explore the relationship between immune genetic determinants, 
immune phenotypes and clinical response. 
• 
To explore PK/pharmacodynamic (PDy) relationships. 
STUDY DESIGN 
This is a Phase 2, single arm, multicenter, open label study evaluating the 
efficacy and safety of isatuximab in patients with relapsed or refractory 
T-ALL/T-LBL. 
The study will be conducted in 2 stages: 
• 
Stage 1: an interim analysis of efficacy, safety and PK will be 
performed on the first 19 treated patients. 
• 
Stage 2: 20 additional patients will be treated if the number of 
responses required to proceed to Stage 2 is reached at the interim 
analysis of Stage 1. 
 
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Treatment scheme and duration of treatment 
The dose of isatuximab is 20 mg/kg. The cycle duration is 28 days. 
Induction period: Isatuximab will be administered by IV infusion, once every 
week (QW) for 4 weeks (1 induction cycle = 4 QW doses). If at Day (D)15-22 
of the first induction cycle, bone marrow blast cells remain >5%, a second 
induction cycle will be administered. If bone marrow blast cells are ≤5%, the 
administration of a second induction cycle will be performed at the discretion of 
the Investigator. 
After a maximum of 2 cycles of induction therapy, patients will be withdrawn 
from the study treatment if they do not achieve an objective response, or, in 
case of disease progression, an unacceptable adverse event (AE), consent 
withdrawal or Investigator’s decision (eg, patient is candidate for 
transplantation). 
Maintenance: In patients achieving an objective response following the 
induction period, isatuximab will be given once every 2 weeks (Q2W). Patients 
will be allowed to continue maintenance therapy until disease progression, an 
unacceptable AE, consent withdrawal or Investigator’s decision (eg, patient is 
candidate for transplantation). 
STUDY POPULATION  
Selection criteria 
Inclusion criteria: 
I 01. 
Patients must have a known diagnosis of ALL of T cell origin, 
including T-LBL and T-ALL with isolated extramedullary involvement 
at relapse confirmed by biopsy. 
I 02. 
Patients must be previously treated for T-ALL or T-LBL and have 
relapsed or are refractory to most recent treatment. Patients in first 
relapse will be eligible regardless of the first remission duration. 
I 03. 
Patients must have been previously exposed to nelarabine in 
countries where this drug is available (unless due to a 
contraindication to its use or administrative issue). 
I 04. 
No more than 3 prior salvage therapies. 
I 05. 
Signed written informed consent. 
Exclusion criteria: 
Exclusion criteria related to study methodology 
E 01. Age <16 years. 
E 02. Patients must have been off prior treatment with 
immunotherapy/investigational agents for >3 weeks 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 treatment 
administration. Treatment may start earlier if necessitated by the 
patient's medical condition (eg, rapidly progressive disease) following 
discussion with the Sponsor. 
E 03. Prior stem cell transplant within 4 months and/or evidence of active 
systemic Graft versus Host Disease and/or immunosuppressive 
therapy for Graft versus Host Disease within 1 week before the first 
study treatment administration. 
E 04. Clinical evidence of active central nervous system (CNS) leukemia. 
Lumbar puncture should be negative before Cycle (C)1D1. In case of 
positivity for blast cells before or during the screening period, local 
treatment is allowed. Confirmed negativity of the lumbar puncture is 
mandatory within 3 days before the first administration of isatuximab 
(C1D1). Otherwise, the patient will be considered as non-eligible for 
the study. 
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E 05. T-ALL with testicular involvement alone. 
E 06. Evidence of ongoing infection. 
E 07. Second malignancy other than basal cell or squamous cell carcinoma 
of the skin or in situ carcinoma of the cervix or the breast, unless they 
are successfully treated with curative intent for more than 3 years 
before entering the study. 
E 08. Poor condition/organ functions as defined by 1 of the following: 
• 
Eastern Cooperative Oncology Group (ECOG) performance 
status >2. 
• 
Total bilirubin >1.5 x upper limit of normal (ULN) unless Gilbert’s 
syndrome. 
• 
Alanine aminotransferase, aspartate aminotransferase or alkaline 
phosphatase >2.5 x ULN, unless considered due to the disease. 
• 
Serum creatinine >2 x ULN and/or creatinine clearance <30 mL/min 
(Modification of Diet in Renal Disease formula; see Appendix A). 
E 09. Radiation therapy within 14 days prior to study treatment 
administration (this delay could be reduced if necessitated by 
patient’s medical condition following discussion with Sponsor). 
E 10. Any serious active disease or co-morbid condition which, in the 
opinion of the Investigator, may interfere with the safety of the study 
treatment or the compliance with the study protocol. 
E 11. Any other severe underlying medical or administrative conditions, 
which could impair the ability to participate in the study or the 
interpretation of its results. 
E 12. Patient is the Investigator, Subinvestigator, research assistant, 
Pharmacist, study coordinator, other staff or relative thereof directly 
involved in the conduct of the protocol. 
E 13. Any technical/administrative reason (eg, patient homeless) that 
makes study participation impossible. 
E 14. Patient who has previously participated/Patient who has previously 
been treated in any clinical study with isatuximab or with a same class 
compound. 
E 15. Conditions/situations such as: Patient not suitable for participation, 
whatever the reason, as judged by the Investigator, or patients 
potentially at risk of noncompliance to study procedures. 
Exclusion criteria related to the current knowledge of 
Sanofi compound  
 
E 17. Known human immunodeficiency virus positivity. 
E 18. Active hepatitis B virus (hepatitis B surface antigen, hepatitis B 
envelope antigen and viral DNA positive, with absence of  
antihepatitis B envelope antibody) or hepatitis C virus infection 
(presence of circulating antihepatitis C virus antibodies); nonactive 
disease that may flare up following the treatment (carriers for hepatitis 
B surface antigen with presence of hepatitis B core antibodies). 
E 19. Pregnant and breast-feeding women, female patients of childbearing 
potential and male patients with female partners of childbearing 
potential who are not willing to avoid pregnancy by using an adequate 
method of contraception (2 barrier method or 1 barrier method with a 
spermicide, intrauterine device, or hormonal contraception with 
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inhibition of ovulation, for 2 weeks prior to the first dose of isatuximab, 
during treatment and 12 weeks after the last dose of study treatment). 
A woman is considered of childbearing potential, ie, fertile, following 
menarche and until becoming postmenopausal unless permanently 
sterile. 
E 20. Any country-related specific regulation that would prevent the subject 
from entering the study. 
Total expected number of patients:
Expected number of sites: 
Approximately 39. 
Approximately 15-20. 
STUDY TREATMENT  
Investigational medicinal product 
 
 
Isatuximab (SAR650984) 
The drug product (isatuximab) is presented as a concentrate for solution for 
infusion in vials containing 20 mg/mL (500 mg/25 mL) isatuximab 
 
 
 
 
 
. 
Route of administration: 
Isatuximab will be administered by the IV route. Within a cycle, the first day of 
isatuximab administration is D1. 
Dose regimen: 
Isatuximab will be administered QW for 4 doses at the dose of 20 mg/kg 
(1 induction cycle). If at D15-22 of the first induction cycle, bone marrow blast 
cells remain >5%, a second induction cycle will be administered. If bone 
marrow blast cells are ≤5%, the administration of a second induction cycle will 
be performed at the discretion of the Investigator. 
Following the induction period, isatuximab will be administered Q2W at the 
dose of 20 mg/kg. 
Non investigational medicinal 
products 
Isatuximab premedication to prevent infusion associated 
reactions 
Prior to the first isatuximab infusion 
Dexamethasone 20 mg (IV or orally [PO]) administration at first infusion: as the 
risk of infusion associated reactions (IARs) to isatuximab is typically higher at 
the first infusion, dexamethasone will be administered 3 times before (once per 
day on D-2, D-1 and D1), and twice after (once per day on D2 and D3) the first 
study treatment administration. 
Prior to each isatuximab infusion 
All patients will receive the following premedication for prevention of IARs at 
least 15 to 30 minutes (but no longer than 60 minutes) prior to each isatuximab 
infusion: 
• 
Acetaminophen 650-1000 mg PO. 
• 
Ranitidine 50 mg IV (or equivalent). 
• 
Diphenhydramine 25-50 mg IV (or equivalent). 
• 
Dexamethasone 20 mg (IV or PO). 
Whatever the route of administration (IV or PO), dexamethasone will be 
administered only once per use of premedication. 
When dexamethasone is administered PO, the following order is 
recommended: dexamethasone, acetaminophen, ranitidine and 
diphenhydramine. 
When dexamethasone is administered IV, the following order is 
recommended: acetaminophen, ranitidine, diphenhydramine and 
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dexamethasone. 
Other medications: 
In order to have rapid control of the tumor burden, the administration of 
cyclophosphamide 200 mg/m² before the first study treatment administration 
(up to 4 times, on D-3, D-2, D-1 and D1) is permitted for patients with 
hyperleucocytosis >50 000/mm3. 
Before C1D1, as per the institution’s clinical practice, all patients will receive 
CNS relapse prophylaxis (eg, intrathecal methotrexate 15 mg and/or 
cytarabine 40 mg and/or dexamethasone 4 mg). 
Prophylaxis for tumor lysis syndrome and CNS relapse may be administered 
at the discretion of the treating physician during the treatment period. 
ENDPOINTS 
 
Primary endpoints:  
The primary efficacy endpoint is the ORR. Overall response rate is based on 
NCCN guidelines and is defined as the proportion of patients with complete 
response (CR) or CR with incomplete peripheral recovery (CRi) for blood and 
bone marrow disease; partial response will be considered in case of 
mediastinal or any extramedullary disease. 
Secondary endpoints: 
Secondary efficacy endpoints: 
• 
DOR 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. 
• 
PFS defined as the time from the date of first study treatment 
administration to the date of first disease progression or the date of 
death from any cause, whichever happens first. 
• 
OS defined as the time interval from the date of first study treatment 
administration to death from any cause. 
Other secondary endpoints: 
• 
Safety assessment, in terms of AEs/serious adverse events (SAEs), 
laboratory parameters, vital signs, and physical examination. 
• 
PK parameters of isatuximab calculated using a non-compartmental 
and population PK approach. 
• 
Immunogenicity of isatuximab assessed throughout the study by 
detecting the presence of antidrug antibodies. 
• 
MRD by sequencing and/or flow cytometry in patients achieving CR 
and Cri. 
Exploratory endpoints 
Exploratory biomarkers: 
• 
Bone marrow and blood samples analyzed for CD38 receptor 
density and receptor occupancy on blast cells. 
• 
Bone marrow and blood samples analyzed for CD38 expression on 
blast cells (proportion of CD38 positive cells). 
• 
Bone marrow samples analyzed for tumor molecular alterations. 
• 
Blood samples analyzed to investigate the relationship between 
soluble CD38 and parameters of PK. 
• 
Blood samples analyzed for immune genetic determinants (including 
FcγR polymorphism genotyping and T cell receptor repertoire). 
Other genetic determinants, related to the drug action and/or effect 
of isatuximab, may be conducted on these samples during the study 
pending evolving literature. 
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• 
Bone marrow and blood samples analyzed for immunophenotypes 
(such as B cell, T cell, and natural killer cell subsets). 
• 
Additional biomarker analysis, not specified in the protocol but 
related to the drug action and/or effect of isatuximab, may be 
conducted on remaining samples pending evolving literature. 
Exploratory PK/PDy evaluation 
• 
PK/PDy parameter estimates will be investigated as prognostic 
factors for clinical outcome including safety and efficacy endpoints, if 
possible. 
ASSESSMENT SCHEDULE 
Efficacy data 
Bone marrow aspirate and/or biopsy will be done at screening, between D15 
and D22 during the first cycle (after the third isatuximab infusion), or to confirm 
response at the end of induction period (after 4, or 8 isatuximab infusions for 
patients receiving 2 induction cycles) and then every 2 cycles and when 
clinically indicated. No bone marrow is necessary if nonresponse or 
progressive disease can be diagnosed from peripheral blood evaluation, or, in 
patients with a white blood cell count <300/mm3, if the bone marrow test is 
considered noncontributory by the Investigator.  
In case of T-LBL or for any extramedullary location, computed tomography 
(CT)/positron emission tomography-CT scan has to be performed at 
screening, then repeated every 2 cycles or when clinically indicated. 
Safety data 
Safety evaluation will be performed continuously throughout the study period.  
The following assessments will be obtained and reviewed by the Investigator 
prior to study treatment administration and at designated intervals throughout 
the study: 
• 
Vital signs, 12-lead electrocardiogram, physical examinations, 
respiratory assessment. 
• 
AEs. 
• 
Laboratory tests (complete blood counts, serum chemistry, 
coagulation tests). 
• 
ECOG performance status. 
• 
Immunogenicity. 
• 
Blood cytokines (tumor necrosis factor α, interleukin [IL]-1β, IL-4,  
IL-6, interferon γ), serum tryptase, markers of activated complement 
(C3a, C4, CH50) and tumor lysis syndrome markers.  
Adverse events will be collected from the signing of the study informed 
consent up to at least 30 days after the last dose of study treatment, or a new 
anticancer therapy is started, whichever is first. Adverse events will be graded 
according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE), version 4.03 and coded according to the 
Medical Dictionary for Regulatory Activities. During the follow-up period, 
ongoing SAEs regardless of relationship to study treatment and ongoing or 
new study treatment-related AEs/SAEs will be followed until resolution or 
stabilization. 
Pharmacokinetic data 
Full PK profile sampling will be collected from patients in Stage 1 during the 
first induction cycle, to assess the PK profile of isatuximab using a 
non-compartmental analysis (including concentration at the end of infusion 
[Ceoi], maximum plasma concentration [Cmax] and area under the plasma 
concentration versus time curve at Week 1 [AUCweek1] after the first 
administration [C1 Week 1] and trough plasma concentration [Ctrough] 
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throughout C1). 
Blood samples will be collected using a sparse sampling strategy in patients 
from Stage 1 from C2 onwards and in the remaining patients in Stage 2.  
All blood samples will be used to assess the PK profile of isatuximab using a 
population PK approach. This analysis will involve an estimation of the 
interpatient PK variability, the interoccasion PK variability, and the population 
PK parameters estimates of pathophysiologic covariate effects on the main  
PK parameters. Empirical Bayesian estimation of individual parameters and of 
individual exposure will also be performed. 
Other data 
• 
Immunophenotyping on bone marrow and blood cells at screening, 
between D15 and D22 during the first cycle (after the third 
isatuximab infusion), and end of treatment (EOT). 
• 
Molecular alteration data on blast cells in bone marrow at screening 
and immune genetic determinants in leukocytes in peripheral blood 
at C1D1 and before the start of first maintenance cycle, or at the end 
of the induction period (after 1 or 2 cycles) for patients who 
discontinue the study before the first maintenance cycle. 
• 
CD38 receptor occupancy (Stage 1 only), CD38 expression and 
CD38 receptor density on blast cells in bone marrow and blood 
samples at screening. Receptor occupancy will also be analyzed 
between D15 and D22 during the first cycle (after the third 
isatuximab infusion). 
• 
Soluble CD38 at C1D1. 
• 
MRD at screening and at CR. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination 
A 2-stage Simon’s Optimum design was used for sample size calculation. A 
maximum of 39 evaluable patients will be enrolled in the study. This sample 
size will provide 80% power to reject the null hypothesis that the true ORR is 
≤15% if the true ORR rate is ≥30%, based on a 1-sided exact binomial test at 
a significance level of 0.1. 
• 
Stage 1: 19 patients. Proceed to Stage 2 if >3 responses are 
observed. 
• 
Stage 2: 39 patients (20 additional patients). If >8 responses are 
observed among the 39 patients analyzed, the null hypothesis will be 
rejected. 
Interim analysis 
An interim analysis of efficacy, safety and other data (including PK) will be 
performed after the completion of enrollment in Stage 1. This interim analysis 
will be performed when all patients have completed either 2 induction cycles 
plus D1 of the first maintenance cycle or 1 induction cycle plus 1 maintenance 
cycle. Enrollment will 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. 
Analysis population 
The all-treated/safety population will include all patients who received at least 
1 dose (even incomplete) of isatuximab. This population is the primary 
population for the analyses of efficacy and safety parameters.  
The PK population will include all patients from the all-treated/safety 
population with at least 1 PK parameter available. 
The PDy population will include patients from the all-treated/safety population 
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who had data for at least 1 PDy parameter available. 
 
General statistical approach 
Analysis of primary endpoint 
The ORR will be summarized with descriptive statistics. Confidence intervals 
will be computed using the Clopper-Pearson method. 
Analysis of secondary endpoints 
The DOR, PFS and OS will be analyzed using the Kaplan-Meier method. 
Among patients who achieved a CR, the number of patients without MRD will 
be provided. 
Pharmacokinetics: individual plasma concentrations and PK parameters of 
isatuximab will be summarized by descriptive statistics. 
Analysis of safety endpoints 
Number (%) of patients experiencing treatment-emergent AEs (TEAEs) by 
primary system organ class and preferred term will be summarized by 
NCI-CTCAE grade (all grades and Grade ≥3) for the all-treated/safety 
population. Similar tables will be prepared for treatment related TEAEs, IARs, 
TEAEs leading to isatuximab discontinuation, TEAEs leading to dose 
modification, serious TEAEs, and AEs/SAEs occurring during the 
posttreatment dosing period. For patients with multiple occurrences of the 
same preferred term, the maximum grade within the analyzed observation 
period will be used. 
Complete blood counts and serum chemistry results will be graded according 
to the NCI-CTCAE version 4.03, when applicable. Number (%) of patients with 
laboratory abnormalities (ie, all grades and Grade ≥3) using the worst grade 
during the on-treatment period will be provided for the all-treated/safety 
population.  
Analysis of exploratory endpoints 
At the end of each stage, additional statistical analyses could be performed in 
order to identify a subpopulation who would respond better to the treatment. If 
a relevant biomarker is actually identified, then a relevant threshold could be 
explored to define a subgroup of better responders.  
Cutoff dates/Planned database lock date 
The cutoff date for interim analysis (Stage 1) will be approximately 2 months 
after last patient is treated in Stage 1. 
The cutoff date for primary analysis of ORR and other secondary endpoints 
will be 6 months after the last patient has had their first study treatment 
administration. Then, the final analysis cutoff date for analysis of OS and 
updated analyses of ORR and other secondary endpoints will be 12 months 
after the last patient has had their first study treatment administration.  
DURATION OF STUDY PERIOD 
(per patient)  
The duration of the study for an individual patient will include: 
• 
The screening period of up to 3 weeks prior to the first study 
treatment administration. 
• 
The treatment period (in each period, the cycle duration is 28 days): 
- 
Induction period = QW dosing for 4 or 8 weeks, 
- 
Maintenance = dose Q2W. 
• 
An EOT visit 30 days after the last study treatment administration. 
• 
Follow-up period. 
Patients with documented disease progression at the EOT visit will be followed 
every 2 months until death or final analysis cutoff date, whichever comes first. 
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Patients 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 month until initiation of another anticancer therapy, 
disease progression, death or final analysis cutoff date, whichever comes first. 
Then, after disease progression, or after initiation of further anticancer therapy 
for patients without disease progression, patients will be followed every 
2 months until death or final analysis cutoff date, whichever comes first. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
 
ORR: overall response rate; PK: pharmacokinetics; Q2W: once every 2 weeks; QW: once every week. 
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1.1.1 Graphical representation of study treatment 
 
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1.2 
STUDY FLOW CHART 
Treatment period 
Screening period 
(up to 3 weeks) 
Induction period (QW administration) 
1 or 2 28-day cycles 
Maintenance 
period 
(Q2W 
administration) 
28-day cycles 
Assessment 
Within 
≤21days of 
Day 1 
Within 1 
week of 
Day 1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
End of 
Treatment 
(30 days 
after the last 
treatment 
dose 
±5 days) 
Follow-
up 
perioda 
Informed consent/Inclusion and exclusion criteria 
X 
 
X (C1D1) 
 
 
 
 
 
 
 
Demography, study patient card, medical/surgical 
and disease historyb 
X 
 
 
 
 
 
 
 
 
 
Blood type phenotyping/genotyping, screenc 
X 
 
 
 
 
 
 
 
 
 
Physical exam including respiratory function and 
ECOG PSd 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Lumbar puncture (to exclude CNS involvement) 
X 
 
X (when clinically indicated) 
 
 
Weight/height (height at screening only) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital signse 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
12-lead ECGf 
X 
 
When clinically indicated 
X 
 
Chest X-ray 
X 
 
 
 
 
CT/PET-CT scang  
X 
 
At  CR confirmation then every 2 cycles if extramedullary involvement or 
when clinically indicatedg 
X 
 
Blood cell countsh 
X 
X 
X (C2 if 
applicable) 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry testsi 
X 
X 
X (C2 if 
applicable) 
X 
X 
X 
X 
X 
X 
 
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Page 15 
Treatment period 
Screening period 
(up to 3 weeks) 
Induction period (QW administration) 
1 or 2 28-day cycles 
Maintenance 
period 
(Q2W 
administration) 
28-day cycles 
Assessment 
Within 
≤21days of 
Day 1 
Within 1 
week of 
Day 1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
End of 
Treatment 
(30 days 
after the last 
treatment 
dose 
±5 days) 
Follow-
up 
perioda 
Coagulation testsj 
 
X 
X (C2 if 
applicable) 
 
 
 
 
 
 
 
Pregnancy test for WOCBPk 
 
X 
X (C2 if 
applicable) 
 
 
 
X 
 
X 
X 
Hepatitis B and C virus serology 
X 
 
 
 
 
 
 
 
 
 
Exploratory laboratory assessments (central laboratory) 
Soluble CD38 (blood)l  
 
 
X (predose 
C1D1) 
 
 
 
 
 
 
 
Immunophenotyping (bone marrow and blood)m  
X 
 
 
 
X (C1D15-D22) 
 
 
X 
 
CD38 receptor positivity and density (RD, bone 
marrow and blood)n  
X 
 
 
 
 
 
 
 
 
 
CD38 receptor occupancy (RO, bone marrow and 
blood)o  
X 
 
 
 
X (C1D15-D22) 
 
 
 
 
Tumor molecular alterations (bone marrow)p  
X 
 
 
 
 
 
 
 
 
 
Immune genetic determinants (blood)q  
 
 
X (predose 
C1D1) 
 
 
 
X 
 
 
 
Optional pharmacogenetic sample (blood)r 
 
 
X (predose 
C1D1) 
 
 
 
 
 
 
 
Safety laboratory assessment 
TLS markers (blood; local laboratory) s 
 
 
X (predose 
C1D1) 
When IAR ≥ Grade 2 occurs 
 
 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 16 
Treatment period 
Screening period 
(up to 3 weeks) 
Induction period (QW administration) 
1 or 2 28-day cycles 
Maintenance 
period 
(Q2W 
administration) 
28-day cycles 
Assessment 
Within 
≤21days of 
Day 1 
Within 1 
week of 
Day 1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
End of 
Treatment 
(30 days 
after the last 
treatment 
dose 
±5 days) 
Follow-
up 
perioda 
Cytokines (TNFα, IL-1β, IL-4, IL-6, IFNγ) (blood; 
central laboratory)  
See PK/PDy flowchart 
Markers of activated complement (C3a, C4, CH50), 
and serum tryptase (blood; central laboratory)  
See PK/PDy flowchart 
Immunogenicity (ADAs)(blood; central laboratory)  
See PK/PDy flowchart 
Disease assessment 
Bone marrow aspirate / biopsyt 
X 
 
 
 
X 
X (before start of 
maintenance, then 
every 2 cycles or if 
clinically indicated) 
 
X 
MRD assessment (bone marrow or blood)u  
X 
 
X (at CR) 
 
 
Administration of isatuximab 
Isatuximab intravenous infusion  
 
 
X 
X 
X 
X 
X 
X 
 
 
Premedication 
 
X (D-2, D-1, D1, D2, D3) 
X 
X 
X 
X 
X 
 
 
CNS relapse prophylaxis 
X 
 
X (as per the institution’s clinical practice) 
 
 
PK assessment 
See PK/PDy flowchart 
AE/SAE assessmentv 
Continuously 
Prior/concomitant medicationsw 
Continuously 
 
Post-IMP anticancer therapies 
Not applicable 
X 
X 
Survival 
Not applicable 
 
X 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 17 
Treatment period 
Screening period 
(up to 3 weeks) 
Induction period (QW administration) 
1 or 2 28-day cycles 
Maintenance 
period 
(Q2W 
administration) 
28-day cycles 
Assessment 
Within 
≤21days of 
Day 1 
Within 1 
week of 
Day 1 
Day 1 
Day 8 
Day 15 
Day 22 
Day 1 
Day 15 
End of 
Treatment 
(30 days 
after the last 
treatment 
dose 
±5 days) 
Follow-
up 
perioda 
ADA: antidrug antibody; AE: adverse event; ALL: acute lymphoblastic leukemia; C: cycle; CNS: central nervous system; CR: complete response; CT: computed tomography; D: day; ECG: electrocardiogram; ECOG 
PS: Eastern Cooperative Oncology Group performance status; eCRF: electronic case report form; EOT: End of Treatment; IAR: infusion associated reaction; IFNγ: interferon gamma; IL: interleukin; IMP: investigative 
medicinal product; LBL: lymphoblastic lymphoma; LDH: lactate dehydrogenase; MRD: minimal residual disease; PDy: pharmacodynamics; PET: positron emission tomography; PK: pharmacokinetics; Q2W: once 
every 2 weeks; QW: once every week; SAE: serious adverse event; RD: receptor density; RO: receptor occupancy; TLS: tumor lysis syndrome; TNFα: tumor necrosis factor alpha; WOCBP: women of childbearing 
potential. 
 
a Follow-up: First follow-up visit will be 60 days after last treatment dose (±5 days). Patients with documented disease progression at the EOT visit will be followed every 2 months until death or final analysis cutoff 
date, whichever comes first. Patients 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 month until 
initiation of another anticancer therapy, disease progression, death or final analysis cutoff date, whichever comes first. Then, after disease progression, or after initiation of further anticancer therapy for patients 
without disease progression, patients will be followed every 2 months until death or final analysis cutoff date, whichever comes first. 
b Demography, medical/surgical and disease history: Includes age, gender, race, relevant medical/surgical history, disease history including date of initial diagnosis, type of disease (T-ALL/T-LBL, 
immunophenotypic and cytogenetic), previous anti-leukemia treatment (reason for discontinuation, date of relapse and best overall response to prior treatments). History of asthma, chronic obstructive 
bronchopneumonia,dyspnea and tobacco consumption will be collected and reported in the eCRF. 
c Blood type phenotyping/genotyping, screen: If not previously performed, blood type phenotyping (or genotyping) and screen to be done after enrolment in the study and prior to first study treatment 
administration. The transfusion service should be made aware that the patient is receiving an anti-CD38 treatment (SAR650984). During the study treatment 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 patient card  
(see Appendix F). Patients should keep together their study patient card with their blood type card throughout the duration of the study treatment. 
d Physical examination: Examination of major body systems including neurological examination, digestive, skin/mucosae, mediastinal, testicular localizations, respiratory, hepatomegaly, splenomegaly, and 
lymphadenopathy. Respiratory function will be monitored at C1D1 and before each study treatment administration, and at EOT visit including respiratory frequency, pulmonary auscultation, signs and symptoms 
such as cough, dyspnea, and expectoration. Patients with respiratory signs/symptoms Grade ≥2 that could be attributed to the study treatment, will have the respiratory evaluation repeated QW until improvement 
to Grade 1. Physical examination to be performed every 4 weeks during follow-up for patients who discontinue treatment for other reason than disease progression until initiation of another anticancer therapy, 
disease progression, death or final analysis cutoff date, whichever comes first. ECOG PS will be evaluated at screening, before each study treatment and at EOT visit. 
e 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 infusion on D1, D8, D15 and D22 of 
induction cycle(s), then preinfusion and as clinically indicated for subsequent cycles. The final measurements will be performed at the EOT visit. 
f 
12-lead ECG: To be performed at screening, at EOT visit and when clinically indicated. 
g CT/PET-CT scan: A CT of chest with IV contrast and/or PET-CT scan (CT/PET-CT scan) should be performed at screening and at the EOT visit. In case of extramedullary involvement or T-LBL, both CT and PET-
CT should be performed at baseline and at CR confirmation, whenever possible. Then CT and/or PET-CT scan every 2 cycles thereafter. 
h Blood cell counts: Complete blood count with differential, hemoglobin and platelets to be performed at screening. To be repeated within 3 days before the first study treatment administration if performed >7 days 
before the first study treatment administration. To be performed at the time points specified in the table and when clinically indicated. To be performed every 4 weeks during follow-up for patients who discontinue 
treatment for other reason than disease progression until initiation of another anticancer therapy, disease progression, death or final analysis cutoff date, whichever comes first.  
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
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ACT14596 -  isatuximab 
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Page 18 
i 
Serum chemistry: To be repeated within 3 days before the first study treatment administration if performed >7 days before the first study treatment administration. From C1D8 onwards, to be performed and 
reviewed by the Investigator within 24 hours before the day of dosing. To be performed at the time points specified in the table and when clinically indicated. Chemistry includes: glucose (fasting), albumin, total 
protein, aspartate aminotransferase, alanine aminotransferase, bilirubin (total and direct), alkaline phosphatase, LDH, sodium, potassium, chloride, bicarbonate/carbon dioxide, total calcium, magnesium, 
phosphate, uric acid, blood urea nitrogen, serum creatinine and estimated creatinine clearance (Modification of Diet in Renal Disease formula; see Appendix A). In case of Grade 3 or 4 abnormalities, additional 
tests will be repeated every 2 to 3 days until recovery to baseline value or Grade≤1. 
j 
Coagulation tests: To be performed within 7 days before the first study treatment administration and as clinically indicated. Coagulation includes: prothrombin time or international normalized ratio, and activated 
partial thromboplastin time. 
k Serum or urine pregnancy test: Performed for WOCBP. To be repeated within 3 days before the first study treatment administration if performed >7 days before the first study treatment administration. To be 
performed every 4 weeks (before D1 of each cycle of study treatment administration). To be performed up to 3 months after the last administration of study treatment, or before starting further anticancer therapy. 
l 
Blood sample for soluble CD38: To be performed on C1D1 prior to first study treatment administration. Analysis will be performed by central laboratory. 
m Immunophenotyping: From bone marrow aspirate at screening only and from peripheral blood at screening, between D15 and D22 during the first cycle (after the third isatuximab infusion), and at the EOT visit. 
Sample collection from blood must be done before dexamethasone premedication. Analysis will be performed by central laboratory. 
n CD38 receptor positivity and density: From bone marrow aspirate and peripheral blood collected at screening within 21 days before first study treatment administration. Sample collection from blood must be 
done before dexamethasone premedication. Analysis will be performed by central laboratory. This sample collection will be applicable in selected countries only. 
o CD38 receptor occupancy: Stage 1 only. From bone marrow aspirate and peripheral blood collected at screening within 21 days before first study treatment administration, and between D15 and D22 during the 
first cycle (after the third isatuximab infusion). Sample collection from blood must be done before dexamethasone premedication. Analysis will be performed by central laboratory. This sample collection will be 
applicable in selected countries only. 
p Bone marrow aspirate for tumor molecular alteration assessment: To be performed at screening. Analysis will be performed by central laboratory. In parallel, the local data will also be collected through report 
or access to data established at diagnosis or at the most recent relapse available. 
q Blood sample for immune genetic determinants: To be performed on C1D1, prior to first study treatment administration and during the treatment period (before start of first maintenance cycle, or at the end of 
the induction period [after 1 or 2 cycles] for patients who discontinue the study before the first maintenance cycle) for some specific markers. Analysis will be performed by central laboratory. 
r 
Pharmacogenetics (optional): To be performed on C1D1, prior to study treatment administration. 
s TLS markers and isatuximab safety labs: Baseline sample to be drawn prior to first study treatment administration at C1D1. Should a isatuximab IAR of Grade ≥2 occur (as per National Cancer Institute 
Common Terminology Criteria for Adverse Events, version 4.03), additional blood sampling during the AE is required for analysis of markers of potential TLS (uric acid, LDH, blood urea nitrogen/creatinine, 
potassium, phosphate, and ionized and corrected calcium). Analysis of TLS markers will be performed by a local laboratory. 
t 
Bone marrow aspirate/biopsy for disease assessment: To be performed at screening, between D15 and D22 (after the third isatuximab infusion), to confirm response at the end of induction period (after 
4 isatuximab infusions, or 8 for patients receiving 2 induction cycles) and then before D1 of every other cycle (every 2 cycles) or when clinically indicated. Patients who discontinue for other reasons than disease 
progression will be followed every 4 weeks, but bone marrow aspirate will only be performed when clinically indicated. No bone marrow is necessary if nonresponse or progressive disease can be diagnosed from 
peripheral blood evaluation, or, in patients with a white blood cell count <300/mm3, if the bone marrow test is considered noncontributory by the Investigator. Analysis of bone marrow aspirate/biopsy for disease 
assessment will be performed by a local laboratory. 
u MRD assessment: To be performed on bone marrow aspirate at screening and on blood at CR (in case of MRD positivity at first CR observation, assessment will be repeated after 2 to 3 cycles). Analysis will be 
performed by central laboratory. 
v Adverse Event/Serious Adverse Event: The period of safety observation extends from the date informed consent is signed, until the end of treatment (at least 30 days after the last dose of study treatment, 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 IMP that are 
new during the follow-up period will be reported and followed until recovery or stabilization. 
w Concomitant medication: All treatments being taken by the patient for up to 7 days prior to the first dose of IMP, and at any time during the treatment period and for up to 30 days after the last dose are regarded 
as prior and concomitant treatments, respectively. After the end of treatment, only further anticancer therapy will be reported. 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
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Property of the Sanofi Group - strictly confidential 
Page 19 
1.3 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART: STAGE 1 
Study 
Period 
Induction Cycle 1 +/- Cycle 2 
Maintenance Period 
EOT 
Follow-up 
Cycle 
Cycle 1 
Cycle 2 (optional) 
1st Cycle 
2nd Cycle 
Subsequent 
cycles 
30 
days 
after 
last 
IMP 
admin 
60 
days 
after 
last 
IMP 
admin 
Monthly/ 
Bi-
monthlyg 
Day 
1 
1 
1 
2 
3 
4 
8 
15 
22 
1 
8 
15 
22 
1 
1 
15 
1 
1 
1 
15 
1 
15 
 
 
 
Time (decimal 
hours) 
0hb 
EOIc 
EOI + 
4hd 
24h 
48h 
72h 
0hb 
0hb 
0hb 
0hb 
0hb 
0hb 
0hb 
0hb 
EOIc 
0hb 
0hb 
EOIc 
EOI + 
1he 
0hb 
0hb 
0hb 
 
 
 
Time windowk 
 
±10min 
±30min 
±4h 
±8h 
±12h 
 
 
 
 
 
 
 
 
±10min 
 
 
±10min 
±10min 
 
 
 
±5 
days 
±5 
days 
±5 days 
Indicative  
clock time 
8 am 
12 pm 
4 pm 
8 
am 
8 
am 
8 am 
8 
am 
8 am 
8 
am 
8 am 
8 
am 
8 am 
8 
am 
8 am 
12 pm 
8 
am 
8 am 
12 pm 
1 pm 
8 
am 
8 am 
8 
am 
8 am 
8 am 
8 am 
Isatuximab IV 
infusion 
X--- 
---X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X--- 
---X 
X 
X--- 
---X 
 
X 
X 
X 
 
 
 
Pharmacokineticsa 
Isatuximab 
P00 
P01 
P02 
P03 
P04 
P05 
P06 
P07 
P08 
P00 
P01 
P02 
P03 
P00 
P01 
P02 
P00 
P01 
P02 
P03 
P00 
P01 
PF00 
PF01 
 
Pharmacodynamicsa 
Immunogenicity 
(ADA) 
AB00 
 
 
 
 
 
 
AB01 
 
AB00 
 
AB01 
 
AB00 
 
 
AB00 
 
 
 
AB00 
 
ABF00 
ABF01f 
ABF0xf 
C3a, C4, CH50 
& serum 
tryptaseh,i 
S00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokines 
(TNFα, IL-1β, 
IL-4 IL-6 & 
IFNγ)i,j 
P00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AB: antibody; ADA: antidrug antibody;  EOI: end of infusion; EOT: end of treatment; h: hour; IMP: investigational medicinal product; IFNγ: interferon gamma; IL: interleukin; IV: intravenous; min: minutes; P: plasma; S: serum; TNFα: tumor 
necrosis factor alpha. 
For the comfort of patients, some PK, PDy and/or ADA samplings may be deleted during the course of the study if they are no longer deemed necessary by the sponsor. 
a Refer to Laboratory Manual for sample collection, processing and shipment. 
b Start of infusion: sample collected just and strictly prior to study treatment administration. 
c Sample collected immediately prior to actual EOI. A time window of ±10 minutes around the actual EOI is permitted. 
d Sample collected 4 hours after the actual EOI. 
e Sample collected 1 hour after the actual EOI. 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 20 
f At 60 days. If patient is positive or inconclusive for ADAs, additional ADA sampling is required every 30 days (±5 days) until sample is negative (sample ID: ABF02, ABF03, etc). 
g First follow-up visit will be 60 days after last treatment dose (±5 days). Patients with documented disease progression at the EOT visit will be followed every 2 months until death or final 
analysis cutoff date, whichever comes first. Patients 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 month until initiation of another anticancer therapy, disease progression, death or final analysis cutoff date, whichever comes first. Then, after disease 
progression, or after initiation of further anticancer therapy for patients without disease progression, patients will be followed every 2 months until death or final analysis cutoff date, whichever 
comes first. 
h In case of infusion associated reaction ≥Grade 2, an additional sample will be collected as SF00. 
i 
Samples will be drawn before first study treatment administration. The sample ID should be reported for each C3a, C4, CH50, serum tryptase, TNFα, IL-1β, IL-4, IL-6 and IFNγ. 
j 
In case of infusion associated reaction ≥Grade 2, an additional sample will be collected as PF00. 
k Time window permitted for PK/PDy sampling. 
 
 
 
 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 21 
1.4 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART: STAGE 2 
Study Period 
Induction Cycle 1 +/- Cycle 2 
Maintenance Period 
EOT 
Follow-up 
Cycle 
Cycle 1 +/- Cycle 2 
1st Cycle 
2nd Cycle 
Subsequent 
cycles 
30 days 
after last 
IMP admin 
60 days 
after last 
IMP admin 
Monthly/ 
Bi-monthlyf  
Day 
1 
1 
1 
8 
15 
15 
22 
1 
1 
15 
1 
1 
1 
15 
1 
15 
 
 
 
Time (decimal 
hours) 
0hb 
EOIc 
EOI + 
1hd 
0hb 
0hb 
EOIc 
0hb 
0hb 
EOIc 
0hb 
0hb 
EOIc 
EOI + 
1hd 
0hb 
0hb 
0hb 
 
 
 
Time window j 
 
±10min 
±10min 
 
 
±10min 
 
 
±10min 
 
 
±10min 
±10min 
 
 
 
±5 days 
±5 days 
±5 days 
Indicative clock 
time 
8 am 
12 pm 
1 pm 
8 
am 
8 am 
12 pm 
8 
am 
8 am 
12 pm 
8 
am 
8 am 
12 pm 
1 pm 
8 
am 
8 am 
8 am 
8 am 
8 am 
8 am 
Isatuximab IV 
infusion 
X--- 
---X 
 
X 
X--- 
---X 
X 
X--- 
---X 
X 
X--- 
---X 
 
X 
X 
X 
 
 
 
Pharmacokineticsa 
Isatuximab 
P00 
P01 
P02 
P03 
P04 
P05 
P06 
P00 
P01 
P02 
P00 
P01 
P02 
P03 
P00 
P01 
PF00 
PF01 
 
Pharmacodynamicsa 
Immunogenicity 
(ADA) 
AB00 
 
 
 
AB01 
 
 
AB00 
 
 
AB00 
 
 
 
AB00 
 
ABF00 
ABF01e 
ABF0xe 
C3a, C4, CH50 & 
serum tryptaseg,h  
S00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cytokines (TNFα, 
IL-1β, IL-4, IL-6 & 
IFNγ),h,i  
P00 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AB: antibody; ADA: antidrug antibody; EOI: end of infusion; EOT: end of treatment; h: hour; IMP: investigational medicinal product; IFNγ: interferon gamma; IL: interleukin; IV: intravenous; P: plasma; S: serum; TNFα: 
tumor necrosis factor alpha. 
For the comfort of patients, some PK, PDy and/or ADA samplings may be deleted during the course of the study if they are no longer deemed necessary by the sponsor. 
a Refer to Laboratory Manual for sample collection, processing and shipment. 
b Start of infusion: sample collected immediately just and strictly prior to study treatment administration. 
c Sample collected immediately prior to actual EOI. A time window of ±10 minutes around the actual EOI is permitted. 
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 22 
d Sample collected 1 hour after the actual EOI. 
e At 60 days. If patient is positive or inconclusive for ADAs, additional ADA sampling is required every 30 days (±5 days) until sample is negative (sample ID: ABF02, ABF03, etc). 
f First follow-up visit will be 60 days after last treatment dose (±5 days). Patients with documented disease progression at the EOT visit will be followed every 2 months until death or final 
analysis cutoff date, whichever comes first. Patients 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 month until initiation of another anticancer therapy, disease progression, death or final analysis cutoff date, whichever comes first. Then, after disease 
progression, or after initiation of further anticancer therapy for patients without disease progression, patients will be followed every 2 months until death or final analysis cutoff date, whichever 
comes first. 
g In case of infusion associated reaction ≥Grade 2, an additional sample will be collected as SF00. 
h Samples will be drawn before first study treatment administration. The sample ID should be reported for each C3a, C4, CH50, serum tryptase, TNFα, IL-1β, IL-4, IL-6 and IFNγ. 
i 
In case of infusion associated reaction ≥Grade 2, an additional sample will be collected as PF00. 
j 
Time window permitted for PK/PDy sampling.
(electronic 
 
 
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Amended Clinical Trial Protocol NO. 01  
27-Feb-2017 
ACT14596 -  isatuximab 
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Property of the sanofi Group - strictly confidential 
Page 23 
2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................12 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................12 
1.1.1 
Graphical representation of study treatment..................................................................................13 
1.2 
STUDY FLOW CHART ..................................................................................................................14 
1.3 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART: STAGE 1 ...............................19 
1.4 
PHARMACOKINETICS/PHARMACODYNAMICS FLOWCHART: STAGE 2 ...............................21 
2 
TABLE OF CONTENTS ................................................................................................................23 
2.1 
LIST OF TABLES...........................................................................................................................29 
2.2 
LIST OF FIGURES.........................................................................................................................29 
3 
LIST OF ABBREVIATIONS ..........................................................................................................30 
4 
INTRODUCTION AND RATIONALE.............................................................................................32 
4.1 
ACUTE LYMPHOBLASTIC LEUKEMIA ........................................................................................32 
4.2 
DESCRIPTION OF ISATUXIMAB..................................................................................................33 
4.3 
PHARMACOLOGY ........................................................................................................................34 
4.3.1 
Toxicology......................................................................................................................................34 
4.3.2 
Metabolism and pharmacokinetic profile in animals ......................................................................34 
4.4 
BACKGROUND INFORMATION ON CD38 IN ACUTE LYMPHOBLASTIC LEUKEMIA..............34 
4.4.1 
Preclinical data...............................................................................................................................34 
4.4.1.1 
Isatuximab activity in ALL cell lines and patient-derived ALL cells................................................34 
4.4.1.2 
Isatuximab in vivo activity in xenograft mouse models..................................................................35 
4.4.2 
Clinical data....................................................................................................................................36 
4.4.2.1 
CD38 expression in T-ALL.............................................................................................................36 
4.4.2.2 
Isatuximab clinical data..................................................................................................................37 
4.5 
RATIONALE...................................................................................................................................38 
4.5.1 
Study design rationale ...................................................................................................................38 
4.5.1.1 
Dose selection rationale in multiple myeloma................................................................................38 
4.5.1.2 
Acute Lymphoblastic Leukemia .....................................................................................................39 
5 
STUDY OBJECTIVES ...................................................................................................................40 
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Page 24 
5.1 
PRIMARY.......................................................................................................................................40 
5.2 
SECONDARY ................................................................................................................................40 
5.3 
EXPLORATORY ............................................................................................................................40 
6 
STUDY DESIGN ............................................................................................................................41 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................41 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................41 
6.2.1 
Duration of study participation for each patient .............................................................................41 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................42 
6.3 
RETREATMENT OF PATIENTS ...................................................................................................42 
6.4 
DOSE DELAYS/DOSE MODIFICATIONS.....................................................................................42 
6.5 
INTERIM ANALYSIS......................................................................................................................42 
6.6 
STUDY COMMITTEE ....................................................................................................................43 
7 
SELECTION OF PATIENTS..........................................................................................................44 
7.1 
INCLUSION CRITERIA..................................................................................................................44 
7.2 
EXCLUSION CRITERIA ................................................................................................................44 
7.2.1 
Exclusion criteria related to study methodology ............................................................................44 
7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound......................................45 
8 
STUDY TREATMENTS .................................................................................................................46 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................46 
8.1.1 
Pharmaceutical form ......................................................................................................................46 
8.1.2 
Dose of drug per administration.....................................................................................................46 
8.1.3 
Dilution method ..............................................................................................................................47 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS.....................................................................47 
8.3 
BLINDING PROCEDURES............................................................................................................48 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................48 
8.5 
PACKAGING AND LABELING ......................................................................................................48 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................48 
8.7 
RESPONSIBILITIES ......................................................................................................................49 
8.7.1 
Treatment accountability and compliance......................................................................................49 
8.7.2 
Return and/or destruction of treatments ........................................................................................50 
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Page 25 
8.8 
CONCOMITANT MEDICATION.....................................................................................................50 
8.8.1 
Permitted concomitant therapy ......................................................................................................50 
8.8.2 
Prohibited concomitant therapy .....................................................................................................51 
8.8.3 
Contraceptive measures ................................................................................................................51 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................52 
9.1 
ENDPOINTS ..................................................................................................................................52 
9.1.1 
Primary endpoints ..........................................................................................................................52 
9.1.2 
Secondary endpoints .....................................................................................................................52 
9.1.3 
Exploratory endpoints ....................................................................................................................53 
9.2 
SAFETY .........................................................................................................................................53 
9.2.1 
Adverse events ..............................................................................................................................53 
9.2.2 
Laboratory safety variables............................................................................................................54 
9.2.3 
Physical examination .....................................................................................................................55 
9.2.4 
Vital signs.......................................................................................................................................55 
9.2.5 
12-lead electrocardiogram .............................................................................................................55 
9.2.6 
Immunogenicity..............................................................................................................................55 
9.3 
EFFICACY .....................................................................................................................................56 
9.4 
PHARMACOKINETIC EVALUATION ............................................................................................57 
9.4.1 
Sampling time and sample blood volume ......................................................................................57 
9.4.2 
Pharmacokinetics handling procedure...........................................................................................57 
9.4.3 
Isatuximab bioanalytical method....................................................................................................57 
9.4.4 
Pharmacokinetics parameters .......................................................................................................57 
9.4.4.1 
Non-compartmental pharmacokinetic analysis ..............................................................................57 
9.4.4.2 
Pharmacokinetic population analysis.............................................................................................58 
9.5 
SPECIFIC ASSESSMENTS ..........................................................................................................58 
9.5.1 
Sample times, handling procedures, and bioanalytical methods...................................................58 
9.5.2 
Cytokines .......................................................................................................................................59 
9.5.3 
Markers of activated complement and serum tryptase..................................................................59 
9.6 
EXPLORATORY BIOMARKERS ANALYSES...............................................................................59 
9.6.1 
Receptor density, receptor occupancy, and CD38 expression......................................................59 
9.6.2 
Other biomarkers ...........................................................................................................................60 
9.6.3 
Pharmacogenetic assessment.......................................................................................................61 
9.6.3.1 
Mandatory or optional drug metabolizing enzymes DNA sample..................................................61 
9.6.3.2 
Optional stored DNA sample .........................................................................................................61 
9.7 
FUTURE USE OF SAMPLES ........................................................................................................62 
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9.8 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................62 
10 
STUDY PROCEDURES ................................................................................................................63 
10.1 
VISIT SCHEDULE..........................................................................................................................63 
10.1.1 
Screening .......................................................................................................................................63 
10.1.2 
Induction period..............................................................................................................................64 
10.1.2.1 Cycle 1 (and Cycle 2, if applicable): Day 1 ....................................................................................64 
10.1.2.2 Cycle 1 (and 2, if applicable): Days 8, 15, and 22 .........................................................................65 
10.1.3 
Maintenance...................................................................................................................................66 
10.1.3.1 Maintenance cycles: Days 1 and 15 ..............................................................................................66 
10.1.4 
Post-treatment period.....................................................................................................................67 
10.1.4.1 End of treatment.............................................................................................................................67 
10.1.4.2 Follow-up........................................................................................................................................68 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................68 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................69 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................69 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................69 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................69 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................70 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................70 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................71 
10.4.1 
Definitions of adverse events.........................................................................................................71 
10.4.1.1 Adverse event ................................................................................................................................71 
10.4.1.2 Serious adverse event ...................................................................................................................71 
10.4.1.3 Adverse event of special interest...................................................................................................72 
10.4.2 
General guidelines for reporting adverse events ...........................................................................72 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................73 
10.4.4 
Instructions for follow-up of adverse events ..................................................................................73 
10.4.5 
Treatment discontinuation due to nonserious adverse event ........................................................74 
10.5 
OBLIGATIONS OF SANOFI ..........................................................................................................74 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................74 
10.6.1 
Guidelines for the management of potential infusion associated reactions...................................74 
10.6.2 
Guidelines for the management of tumor lysis syndrome .............................................................76 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................76 
11 
STATISTICAL CONSIDERATIONS..............................................................................................77 
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11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................77 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................77 
11.3 
ANALYSIS POPULATIONS...........................................................................................................77 
11.3.1 
All-treated/safety population ..........................................................................................................77 
11.3.2 
Pharmacokinetic population...........................................................................................................77 
11.3.3 
Pharmacodynamic population........................................................................................................77 
11.4 
STATISTICAL METHODS .............................................................................................................78 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................78 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................79 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................79 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................79 
11.4.2.3 Multiplicity considerations ..............................................................................................................79 
11.4.3 
Analyses of safety data..................................................................................................................79 
11.4.3.1 Adverse events ..............................................................................................................................79 
11.4.3.2 Treatment-emergent adverse events.............................................................................................80 
11.4.3.3 Deaths............................................................................................................................................80 
11.4.3.4 Other safety variables ....................................................................................................................81 
11.4.3.5 Immunogenicity..............................................................................................................................81 
11.4.4 
Analyses of pharmacokinetic variables..........................................................................................82 
11.4.5 
Analyses of pharmacodynamic variables.......................................................................................82 
11.5 
INTERIM ANALYSIS......................................................................................................................83 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................84 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................84 
12.2 
INFORMED CONSENT .................................................................................................................84 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................85 
13 
STUDY MONITORING...................................................................................................................86 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................86 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................86 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................86 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST .............87 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................87 
14 
ADDITIONAL REQUIREMENTS...................................................................................................88 
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14.1 
CURRICULUM VITAE....................................................................................................................88 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................88 
14.3 
CONFIDENTIALITY .......................................................................................................................88 
14.4 
PROPERTY RIGHTS.....................................................................................................................89 
14.5 
DATA PROTECTION.....................................................................................................................89 
14.6 
INSURANCE COMPENSATION....................................................................................................89 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................90 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................90 
14.8.1 
By the Sponsor...............................................................................................................................90 
14.8.2 
By the Investigator .........................................................................................................................91 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................91 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................91 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................92 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................93 
APPENDICES ...............................................................................................................................................95 
APPENDIX A 
MODIFICATION OF DIET IN RENAL DISEASE FORMULA ..............................................96 
APPENDIX B 
EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS 
SCALE ...........................................................................................................................................97 
APPENDIX C NATIONAL COMPREHENSIVE CANCER NETWORK GUIDELINES ...............................98 
APPENDIX D NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS.....................................................................................................................100 
APPENDIX E 
TYPES OF INFUSION ASSOCIATED REACTIONS AND TYPICALLY 
ASSOCIATED SYMPTOMS ........................................................................................................101 
APPENDIX F CD38 BLOOD TEST INTERFERENCE GUIDELINE ........................................................103 
 
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2.1 
LIST OF TABLES 
Table 1 - Bioanalytical method for isatuximab immune response assessment ............................................56 
Table 2 - Bioanalytical method for isatuximab pharmacokinetic analysis.....................................................57 
Table 3 - List of isatuximab pharmacokinetic parameters and definitions calculated by non-compartmental 
analysis after the first cycle of treatment.......................................................................................................58 
Table 4 - Bioanalytical methods for cytokine analysis...................................................................................59 
Table 5 - Bioanalytical methods for markers of activated complement and serum tryptase.........................59 
Table 6 - Summary of handling procedures for pharmacogenetic samples..................................................61 
Table 7 - Management of infusion associated reaction.................................................................................75 
Table 8 - Management of tumor lysis syndrome ...........................................................................................76 
 
2.2 
LIST OF FIGURES 
Figure 1 - Isatuximab activity in T-ALL cell lines ...........................................................................................35 
Figure 2 - Disseminated T-ALL xenograft model of survival (isatuximab versus control vehicle).................35 
Figure 3 - Disseminated syngeneic model of survival (isatuximab versus control vehicle) ..........................36 
Figure 4 - CD38 positivity and receptor density in T-ALL patients above or below 16 years of age ............37 
 
 
 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
antidrug antibody 
ADCC: 
antibody-dependent cellular cytotoxicity 
ADCP: 
antibody-dependent cellular phagocytosis 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALL: 
acute lymphoblastic leukemia 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AUC: 
area under the plasma concentration versus time curve 
AUClast: 
area under the plasma concentration versus time curve calculated using the 
trapezoidal method from time 0 to the time of last concentration observed above 
the lower limit of quantification 
AUCWeek1: 
area under the plasma concentration versus time curve calculated using the 
trapezoidal method over the first week of treatment 
C: 
cycle 
CDC: 
complement-dependent cytotoxicity 
Ceoi: 
concentration at the end of an intravenous infusion 
Clast: 
last concentration observed above the lower limit of quantification 
Cmax: 
maximum plasma concentration observed 
CNS: 
central nervous system 
CR: 
complete response 
CRi: 
incomplete peripheral recovery 
Ctrough: 
plasma trough concentration 
D: 
day 
DOR: 
duration of response 
ECG: 
electrocardiogram 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic Case Report Form 
ELISA: 
enzyme-linked immunosorbent assay 
EOT: 
end of treatment 
GCP: 
good clinical practice 
IAR: 
infusion associated reaction 
ICH: 
International Council for Harmonisation 
IEC: 
independent ethics committee 
IFNγ: 
interferon gamma 
IL: 
interleukin 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IV: 
intravenous 
LBL: 
lymphoblastic lymphoma 
mAb: 
monoclonal antibody 
MedDRA: 
Medical Dictionary for Regulatory Activities 
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MRD: 
minimal residual disease 
NCCN: 
National Comprehensive Cancer Network 
NCI-CTCAE: 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NIMP: 
noninvestigational medicinal products 
NK: 
natural killer 
ORR: 
overall response rate 
OS: 
overall survival 
 
 
PCSA: 
potentially clinically significant abnormality 
PDy: 
pharmacodynamics 
PFS: 
progression free survival 
PK: 
pharmacokinetic 
PO: 
orally 
PS: 
performance status 
PT: 
preferred term 
Q2W: 
once every 2 weeks 
QW: 
once every week 
RD: 
receptor density 
RO: 
receptor occupancy 
SAE: 
serious adverse event 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
TLS: 
tumor lysis syndrome 
tmax: 
time to reach Cmax 
TNFα: 
tumor necrosis factor alpha 
ULN: 
upper limit of normal 
WOCBP: 
woman of childbearing potential 
 
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4 
INTRODUCTION AND RATIONALE 
CD38 is a type II glycosylated 45 kilodalton membrane protein that was identified as a 
lymphocyte marker (1). CD38 has a role in leukocyte homeostasis through modulation of 
hematopoietic cell survival and differentiation (2). CD38 functions as a receptor binding to CD31 
and is involved in cell adhesion and signal transduction. The function of CD38 in signal 
transduction appears to be versatile depending on the cell lineage, the differentiation stage, and, 
possibly, the association with different coreceptors (2). CD38 is also an ectoenzyme catalyzing 
the synthesis and hydrolysis of cyclic adenosine-diphosphate-ribose from nicotinamide adenine 
dinucleotide to adenosine diphosphate-ribose (3). These reaction products are implicated in 
calcium mobilization and intracellular signaling. 
The expression of CD38 in healthy humans can be detected on natural killer (NK) cells, 
monocytes, dendritic cells, macrophages, granulocytes, activated T and B cells, and plasma cells. 
In contrast, expression has not been detected in hematopoietic stem cells, resting T and B cells, or 
tissue macrophages. Several hematological malignancies express CD38 including those of B cell, 
T cell and myeloid origin. Moreover, CD38 was identified as a negative prognostic marker in 
some hematological malignancies, such as chronic lymphocytic leukemia. 
In acute lymphoblastic leukemia (ALL), limited and conflicting data are available. One study 
showed that an increased CD38 expression was associated with favorable prognosis in newly 
diagnosed adult ALL (4). In adult patients with ALL (N=134), CD38 expression was associated 
with higher complete response (CR) duration (p=0.0220) but the difference in overall survival 
(OS) was not statistically different (p=0.12). The difference may have been accounted for by the 
significant association of low CD38 expression and the Philadelphia chromosome-positive 
subtype of ALL. Another study (5), concluded that CD38 expression was not related to any 
clinical or biological feature and that event-free survival did not differ significantly between 
CD38+ and CD38- cases of childhood ALL (N=325). 
4.1 
ACUTE LYMPHOBLASTIC LEUKEMIA 
Acute lymphoblastic leukemia is a heterogeneous hematological disease characterized by the 
proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. 
The incidence rate of ALL in the United States is 1.77 per 100 000 individuals per year, with 
approximately 6250 new cases and 1450 deaths estimated in 2015 (6).  
The risk for developing ALL is highest in children younger than 5 years of age. The risk then 
declines slowly until the mid-20s, and begins to rise again slowly after age 40, with a peak of 
incidence around 50 years. The median age at diagnosis is 14 years with 58.8% of patients 
diagnosed at younger than 20 years of age. In contrast, 25.5% of cases are diagnosed at 45 years 
or older and only approximately 11% of patients are diagnosed at 65 years or older. Acute 
lymphoblastic leukemia represents 75% to 80% of acute leukemias among children, but only 
approximately 20% of all leukemias among adults. 
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There are 2 main ALL subtypes, B-cell ALL and T-cell ALL (T-ALL): T-ALL accounts for  
15% of pediatric cases and 20% of adults cases.  
Lymphoblastic lymphoma (LBL) is in the same disease entity as ALL. The term LBL has been 
used to describe predominantly lymph node–based disease; however, clinical distinction between 
LBL and ALL has been arbitrary and has varied among different studies and institutions. 
Lymphoblastic lymphoma is relatively rare, comprising only 2% of all non-Hodgkin lymphomas. 
The diagnosis of ALL generally requires demonstration of 20% or greater bone marrow 
lymphoblasts on bone marrow aspirates and biopsy materials. The 2008 World Health 
Organization classification lists ALL and LBL as the same entity, distinguished only by the 
primary location of the disease (7, 8). When the disease is restricted to a mass lesion primarily 
involving nodal or extranodal sites with no or minimal involvement in blood or bone marrow 
(generally defined as <20% lymphoblasts in the marrow), the case would be consistent with a 
diagnosis of LBL.  
The cure rates and survival outcomes for patients with ALL have improved over the past decades, 
primarily among children. Adults have the poorest 5-year OS rate of 24.1% for patients between 
the ages of 40 and 59 years and an even lower rate of 17.7% for patients between the ages of 
60 and 69 years. 
Adult patients with ALL who relapse after initial therapy have extremely poor long-term 
outcomes. The median OS after relapse is only 4.5 to 6 months; the 5-year OS rate is 7% to 10% 
(8, 9). Approximately 20% to 30% of patients experience a second CR with second-line therapies 
(10). Treatment of adult patients with relapsed and/or refractory ALL remains a challenge.  
Clofarabine, a nucleoside analog, has shown to be active in combination with other chemotherapy 
regimens in adults with relapsed/refractory disease, with a CR rate ranging from 44% to 73%, 
median OS of 6.5 to 7.7 months (11, 12). The most common Grade 3 and 4 toxicities included 
infection (58%) and liver toxicities (24%). 
Nelarabine is a nucleoside analog that is currently approved in many European countries and the 
United States for the treatment of patients with T ALL who have not experienced either a disease 
response or who have relapsed disease after at least 2 chemotherapy regimens (13). In a Phase 2 
study in 39 adult patients, the CR rate was 31%. Median disease-free survival and OS were both 
20 weeks and the 1-year OS rate was 28% (14). Grade 3 and 4 myelosuppression was common. 
Since Nelarabine approval (more than 10 years ago), no other drug has been approved in relapsed 
or refractory T-ALL, making this indication a real unmet medical need. 
4.2 
DESCRIPTION OF ISATUXIMAB 
Isatuximab (SAR650984) is a chimeric IgG1 monoclonal antibody (mAb) directed against CD38 
that was derived from mu38SB19, a murine anti-CD38 antibody, raised by immunizing mice with 
a murine pre-B cell over-expressing cell surface human CD38. The humanized version displays 
the same affinity for CD38 as the murine version with isatuximab selectively binding to human 
CD38 with an affinity of 2 x 10-10 M. 
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4.3 
PHARMACOLOGY 
Isatuximab targets CD38, an antigen expressed in hematological malignancies and represents a 
new treatment entity displaying 3 key biological properties of tumor cell lysis in vitro: 
antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) 
and induction of apoptosis. Isatuximab also demonstrated in vivo antitumor activity as a single 
agent and in combination with reference treatments in several CD38+ tumor models. In addition, 
isatuximab demonstrated antitumor activity against primary patient-derived tumor cells ex vivo 
without significant cytokine release, cellular activation, or depletion in vitro assays with normal 
human peripheral blood mononuclear cells supporting its clinical evaluation in  
CD38+ hematological malignancies. 
4.3.1 Toxicology 
Isatuximab is specific for human CD38 protein. In the absence of a relevant animal species for 
toxicity testing with isatuximab, no single or repeated dose toxicity studies were performed. No 
studies have been performed to evaluate genotoxicity, as this drug is a mAb with no potential to 
interact with cellular DNA. No carcinogenicity studies will be conducted, as this drug is a 
therapeutic mAb being developed for oncology indications. There is no evidence or scientific 
rationale indicating a potential risk for tumorigenicity. Reproductive toxicology studies have not 
yet been performed. 
For more information please refer to the product Investigator’s Brochure. 
4.3.2 Metabolism and pharmacokinetic profile in animals 
Not applicable. 
4.4 
BACKGROUND INFORMATION ON CD38 IN ACUTE LYMPHOBLASTIC LEUKEMIA 
4.4.1 Preclinical data 
4.4.1.1 Isatuximab activity in ALL cell lines and patient-derived ALL cells 
The different mechanisms by which isatuximab can trigger destruction of a CD38 expressing 
tumor cell were evaluated on a panel of T-ALL cell lines (N=16).  
The pro-apoptotic activity of isatuximab was tested in 11 cell lines and the CDC activity of 
isatuximab was tested in 13 cell lines. Only the cell line with the highest receptor density (RD; 
DND-1) was sensitive to these 2 mechanisms. 
A total of 10 and 16 cell lines were tested for antibody-dependent cellular phagocytosis (ADCP) 
and ADCC, respectively. Most cell lines are killed by isatuximab in the presence of effector NK 
cells and macrophages; 9 of 10 T-ALL cell lines were sensitive to ADCP. Twelve of 16 T-ALL 
cell lines were ADCC-sensitive (Figure 1). 
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Figure 1 - Isatuximab activity in T-ALL cell lines 
 
ADCC: antibody-dependent cellular cytotoxicity; ADCP: antibody-dependent cellular phagocytosis; CDC: 
complement-dependent cytotoxicity. 
4.4.1.2 Isatuximab in vivo activity in xenograft mouse models 
Isatuximab was evaluated in a disseminated T-ALL xenograft model, where 2 million 
CCRF-CEM cells were implanted via intravenous (IV) injection into severe combined 
immunodeficiency mice and isatuximab was dosed at 40 mg/kg every 3 days for 3 weeks. The 
median survival increased from 47 days in the control group to 98 days in the treatment group. 
Two animals survived until the end of the study, 147 days postimplantation (Figure 2). 
Figure 2 - Disseminated T-ALL xenograft model of survival (isatuximab versus control vehicle) 
 
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Isatuximab was also evaluated in a disseminated syngeneic model, where 0.5 million of EL4 
murine T cell lymphoma cells engineered to express approximately 100 000 human 
CD38 molecules/cell were implanted via IV injection into immunocompetent C57Bl/6 mice and 
isatuximab was dosed at 10 mg/kg and 20 mg/kg every 3 days for 2 weeks. Median survival in the 
control group was 39 days. In the low dose group, 5 of 10 animals survived until the end of the 
study (Day [D] 70), and in the 20 mg/kg group, 9 of 10 animals were alive at D70 (Figure 3). 
Figure 3 - Disseminated syngeneic model of survival (isatuximab versus control vehicle) 
 
4.4.2 Clinical data 
4.4.2.1 CD38 expression in T-ALL 
A total of 50 samples from the bone marrow (n=44) or peripheral blood (n=6) of patients with 
T-ALL with a median age of 12.5 years (1.5 to 53 years) were tested for CD38 expression by flow 
cytometry (internal data). The percentage of T cell lymphoblasts in the white blood cells from 
these patients varied from 1.1% to 91% (median value of 13.1%). 
The percentage of CD38 expressing cells within the abnormal T cell populations ranged from 
2.9% to 100% (median value of 92.9%). The estimated CD38 RD for the 50 samples varied 
between 0 and 290 000 molecules/cell, with a median value of 41 000 molecules/cell, similar to 
that in a panel of T-ALL cell lines (N=16), with a median CD38 RD of 46 000 CD38 
molecules/cell (0 to 212 000 molecules/cell). The percentage of CD38 positivity and RD was not 
significantly different in patients above or below 16 years of age (Figure 4).  
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Figure 4 - CD38 positivity and receptor density in T-ALL patients above or below 16 years of age 
 
ALL: acute lymphoblastic leukemia; RD: receptor density; y: years. 
4.4.2.2 Isatuximab clinical data 
Please refer to the current Investigator’s Brochure of isatuximab for details on the clinical 
experience to date. 
As of 05 January 2016, 263 patients have been treated with isatuximab in 5 clinical studies. No 
patients with T-ALL have been treated with isatuximab in ongoing studies at the data lock point.  
In the 186 patients who received isatuximab as single agent in the TED10893 study, isatuximab 
appeared to be well tolerated at all dose levels tested. At doses ≥10 mg/kg, preliminary data show 
no difference in terms of type, incidence and severity of treatment-emergent adverse events 
(TEAEs). The most common TEAEs (in ≥20% of patients) consisted of infusion related reaction 
(49.4%), fatigue (37.1%), nausea (32.6%), anemia (28.1%), cough (22.5%), upper respiratory tract 
infection (22.5%), back pain (20.2%), and diarrhea (20.2%). Infusion associated reactions (IARs) 
occurred in approximately half of all patients. Symptoms of IARs were of Grade ≥3 severity in 
13 (7.0%) patients and 4 (2.2%) patients discontinued treatment due to Grade 3 or 4 IARs. Ninety 
percent of the IARs occurred upon the first administration of isatuximab. Eight (4.3%) patients 
had an IAR during their second or subsequent infusions. All IARs resolved with or without 
treatment. 
Of the 97 patients enrolled in the Phase 2 part, at the highest dose levels of 10 and 20 mg/kg, the 
most common non-hematological TEAEs were nausea (36.5%), cough and fatigue (33.8% each), 
diarrhea (27%), and dyspnea (25.7%). 
Preliminary efficacy data of the Phase 2 part of TED10893 showed a dose response effect 
between the 3 mg/kg once every 2 weeks (Q2W) dose (overall response rate [ORR] <10%) and 
the doses ≥10 mg/kg (ORR ≥20% in all arms: 10 mg/kg Q2W, 10 mg/kg Q2W then every 4 weeks 
and 20 mg/kg once every week [QW] followed by Q2W). At doses of 10 mg/kg and 20 mg/kg, the 
response rate ranged from 20% to 29%, without a clear dose response between the 10 mg/kg and 
20 mg/kg arms. For the patients enrolled in the 10 mg/kg arms, the median duration of response 
(DOR) was 9.2 to 12.9 months (6/12 responder patients had progressive disease). For patients in 
the  
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20 mg/kg group, DOR data is still maturing and at time of the analysis, median duration of 
response was >8 months (4/6 responders patients had progressive disease) (15). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5 
RATIONALE 
4.5.1 Study design rationale 
4.5.1.1 Dose selection rationale in multiple myeloma 
Clinical data from the TED10893 trial did not show an obvious difference between 10 and 
20 mg/kg isatuximab. A preliminary PK/PDy analysis to evaluate the relationship between ORR 
and PK parameters was performed using a generalized additive model with pooled Phase 1 and 
Phase 2 data from the TED10893 study. This analysis showed that plasma trough concentration 
(Ctrough) at Week 4 was a significant predictor of ORR. The probability of response to treatment 
increases as Ctrough at Week 4 increases up to a plateau. This plateau was reached for Ctrough at 
Week 4 following a weekly administration at 20 mg/kg, indicating that frequent administration 
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together with a high dose in the first cycle is needed to optimize the response (4 once weekly 
administrations at 20 mg/kg).  
In addition, modeling and simulations of exposure-response to isatuximab, based on the M-protein 
concentration-time profile, showed a higher response to treatment in terms of reduction in 
myeloma-protein at 8 or 12 weeks following 20 mg/kg QW for 4 weeks followed by 20 mg/kg 
Q2W compared to lower doses (ie, 10 mg/kg QW for 4 weeks followed by 10 mg/kg Q2W).  
Therefore, based on safety, efficacy and PK/PDy modeling and simulation, the selected dose and 
schedule of administrations of isatuximab as a single agent for multiple myeloma patients is 
20 mg/kg QW for 1 cycle, followed by 20 mg/kg Q2W for subsequent cycles 
4.5.1.2 Acute Lymphoblastic Leukemia 
Despite improvements in the achievement of CR and progress in the supportive care of adults 
with ALL during the last decade, the majority of patients will relapse. The recent approach of 
adapting therapy according to biological features appears to be resulting in significant progress. 
Thus, studies of targeted therapy like isatuximab in T-ALL would be highly attractive, because of 
the potential efficacy and with an acceptable safety profile and a population with an unmet 
medical need. This Phase 2, single arm study of isatuximab will explore the efficacy and safety of 
single agent isatuximab in patients with relapsed/refractory T-ALL or T-LBL. 
The treatment period will consist of an induction period followed by a maintenance period. The 
induction treatment will consist of 4 QW administrations of isatuximab. A second induction cycle 
will be permitted under certain conditions (see Section 6.1). The maintenance period will consist 
of administration of isatuximab at the same dose as for the induction period, with a Q2W 
schedule. Patients will be allowed to continue maintenance therapy until disease progression, an 
unacceptable adverse event (AE), consent withdrawal or Investigator’s decision.  
The dose of isatuximab in this study will be 20 mg/kg, following results in Phase 1 and 2 studies 
in multiple myeloma (see Section 4.5.1.1). An interim analysis will be performed when all 
patients in Stage 1 (19 treated patients) have completed either 2 induction cycles plus D1 of the 
first maintenance cycle or 1 induction cycle plus 1 maintenance cycle. 
Although 80% to 95% of adult patients with ALL achieve complete clinical remission with 
current treatment protocols, a significant proportion of them ultimately relapse. Relapses are 
caused by residual malignant cells that are undetectable by standard diagnostic techniques. With 
the development of sensitive molecular and flow cytometric techniques for the quantitative 
detection of residual leukemic cells, the presence of minimal residual disease (MRD) in patients 
in complete clinical remission has clearly been demonstrated. Several studies have shown that 
detection of MRD in adult ALL is an independent risk parameter of high clinical relevance, both 
in de novo and relapsed ALL. 
The risk-benefit balance inherent to the therapy with isatuximab has been carefully considered in 
the planning of this study. The design of the study and the dosage regimen of the study treatment 
are considered justified on the basis of the nonclinical and clinical isatuximab experience 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to evaluate the efficacy of isatuximab in patients with 
relapsed or refractory T-ALL or T-LBL as measured by ORR (as per National Comprehensive 
Cancer Network [NCCN] guidelines; Appendix C). 
5.2 
SECONDARY 
• 
To evaluate the safety profile of isatuximab. 
• 
To evaluate the duration of response (DOR). 
• 
To evaluate progression free survival (PFS) and OS. 
• 
To evaluate the PK of isatuximab in patients with T-ALL or T-LBL. 
• 
To evaluate immunogenicity of isatuximab in patients with T-ALL or T-LBL. 
• 
To assess MRD and correlate it with clinical outcome. 
5.3 
EXPLORATORY 
• 
To explore the relationship between CD38 expression and clinical response. 
• 
To explore the relationship between CD38 receptor occupancy (RO) and CD38 RD on 
blast cells (peripheral blood and bone marrow) and clinical response. 
• 
To explore the relationship between acute leukemia tumor molecular alterations and 
clinical response. 
• 
To explore the relationship of soluble CD38, the PK of isatuximab and clinical response. 
• 
To explore the relationship between immune genetic determinants, immune phenotypes 
and clinical response. 
• 
To explore PK/PDy relationships. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
This is a Phase 2, single arm, multicenter, multinational, open label study evaluating the efficacy 
and safety of isatuximab in patients with relapsed or refractory T-ALL/T-LBL. 
The study will be conducted in 2 stages. Approximately 39 evaluable patients previously treated 
for T-ALL/T-LBL will be enrolled in the study across approximately 15 to 20 sites globally. A 
Simon’s 2-stage optimum design will be used.  
• 
Stage 1: an interim analysis of efficacy, safety and PK will be performed on the first 
19 treated patients. The study will proceed to Stage 2 if >3/19 responses are observed in 
Stage 1. 
• 
Stage 2: 20 additional patients will be treated if the number of responses required to 
proceed to Stage 2 is reached at the interim analysis of Stage 1. 
The dose of isatuximab is 20 mg/kg. The cycle duration is 28 days. 
During the induction period, isatuximab will be administered by IV infusion, QW for 4 weeks 
(1 induction cycle = 4 QW doses). If at D15-22 of the first induction cycle, bone marrow blast 
cells remain >5%, a second induction cycle will be administered. If bone marrow blast cells are 
≤5%, the administration of a second induction cycle will be performed at the discretion of the 
Investigator.  
After a maximum of 2 cycles of induction therapy, patients will be withdrawn from the study 
treatment if they do not achieve an objective response, or, in case of disease progression, an 
unacceptable AE, consent withdrawal or Investigator’s decision (eg, patient is candidate for 
transplantation). 
During maintenance, in patients achieving an objective response following the induction period, 
isatuximab will be given Q2W. Patients will be allowed to continue maintenance therapy until 
disease progression, an unacceptable AE, consent withdrawal or Investigator’s decision 
(eg, patient is a candidate for transplantation). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of the study for an individual patient will include: 
• 
The screening period of up to 3 weeks prior to the first study treatment administration. 
• 
The treatment period (in each period, the cycle duration is 28 days): 
- 
Induction period = QW dosing for 4 or 8 weeks, 
- 
Maintenance period = Q2W dosing. 
• 
An end of treatment (EOT) visit 30 days after the last study treatment administration. 
• 
Follow-up period. 
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Patients with documented disease progression at the EOT visit will be followed every 2 months 
until death or final analysis cutoff date, whichever comes first. 
Patients without documented disease progression at the EOT visit and who have not yet started 
treatment with another anticancer therapy will perform follow-up visits every month until 
initiation of another anticancer therapy, disease progression, death or final analysis cutoff date, 
whichever comes first. Then, after disease progression, or after initiation of further anticancer 
therapy for patients without disease progression, patients will be followed every 2 months until 
death or final analysis cutoff date, whichever comes first.  
6.2.2 Determination of end of clinical trial (all patients) 
The cutoff date for primary analysis of ORR and other secondary endpoints will be 6 months after 
the last patient has had his/her first study treatment administration. Then, the final analysis cutoff 
date for analysis of OS and updated analyses of ORR and other secondary endpoints will be 
12 months after the last patient has had his/her first study treatment administration. Patients still 
on treatment at time of the final analysis cutoff date and who still continue to benefit from 
treatment with isatuximab will have the option to continue treatment under this protocol. 
6.3 
RETREATMENT OF PATIENTS 
In case of AEs, the patient must have improved to Grade ≤1 or to his/her baseline status before 
being considered for the next administration of isatuximab. Patients can continue the study 
treatment until disease progression, an unacceptable AE, consent withdrawal or Investigator’s 
decision (eg, patient is a candidate for transplantation). 
6.4 
DOSE DELAYS/DOSE MODIFICATIONS 
No dose reduction is authorized for isatuximab in an individual patient.  
Cycle delay up to 14 days is allowed. If administration within 14 days following the planned date 
is not possible, the patient will discontinue the study treatment unless in case of clinical benefit 
and in agreement with the Sponsor. 
Within a cycle (induction or maintenance), an isatuximab administration can be delayed for up to 
3 days. 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. 
If a patient experiences several AEs and there are conflicting recommendations, the most 
conservative dose adjustment recommended (dose delay/omission appropriate to the most severe 
AE) should be followed.  
6.5 
INTERIM ANALYSIS 
Interim analysis is described in Section 11.5. 
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6.6 
STUDY COMMITTEE 
The Study Committee will be comprised of the Coordinating Investigator, at least 2 additional 
study investigators and Sponsor representatives. Regular meetings will be organized as 
appropriate throughout the study. They will be responsible for: 
• 
Reviewing the conduct of the study. 
• 
Reviewing the efficacy and safety results from the Stage 1 analysis. 
• 
Reviewing the overall efficacy and safety data at the end of the study. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients must have a known diagnosis of ALL of T cell origin, including T-LBL and 
T-ALL with isolated extramedullary involvement at relapse confirmed by biopsy. 
I 02. Patients must be previously treated for T-ALL or T-LBL and have relapsed or are 
refractory to most recent treatment (see Appendix C). Patients in first relapse will be 
eligible regardless of the first remission duration. 
I 03. Patients must have been previously exposed to nelarabine in countries where this drug is 
available (unless due to a contraindication to its use or administrative issue). 
I 04. No more than 3 prior salvage therapies. 
I 05. Signed written informed consent. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 2 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <16 years. 
E 02. Patients must have been off prior treatment with immunotherapy/investigational agents for 
>3 weeks 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 treatment administration. Treatment may start earlier if necessitated 
by the patient's medical condition (eg, rapidly progressive disease) following discussion 
with the Sponsor. 
E 03. Prior stem cell transplant within 4 months and/or evidence of active systemic Graft versus 
Host Disease and/or immunosuppressive therapy for Graft versus Host Disease within 
1 week before the first study treatment administration. 
E 04. Clinical evidence of active central nervous system (CNS) leukemia. Lumbar puncture 
should be negative before C1D1. In case of positivity for blast cells before or during the 
screening period, local treatment is allowed. Confirmed negativity of the lumbar puncture 
is mandatory within 3 days before the first administration of isatuximab (C1D1). 
Otherwise, the patient will be considered as non-eligible for the study. 
E 05. T-ALL with testicular involvement alone. 
E 06. Evidence of ongoing infection. 
E 07. Second malignancy other than basal cell or squamous cell carcinoma of the skin or in situ 
carcinoma of the cervix or the breast, unless they are successfully treated with curative 
intent for more than 3 years before entering the study. 
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E 08. Poor condition/organ functions as defined by 1 of the following:  
- 
Eastern Cooperative Oncology Group (ECOG) performance status (PS) >2  
(Appendix B). 
- 
Total bilirubin >1.5 x upper limit of normal (ULN) unless Gilbert’s syndrome. 
- 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline 
phosphatase >2.5 x ULN, unless considered due to the disease. 
- 
Serum creatinine >2 x ULN and/or creatinine clearance <30 mL/min (Modification of 
Diet in Renal Disease formula; Appendix A). 
E 09. Radiation therapy within 14 days prior to study treatment administration (this delay could 
be reduced if necessitated by patient’s medical condition following discussion with 
Sponsor). 
E 10. Any serious active disease or comorbid condition which, in the opinion of the Investigator, 
may interfere with the safety of the study treatment or the compliance with the study 
protocol. 
E 11. Any other severe underlying medical or administrative conditions, which could impair the 
ability to participate in the study or the interpretation of its results. 
E 12. Patient is the Investigator, Subinvestigator, research assistant, Pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
E 13. Any technical/administrative reason (eg, patient homeless) that makes study participation 
impossible. 
E 14. Patient who has previously participated/Patient who has previously been treated in any 
clinical study with isatuximab or with a same class compound. 
E 15. Conditions/situations such as: Patient not suitable for participation, whatever the reason, as 
judged by the Investigator, or patients potentially at risk of noncompliance to study 
procedures. 
7.2.2 Exclusion criteria related to the current knowledge of Sanofi compound  
 
E 17. Known human immunodeficiency virus positivity. 
E 18. Active hepatitis B virus (hepatitis B surface antigen, hepatitis B envelope antigen and viral 
DNA positive, with absence of antihepatitis B envelope antibody) or hepatitis C virus 
infection (presence of circulating antihepatitis C virus antibodies); nonactive disease that 
may flare up following the treatment (carriers for hepatitis B surface antigen with presence 
of hepatitis B core antibodies). 
E 19. Pregnant and breastfeeding women, female patients of childbearing potential (WOCBP) 
and male patients with female partners of childbearing potential who are not willing to 
avoid pregnancy by using an adequate method of contraception (2 barrier method or 
1 barrier method with a spermicide, intrauterine device, or hormonal contraception with 
inhibition of ovulation for 2 weeks prior to the first dose of isatuximab, during treatment 
and 12 weeks after the last dose of study treatment). See Section 8.8.3. A woman is 
considered of childbearing potential, ie, fertile, following menarche and until becoming 
postmenopausal unless permanently sterile. 
E 20. Any country-related specific regulation that would prevent the subject from entering the 
study. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Isatuximab (SAR650984) is the only investigational medicinal product (IMP) in this study. 
8.1.1 Pharmaceutical form 
The drug product (isatuximab, SAR650984) is presented as a concentrate for solution for infusion 
in vials containing 20 mg/mL (500 mg/25 mL) isatuximab 
 
. 
It is supplied for parenteral administration as a sterile, nonpyrogenic, injectable, colorless, 
20 mg/mL concentrate for solution for infusion that may contain white to off-white particulates 
and is packaged in 30 mL glass vials fitted with elastomeric closure. Each vial contains a nominal 
content of 500 mg of isatuximab 
. The fill volume has been established to ensure removal of 
25 mL. 
 
For administration to patients, the appropriate volume of isatuximab will be diluted in an infusion 
bag of 0.9% sodium chloride solution. The final infusion volume corresponding to the dose of 
isatuximab will be administered for a period of time that will depend on dose administered and 
will be based on protein amount given per hour. 
8.1.2 Dose of drug per administration 
The dose of isatuximab is 20 mg/kg. 
The patient’s weight should be measured prior to each treatment administration to allow 
calculation of the dose. 
Induction period: isatuximab will be administered by IV infusion QW for 4 weeks (1 induction 
cycle = 4 QW doses). If at D15-22 of the first induction cycle, bone marrow blast cells remain 
>5%, a second induction cycle will be administered. If bone marrow blast cells are ≤5%, the 
administration of a second induction cycle will be performed at the discretion of the Investigator. 
Maintenance period: In patients achieving an objective response following the induction period, 
isatuximab will be given Q2W, see Section 6.1.  
The rate of infusion should be initiated at 175 mg/hour. 
In the absence of IARs after 1 hour of the first infusion, the infusion rate should be increased by 
50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.  
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For subsequent infusions: the infusion should be initiated at 175 mg/hour. In the absence of IARs 
after 1 hour of infusion, the infusion rate should be increased by 100 mg/hour increments every 
30 minutes, to a maximum of 400 mg/hour. 
In case of infusion interruption due to IAR, the infusion can be restarted after the IAR improves to 
Grade ≤1. The infusion rate should be one half of the original infusion rate. If symptoms do not 
recur after 30 minutes, the infusion rate may be increased by 50 mg/hour increments every 
30 minutes, to a maximum of 400 mg/hour. 
Examples of IARs and typically associated symptoms are presented in Appendix E. Instructions 
for the management of IARs are presented in Section 10.6.1. 
8.1.3 Dilution method 
The isatuximab concentrate for solution for infusion will be diluted in an infusion bag with 0.9% 
sodium chloride solution to achieve the appropriate drug concentration for infusion. 
Infusion via a central line is preferred if available. Patients with local intolerance after peripheral 
IV infusion should receive next dose(s) using a central line. The final infusion volume 
corresponding to the dose of isatuximab will be administered by IV infusion for the period of time 
that will depend on dose administered and on the protein amount administered per hour 
(Section 8.1.2). 
Prior to dosing, each patient’s dose will be individually prepared by the study Pharmacist and 
labeled with protocol number, patient number, and treatment description. 
A 0.2 µm in-line filter is required for administration. 
Therefore, for IV infusion, an IV tubing administration set with a 0.20-micron in-line filter will be 
used; if an in-line filter is unavailable, a 0.2 µm filter unit may be attached to the administration 
set before administration. 
Detailed instruction for dilution of the isatuximab concentrate for solution for infusion is provided 
in the Pharmacy Manual. 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS 
Premedication (noninvestigational medicinal products [NIMP]) must be given to patients to 
prevent IARs. A graphical representation of study treatment is provided in Section 1.1.1. 
Prior to the first isatuximab infusion:  
Dexamethasone 20 mg (IV or orally [PO]) administration at first infusion: as the risk of IARs to 
isatuximab is typically higher at the first infusion, dexamethasone will be administered 3 times 
before (once per day on D-2, D-1 and D1), and twice after (once per day on D2 and D3) the first 
study treatment administration. 
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Prior to each isatuximab infusion: 
All patients will receive the following premedication for prevention of IARs at least 15 to 
30 minutes (but no longer than 60 minutes) prior to each isatuximab infusion: 
• 
Acetaminophen 650-1000 mg PO.  
• 
Ranitidine 50 mg IV (or equivalent). 
• 
Diphenhydramine 25-50 mg IV (or equivalent).  
• 
Dexamethasone 20 mg (IV or PO). 
On the day of isatuximab administration, dexamethasone will be administered only once per use 
of premedication/backbone therapy, whatever the route of administration (IV or PO). 
When dexamethasone is administered PO, the following order is recommended: dexamethasone, 
acetaminophen, ranitidine and diphenhydramine. 
When dexamethasone is administered IV, the following order is recommended: acetaminophen, 
ranitidine, diphenhydramine and dexamethasone.  
8.3 
BLINDING PROCEDURES 
Not applicable as this is an open label and single arm study of isatuximab monotherapy. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
This is an open label, single arm, non-randomized study.  
Patients who meet all the inclusion criteria, and none of the exclusion criteria, will be enrolled in 
the study. Each patient will be enrolled and receive an incremental identification number per site 
corresponding to the chronological order of inclusion.  
Only screen failure patients will be replaced. 
8.5 
PACKAGING AND LABELING 
The IMP is packaged in 30 mL glass vials fitted with elastomeric closure. See Section 8.1.1 for 
further details. 
The content of the labeling is in accordance with the local regulatory specifications and 
requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing the IMP in 
a secure and safe place with restricted access in accordance with local regulations, labeling 
specifications, policies, and procedures.  
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Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the sanofi compound should be 
managed according to the rules provided by the Sponsor. 
The IMP is to be stored at +2°C to +8°C (36°F to 46°F). All vials must be kept in their box until 
use. 
No protection from light is required for storage in the infusion bags. 
Details of the storage conditions for the diluted solution are provided in the Pharmacy Manual. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital Pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical study is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances the Investigator will supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical study protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
Administration of the IMP will be supervised by the Investigator or Subinvestigator. 
The person responsible for drug dispensing is required to maintain adequate records of the IMP. 
These records (eg, drug movement form) include the date the IMP is received from the Sponsor, 
dispensed for patient and destroyed or returned to the Sponsor. The packaging batch number on 
the vial must be recorded on the drug accountability form. 
The person responsible for study treatment administration to the patient will record precisely the 
date and the time of the study treatment administration to the patient. 
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8.7.2 Return and/or destruction of treatments 
Partially used and used vials of isatuximab will be destroyed at the study site according to the 
standard practices of the site after an accurate accountability has been performed and signed by 
the Investigator (or the Pharmacist). A detailed treatment log form of the destroyed IMP will be 
established with the Investigator (or the Pharmacist) and countersigned by the Investigator and the 
Monitoring Team. 
The Investigator will not destroy the unused IMP unless the Sponsor provides written 
authorization. 
8.8 
CONCOMITANT MEDICATION 
8.8.1 Permitted concomitant therapy 
All treatments being taken by the patient for up to 7 days prior to the first dose of IMP, and at any 
time during the treatment period and for up to 30 days after the last dose are regarded as prior and 
concomitant treatments, respectively, and will be reported on the appropriate pages of the 
electronic Case Report Form (eCRF). 
The type, dose and route of administration must be documented on the appropriate pages of the 
eCRF. 
Concomitant medications should be kept to a minimum during the study. However, if these are 
considered necessary for the patient’s welfare and are unlikely to interfere with the study 
treatment, they may be given at the discretion of the Investigator and recorded in the eCRF. 
Supportive treatment as medically indicated for the patient’s well-being may be prescribed at the 
Investigator’s discretion. Every medication or treatment taken by the patient during the study and 
the reason for its administration must be recorded on the eCRF. 
In order to have rapid control of the tumor burden, the administration of cyclophosphamide 
200 mg/m² before the first study treatment administration (up to 4 times, on D-3, D-2, D-1 and 
D1) is permitted for patients with hyperleucocytosis >50 000/mm3.  
Before C1D1, as per the institution’s clinical practice, all patients will receive CNS relapse 
prophylaxis (eg, intrathecal methotrexate 15 mg and/or cytarabine 40 mg and/or dexamethasone 
4 mg). 
Prophylaxis for tumor lysis syndrome (TLS) and CNS relapse may be administered at the 
discretion of the treating physician during the treatment period, following local standard practice. 
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8.8.2 Prohibited concomitant therapy 
The following concomitant therapies are not permitted during this study: 
• 
Concurrent treatment with other investigational drugs. 
• 
Concurrent treatment with any other anticancer therapy not specified in Section 8.8.1, 
including immunotherapy, hormonal therapy, targeted therapy, steroid therapy or 
biological therapies. 
8.8.3 Contraceptive measures 
Female patients of childbearing potential and male patients with female partners of childbearing 
potential shall be required to use effective contraceptive methods (2 barrier method or 1 barrier 
method with a spermicide, intrauterine device, or hormonal contraception with inhibition of 
ovulation) starting 2 weeks prior to the first dose of isatuximab, while on treatment and for  
12 weeks following the last dose of study treatment. A WOCBP, ie, fertile, following menarche 
and until becoming postmenopausal unless permanently sterile. The following highly effective 
methods of contraception are accepted: 
• 
Established use of oral, intravaginal, or transdermal combined (estrogen and progestogen 
containing) hormonal contraception associated with inhibition of ovulation. 
• 
Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation. 
• 
Placement of an intrauterine device or intrauterine hormone-releasing system. 
• 
Barrier methods of contraception: male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods). The use of double barrier methods should always be 
supplemented with the use of a spermicide. Female condom and male condom should not 
be used together. 
• 
Male sterilization (provided that the partner is the sole sexual partner of the patient and 
that the sterilized partner has received medical assessment of the surgical success). 
• 
Sexual abstinence. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
ENDPOINTS 
9.1.1 Primary endpoints 
The primary efficacy endpoint is ORR. ORR is based on NCCN guidelines and is defined as the 
proportion of patients with CR or incomplete peripheral recovery (CRi) for blood and bone 
marrow disease; partial response will be considered in case of mediastinal or any extramedullary 
disease (Appendix C). 
9.1.2 Secondary endpoints 
The secondary efficacy endpoints are: 
• 
DOR 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. The same censoring rules as 
PFS will be used (see below). 
• 
PFS, defined as the time from the date of first study treatment administration to the date of 
first disease progression or the date of death from any cause, whichever happens first. If 
progression and death are not observed before the analysis cutoff date, PFS will be 
censored at the earlier of the date of the last valid disease assessment not showing disease 
progression performed prior to initiation of a new anti-cancer treatment (if any) and the 
analysis cutoff date, whichever comes first. 
• 
OS defined as the time interval from the date of first study treatment administration to 
death from any cause. Patients without death prior to the analysis cutoff date will be 
censored at the earlier of the last date the patient was known to be alive and the analysis 
cutoff date, whichever comes first. 
Other secondary endpoints: 
• 
Safety assessment, in terms of AEs/SAEs, laboratory parameters, vital signs, and physical 
examination. 
• 
PK parameters of isatuximab calculated using a non-compartmental and population PK 
approach. 
• 
Immunogenicity of isatuximab assessed throughout the study by detecting the presence of 
antidrug antibodies (ADAs). 
• 
MRD, measured by sequencing and/or flow cytometry in patients achieving CR and CRi. 
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9.1.3 Exploratory endpoints 
The exploratory biomarkers endpoints are: 
• 
Bone marrow and blood samples analyzed for CD38 receptor density and receptor 
occupancy on blast cells. 
• 
Bone marrow and blood samples analyzed for CD38 expression on blast cells (proportion 
of CD38 positive cells). 
• 
Bone marrow samples analyzed for tumor molecular alterations. 
• 
Blood samples analyzed to investigate the relationship between soluble CD38 and 
parameters of PK. 
• 
Blood samples analyzed for immune genetic determinants (including FcγR polymorphism 
genotyping and T cell receptor repertoire). Other genetic determinants, related to the drug 
action and/or effect of isatuximab, may be conducted on these samples during the study 
pending evolving literature. 
• 
Bone marrow and blood samples analyzed for immunophenotypes (such as B cell, T cell, 
and NK cell subsets). 
• 
Additional biomarker analysis, not specified in the protocol but related to the drug action 
and/or effect of isatuximab, may be conducted on remaining samples pending evolving 
literature. 
Exploratory PK/PDy endpoint: 
• 
PK/PDy parameter estimates will be investigated as prognostic factors for clinical 
outcome including safety and efficacy endpoints, if possible. 
9.2 
SAFETY 
Safety evaluation will be performed continuously throughout the study period. The following 
assessments will be obtained and reviewed by the Investigator prior to study treatment 
administration and at designated intervals throughout the study: vital signs, 12-lead 
electrocardiogram (ECG), physical examinations, respiratory assessment, AEs, laboratory tests 
(complete blood counts, serum chemistry, and coagulation tests), ECOG PS, immunogenicity, 
blood cytokines (tumor necrosis factor alpha [TNFα], interleukin [IL]-1β, IL-4, IL-6, interferon 
gamma [IFNγ]), serum tryptase, markers of activated complement (C3a, C4, CH50), and TLS 
markers.  
9.2.1 Adverse events 
Adverse events will be collected from the date informed consent is signed until at least 30 days 
after the last administration of isatuximab, or a new anticancer therapy is started, whichever is 
first. Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 (Appendix D) and coded 
according to the Medical Dictionary for Regulatory Activities (MedDRA). During the follow-up 
period, ongoing SAEs regardless of relationship to study treatment and ongoing or new study 
treatment-related AEs/SAEs will be followed until resolution or stabilization. 
Refer to Section 10.4 to Section 10.7 for further details. 
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9.2.2 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (complete blood counts, serum chemistry, 
and coagulation tests). These tests will be performed by the local laboratory. 
Further details are provided in the flowchart and footnotes in Section 1.2.  
The complete blood counts and serum chemistry analyses are to be performed at screening, at the 
time points specified in the flowchart (Section 1.2), and when clinically indicated. Tests 
performed at screening must be repeated within 3 days before the first study treatment 
administration if performed >7 days before the first study treatment administration (ie, C1D1).  
From C1D8 onwards, serum chemistry analyses will be performed and reviewed by the 
Investigator within 24 hours before the day of dosing. In case of Grade 3 or 4 abnormalities, 
additional tests will be repeated every 2 to 3 days until recovery to baseline value or Grade ≤1 
(see Section 6.3). 
Coagulation tests are to be performed within 7 days before initiation of C1D1 and as clinically 
indicated.  
A serum or urine pregnancy test must be performed for WOCBP. Tests must be repeated within 
3 days before the first study treatment administration if performed >7 days before the first study 
treatment administration (ie, C1D1). Pregnancy tests must be repeated every 4 weeks (before D1 
of each cycle of study treatment administration) and for up to 3 months after the last 
administration of the study treatment (or before start of another anticancer therapy). 
Blood samples for cytokines, markers of activated complement, serum tryptase, and markers of 
TLS are to be drawn at C1D1 before first study treatment administration, and when clinically 
indicated (ie, in cases of IAR of Grade ≥2 as described below). Analysis of cytokines, serum 
tryptase and markers of complement activation will be performed by central laboratory. Analysis 
of TLS markers will be performed by a local laboratory. 
Should an isatuximab IAR of Grade ≥2 occur (as per NCI-CTCAE, version 4.03), additional 
blood sampling during the AE is required for analysis of cytokine release, markers of activated 
complement, serum tryptase, and markers of potential TLS.  
A Patient Card will be issued to the patient indicating that the patient is enrolled in a clinical trial 
evaluating isatuximab, an antiCD38 compound, and specifying the study medications they are 
receiving. Due to the potential interference of antiCD38 compounds such as isatuximab with 
blood bank serological testing, Investigators should ensure that the recommendations proposed by 
the American Association of Blood Banks are followed (see Appendix F). Investigators should 
instruct patients to carry their Blood Type Card and Patient Card with them at all times and 
present them if they need to receive medical treatment from someone other than the Investigator 
or his/her staff. 
Further details of central laboratory testing are provided in the Laboratory Manual. 
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9.2.3 Physical examination 
Physical examination of major body systems will include neurological examination, digestive, 
skin/mucosae, mediastinal, testicular localizations, respiratory, hepatomegaly, splenomegaly, and 
lymphadenopathy. Physical examination should preferably be performed by the same physician.  
Respiratory function will be monitored at C1D1 and before each study treatment administration, 
and at the end of study treatment including respiratory frequency, pulmonary auscultation, signs 
and symptoms such as cough, dyspnea, and expectoration. Additional tests such as chest X-ray 
will be performed when clinically indicated at the discretion of the Investigator. Patients with 
respiratory signs/symptoms Grade ≥2 that could be attributed to the study treatment, will have the 
respiratory evaluation repeated QW until improvement to Grade 1.  
The ECOG PS will be evaluated at screening, before each study treatment and at the end of 
treatment (Appendix B). 
Only clinically relevant findings will be reported in the eCRF as AEs. 
9.2.4 Vital signs 
Vital signs, including blood pressure, heart rate, temperature, and respiration rate, will be 
performed at screening and at preinfusion, 1 hour after starting the infusion, and at the end of 
infusion on D1, D8, D15 and D22 of the induction cycle(s), then preinfusion and as clinically 
indicated for subsequent cycles. The final measurements will be performed at the EOT visit  
(see flowchart in Section 1.2). 
9.2.5 12-lead electrocardiogram 
A 12-lead ECG will be performed at screening, at EOT and when clinically indicated (see 
flowchart in Section 1.2). 
Electrocardiogram data will be assessed by the Investigator based on the automatic device 
reading. 
9.2.6 Immunogenicity 
Antidrug antibody (ADA) against isatuximab will be assessed throughout the study. The sampling 
times for blood collection are provided in the flowcharts in Section 1.3 and Section 1.4. 
It is of utmost importance to collect all blood samples at the specified times. 
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 
treatment administration should also be precisely recorded.  
For the comfort of patients, some ADA samplings may be deleted during the course of the study if 
they are no longer deemed necessary by the sponsor. 
Special procedures for collection, storage, and shipment should be provided in a separate 
Laboratory Manual. 
Bioanalytical method used for immunogenicity assessment is summarized in Table 1.  
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Table 1 - Bioanalytical method for isatuximab immune response assessment 
Analyte 
ANTIDRUG ANTIBODY 
Matrix 
Plasma 
Analytical technique 
PandA method 
Lower Limit of Quantification 
Not applicable 
Assay volume 
100 µL 
Site of bioanalysis 
Refer to laboratory manual 
 
In case of a positive or inconclusive sample for ADA at 60 days after the last study treatment 
administration, additional assessment of ADA will be performed every 30 days (±5 days) until 
sample is negative. 
The ADA results will be communicated to investigational sites on an ongoing basis. 
9.3 
EFFICACY 
To assess response (NCCN guideline), bone marrow aspiration, or biopsy if clinically indicated 
(bone marrow aspirate/biopsy), as well as CT of chest with IV contrast and/or PET-CT scan 
(CT/PET-CT scan) will be performed for disease assessment at the time points indicated in the 
flowchart (Section 1.2) and as summarized hereafter.  
Bone marrow aspirate and/or biopsy will be done at screening, between D15 and D22 during the 
first cycle (after the third isatuximab infusion), or to confirm response at the end of induction 
period (after 4, or 8 isatuximab infusions for patients receiving 2 induction cycles) and then every 
2 cycles and when clinically indicated. No bone marrow is necessary if nonresponse or 
progressive disease can be diagnosed from peripheral blood evaluation, or, in patients with a 
white blood cell count <300/mm3, if the bone marrow test is considered noncontributory by the 
Investigator. Patients who discontinue for other reasons than disease progression will be followed 
every 4 weeks, but bone marrow aspirate will be performed only when clinically indicated.  
Analysis of bone marrow aspirate/biopsy for disease assessment will be performed by a local 
laboratory. 
CT/PET-CT scan should be performed at screening and at the EOT visit. In case of 
extramedullary involvement or T-LBL, both CT and PET-CT should be performed at baseline and 
at CR confirmation, whenever possible. Then CT and/or PET-CT scan every 2 cycles or 
thereafter. 
Lumbar puncture to exclude CNS involvement will be performed at screening and when clinically 
indicated (see exclusion criterion E04, Section 7.2.1). 
An assessment of MRD will be performed on bone marrow aspirate at screening and on blood at 
CR (in case of MRD positivity at first CR observation, assessment will be repeated after 2 to 
3 cycles). The assessment of MRD will be performed by a central laboratory. 
Detailed instructions for blood and bone marrow samples preparation and shipment will be 
provided to the study sites in a separate Laboratory Manual. 
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9.4 
PHARMACOKINETIC EVALUATION 
9.4.1 Sampling time and sample blood volume 
Additional details of PK sampling are provided in the PK/PDy flowcharts in Section 1.3 and 
Section 1.4. 
It is of utmost importance to collect all blood samples at the specified times. 
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 
treatment administration should also be precisely recorded. 
9.4.2 Pharmacokinetics handling procedure 
Special procedures for collection, storage, and shipment will be provided in a separate Laboratory 
Manual. 
9.4.3 Isatuximab bioanalytical method 
Bioanalytical method is summarized in Table 2.  
Table 2 - Bioanalytical method for isatuximab pharmacokinetic analysis 
Analyte 
Isatuximab 
Matrix 
plasma 
Analytical technique 
ELISA 
Lower limit of quantification 
0.500 ng/mL 
Assay volume 
100 µL 
Site of bioanalysis 
Refer to laboratory manual 
ELISA: enzyme-linked immunosorbent assay 
9.4.4 Pharmacokinetics parameters 
9.4.4.1 Non-compartmental pharmacokinetic analysis 
Full PK profile sampling will be collected from patients in Stage 1 during the first induction 
cycle, to assess the PK profile of isatuximab using a non-compartmental analysis. Blood samples 
will be collected using a sparse sampling strategy in patients from Stage 1 from C2 onwards and 
in the remaining patients in Stage 2. For the comfort of patients, some PK samplings may be 
deleted during the course of the study if they are no longer deemed necessary by the sponsor. 
Plasma concentrations of isatuximab and actual time values will be used to calculate the following 
PK parameters using non-compartmental analysis with validated software. The parameters will 
include, but may not be limited to Ceoi, Cmax, Ctrough, tmax, AUCWeek1, AUClast and Clast (defined in 
Table 3).  
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Table 3 - List of isatuximab pharmacokinetic parameters and definitions calculated by 
non-compartmental analysis after the first cycle of treatment 
Parameters 
Definition/calculation 
Ceoi 
Concentration at the end of an intravenous infusion 
Cmax 
Maximum plasma concentration observed 
Ctrough 
Plasma concentration observed just before treatment administration during repeated dosing 
tmax 
Time to reach Cmax 
AUCWeek1 
Area under the plasma concentration versus time curve calculated using the trapezoidal method over the first 
week of treatment 
AUClast 
Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to 
the time of last concentration observed above the lower limit of quantification (tlast) 
Clast 
Last concentration observed above the lower limit of quantification 
Also, Ctrough will be reported at subsequent cycles. 
9.4.4.2 Pharmacokinetic population analysis 
Blood concentrations of isatuximab will be used for population PK analysis by non-linear 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 interpatient PK variability, the 
population PK parameters estimates and the assessments of pathophysiologic covariate effects on 
clearance and possibly on volume if warranted. Empirical Bayesian estimation of individual 
parameters and of individual exposure (area under the plasma concentration versus time curves; 
AUCs) will also be performed. The PK parameter estimates will then be investigated as 
prognostic factors for clinical outcome including safety and efficacy endpoints, if possible. 
9.5 
SPECIFIC ASSESSMENTS 
9.5.1 Sample times, handling procedures, and bioanalytical methods 
Additional details of sampling are provided in the PK/PDy flowcharts in Section 1.3 and 
Section 1.4. 
It is of utmost importance to collect all blood samples at the specified times. 
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 
treatment administration should also be precisely recorded. 
Special procedures for collection, storage, and shipment will be provided in a separate Laboratory 
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9.5.2 Cytokines 
Bioanalytical methods for assessment of cytokines are summarized in Table 4.  
Table 4 - Bioanalytical methods for cytokine analysis 
Analyte 
IL-1β, IL-4, IL-6, TNFα, IFNγ 
Matrix 
Serum 
Analytical technique 
Immunoassay 
Site of bioanalysis 
Refer to laboratory manual 
IFNγ : interferon gamma ; IL : interleukin ; TNFα : tumor necrosis factor alpha 
9.5.3 Markers of activated complement and serum tryptase 
Bioanalytical methods for assessment of activated complement and serum tryptase are 
summarized in Table 5. 
Table 5 - Bioanalytical methods for markers of activated complement and serum tryptase 
Analyte 
C3a 
C4 
CH50 
Serum tryptase 
Matrix 
Plasma EDTA 
Serum 
Serum 
Serum 
Analytical technique 
Enzyme 
Immunoassay 
Immunonephelometry 
Hemolytic assay 
Enzyme Immunoassay 
Site of bioanalysis 
Refer to laboratory 
manual 
Refer to laboratory 
manual 
Refer to laboratory 
manual 
Refer to laboratory manual 
 
9.6 
EXPLORATORY BIOMARKERS ANALYSES 
9.6.1 Receptor density, receptor occupancy, and CD38 expression 
Further details of the RD, RO, and CD38 expression sampling is provided in the flowchart in 
Section 1.2, Section 1.3, and Section 1.4.  
Bone marrow aspirates and blood samples will be collected for assessment of RD and CD38 
expression (proportion of CD38 positive cells) at screening, and, if relevant, correlated with 
clinical response endpoints.  
Bone marrow aspirates and blood samples from patients in Stage 1 only will be taken to assess 
RO at screening and between D15 and D22 during the first cycle (after the third isatuximab 
infusion), for correlation with PK parameters and, if relevant, correlation with clinical response 
endpoints. 
These analyses will be applicable in selected countries only. 
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9.6.2 Other biomarkers 
Bone marrow aspirates and/or blood samples for exploratory analysis will be collected as detailed 
in the flowcharts in Section 1.2, Section 1.3, and Section 1.4. 
The bone marrow and blood samples will be analyzed for the following purposes: 
•
Multiple leukemia tumor molecular alterations will be tested and, if relevant, will be
correlated with clinical response endpoints. Genetic analysis will be performed,
Bone marrow samples will be 
collected at screening. 
For genetic/genomics studies, DNA/RNA may be isolated from tumor cells and sequenced 
to identify somatic mutations present only in the tumor cells (not in the patient’s heritable 
genome). Sequencing studies may include whole exome or whole genome sequencing (for 
DNA), or whole transcriptome sequencing (for RNA) to quantify gene expression or 
identify expressed gene fusions, mutations or other tumor-specific transcripts.  
•
Immune genetic determinants (such as FcγR gene polymorphisms and T cell receptor
repertoire) will be tested and, if relevant, will be correlated with clinical response
endpoints. Blood samples collected on C1D1, prior to first study treatment administration,
and during the treatment period (before the start of first maintenance cycle, or at the end of
the induction period [after 1 or 2 cycles] for patients who discontinue the study before the
first maintenance cycle) for some specific markers, will be used for this analysis. This
germline genetic analysis is a mandatory part of the protocol and will not be performed
under separate pharmacogenetic consent. The germline DNA sequence will not be used in
this case to determine risk or prognosis to any malignancies. Other genetic determinants,
related to the drug action and/or effect of isatuximab, may be conducted on these samples
during the study pending evolving literature.
•
Immune phenotypes in bone marrow and/or peripheral blood will be tested and, if
relevant, will be correlated with clinical response endpoints. Immune cell populations
including B cell, T cell and NK cell subsets will be characterized by multiparametric flow
cytometry based on the expression of cell surface markers. The proportion of cells positive
for a given marker or set of markers (eg, regulatory T cells) may be correlated with clinical
response endpoints. Bone marrow aspirate collected at screening and peripheral blood
samples collected at screening, between D15 and D22 during the first cycle (after the third
isatuximab infusion),  and EOT will be used for this analysis.
•
Soluble CD38 levels in blood samples taken at C1D1, prior to first study treatment
administration, will be correlated with PK parameters and, if relevant, correlated with
clinical response endpoints.
•
Additional biomarker analysis, not specified in the protocol but related to the drug action
and/or effect of isatuximab, may be conducted on remaining samples pending evolving
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9.6.3 Pharmacogenetic assessment 
9.6.3.1 Mandatory or optional drug metabolizing enzymes DNA sample 
Not applicable. 
9.6.3.2 Optional stored DNA sample 
For those patients who sign the specific pharmacogenetic informed consent form, a blood sample 
(10 mL) will be collected at C1D1 prior to first study treatment administration as specified in the 
study flow chart and this sample will be stored. 
This sample may be used to determine how the body processes isatuximab, possible relationship 
between genes and response to treatment with isatuximab, and possible side effects to isatuximab. 
Genes that could be studied include those of the immune system.  
This blood sample will be transferred to a site that will, on behalf of sanofi, extract DNA from the 
sample. This contractor can be located outside of the participating country, within or outside of 
the European Union. 
This blood sample, and the DNA that is extracted from it, will be assigned a second number, a 
Genetic ID (deidentification code) that is different from the Patient ID. This “double coding” is 
performed to separate a patient’s medical information and DNA data. 
The clinical study data (coded by Patient ID) will be stored in the clinical data management 
system, which is a distinct database in a separate environment from the database containing the 
pharmacogenetic data (coded by Genetic ID). The key linking Patient ID and Genetic ID will be 
maintained by a third party, under appropriate access control. The matching of clinical data and 
pharmacogenetic data, for the purpose of data analysis, will be possible only by using this key, 
which will be under strict access control. All data will be reported only in coded form in order to 
maintain confidentiality. 
The DNA will be stored at a secure site under the responsibility of the Sponsor for up to 15 years 
from the completion of the clinical study report. 
Special procedures for storage and shipment of pharmacogenetic samples are described in Table 6 
and more details will be included in a separate Laboratory Manual. 
Table 6 - Summary of handling procedures for pharmacogenetic samples 
Sample type 
Pharmacogenetic 
Blood sample volume 
10 mL for genotyping analysis 
Anticoagulant 
K2 EDTA 
Blood handling procedures 
Keep blood on ice and frozen within 30 minutes of sampling time. DO NOT 
CENTRIFUGE BLOOD (for details refer to Laboratory Manual) 
Storage conditions 
-70°C or colder 
EDTA: ethylenediaminetetraacetic acid 
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9.7 
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be used for the tests planned in this clinical 
study. For patients who have consented to it, the samples that are unused or left over after testing 
may be used for research purposes (excluding genetic analysis providing information on the 
likelihood of developing a disease) related to isatuximab efficacy, safety, metabolism or related to 
T-ALL or T-LBL other than those defined in the present protocol. 
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers used during the study (ie, Patient 
ID). They will be transferred to a sanofi site (or a subcontractor site) which can be located outside 
of the country where the study is conducted. The Sponsor has included safeguards for protecting 
patient confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.8 
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. Although this is the first clinical study 
of isatuximab in T-ALL/T-LBL, suitable steps have been built into each of these assessments to 
ensure their reliability and accuracy. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
During the course of the study, all patients entering the study must be evaluated according to the 
schedule outlined in the flowcharts (see Section 1.2, Section 1.3, and Section 1.4) and described 
below. The results of the evaluation will be recorded in the eCRF pages until the patients are no 
longer followed. 
10.1.1 Screening 
The screening assessments are to be performed within 3 weeks prior to the first study treatment 
administration (C1D1), unless indicated otherwise. All of the inclusion criteria (and none of the 
exclusion criteria) must be met, and informed consent must be signed by the patient before any 
study-specific procedure is performed. 
The following procedures are to be performed/assessed: 
• 
Demography (including age, gender, race). 
• 
A study patient card will be provided to the patient indicating that he/she is receiving an 
anti-CD38 treatment (Appendix F). 
• 
The site will notify its blood bank that the patient is receiving an anti-CD38 treatment  
(see Appendix F). 
• 
Blood type, phenotyping (or genotyping) and screen, if not previously performed  
(see Appendix F). 
• 
Relevant medical/surgical history (including relevant history of previous/associated 
pathologies, other than the tumor, history of asthma, chronic obstructive pulmonary 
disorder, dyspnea and tobacco consumption). 
• 
Disease history including date of initial diagnosis, type of disease (T-ALL/T-LBL, 
immunophenotypic and cytogenetic), previous anti-leukemia treatment (reason for 
discontinuation, date of relapse and best overall response to prior treatments). 
• 
Body weight and height. 
• 
Physical examination and ECOG PS. 
• 
Lumbar puncture to exclude CNS involvement and to confirm patient eligibility. 
• 
Prior medications. 
• 
AEs. 
• 
Vital signs (including blood pressure, heart rate, temperature, and respiration rate). 
• 
12-lead ECG. 
• 
Chest X-ray. 
• 
CT of chest with IV contrast and/or PET-CT scan. In case of extramedullary involvement 
or T-LBL, both CT and PET-CT should be performed. 
• 
Complete blood counts, serum chemistry and coagulation tests. 
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• 
Serum/urine pregnancy test for WOCBP. 
• 
Hepatitis B and C virus serology. 
• 
Bone marrow aspirate/biopsy for disease assessment. 
• 
Bone marrow aspirate for MRD assessment. 
• 
Bone marrow aspirates and blood samples for RO (Stage 1 only), RD and CD38 
expression (in selected countries only). Blood sample collection must be performed before 
dexamethasone premedication as dexamethasone has been shown to kill blast cells in 
blood tubes. 
• 
Bone marrow aspirates and blood samples for exploratory biomarkers analysis (tumor 
molecular alterations and immunophenotyping). Blood sample collection must be 
performed before dexamethasone premedication as dexamethasone has been shown to kill 
blast cells in blood tubes. 
• 
CNS relapse prophylaxis will be administered during screening, and during the treatment 
period, as per the institution’s clinical practice. 
10.1.2 Induction period 
During the induction period, patients will receive 1 or 2 induction cycles of therapy (1 induction 
cycle = 4 QW doses of isatuximab). If at D15-22 of the first induction cycle, bone marrow blast 
cells remain >5%, a second induction cycle will be administered. If bone marrow blast cells are 
≤5%, the administration of a second induction cycle will be performed at the discretion of the 
Investigator. Patients who do not achieve an objective response after a maximum of 2 cycles of 
induction therapy will be withdrawn from the study treatment. 
10.1.2.1 Cycle 1 (and Cycle 2, if applicable): Day 1 
At C1D1, the inclusion/exclusion criteria and informed consent must be rechecked before any 
study-specific procedure is performed.  
The following procedures/information are to be performed/collected prior to study treatment 
administration: 
• 
Body weight. 
• 
Physical examination, respiratory function and ECOG PS. 
• 
Prior medications. 
• 
Complete blood counts and serum chemistry (to be done within 3 days if performed 
>7 days prior to first study treatment administration at screening), and coagulation tests  
(to be done within 7 days if performed >7 days prior to first study treatment administration 
at screening). To be repeated at C2D1, if applicable. 
• 
Serum/urine pregnancy test for WOCBP (to be done within 3 days if performed >7 days 
prior to first study treatment administration at screening). To be repeated at C2D1, if 
applicable. 
• 
ADA sampling (see Section 1.3 and Section 1.4). 
• 
Blood sample for soluble CD38 (C1D1 only). 
• 
Blood sample for immune genetic determinants (C1D1 only). 
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• 
Optional blood sample for pharmacogenetic testing (C1D1 only). 
• 
Preinfusion vital signs (including blood pressure, heart rate, temperature, and respiration 
rate). 
• 
Blood sample for TLS markers, cytokines, markers of activated complement and serum 
tryptase (C1D1 only). 
• 
Preinfusion PK sampling (see Section 1.3 and Section 1.4). 
• 
Premedication (NIMP) administration (D-2, D-1 and D1 for dexamethasone, and 
cyclophosphamide on D-3, D-2, D-1 and D1 for Cycle 1 only; see Section 8.2 and 
Section 8.8.1). For premedication at C2D1, see Section 8.2. 
• 
12-lead ECG or lumbar puncture should be performed when clinically indicated. 
After completion of the above procedures, isatuximab will be administered. 
The following procedures/information are to be performed/collected during and/or after study 
treatment administration: 
• 
Vital signs (including blood pressure, heart rate, temperature, and respiration rate) at 
1 hour after starting the infusion, and at the end of infusion. 
• 
PK sampling (end of infusion, 4, 24, 48 and 72 hours post end of infusion for patients in 
Stage 1, and end of infusion and 1 hour post end of infusion for patients in Stage 2) (see 
Section 1.3 and Section 1.4). 
• 
Cytokines, TLS markers, markers of activated complement, and serum tryptase if an IAR 
≥Grade 2 occurs. 
• 
Premedication (NIMP) administration (D2 to D3 for Cycle 1 only; see Section 8.2). 
• 
Concomitant medications (to be assessed continuously throughout the on-treatment 
period). 
• 
AEs (to be assessed continuously throughout the on-treatment period). 
10.1.2.2 Cycle 1 (and 2, if applicable): Days 8, 15, and 22 
The following procedures/information are to be performed/collected prior to study treatment 
administration: 
• 
Body weight. 
• 
Physical examination, respiratory function and ECOG PS. 
• 
Preinfusion vital signs (including blood pressure, heart rate, temperature, and respiration 
rate). 
• 
Complete blood counts and serum chemistry (to be performed and reviewed by the 
Investigator within 24 hours before the day of dosing). 
• 
ADA sampling on D15 only. 
• 
Preinfusion PK sampling (see Section 1.3 and Section 1.4). 
• 
Premedication (NIMP) administration (see Section 8.2). 
• 
12-lead ECG or lumbar puncture should be performed when clinically indicated. 
After completion of the above procedures, isatuximab will be administered. 
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The following procedures/information are to be performed/collected during and/or after study 
treatment administration: 
• 
Vital signs (including blood pressure, heart rate, temperature, and respiration rate) at  
1 hour after starting the infusion, and at the end of infusion. 
• 
PK sampling at end of infusion on D15 for patients in Stage 2 (see Section 1.4). 
• 
Bone marrow aspirate/biopsy for disease assessment (between D15 and D22, after third 
isatuximab infusion and again at the end of the induction period to confirm response). 
• 
Bone marrow aspirate and blood sample for RO (Stage 1 patients; between D15 and D22 
during the first cycle after the third isatuximab infusion) before dexamethasone 
premedication (in selected countries only). 
• 
Blood sample for immunophenotyping (between D15 and D22 during the first cycle after 
the third isatuximab infusion) before dexamethasone premedication. 
• 
CT of chest with IV contrast and PET-CT scan if extramedullary involvement or T-LBL, 
at the end of induction for CR confirmation. 
• 
Cytokines, TLS markers, markers of activated complement, and serum tryptase if an IAR 
≥Grade 2 occurs. 
• 
Concomitant medications (to be assessed continuously throughout the on-treatment 
period). 
• 
AEs (to be assessed continuously throughout the on-treatment period). 
Assessment of MRD will be performed at CR (in case of MRD positivity at first CR observation, 
assessment will be repeated after 2 to 3 cycles).  
10.1.3 Maintenance  
Patients who achieve an objective response during the induction period can continue on to the 
maintenance period. During maintenance, patients will receive Q2W administration of isatuximab 
(28-day cycles). Patients will be allowed to continue maintenance therapy until disease 
progression, an unacceptable AE, consent withdrawal or Investigator’s decision (eg, patient is a 
candidate for transplantation). 
10.1.3.1 Maintenance cycles: Days 1 and 15 
The following procedures/information are to be performed/collected prior to study treatment 
administration: 
• 
Body weight. 
• 
Physical examination, respiratory function and ECOG PS. 
• 
Vital signs (including blood pressure, heart rate, temperature, and respiration rate) at 
preinfusion, and if clinically indicated. 
• 
Complete blood counts and serum chemistry. 
• 
Serum/urine pregnancy test for WOCBP (D1 only). 
• 
Blood sample for immune genetic determinants (before start of first maintenance cycle, or 
at the end of the induction period [after 1 or 2 cycles] for patients who discontinue the 
study before the first maintenance cycle). 
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• 
ADA sampling at D1 only. 
• 
Bone marrow aspirate/biopsy for disease assessment (prior to the start of maintenance and 
every 2 cycles thereafter, or if clinically indicated). 
• 
Preinfusion PK sampling (see Section 1.3 and Section 1.4). 
• 
Premedication (NIMP) administration (see Section 8.2). 
• 
12-lead ECG or lumbar puncture should be performed when clinically indicated. 
After completion of the above procedures, isatuximab will be administered. 
The following procedures/information are to be performed/collected during and/or after study 
treatment administration: 
• 
PK sampling at end of infusion on D1 of the first and second maintenance cycles, and 
1 hour post end of infusion on D1 of the second maintenance cycle (see Section 1.3 and 
Section 1.4). 
• 
Cytokines, TLS markers, markers of activated complement, and serum tryptase in cases of 
IAR ≥Grade 2. 
• 
Concomitant medications (to be assessed continuously throughout the on-treatment 
period). 
• 
AEs (to be assessed continuously throughout the on-treatment period). 
In case of extramedullary disease or T-LBL, a CT and/or PET-CT scan should be performed every 
2 cycles. 
In case of MRD positivity at first CR observation, assessment will be repeated after 2 to 3 cycles. 
10.1.4 Post-treatment period 
10.1.4.1 End of treatment 
The EOT visit will be performed 30 days (±5 days) after last isatuximab administration, or prior to 
initiation of a new anticancer therapy, whichever is first. 
The following procedures/information are to be performed/collected: 
• 
Body weight. 
• 
Physical examination, respiratory function and ECOG PS. 
• 
Concomitant medications. 
• 
AEs. 
• 
Vital signs (including blood pressure, heart rate, temperature, and respiration rate). 
• 
12-lead ECG. 
• 
CT and/or PET-CT scan. 
• 
Complete blood counts and serum chemistry. 
• 
Serum/urine pregnancy test for WOCBP. 
• 
Blood sample for immunophenotyping. 
• 
Posttreatment anticancer therapy. 
• 
PK sampling (see Section 1.3 and Section 1.4). 
• 
ADA sampling. 
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10.1.4.2 Follow-up 
The first follow-up visit for all patients will be performed 60 days (±5 days) after last isatuximab 
administration. 
Patients with documented disease progression at the EOT visit will be followed every 2 months 
until death or final analysis cutoff date, whichever comes first. 
Patients 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 month until initiation 
of another anticancer therapy, disease progression, death or final analysis cutoff date, whichever 
comes first. Then, after disease progression, or after initiation of further anticancer therapy for 
patients without disease progression, patients will be followed every 2 months until death or final 
analysis cutoff date, whichever comes first. 
The following procedures are to be performed/assessed: 
• 
Physical examination (for patients who discontinue treatment for other reason than disease 
progression). 
• 
Related AEs and any SAE ongoing at the EOT visit must be followed until resolution or 
stabilization. Any related AE or related SAE that is new during the follow-up period must 
be reported and followed until recovery or stabilization.  
• 
Complete blood counts (for patients who discontinue treatment for other reason than 
disease progression). 
• 
Serum/urine pregnancy test for WOCBP (to be performed up to 3 months after the last 
administration of study treatment, or before initiation of anticancer therapy, whichever is 
first). 
• 
Bone marrow aspirate/biopsy for disease assessment, if clinically indicated. 
• 
Posttreatment anticancer therapy. 
• 
Survival status to be collected (eg, alive with date of last contact, death with date of 
death). Efforts should be made by the study staff to contact the patient in order to avoid a 
patient becoming lost to follow-up. 
• 
PK sampling (at 60 days after last isatuximab administration only). 
• 
ADA sampling. If patient is positive or inconclusive for ADAs at 60 days after last 
isatuximab administration, additional ADA sampling is required every 30 days (±5 days) 
until sample is negative.  
10.2 
DEFINITION OF SOURCE DATA 
Not applicable, no results of certain examinations or evaluations will be recorded directly in the 
eCRF. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
Patients are free to withdraw their participation at any time during this study. The Investigator has 
the right to remove any patient from study treatment or participation in the study. However, sanofi 
requests that the Investigator consult with the sanofi Clinical Study Director before prematurely 
removing a patient. 
Patients who decide to withdraw from the study, or meet the withdrawal criteria, should undergo 
an EOT visit (see Section 1.2 and Section 10.1.4.1). 
Any study treatment discontinuation should be fully documented in the eCRF. 
Pregnancy will lead to definitive treatment discontinuation in all cases. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Not applicable, from a hemato-oncology perspective, treatment delays and permitted dose 
omissions are not considered discontinuations (see Section 6.4). 
10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the study 
treatment at any time. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from study treatment if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision.  
All efforts should be made to document the reason(s) for treatment discontinuation and this should 
be documented in the eCRF. 
At the patient’s request, at any time and irrespective of the reason (consent withdrawal), or at the 
request of their legally authorized representative. “Legally authorized representative” is 
considered to be an individual or judicial or other body authorized under applicable law to consent 
on behalf of a prospective patient to the patient’s participation in the procedure(s) involved in the 
research. It is critical to distinguish withdrawal of consent for treatment and withdrawal of 
consent for follow-up visits (see Section 10.3.5). 
• 
Disease progression. 
• 
If, in the Investigator’s opinion, continuation of the study treatment would be detrimental 
to the patient’s well-being, such as: 
- 
An unacceptable AE, 
- 
Poor compliance to the study protocol, 
- 
Any other reason such as intercurrent illness that prevents further administration of 
study treatment (will be specified). 
• 
Investigator’s decision (eg, patient is candidate for transplantation). 
• 
Patient is lost to follow-up. 
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If patients are clinically stable (ie, achieve an objective response [CR or CRi for blood and bone 
marrow disease; partial response will be considered in case of mediastinal or any extramedullary 
disease] after 1 or 2 induction cycles), and possibly deriving clinical benefit from therapy with 
minimal toxicity, the patient will be maintained on treatment for the maximum period of time 
defined in Section 6.2. 
Patients who have been withdrawn from the study treatment cannot be re-included in the study. 
Their inclusion and treatment number must not be re-used. 
10.3.4 Handling of patients after permanent treatment discontinuation 
For details see Section 10.1.4.2. All cases of permanent treatment discontinuation should be 
recorded by the Investigator in the appropriate pages of the eCRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for nonpatient 
contact follow-up, eg, medical records check. The discussion with the patient detailing the level of 
consent withdrawal should be documented in the patient’s medical records. Patients requesting 
withdrawal should be informed that withdrawal of consent for follow-up may jeopardize the 
public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the EOT visit  
(see Section 1.2, Section 1.3, and Section 1.4). 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws consent for follow-up, the 
Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their efficacy 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
A serious adverse event is any untoward medical occurrence that at any dose: 
• 
Results in death, or, 
• 
Is life-threatening, or, 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient 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. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, or, 
• 
Results in persistent or significant disability/incapacity, or, 
• 
Is a congenital anomaly/birth defect. 
• 
Is a medically important AE. 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical AEs that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important AEs is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
• 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm, 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
• 
Development of drug dependence or drug abuse. 
• 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN. 
• 
Suicide attempt or any event suggestive of suicidality. 
• 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• 
Bullous cutaneous eruptions. 
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10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to 
isatuximab, for which ongoing monitoring and immediate notification by the Investigator to the 
Sponsor is required. Such AEs may require further investigation in order to characterize and 
understand them. Adverse events of special interest may be added, modified or removed during a 
study by protocol amendment. 
The following AEs are considered AESIs: 
• 
IARs of Grade ≥3 (see Appendix E for diagnosis and symptoms typical of an IAR). An 
IAR is an AE related to isatuximab with onset typically within 24 hours from the start of 
the infusion. 
• 
Pregnancy occurring in a female patient entered in the clinical study or in a female partner 
of a male patient entered in the clinical study will be recorded as an AE in all cases and 
will be qualified as an SAE only if it fulfills one of the seriousness criteria (see 
Section 10.4.1.2). In the event of pregnancy in a female participant, treatment with the 
study treatment should be discontinued and the Monitoring Team should be informed 
immediately (within 24 hours), even if the event does not fulfill a seriousness criterion, 
using the AE form together with the SAE complementary form to be sent to the 
representative of the Monitoring Team whose name, address and fax number appear on 
page 2 of the clinical trial protocol.  
Follow-up of the pregnancy in a female patient or in a female partner of a male participant 
is mandatory until the outcome has been determined (see Section 10.4.4).  
• 
Symptomatic overdose (serious or non-serious) of study treatment. An overdose 
(accidental or intentional) with the study treatment is an event suspected by the 
Investigator or spontaneously notified by the patient and defined as an increase of at least 
30% of the dose to be administered in the specified duration. Of note, asymptomatic 
overdose has to be reported as a standard AE. In case of accidental or intentional overdose 
with the study treatment, even not fulfilling a seriousness criterion, is to be reported to the 
Sponsor immediately (within 24 hours) using the AE form together with the SAE 
complementary form to be entered in the eCRF. 
10.4.2 General guidelines for reporting adverse events 
All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of the 
informed consent form until the end of the study (at least 30 days after the last dose of study 
treatment, or a new anticancer therapy is started, whichever is first), are to be recorded on the 
corresponding page(s) or screen(s) of the eCRF for included patients. For screen failed patients, 
recording in the eCRF is only performed in case of SAE occurring during the screening period or 
in case of AE when some screening procedures expose the patient to safety risks (eg, any 
substance administered as premedication, invasive tests performed or chronic treatment 
interrupted). 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. The 
Investigator should specify the date of onset, grade, action taken with respect to IMP, corrective 
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treatment/therapy given, additional investigations performed, outcome and his/her opinion as to 
whether there is a reasonable possibility that the AE was caused by the IMP. 
All study treatment-related AEs and all SAEs (regardless of their causal relationship to study 
treatment) ongoing at the time of study treatment discontinuation need to be followed until 
resolution or stabilization. Any AE or SAE assessed as study treatment-related that are new 
during the follow-up period are to be reported and followed until resolution or stabilization.  
When treatment is discontinued, observations will continue for that patient as defined by the 
protocol. 
Vital signs or ECG abnormalities are to be recorded as AEs only if they are symptomatic and/or 
requiring corrective treatment and/or leading to treatment discontinuation and/or modification of 
dosing and/or fulfilling a serious criterion and/or is defined as an AESI. 
Laboratory abnormalities are to be recorded as AEs only if they lead to treatment discontinuation 
and/or modification of dosing and/or fulfill a serious criterion and/or are defined as an AESI. 
Laboratory values will be reported in the appropriate pages of eCRF. 
10.4.3 Instructions for reporting serious adverse events 
In the case of a SAE or an AESI, the Investigator must immediately: 
• 
ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the eCRF; the system will automatically send the notification to the Monitoring Team after 
approval of the Investigator within the eCRF or after a standard delay. 
• 
SEND (preferably by e-mail) the photocopy of all examinations carried out and the dates 
on which these examinations were performed, to the representative of the Monitoring 
Team whose name, fax number and email address appear on the Clinical Trial Protocol;. 
Care should be taken to ensure that the patient’s identity is protected and the patient’s 
identifiers in the Clinical Trial are properly mentioned on any copy of a source document 
provided to sanofi. For laboratory results, include the laboratory normal ranges. 
• 
All further data updates should be recorded in the eCRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medication, patient status) should be sent (by e-mail) to the Monitoring Team within 
24 hours of knowledge. In addition, every effort should be made to further document each 
SAE that is fatal or life threatening within the week (7 days) following initial notification. 
• 
A back-up plan is used (using paper flow) when the eCRF system does not work. 
10.4.4 Instructions for follow-up of adverse events 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably 
he/she should follow up the outcome of any AEs (clinical signs, laboratory values, etc) until the 
return to normal or consolidation of the patient’s condition. 
In case of any SAE, the patient must be followed up until clinical recovery is complete and 
laboratory results have returned to normal, or until outcome has been stabilized. This may imply 
that follow-up may continue after the patient has left the study and that additional investigations 
may be requested by the Monitoring Team. 
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In case of any AE or SAE brought to the attention of the Investigator at any time after cessation of 
IMP and considered by him/her to be caused by the IMP with a reasonable possibility, this should 
be reported to the Monitoring Team. 
10.4.5 Treatment discontinuation due to nonserious adverse event 
In the case of a treatment discontinuation due to a nonserious AE: 
• 
ENTER (within 24 hours) the information related to treatment discontinuation due to a 
nonserious AE in the appropriate screens of the eCRF (AE with the box "action taken with 
IMP" ticked "permanently discontinued", together with the end of treatment form with 
reason that should be ticked "Adverse Event"); the system will automatically send the 
notification to the Monitoring Team after approval of the Investigator within the eCRF or 
after a standard delay. 
10.5 
OBLIGATIONS OF SANOFI 
During the course of the study, the Sponsor will report in an expedited manner: 
• 
All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction), to the regulatory authorities, independent ethics 
committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators, according to local regulations. 
• 
AEs that are considered expected as specified by the reference safety information (see the 
current version of the Investigator’s Brochure). 
Sanofi will report all safety observations made during the conduct of the study in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Guidelines for the management of potential infusion associated reactions 
Patients should routinely receive premedications (NIMP) prior to isatuximab infusion as detailed 
in Section 8.2 to reduce the risk and severity of IARs commonly observed with mAb. Infusion 
associated reactions (NCI-CTCAE, version 4.03 term ‘allergic/hypersensitivity reactions’ or 
‘cytokine release syndrome/acute infusion reaction’) are defined as AEs related to isatuximab 
with onset typically within 24 hours from the start of the infusion. 
Patients who experience Grade 2 IAR(s) may subsequently resume isatuximab infusion under 
close monitoring and supportive care as needed. Patients may receive additional premedication 
per the judgment of the Investigator. Additional recommended premedications are 
diphenhydramine 25 mg IV (or equivalent) and methylprednisolone 100 mg IV (or equivalent). 
These patients must be informed of the potential risk of recurrent allergic reactions.  
Once a Grade 2 IAR has improved to Grade ≤1, the infusion may be restarted at one half the 
original infusion rates. If symptoms do not recur after 30 minutes, the infusion rate may be 
increased by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. 
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Patients with a Grade 3 or 4 isatuximab IAR must have isatuximab permanently discontinued and 
appropriate supportive therapy should be administered.  
Should an isatuximab IAR of Grade ≥2 occur, additional blood sampling during the AE is 
required for analysis of cytokine levels (TNFα, IL-1β, IL-4, IL-6 and IFNγ), markers of activated 
complement (C3a, C4, CH50), serum tryptase, and markers of potential TLS (uric acid, lactate 
dehydrogenase, blood urea nitrogen/creatinine, potassium, phosphate, and ionized and corrected 
calcium). The IAR and the therapy administered must be documented in the eCRF. 
All IARs of Grade ≥3 must be reported as AESIs (see Section 10.4.1.3). Study personnel should 
consult the Medical Monitor for further guidance regarding retreatment of patients with IARs and 
regarding issues of premedication management (eg, alternative medications for patients allergic or 
intolerant to premedication agents) or to determine if locally used equivalent medications are 
acceptable. 
General guidelines for the management of IARs are provided in Table 7.  
Table 7 - Management of infusion associated reaction 
NCI-CTCAE version 4.03 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 patient’s 
clinical status. Isatuximab infusion may be stopped at any time 
if deemed necessary. If stopped, IAR will be classified as a 
Grade 2 as per NCI-CTCAE.  
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 IV 
diphenhydramine 25 mg IV (or equivalent) and/ or IV 
methylprednisolone 100 mg (or equivalent) as needed. 
Isatuximab may be resumed only after patient recovery, with 
slower infusion rate and with close monitoring. Blood samples 
for additional safety labs will be collected. 
Important: additional blood sampling during the AE is required 
for analysis of cytokine levels (TNFα, IL-4, IL-6, IL-1β, and 
IFNγ), markers of activated complement (C3a, C4, CH50), 
serum tryptase, and markers of potential TLS. 
Severe or life-threatening (Grade 3 or 4) 
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 
Grade 4: life-threatening consequences; urgent intervention 
indicated 
Stop isatuximab infusion. Give additional premedication with 
diphenhydramine 25 mg IV (or equivalent) and/ or IV 
methylprednisolone 100 mg (or equivalent) and/or epinephrine 
as needed. Blood samples for additional safety labs will be 
collected. Definitive treatment discontinuation. 
Important: additional blood sampling during the AE is required 
for analysis of cytokine levels (TNFα, IL-4, IL-6, IL-1β, and 
IFNγ), markers of activated complement (C3a, C4, CH50), 
serum tryptase, and markers of potential TLS. 
Note: The infusion should be completed within 7.5 hours from the end of infusion preparation or a new infusion should be prepared with the 
remaining dose to be administered the same day. 
AE: adverse event; IAR: infusion associated reaction; IFNγ: interferon gamma; IL: interleukin; IV: intravenous; NCI-CTCAE: National Cancer 
Institute Common Terminology Criteria for Adverse Events; NSAIDs: nonsteroidal anti-inflammatory drugs; TLS: tumor lysis syndrome; TNFα: 
tumor necrosis factor alpha. 
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10.6.2 Guidelines for the management of tumor lysis syndrome 
General guidelines for the management of TLS are provided in Table 8.  
Table 8 - Management of tumor lysis syndrome 
Symptom 
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 (<0.3mmol/L)a 
Omit study treatment 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 treatment 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, paresthesias, 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. 
Same as above 
TLS: tumor lysis syndrome 
a The corrected calcium level in milligrams per deciliter = measured calcium level in milligrams per deciliter + 0.8 x (4-albumin in grams per 
deciliter) 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
A 2-stage Simon’s Optimum design was used for sample size calculation and a maximum of 
39 evaluable patients will be enrolled in the study. This sample size will provide 80% power to 
reject the null hypothesis that the true ORR is ≤15% if the true ORR rate is ≥30%, based on a 
1-sided exact binomial test at a significance level of 0.1. 
• 
Stage 1: 19 patients will be enrolled. The study will proceed to Stage 2 if >3 responses are 
observed. 
• 
Stage 2: a total of 39 patients (20 additional treated patients). If >8 responses are observed 
among the 39 patients analyzed, the null hypothesis will be rejected. 
11.2 
DISPOSITION OF PATIENTS 
The number of registered patients (patients who signed the informed consent) as well as the 
number and percentage of patients included in the analysis populations defined in Section 11.3 
will be provided.  
Reasons for treatment discontinuation will be summarized using the all-treated/safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 All-treated/safety population 
The all-treated/safety population will include all patients who received at least 1 dose (even 
incomplete) of isatuximab. This population is the primary population for the analyses of efficacy 
and safety parameters. 
11.3.2 Pharmacokinetic population 
The PK population will include all patients from the all-treated/safety population with at least 1 
PK parameter available. 
Patients with at least one evaluable ADA results during the ADA pretreatment period will be 
considered as evaluable at baseline. Patients with at least one evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period. 
11.3.3 Pharmacodynamic population 
The PDy population will include patients from the all-treated/safety population who had data for 
at least 1 PDy parameter available.  
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11.4 
STATISTICAL METHODS 
A list of study endpoints and their definitions are provided in Section 9.1. 
Unless otherwise specified, analyses will be descriptive and performed based on the 
all-treated/safety population. The baseline for a given parameter is defined as the last assessment 
for this parameter before the first study treatment administration. 
Continuous data will be summarized using number of available observations, mean, standard 
deviation, median, minimum, and maximum. Categorical and ordinal data will be summarized 
using number and percentage of patients. 
The cutoff date for interim analysis (Stage 1) will be approximately 2 months after last patient is 
treated in Stage 1. 
The cutoff date for primary analysis of ORR and other secondary endpoints will be 6 months after 
the last patient has had their first study treatment administration. The final cutoff date for OS 
analysis and updated analysis of ORR and other secondary endpoints will be approximately 
12 months after the last patient has had their first study treatment administration.  
11.4.1 Extent of study treatment exposure and compliance 
The following variables will be calculated and summarized with descriptive statistics to describe 
exposure to isatuximab: 
• 
Number of cycles started. 
• 
Duration of exposure in weeks: ([First day of last cycle – first day of first 
cycle + 28 days]/7). 
• 
Cumulative dose (in mg/kg). The cumulative dose is the sum of all doses administered 
from first to last dose. 
• 
Actual dose intensity, defined as the cumulative dose divided by the number of weeks on 
study. 
• 
Relative dose intensity (in %), defined as the ratio of the actual dose intensity to the 
planned dose intensity. The relative dose intensity is an indicator of the feasibility of the 
chosen schedule of administration. 
• 
Dose delays. The start of a cycle can be delayed for up to 14 days. Within a QW or Q2W 
cycle, a dose is deemed to have been delayed if the study treatment is >3 days beyond the 
theoretical day of treatment. 
• 
Dose interruption. 
• 
Dose omission. 
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11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint 
The primary efficacy endpoint is the ORR. The ORR will be summarized with descriptive 
statistics. Confidence intervals will be computed using the Clopper-Pearson method. 
11.4.2.2 Analyses of secondary efficacy endpoints 
The DOR, PFS and OS will be analyzed using Kaplan-Meier methods. Among patients who 
achieved a CR, the number of patients without MRD will be provided. 
11.4.2.3 Multiplicity considerations 
Not applicable. 
11.4.3 Analyses of safety data 
11.4.3.1 Adverse events 
Adverse Events will be collected from the date informed consent is signed, until the end of 
treatment (at least 30 days after the last dose of study treatment, or a new anticancer therapy is 
started, whichever is first). 
Adverse Events will be graded according to the NCI-CTCAE version 4.03 (Appendix D) and 
classified by system organ class (SOC)/preferred term (PT) according to the latest available 
version of the MedDRA dictionary. 
The observation period will be divided into 3 segments: screening, TEAE and posttreatment: 
• 
The screening period is defined as the time informed consent is signed until the first study 
treatment administration.  
• 
The TEAE observation period is defined as the time from the first study treatment 
administration up to at least 30 days after the last study treatment administration, or a new 
anticancer therapy is started, whichever is first.  
• 
The posttreatment period is defined as the time starting 31 days after the last study 
treatment administration or a new anticancer therapy is started (whichever is first) to study 
closure.  
Pretreatment AEs are defined as any AE reported during the screening period. 
Treatment-emergent AEs are defined as AEs that developed, worsened (according to the 
Investigator opinion), or became serious during the TEAE period. 
Posttreatment AEs are defined as AEs that are reported during the posttreatment period. 
The grade will be taken into account in the summary. For patients with multiple occurrences of 
the same PT, the maximum grade within the analyzed observation period will be used. 
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment AEs will be 
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11.4.3.2 Treatment-emergent adverse events 
An overall summary of TEAEs will be provided. The number and percentage of patients who 
experienced any of the following will be provided: 
• 
TEAEs. 
• 
TEAEs of Grade ≥3. 
• 
Treatment-related TEAEs. 
• 
Treatment-related TEAEs of Grade ≥3. 
• 
Serious TEAEs. 
• 
Serious treatment-related TEAEs. 
• 
TEAE with a fatal outcome. 
• 
TEAE leading to permanent treatment discontinuation. 
• 
AESIs. 
• 
AESIs of Grade ≥3. 
• 
IARs. 
• 
IARs of Grade ≥3. 
Number and percentage of patients 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, IARs, TEAEs leading to isatuximab discontinuation, TEAEs leading to 
dose modification, serious TEAEs, TEAEs with a fatal outcome and AEs/SAEs occurring during 
the posttreatment dosing period.  
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (screening, TEAE and posttreatment). For that purpose, the table of all TEAEs 
will be presented by SOC and PT sorted by internationally agreed, order unless otherwise 
specified. 
Infusion associated reactions will be analyzed using both investigator reporting and 
treatment-related TEAEs occurring within 24 hours after isatuximab administration. 
The following listings will be provided if relevant: 
• 
AESI (non-IARs). 
• 
IARs. 
• 
AEs leading to treatment discontinuation. 
• 
AEs leading to dose modification. 
• 
SAEs. 
11.4.3.3 Deaths 
A summary of the number and proportion of patients who died by study period (screening, TEAE 
and posttreatment) and cause will be generated. 
A listing of deaths will be provided. 
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11.4.3.4 Other safety variables 
Incidence of TLS including the description of the TLS criteria will be summarized with 
descriptive statistics. Corresponding listings will be provided.  
Cytokines at baseline will be described with descriptive statistics. For patients with post-baseline 
assessments, maximum change from baseline will be described including time to maximum 
change. 
Potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review. 
The incidence of PCSA for vital signs and at any time during the TEAE period will be 
summarized irrespective of the baseline level (ie, last assessment before the first study treatment 
administration) and according to the following baseline status (ie, status of last assessment before 
the first study treatment administration) categories: 
•
Normal/missing.
•
Abnormal according to PCSA criterion or criteria.
The PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE, including nonscheduled or 
repeated evaluations. 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. Complete blood count and serum 
chemistry results will be graded according to NCI-CTCAE version 4.03, when applicable. For 
patients with multiple occurrences of the same laboratory variable during the on-treatment period 
(ie, TEAE 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. 
The number and proportion of patients with abnormal laboratory tests at baseline (ie, last 
assessment before the first study treatment administration) will be presented for all grades and 
Grades 3 and 4. Similar tables showing abnormalities during the on-treatment period will be 
provided. 
When the NCI-CTCAE version 4.03 scale is not applicable, the number of patients with a 
treatment-emergent out-of-normal laboratory range value will be displayed. 
For drug-induced liver injury, a listing of possible Hy’s law cases identified (eg, patients with any 
elevated AST or ALT of >3 ULN and elevated total bilirubin > ULN), will be provided. 
11.4.3.5 Immunogenicity 
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 treatment administration.
•
The ADA on-study observation period will be defined as the time from the first study
treatment administration until the end of the study.
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Patients with at least one evaluable ADA result during the ADA pretreatment period will be 
considered as evaluable at baseline. Patients with at least one evaluable ADA result during the 
ADA on-study observation period will be considered evaluable during the on-study observation 
period.  
Definitions:  
• 
Pre-existing ADA, defined as ADA that are present in samples drawn during the 
pretreatment period. 
• 
Treatment-induced ADA, defined as ADA that developed at any time during the ADA 
on-study observation period in patients without pre-existing ADA (including patients 
without pretreatment samples). 
• 
Treatment boosted ADA, defined as pre-existing ADA with a significant increase in the 
ADA titer during the study compared to the baseline titer.  
• 
ADA positive patients, defined as patients with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time following the first study treatment 
administration. 
• 
ADA prevalence, defined as the sum of the number of patients with pre-existing ADA and 
the number of patients with treatment induced ADAs, divided by the number of evaluable 
patients. 
• 
ADA incidence, defined as the number of ADA positive patients divided by the number of 
evaluable patients. 
The immunogenicity for isatuximab will be assessed by summarizing the number (%) of patients 
with pre-existing ADA and ADA negative at baseline, and by summarizing the number (%) of 
ADA positive patients (including treatment-induced ADA and treatment boosted ADA) during the 
on-study observation period.  
ADA prevalence and ADA incidence will be also described.   
11.4.4 Analyses of pharmacokinetic variables 
Individual plasma concentrations and PK parameters of isatuximab will be summarized by 
descriptive statistics (such as mean, geometric mean, median, standard deviation, standard error of 
the mean, coefficient of variation, minimum, and maximum) under the responsibility of sanofi. 
Individual and mean profiles will be presented graphically. 
11.4.5 Analyses of pharmacodynamic variables 
The CD38 RO/RD data will be summarized by study visits. Moreover, the set of PDy parameters 
will be described and, if relevant, correlated with the clinical response. 
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11.5 
INTERIM ANALYSIS 
An interim analysis of efficacy, safety and other data (including PK) will be performed after the 
completion of enrollment in Stage 1. This interim analysis will be performed when all patients 
have completed either 2 induction cycles plus D1 of the first maintenance cycle or 1 induction 
cycle plus 1 maintenance cycle. Enrollment will 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 (see Section 6.1). 
At the end of each stage, additional statistical analyses could be performed in order to identify a 
subpopulation who would respond better to the treatment. If a relevant biomarker is actually 
identified, then a relevant threshold could be explored to define a subgroup of better responders.  
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical study will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the International 
Council for Harmonisation (ICH) guidelines for good clinical practice (GCP), all applicable laws, 
rules and regulations. 
This clinical study will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the ethics committee (IRB/IEC). All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical study, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
Prior to collection of blood for pharmacogenetics, the optional pharmacogenetic informed consent 
form (written) should be signed, name filled in, and personally dated by the patient or by the 
patient’s legally acceptable representative, and by the person who conducted the informed consent 
discussion. A copy of the signed and dated written optional informed consent form will be 
provided to the patient. 
The informed consent form and the optional pharmacogenetic informed consent form used by the 
Investigator for obtaining the patient's informed consent must be reviewed and approved by the 
Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) for approval/favorable 
opinion. 
For pediatric patients, the Investigator (according to applicable regulatory requirements), or a 
person designated by the Investigator, should fully inform the patient (and the parent[s] or 
guardian[s]) of all pertinent aspects of the clinical trial including the written information given 
approval/favorable opinion by the ethics committee (IRB/IEC). All participants should be 
informed to the fullest extent possible about the study in language and terms they are able to 
understand. Local law must be observed in deciding whether 1 or both parents/guardians consent 
is required. If only 1 parent or guardian signs the consent form, the Investigator must document 
the reason for only 1 parent or guardian’s signature. 
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In addition, participants will assent as detailed below or will follow the ethics committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center (age of 
assent to be determined by the IRB’s/IEC’s or be consistent with the local requirements): 
Participants who can read the assent form will do so before writing their name and dating or 
signing and dating the form. 
Participants who can write but cannot read will have the assent form read to them before writing 
their name on the form. 
Participants who can understand but who can neither write nor read will have the assent form read 
to them in presence of an impartial witness, who will sign and date the assent form to confirm that 
assent was given. 
The informed consent form and the assent form used by the Investigator for obtaining the 
Patient’s Informed Consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate ethics committee (IRB/IEC) for approval/favorable opinion. 
In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical study 
protocol to the health authorities (competent regulatory authority) and the appropriate IRB/IEC, 
and is required to forward to the respective other party a copy of the written and dated 
approval/favorable opinion signed by the chairman with IRB/IEC composition. 
The clinical study (study number, clinical study protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure with any 
addenda or labeling documents (summary of product characteristics, package insert, Investigator’s 
curriculum vitae, etc) and the date of the review should be clearly stated on the written (IRB/IEC) 
approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical study, any amendment or modification to the clinical trial protocol should be 
submitted to the health authorities (competent regulatory authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case the health authorities (competent 
regulatory authority) and the IRB/IEC should be informed as soon as possible. They should also 
be informed of any event likely to affect the safety of patients or the continued conduct of the 
clinical trial, in particular any change in safety. All updates to the Investigator’s Brochure or 
labeling information, will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical study’s 
outcome at the end of the clinical study.  
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STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the eCRF, Discrepancy Resolution Form or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical study is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical study as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the eCRFs. Thus, the main duty of 
the Monitoring Team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical study. 
At regular intervals during the clinical study, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the Monitoring Team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data.  
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the Monitoring Team must check the eCRF entries against the source 
documents, except for the pre-identified source data directly recorded in the eCRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the eCRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS AND ADDITIONAL REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate eCRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All eCRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the eCRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the eCRF. 
The computerized handling of the data by the Sponsor may generate additional requests 
(Discrepancy Resolution Form) to which the Investigator is obliged to respond by confirming or 
modifying the data questioned. The requests with their responses will be managed through the 
eCRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical study. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical study. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical study completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical study, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the eCRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical study, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical study. 
The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical study, to the exclusion of any use for their own or for a third party's account. 
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14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff/Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical study. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
•
The patient's personal data, which are included in the Sponsor database shall be treated in
compliance with all applicable laws and regulations.
•
When archiving or processing personal data pertaining to the Investigator and/or to the
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to
this data by any unauthorized third party.
•
The Sponsor also collects specific data regarding Investigator as well as personal data
from any person involved in the study which may be included in the Sponsor’s databases,
shall be treated by both the Sponsor and the Investigator in compliance with all applicable
laws and regulations.
Patient race or ethnicity (including ‘Caucasian/white, Black, Asian/Oriental’) will be collected in 
this study because these data are required by several regulatory authorities (eg, on Afro-American 
population for the Food and Drug Administration, on the Japanese population for the 
Pharmaceuticals and Medical Devices Agency in Japan, or on the Chinese population for the 
China Food and Drug Administration in China). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical studies 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel are bound by professional secrecy, and 
as such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• 
The information on the product leads to doubt as to the benefit/risk ratio. 
• 
Patient enrollment is unsatisfactory. 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon. 
• 
Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• 
The total number of patients is included earlier than expected. 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon 30 days' prior written notice if the study 
site or the Investigator for any reason becomes unable to perform or complete the clinical study.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within 12 months of the completion of this study at all sites, the Investigator shall have 
the right to publish or present independently the results of this study in agreement with other 
Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of any such 
presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical study patients, or when the change(s) involves only logistical or 
administrative aspects of the study. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Reinherz EL, Kung PC, Goldstein G, Levey RH, Schlossman SF. Discrete stages of 
human intrathymic differentiation: analysis of normal thymocytes and leukemic lymphoblasts of 
T- cell lineage. Proc Natl Acad Sci USA.1980;77:1588-92. 
2. 
Campana D, Suzuki T, Todisco E, Kitanaka A. CD38 in hematopoiesis. Chem Immunol. 
2000;75:169-88. 
3. 
Howard M, Grimaldi JC, Bazan JF, Lund FE, Santos-Argumedo L, Parkhouse RM, et al. 
Formation and hydrolysis of cyclic ADP-ribose catalyzed by lymphocyte antigen CD38. Science. 
1993;262:1056-9. 
4. 
Keyhani A, Huh YO, Jendiroba D, Pagliaro L, Cortez J, Pierce S, et al. Increased CD38 
expression is associated with favorable prognosis in adult acute leukemia. Leuk Res. 
2000;24:153-9. 
5. 
Koehler M, Behm F, Hancock M, Pui CHL. Expression of activation antigen CD38 and 
CD71 is not clinically important in childhood acute lymphoblastic leukemia Leukemia. 
1993;7:41-5. 
6. 
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5-29. 
7. 
Borowitz MJ, Chan JKC. B lymphoblastic leukemia/lymphoma, not otherwise specified 
In: Swerdlow SH, Campo E, Harris NL, et al., eds. WHO classification of tumours of 
haematopoietic and lymphoid tissues (ed 4th). Lyon: IARC;2008:168-70. 
8. 
Borowitz MJ, Chan JKC. T lymphoblastic leukemia/lymphoma. In: Swerdlow SH, Campo 
E, Harris NL, et al.,eds. WHO classification of tumours of haematopoietic and lymphoid tissues 
(ed 4th). Lyon: IARC; 2008:176-8. 
9. 
Fielding AK, Richards SM, Chopra R, Lazarus HM, Litzow MR, Buck G, et al. Outcome 
of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL 12/ECOG 
2993 study. Blood 2007;109:944-50. 
10. 
Oriol A, Vives S, Hernandez-Rivas JM, Tormo M, Heras I, Rivas C, et al. Outcome after 
relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-
adapted trials by the PETHEMA Study Group. Haematologica. 2010;95:589-96. 
11. 
Pigneux A, Sauvezie M, Vey N, Raffoux E, Marcais A, Huguet F, et al. Clofarabine 
combinations in adults with refractory/relapsed acute lymphoblastic leukemia (ALL) : A 
GRAALL Report. Blood 2011;118:Abstract 2586. 
12. 
Schiller G, Lee M, Territo M, Gajewski J and Nimer S. Phase II study of etoposide, 
ifosfamide and mitoxantrone for the treatment of resistant adult acute lymphoblastic leukemia. 
Am J Hematol. 1993;43:195-9. 
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13.
GlaxoSmithKline. Prescribing information. ARRANON (nelarabine) injection. 2014.
14.
DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, et al. Nelarabine
induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic 
leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood 
2007;109:5136-42. 
15.
ASCO 2016; Abstract Title: Updated data from a phase II dose finding trial of single agent
isatuximab (SAR650984, anti-CD38 mAb) in relapsed/refractory multiple myeloma (RRMM). 
Abstract ID: 8005 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A phase 2, safety and efficacy study of isatuximab (SAR650984), an anti-CD38 
monoclonal antibody, administered by intravenous infusion in patients with 
relapsed or refractory T-acute lymphoblastic leukemia or T-lymphoblastic 
lymphoma  
SAR650984-ACT14596 
DATE OF ISSUE: 13-Dec-2017 
Total number of pages: 
42 
(electronic 2.0)
NCT Number: NCT02999633


Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................6 
1.1 
STUDY DESIGN ..............................................................................................................................6 
1.2 
OBJECTIVES...................................................................................................................................6 
1.2.1 
Primary objectives............................................................................................................................6 
1.2.2 
Secondary objectives.......................................................................................................................6 
1.2.3 
Exploratory objectives......................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................7 
1.4 
STUDY PLAN...................................................................................................................................7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL..................................7 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .......................7 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ......................................................................8 
2.1 
ANALYSIS ENDPOINTS .................................................................................................................8 
2.1.1 
Demographic and baseline characteristics ......................................................................................8 
2.1.2 
Prior or concomitant medications (other than anticancer therapies) ...............................................9 
2.1.3 
Efficacy endpoints..........................................................................................................................10 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................10 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................11 
2.1.4 
Safety endpoints ............................................................................................................................11 
2.1.4.1 
Adverse events variables...............................................................................................................12 
2.1.4.2 
Deaths............................................................................................................................................13 
2.1.4.3 
Laboratory safety variables............................................................................................................13 
2.1.4.4 
Vital signs variables .......................................................................................................................14 
2.1.4.5 
Electrocardiogram variables ..........................................................................................................14 
2.1.4.6 
Other safety endpoints...................................................................................................................14 
2.1.5 
Pharmacokinetic variables .............................................................................................................14 
2.1.6 
Pharmacodynamic variables..........................................................................................................15 
2.1.7 
Immunogenicity endpoints .............................................................................................................15 
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2.1.8 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................16 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................16 
2.3 
ANALYSIS POPULATIONS...........................................................................................................17 
2.3.1 
All-treated/Safety population..........................................................................................................17 
2.3.2 
Pharmacokinetics population.........................................................................................................17 
2.3.3 
Pharmacodynamic population........................................................................................................17 
2.3.4 
ADA population ..............................................................................................................................18 
2.4 
STATISTICAL METHODS .............................................................................................................18 
2.4.1 
Demographics and baseline characteristics ..................................................................................18 
2.4.2 
Prior or concomitant medications (other than anticancer therapies) .............................................18 
2.4.3 
Extent of investigational medicinal product exposure and compliance .........................................18 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................20 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................20 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................20 
2.4.4.3 
Multiplicity issues ...........................................................................................................................21 
2.4.5 
Analyses of safety data..................................................................................................................21 
2.4.5.1 
Analyses of adverse events ...........................................................................................................21 
2.4.5.2 
Deaths............................................................................................................................................25 
2.4.5.3 
Analyses of laboratory variables....................................................................................................25 
2.4.5.4 
Analyses of vital sign variables ......................................................................................................26 
2.4.5.5 
Analyses of electrocardiogram variables .......................................................................................26 
2.4.5.6 
Analyses of other safety endpoints................................................................................................26 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................27 
2.4.7 
Analyses of immunogenicity variables...........................................................................................27 
2.4.8 
Further therapy after discontinuation of investigational medicinal product administration 
during the study..............................................................................................................................27 
2.5 
DATA HANDLING CONVENTIONS ..............................................................................................27 
2.5.1 
General conventions ......................................................................................................................27 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................28 
2.5.3 
Missing data...................................................................................................................................28 
2.5.4 
Windows for time points.................................................................................................................29 
2.5.5 
Unscheduled visits .........................................................................................................................30 
2.5.6 
Pooling of centers for statistical analyses......................................................................................30 
2.5.7 
Statistical technical issues .............................................................................................................30 
3 
INTERIM ANALYSIS .....................................................................................................................31 
4 
DATABASE LOCK........................................................................................................................32 
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5 
SOFTWARE DOCUMENTATION .................................................................................................33 
6 
REFERENCES...............................................................................................................................34 
7 
LIST OF APPENDICES.................................................................................................................35 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ......................36 
APPENDIX B 
SOC SORTING ORDER......................................................................................................37 
APPENDIX C GENERIC RANGES FOR HEMATOLOGICAL AND BIOCHEMISTRY 
PARAMETERS ..............................................................................................................................39 
APPENDIX D NATIONAL COMPREHENSIVE CANCER NETWORK GUIDELINES ...............................41 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibody 
ADI: 
actual dose intensity 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANC: 
absolute neutrophils count 
AST: 
activated partial thromboplastin time, aspartate aminotransferase 
ATC: 
anatomic category 
AUC: 
area under the curve 
BOR: 
best overall response 
CR: 
complete response 
CTCAE: 
common terminology criteria for adverse events 
DOR: 
duration of response 
ECOG: 
Eastern Cooperative Oncology Group 
eCRF: 
electronic case report form 
HLGT: 
high level group term 
HLT: 
high level term 
IAR: 
infusion associated reaction 
IMP: 
Investigational medicinal product 
INR: 
International normalized ratio 
MedDRA: 
Medical Dictionary of Regulatory Activities 
MRD: 
minimal residual disease 
NCI: 
National Cancer Institute 
ORR: 
overall response rate 
OS: 
overall survival 
PCSA: 
potentially clinically significant abnormality 
PD: 
progressive disease 
PDy: 
pharmacodynamic 
PFS: 
progression free survival 
PK: 
Pharmacokinetic 
PR: 
partial response 
PS: 
performance status 
PT: 
preferred term 
RBC: 
red blood cell 
SAE: 
serious adverse event 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
WBC: 
white blood cell 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN 
This is a Phase 2, single arm, multicenter, multinational, open-label study evaluating the efficacy 
and safety of isatuximab in patients with relapsed or refractory T-ALL/T-LBL. 
The study will be conducted in 2 stages. Approximately 39 patients previously treated for  
T-ALL/T-LBL will be enrolled in the study across approximately 15 to 20 sites globally. A 
Simon’s 2-stage optimum design will be used. 
• 
Stage 1: an interim analysis of efficacy, safety and PK will be performed on the first 19 
treated patients. The study will proceed to Stage 2 if >3/19 responses are observed in  
Stage 1. 
• 
Stage 2: 20 additional patients will be treated if the number of responses required to 
proceed to Stage 2 is reached at the interim analysis of Stage 1. 
The duration of the study for a patient will include a period for screening of up to 3 weeks. The 
cycle duration is 28 days. The treatment period will include an induction period (QW dosing) for 
4 or 8 weeks, followed by a maintenance period (Q2W). Patients will continue maintenance 
therapy until disease progression, unacceptable AE, consent withdrawal or Investigator’s decision 
(eg, patient is a candidate for transplantation). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to evaluate the efficacy of isatuximab in patients with 
relapsed or refractory T-ALL or T-LBL as measured by overall response rate (ORR) (as per 
National Comprehensive Cancer Network [NCCN] guidelines; Appendix D). 
1.2.2 Secondary objectives 
The secondary objectives are: 
• 
To evaluate the safety profile of isatuximab. 
• 
To compare the duration of response (DOR). 
• 
To evaluate progression free survival (PFS) and overall survival (OS). 
• 
To evaluate the PK of isatuximab in patients with T-ALL or T-LBL. 
• 
To evaluate immunogenicity of isatuximab in patients with T-ALL or T-LBL. 
• 
To assess minimal residual disease (MRD) and correlate it with clinical outcome. 
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1.2.3 Exploratory objectives 
The exploratory objectives are: 
• 
To explore the relationship between CD38 expression and clinical response. 
• 
To explore the relationship between CD38 receptor occupancy (RO) and CD38 receptor 
density (RD) on blast cells (peripheral blood and bone marrow) and clinical response. 
• 
To explore the relationship between acute leukemia tumor molecular alterations and 
clinical response. 
• 
To explore the relationship of soluble CD38, the PK of isatuximab and clinical response. 
• 
To explore the relationship between immune genetic determinants, immune phenotypes 
and clinical response. 
• 
To explore PK/PDy relationships. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation is based on the primary efficacy endpoint (ie, ORR). The following 
assumptions were used: 
• 
Null hypothesis: ORR ≤15%.  
• 
Alternative hypothesis: ORR ≥30%.  
• 
A two-stage Simon’s Optimum design at a one-sided 10% significance level. 
Based on the above assumptions, approximately 39 patients are needed to achieve an 80% power 
for the study. 
• 
Stage 1: 19 patients will be enrolled. The study will proceed to stage 2 if >3 responses are 
observed. 
• 
Stage 2: a total of 39 patients (20 additional treated patients). If >8 responses are observed 
among the 39 patients analyzed, the null hypothesis will be rejected. 
1.4 
STUDY PLAN 
The complete study plan is presented in section 1.1 of the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
To avoid inconsistencies between parts of the protocol, a clarification is required regarding the 
population used for analyses. All analyses will be done on the primary population which is the all-
treated population. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. This is not an amended SAP. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined as the last value or measurement taken up to the date and time of the 
first study treatment administration. This definition applies for all variables unless otherwise 
specified.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with summary statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic variables include gender (Male, Female), race (White, Black, Asian, American 
Indian/Alaska Native, Native Hawaiian/Other Pacific Islander, Not reported, Unknown), ethnicity 
(Hispanic or Latino, Not Hispanic or Latino, Not reported, Unknown), age in years, weight (kg), 
and eastern cooperative oncology group (ECOG) performance status (PS) at baseline. 
Medical or surgical history 
Medical or surgical history includes relevant history of previous or associated pathologies other 
than the tumor, history of asthma, chronic obstructive pulmonary disorder, dyspnea and tobacco 
consumption.  
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. Respiratory function history 
will be analyzed using two groupings (see details in Section 2.1.4.1) 
Disease characteristics at baseline   
The following leukemia/lymphoma characteristics at initial diagnosis will be described: 
• 
Time from initial diagnosis of leukemia/lymphoma to first study treatment administration 
(in months). 
• 
Leukemia/lymphoma type (T-ALL/T-LBL, cell type)  (as collected in eCRF). 
• 
Cytogenetic abnormality (as collected in eCRF). 
• 
Disease involvement location (as collected in eCRF). 
Disease characteristics at study entry 
The following leukemia/lymphoma characteristics at study entry will be described: 
• 
Refractory status. 
- 
Relapsed: patients who achieve CR of any duration with the last treatment and 
progressed before entering the study, 
- 
Refractory: failure to achieve CR with the last treatment received. 
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Prior anticancer therapies 
• 
Prior anti-CD38 treatments 
Prior anti-leukemia/lymphoma treatments are collected by regimen in the eCRF. The 
following variables will be collected/derived: 
- 
Number of prior regimens, 
- 
Number of prior salvage therapies,  
- 
Intent of prior anti-leukemia/lymphoma therapies, 
- 
Reason for discontinuation, 
- 
Best overall response (BOR), 
- 
Transplant Type: number (%) of patients with allogeneic transplant, number (%) of 
patients with autologus transplant, 
- 
Nelarabine: number (%) of patients who have been previously exposed to nelarabine. 
• 
Prior surgery: number (%) of patients with any prior surgery related to 
leukemia/lymphoma, type of procedure and time from last surgery to first study treatment 
administration (months). 
• 
Prior radiotherapy: number (%) of patients with any prior radiotherapy related to 
leukemia/lymphoma, intent and time from last radiotherapy to first study treatment 
administration (months).   
2.1.2 Prior or concomitant medications (other than anticancer therapies) 
All treatments being taken by the patient for up to 7 days prior to the first dose of IMP, and at any 
time during the treatment period and for up to 30 days after the last dose are regarded as prior and 
concomitant treatments, respectively, and will be reported on the appropriate pages of the 
electronic Case Report Form (eCRF). 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
version currently in effect at Sanofi at the time of database lock. 
Post treatment medications are those the patient took in the period running from 30 days after the 
last dose up to the end of the study. After the end of treatment, only further anticancer therapy will 
be reported. 
IAR medications 
As defined in Section 8.2 of the study protocol, patients will routinely receive premedications 
prior to infusion to reduce the risk and severity of infusion associated reactions (IARs) commonly 
observed with monoclonal antibodies.  Premedications are defined in the protocol as non-
investigational medicinal product(s) and should be reported in a specific form of the eCRF. 
Analysis of premedications will focus on those given (drug class, start and stop dates) on the days 
of isatuximab administrations for prophylaxis reason.  
Medication given in curative intent of IAR will be also analyzed (drug class, start and stop dates).    
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
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2.1.3 Efficacy endpoints 
2.1.3.1 Primary efficacy endpoint(s) 
The primary endpoint is the Overall Response Rate (ORR) defined as the proportion of patients 
with complete response (CR) or CR with incomplete peripheral recovery (CRi) for blood and 
bone marrow disease; partial response will be considered in case of mediastinal or any 
extramedullary disease. CR, CRi and PR are defined in Appendix D. 
An assessment will be performed during induction cycles, then every 2 months and as clinically 
indicated until disease progression or further therapy. 
Best Overall Response (BOR) 
BOR is the best tumor response observed from the first study drug intake until disease 
progression, death, study cutoff date, initiation of post-treatment anti-cancer therapy, whichever 
occurs first. 
The BOR can be either Progressive Disease (PD), Partial Response (PR), Complete Response 
(CR), Complete response with incomplete peripheral recovery (CRi) or unevaluable. 
• 
If there is 1 involvement in bone marrow (BM), or extramedullary involvement, the BOR 
will be the only response from the given involvement. In case of refractory disease, 
relapsed disease or no response, the BOR will be set as PD. 
• 
If there are 2 involvements: BM and extramedullary  
- 
BOR = PD when: 
- 
BM response is either PD, refractory disease or relapsed disease whatever the 
response for extramedullary involvement 
- 
Extramedullary response is either PD, no response or relapsed disease whatever 
the response for BM 
- 
BOR = PR when: BM response is CR or CRi  and extramedullary response is PR  
- 
BOR = CR when: BM response is CR and extramedullary response is CR  
- 
BOR = CRi when: BM response is CRi and extramedullary response is CR 
- 
BOR = unevaluable when: 
- 
BM response is unevaluable and extramedullary response is either CR, PR or 
unevaluable 
- 
BM response is CR or CRi and extramedullary response is unevaluable 
Per inclusion criteria, all patients should be CNS negative at screening. If a patient is CNS 
positive during the course of the study, the BOR will be PD. 
We may combine assessments (involvement in BM or extramedullary involvement) if they are 
performed at different visits within the same assessment period: 
• 
Between screening and first infusion of the study drug 
• 
Between Cycle 1 and Cycle 2 
• 
After Cycle 2 and before maintenance period 
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2.1.3.2 Secondary efficacy endpoint(s) 
Three secondary efficacy endpoints are considered:  
• 
Duration of Response (DOR).  
• 
Progression Free Survival (PFS). 
• 
Overall Survival (OS). 
Date of disease progression determination 
The date of the disease progression is the earliest date that indicates disease progression. 
Duration of response (DOR)  
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 the absence of the confirmation 
of subsequent disease progression or death before the analysis cut-off date the DOR will be 
censored at the date of the last valid disease assessment not showing disease progression 
performed prior to initiation of a further anti-leukemia or anti-lymphoma treatment or the analysis 
cut-off date, whichever is earlier.  
Duration of response is determined only for patients who have achieved a response of PR or better 
(subsequently confirmed). 
Progression free survival (PFS) 
PFS is the defined as the time from the date of first study treatment administration to the date of 
first disease progression or the date of death from any cause, whichever happens first. If 
progression and death are not observed before the analysis cutoff date, PFS will be censored at the 
earlier of the date of the last valid disease assessment not showing disease progression performed 
prior to initiation of a new anti-cancer treatment (if any) and the analysis cutoff date, whichever 
comes first. 
Overall survival (OS)  
OS is as the time interval from the date of first study treatment administration to death from any 
cause. If death is not observed before the analysis data cut-off date, OS will be censored at the last 
date that the patient is known to be alive or at the cut-off date, whichever comes first. 
Minimal Residual Disease (MRD)  
MRD will be measured by sequencing and/or flow cytometry in patients achieving CR and CRi, 
to determine the depth of response at a molecular level. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data, vital signs, weight and Eastern Cooperative 
Oncology Group (ECOG) performance status (PS). 
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Observation period  
The observation period starts from the time when the patient gives informed consent and is 
divided into 3 periods: 
• 
The pre-treatment period is defined as the time from the signed informed consent date up 
to the first dose of study treatment.  
• 
The treatment period is defined as the time from the first dose of study treatments 
administration to the last dose of study treatment + 30 days. 
• 
The post treatment period is defined as the period of time starting the day after the end of 
the treatment period up to the end of the study (as defined in the protocol). 
2.1.4.1 Adverse events variables 
AEs (including serious adverse events [SAEs] and AEs of special interest [AESI]) will be 
collected from the time of signed informed consent until the end of study. 
Adverse event observation period 
• 
Pre-treatment adverse events are defined as any adverse event reported during the  
pre-treatment period. 
• 
Treatment-emergent adverse events (TEAEs) are adverse events that developed or 
worsened or became serious during the treatment period. 
• 
Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period. 
All AEs (including SAEs and AESI) will be graded according to National cancer institute 
common terminology for adverse events (NCI-CTCAE) v4.03 and coded to a lower-level term 
(LLT), preferred term (PT), high-level term (HLT), high-level group term (HLGT) and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database lock. 
Adverse events of special interest 
AESI include the following terms: 
• 
Acute infusion associated reactions (IARs) of Grade ≥3  
• 
Pregnancy of female patient entered in a study as well as pregnancy occurring in a female 
partner of a male entered in a study with IMP 
• 
Symptomatic overdose (serious or non-serious) of study treatment.   
Infusion associated reactions 
IARs are commonly observed with monoclonal antibodies, and generally include AEs with onset 
typically within 24 hours from the start of the isatuximab infusion.  
The main IAR analysis will be based on the Investigator’s reporting of IARs. For each IAR, the 
sites are instructed to report as an AE a generic term (infusion associated reaction). Symptoms of 
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the IAR will be reported in a separate form providing symptoms severity, start and end date and 
will be analyzed in specific analyses describing IARs.  
An additional analysis will include TEAEs occurring within 24 hours from the start of each 
isatuximab infusion (selecting any TEAEs starting the day of the isatuximab infusion or the day 
after).  
Respiratory TEAEs 
Analysis of selected respiratory TEAEs will focus particularly on the following groupings:                        
• 
Lower Respiratory events, selected using HLGT ‘Bronchial disorders (excluding 
neoplasms)’,  HLGT ‘Lower respiratory tract disorders (excluding obstruction and 
infection)’ excluding HLT ‘Lower respiratory tract radiation disorders’  and HLGT 
‘Respiratory disorders NEC’ (excluding ‘Upper respiratory tract signs and symptoms’ 
HLT), 
• 
Respiratory infections, selected using HLGT ‘Respiratory tract infections’ from 
“Respiratory, thoracic and mediastinal disorders” SOC,  HLT ‘Lower respiratory tract and 
lung infections’ and HLT ‘Upper respiratory tract infection’ from infection and infestation 
SOC 
Late respiratory events (ie, occurring, worsening or becoming serious more than 30 days after last 
dose) will be analyzed as part of the post-TEAEs analysis. 
Specific hematological analysis 
Neutropenia (from laboratory abnormalities) will be displayed along with neutropenic 
complications (eg, neutropenic infections, febrile neutropenia). 
2.1.4.2 Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-treatment:  deaths occurring during the TEAE period.  
• 
Death post-treatment:  deaths occurring during the post-treatment period.  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis (including hematology, biochemistry). Clinical 
laboratory values will be converted into standard international units and international units that 
will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken as defined in the study flowchart and as 
clinically indicated.  The laboratory parameters (excluding those used for disease assessment) will 
be classified as follows: 
• 
Hematology  
- 
Red blood cells (RBC) and coagulation: hemoglobin, blasts,  RBC, prothrombin time 
(PT) or international normalized ratio (INR), activated partial thromboplastin time 
(aPTT), 
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- 
Platelet count, 
- 
White blood cells (WBC): WBC with differential, absolute neutrophil count (ANC), 
lymphocyte count. 
• 
Biochemistry 
- 
Metabolism: fasting glucose, total protein, albumin, 
- 
Electrolytes: sodium, potassium, chloride, calcium, corrected serum calcium, 
bicarbonate/carbon dioxide, magnesium, phosphate, 
- 
Renal function: serum creatinine, estimated creatinine clearance by MDRD formula, 
blood urea nitrogen (BUN), uric acid, 
- 
Liver parameters: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), alkaline phosphatase, lactate dehydrogenase (LDH), total and direct bilirubin, 
- 
Pregnancy test: female patients of childbearing potential. 
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include: heart rate, systolic and diastolic blood pressure, weight and ECOG PS (0, 1, 2, 
3, 4). 
2.1.4.5 Electrocardiogram variables 
Electrocardiogram assessments will be described as normal or abnormal.  
2.1.4.6 Other safety endpoints 
Other safety endpoints include: 
• 
IAR laboratory tests : 
- 
Cytokines (TNF-α, IL-1-β, IL-4, IL-6, IFN-γ) 
- 
Markers of complement (C3a, C4, CH50) 
- 
Serum tryptase 
2.1.5 Pharmacokinetic variables 
The population PK parameters of isatuximab, their inter-patients PK variability and inter-occasion 
PK variability will be estimated. The effect of pathophysiological and demographic covariates on 
main PK parameters will be assessed. 
Empirical Bayesian estimation of individual parameters and of individual exposure (Area Under 
the Curve [AUC]) will also be performed. 
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2.1.6 Pharmacodynamic variables 
Bone marrow aspirates and blood samples will be collected for assessment of receptor density 
(RD) and CD38 expression (proportion of CD38 positive cells) at screening, and, if relevant, 
correlated with clinical response endpoints. 
Bone marrow aspirates and blood samples from patients in Stage 1 only will be taken to assess 
receptor occupancy (RO) at screening and between Day 15 and Day 22 during the first cycle (after 
the third isatuximab infusion), for correlation with PK parameters and, if relevant, correlation with 
clinical response endpoints. 
CD38 receptor occupancy and receptor density will be summarized by study visit. Moreover, the 
set of PDy parameters will be described and, if relevant, correlated with the clinical response. 
These analyses will be applicable in selected countries only. 
2.1.7 Immunogenicity endpoints 
Human anti-drug antibodies (ADAs) to isatuximab will be assessed during the study as described 
in the protocol and will be analyzed using patients evaluable for ADAs. 
Periods of observation: 
• 
ADA pre-treatment period: The ADA pre-treatment period is defined as the time from 
signed informed consent to the first isatuximab administration.  
• 
ADA on-study observation period: the ADA on-study observation period is defined as the 
time from first isatuximab administration until the end of the study. 
ADA attributes: 
• 
Pre-existing ADAs are defined as ADAs that were present in samples drawn during the 
pre-treatment period. 
• 
Treatment boosted ADAs are defined as pre-existing ADA with a significant increase in 
titer during the study compared to the baseline titer.  
• 
Treatment induced ADAs are defined as ADAs that developed at any time during the 
ADA on-study observation period in patients without pre-existing ADA, including patients 
without pre-treatment samples. 
• 
Transient ADA response is defined by:  
- 
Treatment-induced ADA detected only at one sampling time point during the ADA on-
study observation period (excluding the last sampling time point) OR,  
- 
Treatment-induced ADA detected at two or more sampling time points during the on-
study observation period, 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 subject’s last sampling time point is ADA-negative.  
• 
Persistent ADA response is defined by:  
- 
Treatment-induced ADA detected at two or more sampling time points during the 
ADA on-study observation period, where the first and last ADA-positive on-study 
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samples are separated by a period of 16 weeks or longer (irrespective of any negative 
samples in between), OR,  
- 
Treatment-induced ADA detected in the last two sampling time points (both positive), 
irrespective of the time period in between.  
• 
Indeterminate ADA is defined by treatment induced ADA detected only the last sampling 
time point with all previous samples being negative or the last two samples are ADA-
positive and separated by a period of less than 16 weeks.  
ADA response endpoints: 
• 
ADA negative patients are patients without any treatment induced or treatment boosted 
ADA during the on –study observation period. 
• 
ADA positive patients, defined as patients with at least one treatment-induced or 
treatment-boosted ADA positive sample at any time following the first study treatment 
administration. 
• 
ADA incidence is defined of the number of ADA positive patients divided by the number 
of evaluable patients. 
• 
ADA prevalence is defined as proportion of all patients tested positive for ADAs 
(including preexisting ADAs, treatment boosted ADAs and treatment induced ADAs) at 
any time point. 
2.1.8 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
Further therapies after discontinuation of IMP include further anti-leukemia/lymphoma 
treatments. 
Time to Next Treatment 
TNT is defined as the time from first study treatment administration to the start of further  
anti-leukemia/lymphoma treatment. Patients who do not receive any further anti- 
leukemia/lymphoma treatment will be censored at the date of their last FU visit or the cut-off date, 
whichever comes first. Patients with no FU visit will be censored at their last study treatment 
administration or the cut-off date whichever comes first. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the study informed consent. 
For patient study status, patients in each of the following categories will be presented in the 
clinical study report using a flowchart diagram or summary table: 
• 
Screened patients 
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• 
Screen failure patients and reasons for screen failure (if any) 
• 
Patients who discontinued study treatment  
• 
Patients still on treatment  
• 
Status at last study contact  
• 
Patients with date of last contact obtained before the cutoff date and duration from last 
contact to cut-off date (0-2 weeks, 2-4 weeks, 4-8 weeks, >8 weeks) 
A summary of the reasons for definitive treatment discontinuation will be provided. Definitive 
treatment discontinuation is defined as the discontinuation of the study drug. For all categories of 
patients (except for the screened) percentages will be calculated using the number of patients in 
the all-treated/safety population as the denominator. 
All critical or major deviations potentially impacting efficacy analyses, and other major or critical 
deviations will be summarized in tables giving numbers and percentages of deviations. 
Additionally, the following analysis populations will be summarized in a table by number of 
patients on the all-treated/safety population: 
• 
All-treated/safety population: primary population for efficacy and safety analyses.  
• 
Pharmacokinetics population. 
• 
Pharmacodynamic population. 
• 
ADA population.  
Definition of study populations are provided in Section 2.3. 
2.3 
ANALYSIS POPULATIONS 
2.3.1 All-treated/Safety population 
The all-treated/safety population will include patients who received at least 1 dose (even 
incomplete) of isatuximab. This population is the primary population for the analyses of efficacy 
and safety parameters. 
2.3.2 Pharmacokinetics population 
The PK population will include all patients from the all-treated/safety population, with at least 1 
PK parameter available. 
2.3.3 Pharmacodynamic population 
The PDy population will include patients from the all-treated/safety population who had data for 
at least 1 PDy parameter available. 
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2.3.4 ADA population 
The ADA population will include safety population patients with at least one ADA assessment 
during the ADA on-study observation period with a reportable result. 
2.4 
STATISTICAL METHODS 
Unless otherwise specified, analyses will be descriptive and performed based on the all-
treated/safety population. 
Continuous data will be summarized using the number of available data, mean, standard deviation 
(SD), median, minimum and maximum. Categorical and ordinal data will be summarized using 
the number and percentage of patients. 
2.4.1 Demographics and baseline characteristics 
Parameters described in Section 2.1.1 will be summarized on the all-treated population using 
descriptive statistics. 
Past medical or surgical history will be summarized by SOC and PT (SOC will be sorted 
according to the internationally agreed order and PT by decreasing frequency). 
2.4.2 Prior or concomitant medications (other than anticancer therapies) 
The prior and concomitant medications will be presented for the all-treated population 
Medications will be summarized according to the WHO-DD dictionary, considering the first digit 
of the anatomic category (ATC) class (anatomic category) and the first 3 digits of the ATC class 
(therapeutic category). All ATC codes corresponding to a medication will be summarized, and 
patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore patients may be counted several times for the same medication. 
IAR medications 
Number (%) of patients with IAR medications (prophylaxis and curative intent) including 
diphenhydramine (or equivalent) and steroids as defined in Section 2.1.2 will be provided. 
Number of infusions with prophylactic IAR medications and number of infusions with curative 
IAR medications will also be summarized. Further analyses on cumulative steroids exposure may 
be performed as needed. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The following variables will be calculated and summarized with descriptive statistics to describe 
exposure of isatuximab: 
• 
Number of cycles started. 
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• 
Duration of exposure (in weeks), defined as follow: 
- 
[First day of last cycle - first day of first cycle + 28 days]/7  
• 
Cumulative dose (mg/kg): the cumulative dose is the sum of all doses administered from 
first to last dose. 
• 
Actual dose intensity (ADI) in mg/kg/week: defined as the cumulative dose (in mg/kg) 
divided by the number of weeks on study. 
• 
Planned dose intensity in mg/kg/week corresponds to the planned dose (mg/kg) at C1D1, 
regardless of dose changes, multiplied by the theoretical total number of doses during the 
started cycles (4 for weekly dose, 2 for Q2W dose), and divided by the theoretical cycle 
duration expressed in weeks (ie, 4 weeks per cycle started) 
• 
Relative dose intensity (RDI) in % is an indicator of the feasibility of the chosen schedule 
of administration and is defined as follow 
 
(
)
)
/
/
(
/
/
100
week
kg
mg
Intensity
Dose
Planned
week
kg
mg
ADI
×
 
Total number of cycles started, number of cycles started by patient as a quantitative variable and 
by category (ie, number (%) of patients receiving at least 1 cycle, at least 2 cycles, etc), duration 
of exposure, cumulative dose, ADI and RDI will be summarized by descriptive statistics. 
The following variables will be computed to describe isatuximab dose modifications 
(delay/omission/interruption): 
• 
Infusion delays: within a QW or Q2W cycle, a dose is deemed to have been delayed if the 
study treatment is >3 days beyond the theoretical day of treatment. 
• 
Cycle delay: the start of a cycle can be delayed for up to 14 days. 
• 
Infusion interruption: an infusion is considered to be interrupted if the administration is 
stopped during an infusion regardless if the infusion is re-started or not.  
• 
Dose omission: a dose is considered omitted if the dose is not administered for the 
scheduled visit and there are positive dose(s) afterwards. 
Dose modification will be analyzed at the patient and total number of isatuximab infusions levels 
as follows: 
• 
Patient level: 
- 
Number of patients treated (used for % calculation for this level). 
- 
Number (%) of patients with at least one infusion delay  
- 
Number (%) of patients with at least one isatuximab dose omission 
- 
Number (%) patients with a least 1 infusion interruption 
• 
Total number of isatuximab infusions level: 
- 
Total number of isatuximab infusions (used for % calculation for this level). 
- 
Number of isatuximab infusions interrupted 
- 
Number (%, calculated using the total number of infusion interrupted) of isatuximab 
administrations interrupted at 
- 
1st infusion 
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- 
2nd infusion 
- 
Subsequent infusions 
- 
Time from infusion start to first interruption in minutes (quantitative and qualitative:  
5 - 10, 11 - 30,  31 - 40, 41 - 50, 51 - 60,  61 - 90, 91 - 120, >120) 
- 
Duration of infusion: defined as the time from the start (date/time) of infusion to the 
end (date/time) of infusion. It will be summarized for first and subsequent infusions. 
2.4.4 Analyses of efficacy endpoints 
All efficacy analyses will be performed in the all-treated/safety population. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
Primary analysis will consist of ORR summarized on the all-treated/safety population with 
descriptive statistics. Confidence intervals will be computed using the Clopper-Pearson method.  
The cutoff date for primary analysis of ORR and other secondary endpoints will be 6 months after 
the last patient has had his/her first study treatment administration. Then, the final analysis cutoff 
date for analysis of OS and updated analyses of ORR and other secondary endpoints will be  
12 months after the last patient has had his/her first treatment administration. Patients still on 
treatment at the time of the final analysis cutoff date and who still continue to benefit from 
treatment with isatuximab will have the option to continue treatment under this protocol.  
Best overall response will be summarized with descriptive statistics. 
2.4.4.2 Analyses of secondary efficacy endpoints 
PFS, DOR and OS 
These time-to-event endpoints will be analyzed using Kaplan-Meier methods.  
The following estimates will be provided for each time-to-event endpoint: 
• 
Data will be analyzed using the Kaplan-Meier method in the all-treated/safety population: 
- 
Kaplan-Meier estimates of the 25th, 50th and 75th  percentiles and  their associated 
95% CIs will be provided 
- 
Number of patients at risk as well as the probabilities of surviving at least 1 and 2 
months with 95% CI will be estimated using the Kaplan-Meier method. 
• 
Kaplan-Meier curves will be plotted   
If progression and death are not observed before the analysis data cut-off date, PFS and DOR will 
be censored at the date of the last valid disease assessment not showing disease progression 
performed prior to initiation of further anti-leukemia or anti-lymphoma treatment (if any) or the 
data cut-off date, whichever comes first.  
Analysis of the pre-specified secondary endpoints will be descriptive only. Any testing procedure 
carried out on these endpoints will be considered as exploratory. 
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Minimal residual disease (MRD) 
Among patients who achieve a CR with MRD assessment, the MRD status (negative, positive) 
will be summarized using descriptive statistics. The timing (study day from first dose) of MRD 
negative status will also be described. 
2.4.4.3 Multiplicity issues 
Not applicable. 
2.4.5 Analyses of safety data 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.1, unless 
otherwise specified.  
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.   
Pre-treatment and post-treatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
The severity grade will be taken into account in the summary. For patients with multiple 
occurrences of the same adverse event, the maximum (worst) grade by period of observation is 
used. Summaries will be provided for all grades and for Grade ≥3 (including Grade 5). Missing 
grades, if any, will be included in the “all grades” category.  
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment, treatment-emergent and post-treatment). For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order (see Appendix B) and decreasing frequency of PTs within SOCs 
will define the presentation order for all other tables unless otherwise specified.  
The AE incidence tables presented by primary SOC, HLGT, HLT and PT will present the number 
(n) and percentage (%) of patients experiencing an AE sorted by SOC internationally agreed 
order, then by alphabetic order of HLGT, HLT and PT.  
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Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the all-treated/safety population. 
• 
Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE, 
- 
TEAE of Grade ≥3, 
- 
TEAE of Grade 3-4, 
- 
TEAE with Grade 5 (any TEAE with fatal outcome during the treatment period), 
- 
Serious TEAE, 
- 
TEAE leading to permanent discontinuation, 
- 
Treatment-related TEAEs, 
- 
Treatment-related TEAEs of Grade ≥3, 
- 
Serious treatment-related TEAE, 
- 
AESIs: AESIs of Grade ≥3, IARs, IARs of Grade ≥3, pregnancy and overdose. 
Analysis of adverse events will be performed according to following domains:  
• 
TEAEs (regardless relationship to study treatment), 
• 
Drug related TEAEs,  
• 
Deaths, serious adverse events, adverse events leading to withdrawal, and other significant 
adverse events (IAR and associated symptoms, Selected respiratory TEAEs, Specific 
hematological analysis , Second primary malignancies, TEAE leading to dose 
modification, pre- and post-treatment AE) 
• 
The following frequency distributions of TEAEs (incidence tables) will be provided for 
the all-treated/safety population, for all grades combined and Grade ≥3:  
- 
All TEAEs by primary SOC, HLGT, HLT and PT, showing number (%) of patients 
with at least 1 TEAE sorted by the SOC internationally agreed order. The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order 
- 
All TEAEs by primary SOC and PT, showing the number (%) of patients with at least 
1 TEAE, sorted by the internationally agreed SOC order and by decreasing incidence 
of PTs within each SOC. This sorting order will be applied to all other tables, unless 
otherwise specified. 
Analysis of all treatment-related TEAEs 
• 
All treatment-related TEAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 TEAE, sorted by the internationally agreed SOC order and decreasing 
frequency of PT. 
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Analysis of infusion associated reactions 
The following summaries of IARs (reported by investigator) will be presented: 
• 
Number (%) of patients with at least one IAR and all the associated symptoms (all grades, 
Grades ≥3), sorted by decreasing incidence of PTs. 
• 
A summary will be provided to further describe the characteristics of the IAR, showing: 
- 
Number (%) of patients by worst grade,  
- 
Number of episodes by patient,  
- 
Number (%) of patients with IAR at the first and subsequent infusions,  
- 
Number (%) of patients with at least two episodes of IARs at the same infusion 
- 
Infusion of occurrence of the first IAR 
- 
Day of onset from the isatuximab infusion  
In addition, the following summaries will be presented: 
• 
Number (%) of patients with at least one TEAE (all grades, Grades ≥3) occurring within 
24 hours from the start of each isatuximab infusion (Day 1-2 from start of each isatuximab 
infusion), by primary SOC and PT.  
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All TEAE leading to treatment discontinuation by primary SOC and PT, showing the 
number (%) of patients with at least 1 TEAE, sorted by the internationally agreed SOC 
order and decreasing frequency of PT. 
Analysis of all treatment-emergent adverse event(s) leading to dose modification 
The following summary tables are based on the investigator's intent reported in the AE page 
("action taken"): 
• 
All TEAEs leading to dose interruption, by primary SOC and PT, showing the number (%) 
of patients, sorted by the sorting order defined above. 
• 
All TEAEs leading to any dose delay by primary SOC and PT, showing the number (%) of 
patients, sorted by the sorting order defined above. 
Analysis of all treatment emergent serious adverse event(s) 
• 
All serious TEAEs by primary SOC and PT, showing the number (%) of patients with at 
least 1 TEAE, sorted by the internationally agreed SOC order and by decreasing incidence 
of PTs within each SOC. 
• 
All serious TEAEs related to treatment, by primary SOC and PT, showing the number (%) 
of patients with at least 1 serious TEAE, sorted by the internationally agreed SOC order.  
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Analysis of all TEAEs with a fatal outcome 
• 
All TEAEs with a fatal outcome by primary SOC and PT, showing the number (%) of 
patients with a TEAE with a fatal outcome, sorted by the internationally agreed SOC order 
and decreasing frequency of PT. 
Analysis of AEs/SAEs occurring during the pre-treatment and post-treatment dosing periods  
• 
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 pre-treatment SAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment SAE, 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 internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
• 
All post-treatment SAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 post-treatment SAE, sorted by internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
Analysis of adverse events of special interest 
Number (%) of patients with at least one AESI cited in Section 2.1.4.1 sorted by decreasing 
incidence of PT (presented separately for each category of AESI) 
Respiratory TEAEs 
Respiratory TEAEs will be analyzed using selections defined in Section 2.1.4.1 and will be 
presented by PT, sorted by decreasing incidence. 
Specific hematological analysis 
• 
Number (%) of patients with neutropenia (from laboratory abnormalities), neutropenic 
infections and febrile neutropenia by grade. 
Second primary malignancies 
A listing of patients who reported second primary malignancies during the study will be provided. 
This listing will include diagnosis, study day of diagnosis (from first dose), number of days from 
last study treatment to diagnosis, prior exposure to anti-leukemia/anti-lymphoma treatments, and 
whether or not patient received subsequent anti-cancer treatment. 
Overdose 
A listing of patients who reported overdose during the study will be provided. This listing will 
include drug with overdose, cycle of occurrence, associated TEAE, outcome. 
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The following listings will be provided if relevant: 
• 
AESIs (non-IARs) 
• 
IARs 
• 
AEs leading to treatment discontinuation 
• 
AEs leading to dose modification 
• 
SAEs 
2.4.5.2 Deaths 
The following summaries of deaths will be generated for the all-treated/safety population. 
• 
Number and proportion (%) of patients who died by study period (screening, TEAE 
observation period and post-treatment) and reasons for death (disease progression, AE, 
other).  
• 
Listing of deaths 
2.4.5.3 Analyses of laboratory variables  
Hematological and clinical biochemistry toxicities will be assessed from laboratory test 
parameters. Each test result will be graded by NCI-CTCAE version 4.03, whenever applicable. 
For hematological parameters and for some selected biochemistry parameters, sanofi sponsor 
generic ranges (LLN, ULN) are defined and will be used for grading (see list of parameters in 
Appendix C). For other biochemistry parameters (eg, for hepatic enzymes ALT, AST, Alkaline 
phosphatase, total bilirubin), grading will be derived using local laboratory normal ranges. 
The number of patients with abnormal laboratory tests at baseline will be presented by grade and 
all grades together. The frequency of patients in each grade and all grades of laboratory 
abnormalities during treatment will be summarized. For patients with multiple occurrences of the 
same laboratory variable during the treatment, the maximum grade (worst) per patient will be 
used. 
The denominator used for percentage calculation is the number of patients with at least 1 
evaluation of the laboratory test during the considered observation period. 
When appropriate, the summary table will present the frequency of patients with any grade of 
abnormal laboratory tests and with Grade 3-4 abnormal laboratory tests.  
For laboratory tests for which NCI-CTCAE V4.03 scale is not applicable, potentially clinically 
significant abnormalities (PCSA) values are defined as abnormal values considered medically 
important by the Sponsor according to predefined criteria/thresholds based on literature review. 
PCSA criteria will determine which patients 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. The incidence of PCSA any time during the on-treatment 
period will be summarized irrespective of the baseline level. 
For drug-induced liver injury, a listing of possible Hy’s law cases identified (eg, patients with 
elevated AST or ALT of >3ULN and elevated total bilirubin >ULN), will be provided. 
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Anemia, thrombocytopenia and neutropenia 
Shift tables showing the number of patients in each grade at baseline by worst grade during the 
on-treatment period and the bone marrow involvement at baseline by worst grade during the on-
treatment period will be provided.  
Further analyses including summary of cycle of onset (all grades and Grade ≥3), duration and 
concomitance with other hematological abnormalities will also be provided  
2.4.5.4 Analyses of vital sign variables 
A shift table of baseline ECOG PS versus best and worst ECOG PS on treatment will be provided.  
For blood pressure/heart rate parameters, potentially clinically significant abnormality (PCSA), 
see Appendix A values are defined as abnormal values considered medically important by the 
Sponsor according to predefined criteria/thresholds based on literature review.  
The incidence of PCSAs for vital signs and at any time during the TEAE period will be 
summarized whatever the baseline level (ie, the last assessment before the first study treatment 
administration) and/or according to the following baseline status (ie, status of last assessment 
before the first study treatment administration) categories: 
• 
Normal/missing. 
• 
Abnormal according to PCSA criterion or criteria 
The PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE, including nonscheduled or 
repeated evaluations. 
2.4.5.5 Analyses of electrocardiogram variables 
The incidence of patients with at least 1 abnormal ECG at any time during the TEAE period will 
be summarized irrespective of the baseline level and/or according to the following baseline status 
categories:  
• 
Normal/missing 
• 
Abnormal  
2.4.5.6 Analyses of other safety endpoints 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of baseline values, peak values, change from baseline and relative change from 
baseline will be calculated for Cytokines (TNF-α, IL-1-β, IL-4, IL-6, IFN-γ), markers of 
complement (C3a, C4, CH50) and serum tryptase when available. 
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2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
Individual plasma concentrations and PK parameters of isatuximab will be summarized by 
descriptive statistics (such as mean, geometric mean, median, standard deviation, standard error of 
the mean, coefficient of variation, minimum, and maximum) under the responsibility of sanofi. 
Individual and mean profiles will be presented graphically. 
The CD38 RO and RD will be summarized by study visits. Moreover, the set of PDy parameters 
will be described and, if relevant, correlated with the clinical response. 
2.4.7 Analyses of immunogenicity variables 
ADA attributes and response endpoints defined in Section 2.1.7 will be summarized in the ADA 
population. Titers will be also described using descriptive statistics. Further analyses may be 
performed, such as time to onset and duration of ADA. 
The impact of positive immune response on efficacy, PK and safety endpoints may be further 
explored by graphical methods or descriptively, depending on ADA prevalence. 
The following summaries of ADA will be generated: 
• 
Number (%) of patients with pre-existing ADA and ADA negative at baseline, for patients 
evaluable at baseline 
• 
Number (%) of ADA positive patients (including treatment-induced ADA and treatment 
boosted ADA) during the on-study observation period, for patients evaluable during the 
on-study observation period. 
ADA prevalence and ADA incidence will be also described.   
2.4.8 Further therapy after discontinuation of investigational medicinal product 
administration during the study 
A summary table, including the number of different regimens, will be provided for further anti-
leukemia or anti-lymphoma treatments based on WHO-DD coding.  
Time to next treatment 
TNT will be analyzed using Kaplan-Meier methods. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
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Renal function formulas  
Creatinine clearance will be estimated using the equation of MDRD: 
GFR (mL/min/1.73 m²) = 175 x (Scr) – 1.154 x (Age) – 0.203 x (0.742 if Female) x (1.212 if 
African-American) 
Corrected calcium formula 
Corrected Calcium = Serum Calcium (in mmol/L) + 0.8 (4 - serum albumin [in G/dL])  
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
2.5.3 Missing data 
The analyses and summaries of continuous and categorical variables will be based on observed 
data only. Percentages will be calculated using as denominator the number of patients with non-
missing observation in the considered population. When relevant, the number of patients with 
missing data is presented. 
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 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. 
Imputation of incomplete date for post leukemia/lymphoma treatments start date  
For post leukemia/lymphoma 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. 
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• 
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. 
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.  
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.  
2.5.4 Windows for time points 
Laboratory data 
An episode occurred during a cycle if the date of sampling is after (>) the first day of the cycle, 
but prior or equal (≤) to the first day of the next cycle. 
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2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline and worst values and/or grades. 
2.5.6 Pooling of centers for statistical analyses 
Not applicable. 
2.5.7 Statistical technical issues 
Not applicable.  
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3 
INTERIM ANALYSIS 
An interim analysis of efficacy, safety and other data (including PK) will be performed after the 
completion of enrollment in Stage 1; this interim analysis will be performed when all patients 
have completed either 2 induction cycles plus D1 of the first maintenance cycle or 1 induction 
cycle plus 1 maintenance cycle. Enrollment will 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. 
At the end of each stage, additional statistical analyses could be performed in order to identify a 
subpopulation who would respond better to the treatment. If a relevant biomarker is actually 
identified, then a relevant threshold could be explored to define a subgroup of better responders.  
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4 
DATABASE LOCK 
Estimated cut-off date for primary analysis of ORR and other secondary endpoints will be 6 
months after the last patient has had its first study treatment administration. The estimated final 
analysis cut-off date for OS analysis and updated analyses of ORR and other secondary endpoints 
will be 12 months after the last patient has had its first study treatment administration.  
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
Biomarkers analyses will be generated using R version 3.3.2. 
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6 
REFERENCES 
 
1. 
National Comprehensive Cancer Network Guidelines for Acute Lymphoblastic Leukemia, 
Version 2.2016. 
2. 
NEJM (N Engl J Med 2004;351:1548-63.): “Laboratory Reference Values”, Alexander 
Kratz, M.D., Ph.D., M.P.H., Maryjane Ferraro, Ph.D., M.P.H., Patrick M. Sluss, Ph.D., and Kent 
B. Lewandrowski, M.D. 
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